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【结 构 式】

【分子编号】10061

【品名】1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine

【CA登记号】109-01-3

【 分 子 式 】C5H12N2

【 分 子 量 】100.16376

【元素组成】C 59.96% H 12.08% N 27.97%
与该中间体有关的原料药合成路线共 81 条
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合成路线1

该中间体在本合成路线中的序号：(B)

3-Chloro-4-fluoroaniline (I), condensed by heating at 125 C with diethyl ethoxymethylenemalonate (A), gives diethyl 3-chloro-4-fluoroanilinomethylenemalonate (II). The thermal cyclization of (II) by reflux in A Dowtherm gives ethyl 6-fluoro-7-chloro-4-hydroxyquinoline-3-carboxylate (III), which, alkylated by ethyliodide in DMF with potassium carbonate, leads to ethyl 1-ethyl-6 fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylate (IV), purified by recrystallization. The ester (IV), after saponification and acidification, provides the corresponding acid (V). 1-Ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (V), heated to 100 C in pyridine with 1-methylpiperazine (B), leads to 1-ethyl-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (VI). The salification of (VI) with methanesulfonic acid provides the salt.

参考文献 中间体
合成目标
【1】 Pesson, M.; Montay, G.; Goueffon, Y.; Roquet, F.; Microbiologie: Sur un nouvel antibacterien de synthese:l¡Acide ethyl-2-fluoro-6-(methyl-4-piperazinyl-1)-oxo-4-dihydro-1,4-quinoleine-3-carboxylique (1589 RB). CR Acad Sci Paris 1981, 292.
【2】 Bellon, A.; Pefloxacin mesylate. Drugs Fut 1982, 7, 9, 646.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(A) 14088 Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate 87-13-8 C10H16O5 详情 详情
(I) 18688 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline 367-21-5 C6H5ClFN 详情 详情
(II) 32073 Diethyl 2-[[(3-chloro-4-fluorophenyl)imino]methyl]malonate; Diethyl 3-chloro-4-fluoroanilinomethylenemalonate C14H15ClFNO4 详情 详情
(III) 32074 Ethyl 7-chloro-6-fluoro-4-hydroxy-1,4-dihydro-3-quinolinecarboxylate C12H11ClFNO3 详情 详情
(IV) 32075 ethyl 7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C14H13ClFNO3 详情 详情
(V) 32076 7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 68077-26-9 C12H9ClFNO3 详情 详情
(VI) 32077 1-ethyl-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C17H20FN3O3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

A new synthesis of fleroxacin, labeled with fluorine-18, has been described: The reaction of 6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (I) with 2-bromoethanol (II) gives 6,7,8-trifluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (III), which is condensed with N-methylpiperazine (IV), yielding 6,8-difluoro-1-(2-hydroxyethyl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (V). The reaction of (V) with methanesulfonyl chloride affords the corresponding mesylate (VI), which is treated with [18F]-KF in dichloromethane at 80 C to give 6,8-difluoro-1-(2-fluoroethyl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (VII). Finally, this compound is hydrolyzed with NaOH.

参考文献 中间体
合成目标
【1】 Liu, Y.Y.; Cleeland, R.; Livni, E.; Rubin, R.H.; Thom, E.; Strauss, H.W.; Fischman, A.J.; Fleroxacin, a quinolone antibacterial agent. Labeling with fluorine-18 for pharmacokinetic studies. J Label Compd Radiopharm 1993, 32, 576.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10058 ethyl 6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate 79660-46-1 C12H8F3NO3 详情 详情
(II) 10059 Ethylene bromohydrin; 2-Bromo-1-ethanol 540-51-2 C2H5BrO 详情 详情
(III) 10060 ethyl 6,7,8-trifluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C14H12F3NO4 详情 详情
(IV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(V) 10062 ethyl 6,8-difluoro-1-(2-hydroxyethyl)-7-(4-methylpiperazino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C19H23F2N3O4 详情 详情
(VI) 10063 ethyl 6,8-difluoro-7-(4-methylpiperazino)-1-[2-[(methylsulfonyl)oxy]ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate C20H25F2N3O6S 详情 详情
(VII) 10064 ethyl 6,8-difluoro-1-(2-fluoroethyl)-7-(4-methylpiperazino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C19H22F3N3O3 详情 详情
(VII) 44571 ethyl 6,8-difluoro-1-(2-fluoroethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C19H22F3N3O3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(IV)

The reaction of 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (I) with 1-bromo-2-fluoroethane (II) by means of NaI in hot DMF gives 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (III), which is then condensed with N-methylpiperazine (IV) in refluxing pyridine.

参考文献 中间体
合成目标
【1】 Irikura, T.; Koga, H.; Murayama, S. (Kyorin Pharmaceutical Co., Ltd.); Quinoline carboxylic acid derivatives and process for the preparation. BE 0887574; DE 3106013; FR 2499990; FR 2507183; US 4398029 .
【2】 Serradell, M.N.; Castaner, J.; AM-833. Drugs Fut 1984, 9, 4, 246.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 30588 6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C10H4F3NO3 详情 详情
(II) 28769 1-bromo-2-fluoroethane 762-49-2 C2H4BrF 详情 详情
(III) 30589 1,4-dihydro-1-(2-fluoroethyl)-4-oxo-6,7,8-trifluoro-3-quinolinecarboxylic acid; 6,7,8-trifluoro-1-(2-fluoroethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C12H7F4NO3 详情 详情
(IV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(C)

Methiothepin can be prepared in several ways, two of which have been described with experimental details. The common intermediate of both is the ketone (VIII). 4-Bromothioanisol (I) is converted to the Grignard reagent, which is treated with sulfur yielding 4-(methylthio)thiophenol (II). The same compound is accessible by reduction of 4-(methylthio)benzenesulfonyl chloride (A), done best with phosphorus and iodine in acetic acid. The potassium salt of (II) is treated with a boiling solution of potassium 2-iodobenzoate (B) in the presence of copper giving 2-(4-methylthiophenylthio)benzoic acid (III). Further reduction with LiAlH4 results in 2-(4-methylthiophenylthio)benzyl alcohol (IV). This reduction proceeds very well with NaAlH2(OCH2CH2OCH3)2 in benzene. (IV) is then converted with SOCl2 in benzene to the chloride (V), which is treated with NaCN or KCN in boiling aqueous ethanol to give the nitrile (VI). Hydroysis with KOH in aqueous ethanol yields 2-(4-methylthiophenylthio)phenylacetic acid (VII), which is cyclized with polyphosphoric acid to 8-(methylthio)dibenzo[b,f]thiepin-10(11H)-one (VIII). The ketone (VIII) may be reduced with NaBH4 to the alcohol (IX), which is transformed by treatment with anhydrous HCl in benzene to the chloride (X). Substitution reaction with 1-methylpiperazine (C) at 120-130 C or more in boiling chloroform gives 80% crude metitepine base, which is transformed to the maleate. The other method consists first in transforming the ketone (VIII) into the methylpiperazine enamine (XI) by treatment with 1-methylpiperazine (C) and TiCl4 in boiling benzene. The enamine (XI) is then reduced to metitepine; the best method of reduction for this particular case seems to be the treatment with diborane generated by interaction of NaBH4 with acetic acid in tetrahydrofuran. An additional three methods of metitepine synthesis are covered by patents; howewer, they do not describe experimental details for the particular case of metitepine.

参考文献 中间体
合成目标
【1】 Jilek, J.O.; et al.; Neurotropic and psychotropic substances. XLIV. 10-Aminoalkoxy and 10-piperazino derivatives of dibenzo[b,f]thiepin and related systems. Czech Chem Commun 1970, 35, 3721-32.
【2】 Kyburz, E.; Methiothepin, octoclothepin and related neuroleptic agents. Commun at the Rest Inst Pharm Biochem in Prague, June 5, 1974 1974, 25, 1, 20.
【3】 Pelz, K.; et al.; Neurotrope und psychotrope Substanzen. XXV. Uber die in 8.Stellung durch die Methyl-, -tert-Butyl-, Methoxy-, Methylthio- und Methansulfonylgruppe substituierten 10-(4-Methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin-Derivate. Coll Czech Chem Commun 1968, 33, 1895-1910.
【4】 Kaplan, J.P.; Kyburz, E.; Process for benzothiepins. CH 555856; CH 563389; DE 2216883; FR 2135174; GB 1361717; US 3811026 .
【5】 Protiva, M.; et al.; Piperazinyldibenzothiepines. DE 1620382; FR 1484332; GB 1123400; US 3379729 .
【6】 Jilek, J.O.; et al.; 8-Chlor-10-(4-methylpiperazino)dibenzo[b,f]thiepin und Analoga; neue hoch wirksame Neuroleptica. Naturwissencshaften 1969, 56, 374.
【7】 Protiva, M.; et al.; Procede de preparation de la methyl-piperazine et de leurs sels, ainsi que les produits obtenus. FR 2151568; ZA 7104647 .
【8】 Protiva, M.; et al.; Procede de preparation d'amines heterocycliques et de leurs sels et produits obtenus par ce procede. ES 394172; FR 2099683 .
【9】 Protiva, M.; et al.; Verfahren zur Herstellung von neuroleptisch wirksamen 10-Piperazino-10,11-dihydrodibenzo[b,f]thiepinen. AT 310170B; CH 544771; ES 385836; NL 7017200; ZA 7007985 .
【10】 Protiva, M.; et al.; Pharmacodynamically effective 10-4-substituted piperazino-10,11- dihydrodibenzo[b,f]thiepins and a method of preparing same. DE 2026027; ES 380127; FR 2043741; GB 1313428 .
【11】 Kyburz, E.; Uber Methiothepin und verwandte Dibenzo[b,f]thiepin und -oxepin-Derivate. Schweiz Chem Ges, Herbstversammlung, Neuchatel, Oct. 12, 1974 1974, 106, 19, Suppl. 2.
【12】 Jilek, J.O.; et al.; 8-Alkylthio-10-piperazinodibenzo[b,f]thiepins. Coll Czech Chem Commun 1974, 39, 3338-51.
【13】 Protiva, M.; Metitepine. Drugs Fut 1977, 2, 4, 250.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 40103 4-methanesulfonylbenzene-1-thiol C7H8O2S2 详情 详情
(B) 40105 potassium 2-iodobenzoate C7H4IKO2 详情 详情
(I) 19266 4-bromophenyl methyl sulfide; 1-bromo-4-(methylsulfanyl)benzene 104-95-0 C7H7BrS 详情 详情
(II) 40104 4-(methylsulfanyl)benzenethiol; 4-(methylsulfanyl)phenylhydrosulfide 1122-97-0 C7H8S2 详情 详情
(III) 40106 2-[[4-(methylsulfanyl)phenyl]sulfanyl]benzoic acid C14H12O2S2 详情 详情
(IV) 40107 (2-[[4-(methylsulfanyl)phenyl]sulfanyl]phenyl)methanol C14H14OS2 详情 详情
(V) 40108 1-(chloromethyl)-2-[[4-(methylsulfanyl)phenyl]sulfanyl]benzene; 2-(chloromethyl)phenyl 4-(methylsulfanyl)phenyl sulfide C14H13ClS2 详情 详情
(VI) 40109 2-(2-[[4-(methylsulfanyl)phenyl]sulfanyl]phenyl)acetonitrile C15H13NS2 详情 详情
(VII) 40114 2-(2-[[4-(methylsulfanyl)phenyl]sulfanyl]phenyl)acetic acid C15H14O2S2 详情 详情
(VIII) 40110 8-(methylsulfanyl)dibenzo[b,f]thiepin-10(11H)-one C15H12OS2 详情 详情
(IX) 40111 8-(methylsulfanyl)-10,11-dihydrodibenzo[b,f]thiepin-10-ol C15H14OS2 详情 详情
(X) 40112 11-chloro-2-(methylsulfanyl)-10,11-dihydrodibenzo[b,f]thiepine; 11-chloro-10,11-dihydrodibenzo[b,f]thiepin-2-yl methyl sulfide C15H13ClS2 详情 详情
(XI) 40113 methyl 11-(4-methyl-1-piperazinyl)dibenzo[b,f]thiepin-2-yl sulfide; 1-methyl-4-[8-(methylsulfanyl)dibenzo[b,f]thiepin-10-yl]piperazine C20H22N2S2 详情 详情
(C) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(A)

The reaction of 2-aminothiophenol (I) with diethyl benzylidenemalonate (II) by heating at 90 C gives diethyl 2-(2-aminophenylthio)-2-phenylethane-1,1-dicarboxylate (III), which is cyclized by heating at 180 C with triethylamine hydrochloride yielding 2,3-dihydro-3-ethoxycarbonyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (IV). The reduction of (IV) with LiAlH4 in THF affords 2,3-dihydro-3-hydroxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (V), which by reaction with SOCl2 in refluxing benzene is converted into 2,3-dihydro-3-chloromethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (VII). Finally, this compound is treated with N-methylpiperazine at reflux temperature, and acidified with HCl. An alternative way is the reaction of (V) with methanesulfonyl chloride in pyridine affording 2,3-dihydro-3-methanesulfonyloxymethyl-2-phenyl-1,5-benzothiazepin-4(5H)-one (VI), which is then treated with N-methylpiperazine and HCl as before.

参考文献 中间体
合成目标
【1】 Izumi, K.; et al.; FR 2416890 .
【2】 Hillier, K.; Castaner, J.; BTM-1042. Drugs Fut 1981, 6, 9, 534.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(I) 25182 2-aminobenzenethiol 137-07-5 C6H7NS 详情 详情
(II) 37482 diethyl 2-benzylidenemalonate 5292-53-5 C14H16O4 详情 详情
(III) 37483 diethyl 2-[[(2-aminophenyl)sulfanyl](phenyl)methyl]malonate C20H23NO4S 详情 详情
(IV) 37484 ethyl (2R,3R)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-3-carboxylate C18H17NO3S 详情 详情
(V) 37485 (2R,3S)-3-(hydroxymethyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H15NO2S 详情 详情
(VI) 37486 (2R,3S)-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C19H21NO2S2 详情 详情
(VII) 37487 (2R,3S)-3-(chloromethyl)-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one C16H14ClNOS 详情 详情

合成路线6

该中间体在本合成路线中的序号：

Condensation of 2,4-dichoro-5-fluoroacetophenone (I) with diethyicarbonate (II) in the presence of sodium hydride gives ethyl 2,4-dichloro-5-fluorobenzoylacetate (III). The condensation of (III) with triethylorthoformate in reftuxing acetic anhydride yields ethyl 2-(2,4-dichloro-5-fluornbenzoyl)-3-ethoxyacrylate (IV), which is treated with p-fluoroaniline in methylene chloride to yield ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(p-fluoroanilino)acrylate (V). Cyclization of (V) with sodium hydride in tetrahydrofuran followed by hydrolysis yields 7-chloro-1-(p-fluorophenyl)-8 fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (VI). Condensation of (VI) with N-methylpiperazine in 1-methyl-2-pyrrolidinone followed by treatment with hydrochloric acid yields A-56619.

参考文献 中间体
合成目标
【1】 Clairbone, A.K.; Pihuleac, E.; Nordeen, C.; Fernandes, P.B.; Pernet, A.; Chu, D.T.W.; O'Donell, T.J.; A-56619 and A-56620: Synthesis and antibacterial activities of the novel aryl-fluoro-quinolones and their analogs. 24th Intersci Conf Antimicrob Agents Chemother (Oct 8-10, Washington, D.C) 1984, Abs 72.
【2】 Granneman, G.R.; Chu, D.T.W.; Fernandes, P.B.; Abbott-56619. Drugs Fut 1985, 10, 7, 543.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
37690 4-fluorophenylamine; 4-fluoroaniline 371-40-4 C6H6FN 详情 详情
(I) 24574 1-(2,4-dichloro-5-fluorophenyl)-1-ethanone 704-10-9 C8H5Cl2FO 详情 详情
(II) 17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
(III) 22096 ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate C11H9Cl2FO3 详情 详情
(IV) 22098 ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate C14H13Cl2FO4 详情 详情
(V) 24578 ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-(4-fluoroanilino)-2-propenoate C18H13Cl2F2NO3 详情 详情
(VI) 24579 7-chloro-6-fluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C16H8ClF2NO3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VII)

The reaction of ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (I) with O-(2,4-dinitrophenyl)hydroxylamine (II) by means of K2CO3 in DMF gives ethyl 1-amino-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (III), which is formylated with HCOOH in acetic anhydride yielding the corresponding 1-(formylamino) compound (IV). The methylation of (IV) with MeI and K2CO3 in DMF affords the 1-(formylmethylamino) compound (V), which is hydrolyzed with NaOH in refluxing water to give 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-(methylamino)quinoline-3-carboxylic acid (VI). Finally, this compound is condensed with N-methylpiperazine (VII) in refluxing pyridine.

参考文献 中间体
合成目标
【1】 Powles, R.G.; Wentland, M.P.; Wagner, R.B.; Dobson, .A.; Bailey, D.M.; Cornett, J.B.; Novel amino-substituted 3-quinolinecarboxylic acid antibacterial agents: Synthesis and stucture-activity relationships. J Med Chem 1984, 27, 9, 1103.
【2】 Wentland, M.P.; Bailey, D.M. (Sterling Winthrop Inc.); New quinolone compounds and preparation thereof. EP 0090424; JP 8401468 .
【3】 Castaner, J.; Serradell, M.N.; Burnie, J.; Matthews, R.; Amifloxacin. Drugs Fut 1985, 10, 3, 183.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19904 ethyl 7-chloro-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C12H9ClFNO3 详情 详情
(II) 29034 1-(aminooxy)-2,4-dinitrobenzene C6H5N3O5 详情 详情
(III) 29035 ethyl 1-amino-7-chloro-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C12H10ClFN2O3 详情 详情
(IV) 29036 ethyl 7-chloro-6-fluoro-1-(formylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C13H10ClFN2O4 详情 详情
(V) 29037 ethyl 7-chloro-6-fluoro-1-[formyl(methyl)amino]-4-oxo-1,4-dihydro-3-quinolinecarboxylate C14H12ClFN2O4 详情 详情
(VI) 29038 7-chloro-6-fluoro-1-(methylamino)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C11H8ClFN2O3 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

By condensation of 3-fluoro-5,6-dihydromorphanthridin-6-one (I) with N-methylpiperazine (II) by means of POCl3 and N,N-dimethylaniline.

参考文献 中间体
合成目标
【1】 Hunziker, F.; Fischer, R.; Morphanthridine derivatives. DE 2748920; FR 2370745; GB 1592329; GB 1592330; JP 53059686; US 4308207 .
【2】 Hunziker, F.; Fischer, R.; 3-Fluor-morphanthridine, ihre Herstellung und Verwengung. DE 2803542 .
【3】 Serradell, M.N.; Castaner, J.; Fluperlapine. Drugs Fut 1984, 9, 5, 326.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 34157 3-fluoro-5,11-dihydro-6H-dibenzo[b,e]azepin-6-one C14H10FNO 详情 详情
(II) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(B)

The condensation of 1 2-benzenediamine (I) with methyltetrahydro-5-methyl 4-oxo-3-thiophenecarboxylate (II) in toluene using a Dean-Stark trap gives the triyclic system (III), which is dehydrogenated to 4,9-dihydro-3-methyl-10H-thienol[3,4-b][1,5]benzodiazepin-10-one (IV). Treatment of (IV) with chloroacetyl chloride in dioxane in the presence of K2CO3 yields 4-chloroacetyl-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one (V), which is finally reacted with N-methylpiperazine to produce telenzepine, which is isolated as the hydrochloride.

参考文献 中间体
合成目标
【1】 Borner, H.; Haffer, G.; Sauer, G. (Schering AG); Process for the preparation of 2-bromo-8-ergolinyl. DE 3340025; US 4970314 .
【2】 Galvan, M.; Eltze, M.; Figala, V.; TELENZEPINE HYDROCHLORIDE < Rec INN >. Drugs Fut 1988, 13, 4, 327.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(B) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(A) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(I) 12824 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine 95-54-5 C6H8N2 详情 详情
(II) 11372 Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate C5H9NO2 详情 详情
(II) 22082 methyl (5R)-5-methyl-4-oxotetrahydro-3-thiophenecarboxylate C7H10O3S 详情 详情
(III) 22083 (3R)-3-methyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one C12H12N2OS 详情 详情
(III) 22088 2-[4-(3,4-dichlorophenyl)-1-piperazinyl]ethyl 3-oxobutanoate C16H20Cl2N2O3 详情 详情
(IV) 22084 3-methyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one C12H10N2OS 详情 详情
(V) 22085 4-(2-chloroacetyl)-3-methyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one C14H11ClN2O2S 详情 详情

合成路线10

该中间体在本合成路线中的序号：(V)

The reaction of 5alpha-androst-2-ene-17-one (I) with isopropenyl acetate (II) by means of H2SO4 as catalyst gives 17beta-acetoxy-5alpha-androsta-2,16-diene (III), which is epoxidized by means of perbenzoic acid (A) in benezene yielding 2alpha, 3alpha:16alpha,17alpha-diepoxy-17beta-acetoxy-5alpha-androstane (IV). The reaction of (IV) with N-methylpiperazine (V) in refluxing water affords 2beta,16beta-bis(4-methyl-1-piperazino)-3alpha-hydroxy-5alpha-androstane-17-one (VI), which is reduced with NaBH4 in THF methanol to give 2,16-bis(4-methyl-1-piperazino)-3alpha,17beta-dihydroxy-5alpha-androstane (VII). The acetylation of (VII) with acetic anhydride by means of ZnCl2 in acetic acid yields 2beta,16beta-bis(4-methyl-1-piperazino)-3alpha, 17beta-diacetoxy-5alpha-androstane (VIII), which is finally treated with methyl bromide in acetone.

参考文献 中间体
合成目标
【1】 US 312398 .
【2】 Tuba, Z.; et al.; GB 1398050 .
【3】 Blancafort, P.; Castaner, J.; Serradell, M.N.; Hopkins, S.J.; Pipecuronium bromide. Drugs Fut 1980, 5, 12, 621.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 39215 benzenecarboperoxoic acid 93-59-4 C7H6O3 详情 详情
(I) 32178 (5S,8R,9S,10S,13S,14S)-10,13-dimethyl-1,4,5,6,7,8,9,10,11,12,13,14,15,16-tetradecahydro-17H-cyclopenta[a]phenanthren-17-one C19H28O 详情 详情
(II) 21178 isopropenyl acetate 108-22-5 C5H8O2 详情 详情
(III) 32179 (5S,8R,9S,10S,13S,14S)-10,13-dimethyl-4,5,6,7,8,9,10,11,12,13,14,15-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate C21H30O2 详情 详情
(IV) 13647 (1aR,2aS,2bS,4aS,5aR,6aS,6bR,8aS,9aS)-2a,4a-dimethylhexadecahydro-4bH-oxireno[2'',3'':4',5']cyclopenta[1',2':7,8]phenanthro[2,3-b]oxiren-4-yl acetate C21H30O4 详情 详情
(V) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(VI) 39216 (2S,3S,5S,8R,9S,10S,13S,14S,16S)-3-hydroxy-10,13-dimethyl-2,16-bis(4-methyl-1-piperazinyl)hexadecahydro-17H-cyclopenta[a]phenanthren-17-one C29H50N4O2 详情 详情
(VII) 39217 (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-10,13-dimethyl-2,16-bis(4-methyl-1-piperazinyl)hexadecahydro-1H-cyclopenta[a]phenanthrene-3,17-diol C29H52N4O2 详情 详情
(VIII) 39218 (2S,3S,5S,8R,9S,10S,13S,14S,16S,17R)-17-(acetoxy)-10,13-dimethyl-2,16-bis(4-methyl-1-piperazinyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate C33H56N4O4 详情 详情

合成路线11

该中间体在本合成路线中的序号：(C)

The reaction of 5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepin-2-thione (I) with glycine (A) by means of Na2CO3 in refluxing ethanol-water gives 2-carboxymethylamino-7-nitro-5-(2-chlorophenyl)-3H-1,4-benzodiazepine (II), which is cyclized by means of dicyclohexylcarbodiimide in methylene chloride to afford 8-nitro-(2-chlorophenyl)-1,2-dihydro-1H,4H-imidazo[1,2-a][1,4]benzodiazepin-1-one (III). The reaction of (III) with dimethylformamide diethylacetal (B) by means of triethylamine in benzene yields 8-nitro-2-(dimethylaminomethylene)-6-(2-chlorophenyl)-1,2-dihydro-1H,4H-imidazo[1,2a][1,4]benzodiazepin-1-one (IV), which is treated with N-methylpiperazine (C) in refluxing toluene to produce 8-nitro-(2-chlorophenyl)-2-(N-methylpiperazin-1-ylmethylene)-1,2-dihydro-1H,4H-imidazo [1,2-a][1,4]benzodiazepin-1-one (V). This compound is finally treated with methanesulfonic acid.

参考文献 中间体
合成目标
【1】 Taylor, J.B.; Harrison D.R.; 1,2-Dihydro-6-phenyl-1H,4H-imidazobenzodiazepin-1-ones. US 4044142 .
【2】 Ager, J.R.; et al.; Central nervous system activity of a novel class of annelated 1,4-benzodiazwpines, aminomethylene-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-ones. J Med Chem 1977, 20, 8, 1035-41.
【3】 Thorpe, P.J.; Castaner, J.; Blancafort, P.; Serradell, M.N.; RU-31,158. Drugs Fut 1980, 5, 3, 144.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
40922 N,N'-dicyclohexylurea 2387-23-7 C13H24N2O 详情 详情
(A) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(B) 31457 N-(diethoxymethyl)-N,N-dimethylamine; diethoxy-N,N-dimethylmethanamine 1188-33-6 C7H17NO2 详情 详情
(I) 32632 5-(2-chlorophenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-thione C15H10ClN3O2S 详情 详情
(II) 32633 2-[[5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepin-2-yl]amino]acetic acid C17H13ClN4O4 详情 详情
(III) 30373 6-(2-chlorophenyl)-8-nitro-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-one C17H11ClN4O3 详情 详情
(IV) 32634 6-(2-chlorophenyl)-2-[(Z)-(dimethylamino)methylidene]-8-nitro-1H-imidazo[1,2-a][1,4]benzodiazepin-1(4H)-one C20H16ClN5O3 详情 详情
(V) 30375 6-(2-chlorophenyl)-2-[(Z)-(4-methyl-1-piperazinyl)methylidene]-8-nitro-1H-imidazo[1,2-a][1,4]benzodiazepin-1(4H)-one C23H21ClN6O3 详情 详情
(C) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线12

该中间体在本合成路线中的序号：(X)

The partial hydrolysis ot 2,3,4-trifluoronitrobenzene (I) with KOH in DMSO gives 2,3-difluoro-6-nitrophenol (II), which by condensation with chloroacetone (III) by means of K2CO3 - KI in refluxing acetone yields 2-acetonyloxy-3,4-difluoronitrobenzene (IV). The reductive cyclization of (IV) with H2 over Raney-Ni in ethanol affords 7,8-difluoro-2,3-dihydro-3-methyl-4H-benzoxazine (V), which is condensed with diethyl ethoxymethylenemalonate (VI) by heating at 145 C giving the malonic derivative (VII). The cyclization of (VII) by heating at 145 C with ethyl polyphosphate (PPE) yields ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (VIII), which is hydrolyzed with HCl in refluxing acetic acid affording the corresponding free acid (IX). Finally, this compound is condensed with N-methylpiperazine (X) in DMSO at 110 C.

参考文献 中间体
合成目标
【1】 Hayakawa, I.; Hiramitsu, T.; Tanaka, Y. (Daiichi Pharmaceutical Co., Ltd.); Benzoxazine derivs.. EP 0047005; US 4382892 .
【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; DL-8280. Drugs Fut 1983, 8, 5, 395.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 30677 1,2,3-trifluoro-4-nitrobenzene; 2,3,4-trifluoronitrobenzene 771-69-7 C6H2F3NO2 详情 详情
(II) 30678 2,3-difluoro-6-nitrophenol 82419-26-9 C6H3F2NO3 详情 详情
(III) 15288 1-Chloroacetone; Chloroacetone 78-95-5 C3H5ClO 详情 详情
(IV) 30679 1-(2,3-difluoro-6-nitrophenoxy)acetone C9H7F2NO4 详情 详情
(V) 30680 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine C9H9F2NO 详情 详情
(VI) 14088 Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate 87-13-8 C10H16O5 详情 详情
(VII) 30681 diethyl 2-[(7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methylene]malonate C17H19F2NO5 详情 详情
(VIII) 30682 ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate C15H13F2NO4 详情 详情
(IX) 12058 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid; 8,9-Difluoro-3-me-6-oxo-2,3-dihydro-6h-1-oxa-3a-aza-phenalene-5-carboxylic acid 82419-35-0 C13H9F2NO4 详情 详情
(X) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线13

该中间体在本合成路线中的序号：(VIII)

9,10-Difluoro-3-(hydroxymethyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid ethyl ester (I), a racemic intermediate in the synthesis of racemic ofloxacin, is esterified with 3,5-dinitrobenzoyl chloride (II) in the usual way to give the racemic ester (III), which is resolved into its optical isomers by HPLC over a SUMIPAX OA-4200 column, using hexane-1,2-dichloroethane-ethanol as carrier solvent. The (-)-optical isomer (IV) is partially hydrolyzed with ethanolic aqueous NaHCO3 to afford the (-)-alcohol (V), which is treated with triphenylphosphite methiodide in DMF giving the corresponding (-)-iodomethyl derivative (VI). The reduction and simultaneous hydrolysis of (VI) with tributyltin hydride in ethanol yields (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (VII), which is finally treated with N-methylpiperazine (VIII) to give (-)-ofloxacin.

参考文献 中间体
合成目标
【1】 Yoneda, N.; Kato, J.; Hayashi, K.; Ochiani, T.; Kinashi, K. (Tanabe Seiyaku Co., Ltd.); Quinolinecarboxylic acid derivs. and method for their preparation. EP 0095163; ES 8603427; US 4508727 .
【2】 Böshagen, H.; Stoltefuss, J.; Berschauer, F.; De Jong, A.; Scheer, M. (Bayer AG); Pure enantiomeric 1,8-bridged-4-quinolo-3-carboxylic acids, process for their preparation and medicaments containing them, and their use in the preparation of medicaments. DE 3543513; EP 0225552; JP 1987145088 .
【3】 Egawa, H.; Miyamoto, H.; Matsumoto, J. (Dainippon Pharmaceutical Co., Ltd.); Method for the preparation of pyridobenzoxazin derivs. and their intermediates. JP 1987215591 .
【4】 Gershon, N.; Wizel, S.; Niddam-Hildesheim, V.; Amir, E. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Preparation of levofloxacin and forms thereof. WO 0328664 .
【5】 Sharma, P.N.; Pernet, A.G.; Shen, L.L.; Mitscher, L.A.; Chu, D.T.W.; Chiral DNA gyrase inhibitors. 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (ofloxacin). J Med Chem 1987, 30, 12, 2283-6.
【6】 Prous, J.; Castaner, J.; Levofloxacin. Drugs Fut 1992, 17, 7, 559.
【7】 Hayakawa, I.; Atarashi, S.; Yokohama, S.; Imamura, M.; Sakano, K.-I.; Furukawa, M.; Synthesis and antibacterial activities of optically active ofloxacin. Antimicrob Agents Chemother 1986, 29, 1, 163-4.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12052 ethyl 9,10-difluoro-3-(hydroxymethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate C15H13F2NO5 详情 详情
(II) 12053 3,5-Dinitrobenzoyl chloride 99-33-2 C7H3ClN2O5 详情 详情
(III) 12054 ethyl 3-[[(3,5-dinitrobenzoyl)oxy]methyl]-9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate C22H15F2N3O10 详情 详情
(IV) 12055 ethyl 3-[[(3,5-dinitrobenzoyl)oxy]methyl]-9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate C22H15F2N3O10 详情 详情
(V) 12056 ethyl 9,10-difluoro-3-(hydroxymethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate C15H13F2NO5 详情 详情
(VI) 12057 ethyl 9,10-difluoro-3-(iodomethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate C15H12F2INO4 详情 详情
(VII) 12058 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid; 8,9-Difluoro-3-me-6-oxo-2,3-dihydro-6h-1-oxa-3a-aza-phenalene-5-carboxylic acid 82419-35-0 C13H9F2NO4 详情 详情
(VIII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线14

该中间体在本合成路线中的序号：(A)

The reaction of 10-bromo-5H-dibenzo[a,d]cyclohepten-5-one (I) with N-methylpiperazine (A) by means of potassium tert-butoxide in refluxing tert-butanol gives 10-(N-methylpiperazin-1-yl)-5H-dibenzo[a,d]cyclohepten-5-one (II), which by treatment first with methyllithium in ether and then with refluxing ethanolic HCl is converted into 5-methylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-one (III). The reaction of (III) with hydroxylamine in refluxing methanol yields 5-methylene-10-hydroxyimino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (IV), which is reduced with sodium cyanoborohydride in methanol to afford 5-methylene-10-hydroxamino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (V). The internal reaction of (V) in refluxing xylene gives 5-(hydroxymethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (V), which is reduced with Zn in hot acetic acid.

参考文献 中间体
合成目标
【1】 Evans, B.E.; Engelhardt, E.L.; Remy, D.C.; Britcher, S.F.; Andderson, P.S.; Colton, C.D.; Christy, M.E.; Transannular reaction of dibenzo[a,d]cycloalkenes. 1. Synthesis of dibenzo[a,d]cycloocten-6,12-imines and dibenzo[a,d]cyclohepten-5,10-imines. J Org Chem 1979, 44, 18, 3117-27.
【2】 Thorpe, P.J.; Castaner, J.; Serradell, M.N.; Blancafort, P.; MK-801. Drugs Fut 1983, 8, 2, 120.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(I) 35924 10-bromo-5H-dibenzo[a,d]cyclohepten-5-one C15H9BrO 详情 详情
(II) 35925 10-(4-methyl-1-piperazinyl)-5H-dibenzo[a,d]cyclohepten-5-one C20H20N2O 详情 详情
(III) 35926 5-methylene-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one C16H12O 详情 详情
(IV) 35927 5-methylene-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one oxime C16H13NO 详情 详情
(V) 35928 10-(hydroxyamino)-5-methylene-5H-dibenzo[a,d]cycloheptene; N-(5-methylene-5H-dibenzo[a,d]cyclohepten-10-yl)hydroxylamine C16H13NO 详情 详情
(VI) 35929 16-azatetracyclo[7.6.1.0(2,7).0(10,15)]hexadeca-2,4,6,10,12,14-hexaen-1-ylmethanol C16H15NO 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XII)

A new synthesis for KB-5246 has been described: The reaction of 2,3,4-trifluoroaniline (I) with carbon disulfide (II) and triethylamine gives the corresponding dithiocarbamate (III), which by cyclization with 1-acetoxy-3-chloro-2-propanone (IV) in ethyl acetate yields 4-(acetoxymethyl)-3-(2,3,4-trifluorophenyl)thiazole-2(3H)-thione (V). The cyclization of (V) with potassium hydroxide in refluxing ethanol-water affords 6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazine-1-thione (VI), which is treated with trichloromethyl chloroformate in hot toluene to give the thiazolium chloride (VII), which is not isolated. The in situ reaction of (VII) with diethyl malonate by means of triethylamine in toluene gives (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonic acid diethyl ester (IX), which is cyclized again with polyphosphoric acid (PPA) at 115 C to afford 7,8-difluoro-5-oxo-9,1-(epoxymethano)-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid ethyl ester (X). The hydrolysis of (X) with oleum gives the corresponding acid (XI), which is finally condensed with N-methylpiperazine (XII) in hot DMSO.

参考文献 中间体
合成目标
【1】 Kondo, H.; Tsukamoto, G.; Taguchi, M.; Jinbo, Y.; Kawahata, Y.; Sakamoto, F.; Inoue, Y.; Synthesis and antibacterial activity of new tetracyclic quinolone antibacterials. J Med Chem 1992, 35, 1, 94.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13059 2,3,4-Trifluorophenylamine; 2,3,4-Trifluoroaniline 3862-73-5 C6H4F3N 详情 详情
(III) 13060 2,3,4-trifluorophenylcarbamodithioate C7H3F3NS2 详情 详情
(IV) 13061 2-(chlorooxy)-2-oxoethyl acetate C4H5ClO4 详情 详情
(V) 13062 [2-thioxo-3-(2,3,4-trifluorophenyl)-2,3-dihydro-1,3-thiazol-4-yl]methyl acetate C12H8F3NO2S2 详情 详情
(VI) 13063 6,7-Difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazine-1-thione C10H5F2NOS2 详情 详情
(VII) 13064 1-Chloro-6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-10-ium chloride C10H5Cl2F2NOS 详情 详情
(VIII) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(IX) 13066 diethyl 2-(6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate C17H15F2NO5S 详情 详情
(X) 13067 ethyl 5,6-difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylate C15H9F2NO4S 详情 详情
(XI) 13068 5,6-Difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylic acid C13H5F2NO4S 详情 详情
(XII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线16

该中间体在本合成路线中的序号：(XI)

The reaction of 2,3,4-trifluoroaniline (I) with carbon disulfide and triethylamine gives triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (II), which by reaction with ethyl chlorocarbonate in chloroform yields the corresponding isothiocyanate (III). The condensation of (III) with diethyl malonate (IV) by means of NaH in THF affords the sodium salt of diethyl [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate (V), which is condensed with 1-acetoxy-3-chloroacetone in DMF to give the substituted thioester (VII). The cyclization of (VII) by means of sulfuric acid yields the thiazoline derivative (VIII), which is cyclized again by means of NaH in refluxing dioxane to afford diethyl (6,7-difluoro-1H,4H-thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate (IX). A final, new cyclization of (IX) by means of ethyl polyphosphate (PPE) at 138 C, followed by hydrolysis of the intermediate ester with sulfuric acid gives 7,8-difluoro-9,1-epoxymethano-5-oxo-5H-thiazolo[3,2-a]quinoline-4-carboxylic acid (X). This compound is then condensed with 1-methylpiperazine (XI) in hot DMSO and treated with aqueous HCl.

参考文献 中间体
合成目标
【1】 Taguchi, M.; Kondo, H.; Inoue, Y.; Kawahata, Y.; Tsukamoto, G. (Kanebo Pharmaceuticals, Ltd.); Quinolinecarboxylic acid derivs., a compsns. comprising the same, process for preparing the same, and the use of the same for the manufacture of medicaments. EP 0286089; JP 1989199979; US 4808584 .
【2】 Prous, J.; Castaner, J.; KB-5246. Drugs Fut 1989, 14, 6, 519.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13059 2,3,4-Trifluorophenylamine; 2,3,4-Trifluoroaniline 3862-73-5 C6H4F3N 详情 详情
(II) 20905 N,N-dipropyl-1-propanaminium 2,3,4-trifluorophenylcarbamodithioate C16H25F3N2S2 详情 详情
(III) 20906 1,2,3-trifluoro-4-isothiocyanatobenzene; 2,3,4-trifluorophenyl isothiocyanate 119474-40-7 C7H2F3NS 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 20908 sodium 3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-(2,3,4-trifluoroanilino)-1-propene-1-thiolate C14H13F3NNaO4S 详情 详情
(VI) 20909 4-chloro-3-oxobutyl acetate C6H9ClO3 详情 详情
(VII) 20910 diethyl 2-[[[2-(acetoxy)acetyl]sulfanyl](2,3,4-trifluoroanilino)methylene]malonate C18H18F3NO7S 详情 详情
(VIII) 20911 diethyl 2-[4-(hydroxymethyl)-3-(2,3,4-trifluorophenyl)-1,3-thiazol-2(3H)-ylidene]malonate C17H16F3NO5S 详情 详情
(IX) 13066 diethyl 2-(6,7-difluoro-4H-[1,3]thiazolo[4,3-c][1,4]benzoxazin-1-ylidene)malonate C17H15F2NO5S 详情 详情
(X) 13068 5,6-Difluoro-8-oxo-3H,8H-4-oxa-1-thia-9b-azacyclopenta[cd]phenalene-9-carboxylic acid C13H5F2NO4S 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线17

该中间体在本合成路线中的序号：

The reaction of 11-methylene-6,11-dihydrodibenzo[b,e]oxepine-2-carboxylic acid methyl ester (I) with N-methylpiperazine and paraformaldehyde by means of trifluoroacetic acid in hot tetrachloroethane gives 11-[2-(4-methylpiperazin-1-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine-2-carboxylic acid methyl ester (II), which by reaction with ethyl chloroformate and sodium acetate in dichloromethane yields the corresponding 2-chloroethylidene derivative (III). The condensation of (III) with 5,6-dimethyl-1H-benzimidazole (IV) in refluxing toluene affords the methyl ester (V) of the desired product, which is finally hydrolyzed with sodium methoxide in methanol.

参考文献 中间体
合成目标
【1】 Oshima, E.; Obase, H.; Karasawa, A.; Kubo, K.; Miki, I.; Ishii, A. (Kyowa Hakko Kogyo Co., Ltd.); Tricyclic cpds. EP 0345747; JP 1990091040; US 4999363; US 5118701; US 5242931; US 5302596 .
【2】 Prous, J.; Castaner, J.; KW-3635. Drugs Fut 1992, 17, 9, 782.
【3】 Ishii, A.; Higo, K.; Miki, I.; Kubo, K.; Ohshima, E.; Takami, H.; Karasawa, A.; Sato, H.; Obase, H.; Shirakura, S.; Synthesis and biological activity of a novel thromboxane A2 receptor antagonist, KW-3635, and its related derivatives. 11th Symp Med Chem (Dec 4-5, Tokushima) 1990, Abst P-6.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(I) 14066 methyl 11-methylene-6,11-dihydrodibenzo[b,e]oxepine-2-carboxylate C17H14O3 详情 详情
(II) 14067 methyl 11-[(E)-2-(4-methylpiperazino)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine-2-carboxylate C23H26N2O3 详情 详情
(III) 14068 methyl 11-[(E)-2-chloroethylidene]-6,11-dihydrodibenzo[b,e]oxepine-2-carboxylate C18H15ClO3 详情 详情
(IV) 14069 5,6-Dimethylbenzimidazole; 5,6-Dimethyl-1H-benzimidazole 582-60-5 C9H10N2 详情 详情
(V) 14070 methyl 11-[(E)-2-(5,6-dimethyl-1H-benzimidazol-1-yl)ethylidene]-6,11-dihydrodibenzo[b,e]oxepine-2-carboxylate C27H24N2O3 详情 详情

合成路线18

该中间体在本合成路线中的序号：(III)

Treatment of thiourea (I) with iodomethane provided S-methylthiouronium iodide (II). This was further condensed with N-methylpiperazine (III) to afford the intermediate piperazine-1-carboxamidine (IV)

参考文献 中间体
合成目标
【1】 Miller, A.A.; Nobbs, M.S.; Hyde, R.M.; Leach, M.J. (Glaxo Wellcome plc); Pharmacologically active CNS cpds.. AU 8945964; EP 0372934; EP 0713703; EP 0715851; EP 0727212; EP 0727213; EP 0727214; JP 1990202876; US 5587380; US 5597828; US 5635507; US 5684005 .
【2】 Patel, R.; Packham, T.W.; Germain, A.L.; Barras, J.R.; Milne, D.J. (GlaxoSmithKline plc); Process of preparing 2,3,5-trihalobenzaldehyde. WO 9507877 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(II) 62329 　 C3H10N2S 详情 详情
(III) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IV) 62330 　 C7H18N4 详情 详情

合成路线19

该中间体在本合成路线中的序号：(IV)

The reaction of 8(S)-(bromomethyl)-4-hydroxy-2-methyl-1-oxo-6-(5,6,7-trimethoxyindol-2-ylcarbonyl)-1,2,3,6,7,8-hexahydrobenzo[1,2-b:4,3-b']dipyrrole-2-carboxylic acid methyl ester (I) with tert-butyl-dimethylsilyl chloride in DMF gives the corresponding O-silyl derivative (II), which is treated with camphorsulfonic acid (CPS) in hot chloroform to afford 8(S)-(bromomethyl)-4-hydroxy-2-methyl-6-(5,6,7-trimethoxyindol-2-ylcarbonyl)-3,6,7,8-tetrahydrobenzo[1,2-b:4,3-b']dipyrrole-1-carboxylic acid methyl ester (III). Finally, this compound is desilylated with tetrabutylammonium fluoride in THF and condensed with N-methylpiperazine (IV) and 4-nitrophenyl chloroformate by means of triethylamine in dichloromethane.

参考文献 中间体
合成目标
【1】 Kanda, Y.; Uosaki, Y.; Saito, H.; Sano, H.; Kobayashi, E.; Morimoto, M.; Nagamura, S. (Kyowa Hakko Kogyo Co., Ltd.); DC-88A derivs. EP 0406749; JP 1991128379; US 5070092; US 5187186 .
【2】 Castaner, J.; Hoshi, A.; KW-2189. Drugs Fut 1993, 18, 12, 1112.
【3】 Saito, H.; Gomi, K.; Nagamura, S.; Kanda, Y.; Asai, A.; Kobayashi, E.; Synthesis, antitumor activity and DNA alkylation of duocarmycin analogs. Development of KW2189. 203rd ACS Natl Meet (April 5-10, San Francisco) 1992, Abst MEDI 44.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14658 methyl (8S)-8-(bromomethyl)-4-hydroxy-2-methyl-1-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indole-2-carboxylate C26H26BrN3O8 详情 详情
(II) 14659 methyl (8S)-8-(bromomethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-1-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,6,7,8-hexahydropyrrolo[3,2-e]indole-2-carboxylate C32H40BrN3O8Si 详情 详情
(III) 14660 methyl (8S)-8-(bromomethyl)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C32H40BrN3O7Si 详情 详情
(IV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线20

该中间体在本合成路线中的序号：(XV)

The condensation of indoline (I) with methyl acetoacetate (II) by means of Ts-OH in refluxing benzene gives the adduct (III), which is cyclized by means of Pd(OAc)2 in hot DMA to yield the pyrroloindole (IV). The hydrolysis of the acetate group of (IV) by means of K2CO3 in methanol affords the hydroxymethyl compound (V), which is treated with CCl4 and PPh3 to provide the chloromethyl derivative (VI). The cleavage of the benzyl protecting group of (VI) by means of HCOONH4 and Pd/C in THF gives the hydroxy derivative (VII), which is N-deprotected by means of HCl in ethyl acetate to yield the intermediate (VIII). The condensation of (VIII) with 5,6,7-trimethoxy-1H-indole-2-carboxylic acid (IX) by means of EDC in DMF affords the carboxamide (X), which is treated with DBU in acetonitrile to provide the cyclopropapyrroloindole (XI). The reaction of (XI) with HBr in acetonitrile gives the bromomethyl derivative (XII), which is treated with 4-nitrophenyl chloroformate (XIII) to yield the active carbonate ester (XIV). Finally, this compound is treated with 1-methylpiperazine (XV) to provide the target Pibrozelesin.

参考文献 中间体
合成目标
【1】 Fukuda, Y.; et al.; Novel syntheses of optically active CC-1065, U-73,975 (adozelesin), U-80,244 (carzelesin), U-77,779 (bizelesin), KW-2189, and DU-86. Heterocycles 1997, 45, 12, 2303.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 59123 tert-butyl (3S)-3-[(acetyloxy)methyl]-5-amino-6-(benzyloxy)-2,3-dihydro-1H-indole-1-carboxylate C23H28N2O5 详情 详情
(II) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情
(III) 61767 tert-butyl (3S)-3-[(acetyloxy)methyl]-6-(benzyloxy)-5-{[(E)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino}-2,3-dihydro-1H-indole-1-carboxylate C28H34N2O7 详情 详情
(IV) 61768 6-(tert-butyl) 1-methyl (8S)-8-[(acetyloxy)methyl]-4-(benzyloxy)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate C28H32N2O7 详情 详情
(V) 61769 6-(tert-butyl) 1-methyl (8S)-4-(benzyloxy)-8-(hydroxymethyl)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate C26H30N2O6 详情 详情
(VI) 61770 6-(tert-butyl) 1-methyl (8S)-4-(benzyloxy)-8-(chloromethyl)-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate C26H29ClN2O5 详情 详情
(VII) 61771 6-(tert-butyl) 1-methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-7,8-dihydropyrrolo[3,2-e]indole-1,6(3H)-dicarboxylate C19H23ClN2O5 详情 详情
(VIII) 61772 methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C14H15ClN2O3 详情 详情
(IX) 61773 5,6,7-trimethoxy-1H-indole-2-carboxylic acid C12H13NO5 详情 详情
(X) 61774 methyl (8S)-8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C26H26ClN3O7 详情 详情
(XI) 40881 methyl (3bR,4aS)-2-methyl-8-oxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate C26H25N3O7 详情 详情
(XII) 61775 methyl (8S)-8-(bromomethyl)-4-hydroxy-2-methyl-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C26H26BrN3O7 详情 详情
(XIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XIV) 61776 methyl (8S)-8-(bromomethyl)-2-methyl-4-{[(4-nitrophenoxy)carbonyl]oxy}-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C33H29BrN4O11 详情 详情
(XV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(V)

The condensation of o-chloronitrobenzene (I) with 2-amino-5-methylthiophene-3-carbonitrile (II) by means of lithium hydroxide in DMSO gives 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile (III). The reductive cyclization of (III) using stannous chloride in aqueous ethanolic hydrochloric acid gives the primary amidine hydrochloride (IV), which is condensed with N-methylpiperazine (V) in a mixture of 4:1 toluene:DMSO.

参考文献 中间体
合成目标
【1】 Larsen, S.D.; Stephenson, G.A.; Bunnell, C.A.; Reutzel, S.M.; Nichols, J.R. (Eli Lilly and Company); Intermediates and process for preparing olanzapine. US 6020487 .
【2】 Moore, N.A.; Hotten, T.M.; Tupper, D.E.; Olanzapine. Drugs Fut 1994, 19, 2, 114.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15248 1-chloro-2-nitrobenzene 88-73-3 C6H4ClNO2 详情 详情
(II) 15249 5-Amino-4-cyano-2-methylthiophene; 2-amino-5-methyl-3-thiophenecarbonitrile 138564-58-6 C6H6N2S 详情 详情
(III) 15250 5-methyl-2-(2-nitroanilino)-3-thiophenecarbonitrile C12H9N3O2S 详情 详情
(IV) 15251 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-ylamine hydrochloride; 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine hydrochloride; 4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride 138564-60-0 C12H12ClN3S 详情 详情
(V) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(V)

2) Synthesis of olanzapine 4'-N-oxide: The condensation of 2-fluoronitrobenzene (I) with 5-methylthiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III), which is cyclized by means of SnCl2 in ethanol yielding 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine-4-amine (IV). The condensation of (IV) with N-methylpiperazine (V) in toluene/DMSO affords 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepin e (olanzapine) (VI), which is finally oxidized with m-chloroperbenzoic acid (m-CPBA) in dichloromethane to give the metabolite 2-methyl-4-(4-methyl-4-oxidopiperazinyl-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine.

参考文献 中间体
合成目标
【1】 Calligaro, D.O.; Moore, N.A.; Tupper, D.E.; Fairhurst, J.; Hotten, T.M.; The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053). Bioorg Med Chem Lett 1997, 7, 1, 25.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13463 o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene 1493-27-2 C6H4FNO2 详情 详情
(II) 15249 5-Amino-4-cyano-2-methylthiophene; 2-amino-5-methyl-3-thiophenecarbonitrile 138564-58-6 C6H6N2S 详情 详情
(III) 15250 5-methyl-2-(2-nitroanilino)-3-thiophenecarbonitrile C12H9N3O2S 详情 详情
(IV) 15255 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-ylamine; 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine C12H11N3S 详情 详情
(V) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(VI) 15262 2-methyl-4-(4-methylpiperazino)-10H-thieno[2,3-b][1,5]benzodiazepine C17H20N4S 详情 详情

合成路线23

该中间体在本合成路线中的序号：(VII)

3) Synthesis of 2-hydroxymethyl olanzapine: The condensation of 2-fluoronitrobenzene (I) with thiophene-2-amine (II) by means of LiOH in DMSO gives the expected secondary amine (III), which is formylated with DMF by means of POCl3 yielding the aldehyde (IV). The reducticyclization of (IV) with SnCl2 in ethanol affords 4-amino-10H-thieno[2,3-b][1,5]benzodiazepine-2-carbaldehyde (V), which is reduced with NaBH4 in ethanol to the corresponding hydroxymethyl derivative (VI). Finally, this compound is condensed with N-methylpiperazine (VII) in toluene/DMSO to give the metabolite 2-(hydroxymethyl)-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benz odiazepine.

参考文献 中间体
合成目标
【1】 Calligaro, D.O.; Moore, N.A.; Tupper, D.E.; Fairhurst, J.; Hotten, T.M.; The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053). Bioorg Med Chem Lett 1997, 7, 1, 25.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13463 o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene 1493-27-2 C6H4FNO2 详情 详情
(II) 15263 2-amino-3-thiophenecarbonitrile 4651-82-5 C5H4N2S 详情 详情
(III) 15264 2-(2-nitroanilino)-3-thiophenecarbonitrile C11H7N3O2S 详情 详情
(IV) 15265 5-formyl-2-(2-nitroanilino)-3-thiophenecarbonitrile C12H7N3O3S 详情 详情
(V) 15266 4-amino-10H-thieno[2,3-b][1,5]benzodiazepine-2-carbaldehyde C12H9N3OS 详情 详情
(VI) 15267 (4-amino-10H-thieno[2,3-b][1,5]benzodiazepin-2-yl)methanol C12H11N3OS 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线24

该中间体在本合成路线中的序号：(XI)

The methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester (I) with hot dimethyl sulfate gives 1-methyl-3-propylpyrazole-5-carboxylic acid ethyl ester (II), which is hydrolyzed with aqueous NaOH to the corresponding free acid (III). The nitration of (III) with oleum/fuming nitric acid yields the 4-nitro derivative (IV), which is treated first with refluxing SOCl2 and then with NH4OH to afford the corresponding carboxamide (V). The reduction of the nitro group of (V) with SnCl2 dihydrate in refluxing ethanol gives 4-amino-1-methyl-3-propylpyrazole-5-carboxamide (VI), which is acylated with 2-ethoxybenzoyl chloride (VII) by means of triethylamine in dichloromethane yielding 4-(2-ethoxybenzamido)-1-methyl-3-propylpyrazole-5-carboxamide (VIII). The cyclization of (VIII) by means of NaOH and H2O2 in refluxing ethanol affords 5-(2-ethoxyphenyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d] pyrimidin-7-one (IX), which is sulfonated with chlorosulfonic acid affording the chlorosulfonyl derivative (X). Finally, this compound is condensed with 1-methylpiperazine in ethanol at room temperature.

参考文献 中间体
合成目标
【1】 Martel, A.M.; Graul, A.; Rabasseda, X.; Castaner, R.M.; Sildenafil. Drugs Fut 1997, 22, 2, 138.
【2】 Terrett, N.K.; Bell, A.S.; Brown, D.; Ellis, P.; Sildenafil (Viagra(TM)), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg Med Chem Lett 1996, 6, 15, 1819-24.
【3】 Bell, A.S.; Brown, D.; Terrett, N.K. (Pfizer Inc.); Pyrazolopyrimidinone antianginal agents. EP 0463756; JP 1994041133; US 5250534; US 5346901 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15622 ethyl 3-propyl-1H-pyrazole-5-carboxylate C9H14N2O2 详情 详情
(II) 15623 ethyl 1-methyl-3-propyl-1H-pyrazole-5-carboxylate C10H16N2O2 详情 详情
(III) 15624 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid C8H12N2O2 详情 详情
(IV) 15625 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxylic acid C8H11N3O4 详情 详情
(V) 15626 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide; 4-Nitro-1-methyl-3-propyl-5-pyrazolecarboxamide 139756-01-8 C8H12N4O3 详情 详情
(VI) 15627 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 4-amino-1-methyl-3-propyl-5-pyrazolecarboxamide 139756-02-8 C8H14N4O 详情 详情
(VII) 15628 2-ethoxybenzoyl chloride 42926-52-3 C9H9ClO2 详情 详情
(VIII) 15629 4-[(2-ethoxybenzoyl)amino]-1-methyl-3-propyl-1H-pyrazole-5-carboxamide C17H22N4O3 详情 详情
(IX) 15630 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-(2-ethoxyphenyl)-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo[4,3-d]pyrimidin-7-one 139756-21-1 C17H20N4O2 详情 详情
(X) 15631 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonyl chloride C17H19ClN4O4S 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线25

该中间体在本合成路线中的序号：(III)

A more efficient process for preparing clinical-grade sildenafil has been described: The reaction of 2-ethoxybenzoic acid (I) with SOCl2 and ClSO3H gives 5-(chlorosulfonyl)-2-ethoxybenzoic acid (II), which is condensed with 1-methylpiperazine (III) by means of triethylamine in water yielding 2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid (IV). The condensation of (IV) with 4-amino-1-methyl-3-propylpyrazole-5-carboxamide (V), obtained by reduction of the corresponding 4-nitro compound (VI) with H2 over Pd/C in ethyl acetate, by means of carbonyldiimidazole (CDI) in refluxing ethyl acetate affords the corresponding amide (VII), which is finally cyclized by means of potassium tert-butoxide in refluxing tert-butanol. Other cyclizing agents such as KOH, KHCO3, BaO, sodium ethoxide, sodium tert-butoxide, NaH, NaNH2, sodium decyloxide, sodium cyclohexylamide, sodium 4-methylpiperazide, Cs2CO3, magnesium ethoxide, barium ethoxide, cupric ethoxide, aluminum tert-butoxide, titanium ethoxide, lithium diisopropylamide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), KF or several Lewis acids, as well as other solvents such as methanol, ethanol, tert-amyl alcohol, 1-methylcyclohexanol, THF, 1,4-dioxan, 1,2-dimethoxyethane, 3,7-dimethyloctan-3-ol, DMSO, pyridine, acetonitrile, or methyl isobutyl ketone have also been used; the reaction temperature is normally 100 C.

参考文献 中间体
合成目标
【1】 Dale, D.J.; et al.; The chemical development of the commercial route to sildenafil: A case history. Org Process Res Dev 2000, 4, 1, 17.
【2】 Dunn, P.J.; Wood, A.S. (Pfizer Inc.); Process for preparing sildenafil. EP 0812845; JP 1998081688; JP 1999171879 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 21185 2-ethoxybenzoic acid 134-11-2 C9H10O3 详情 详情
(II) 21186 5-(chlorosulfonyl)-2-ethoxybenzoic acid 200575-16-2 C9H9ClO5S 详情 详情
(III) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IV) 21188 2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid 194602-23-8 C14H20N2O5S 详情 详情
(V) 15626 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carboxamide; 4-Nitro-1-methyl-3-propyl-5-pyrazolecarboxamide 139756-01-8 C8H12N4O3 详情 详情
(VI) 15627 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 4-amino-1-methyl-3-propyl-5-pyrazolecarboxamide 139756-02-8 C8H14N4O 详情 详情
(VII) 21191 4-([2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoyl]amino)-1-methyl-3-propyl-1H-pyrazole-5-carboxamide C22H32N6O5S 详情 详情

合成路线26

该中间体在本合成路线中的序号：(XV)

Synthesis of sildenafil: Reaction of 5-(chlorosulfonyl)-2-hydroxybenzoic acid (XIV) with 1-methylpiperazine (XV) by means of DIEA gives the sulfonamide (XVI), which is treated with diethyl sulfate yielding 2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)benzoic acid (XVII). The activation of (XVII) with a polymer-supported 1-hydroxybenzotriazole (HOBt) variant (XVIII) and bromotris(pyrrolidino)phosphonium (PyBrOP) as catalyst affords the activated ester (XIX), which is condensed with the aminopyrazole intermediate (XIII), and treated with the methyl isocyanate resin (X) in order to eliminate the excess of aminopyrazole (XIII), to provide the diamide (XX). Finally, the cyclization and dehydration to sildenafil are performed by microwave irradiation of an ethanolic solution of compound (XX) containig a catalytic amount of NaOEt.

参考文献 中间体
合成目标
【1】 Baxendale, I.R.; Ley, S.V.; Polymer-supported reagents for multi-step organic synthesis: Application to the synthesis of sildenafil. Bioorg Med Chem Lett 2000, 10, 17, 1983.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 11019 (Methylimino)(oxo)methane; methyl isocyanate C2H3NO 详情 详情
(XIII) 15627 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 4-amino-1-methyl-3-propyl-5-pyrazolecarboxamide 139756-02-8 C8H14N4O 详情 详情
(XIV) 44346 5-(chlorosulfonyl)-2-hydroxybenzoic acid C7H5ClO5S 详情 详情
(XV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XVI) 44347 2-hydroxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid C12H16N2O5S 详情 详情
(XVII) 21188 2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid 194602-23-8 C14H20N2O5S 详情 详情
(XVIII) 44348 1-hydroxy-1H-1,2,3-benzotriazole-6-carbaldehyde C7H5N3O2 详情 详情
(XIX) 44349 1-([2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoyl]oxy)-1H-1,2,3-benzotriazole-6-carbaldehyde C21H23N5O6S 详情 详情
(XX) 21191 4-([2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoyl]amino)-1-methyl-3-propyl-1H-pyrazole-5-carboxamide C22H32N6O5S 详情 详情

合成路线27

该中间体在本合成路线中的序号：(V)

The condensation of 1-(benzylideneamino)imidazolidine-2,4-dione (I) with 1-bromo-4-chlorobutane (II) by means of NaH in DMF at 100 C yields 1-(benzylideneamino)-3-(4-chlorobutyl)imidazolidine-2,4-dione (III), which is treated with NaI in refluxing acetone affording the corresponding 4-iodobutyl derivative (IV). The thermal condensation of (IV) with 1-methylpiperazine (V) in refluxing DMF gives the expected condensation product (VI), which is debenzylated by hydrogenation with H2 over Pd/C in 2N HCl giving 1-amino-3-[4-(4-methylpiperazin-1-yl)butyl]imidazolidine-2,4-dione (VII). Finally, this compound is condensed with 5-(4-chlorophenyl)furan-2-carbaldehyde (VIII) in DMF at room temperature.

参考文献 中间体
合成目标
【1】 Robinson, C.P.; Robinson, K.A.; Castaner, J.; Azimilide Hydrochloride. Drugs Fut 1997, 22, 6, 601.
【2】 Pelosi, S.S. Jr.; Yu, C.-NN.; Calcagno, M.A. (The Procter & Gamble Co.); Novel 4-oxocyclic ureas useful as antiarrhythmic and antifibrillatory agents. EP 0598061; JP 1994509804; US 5462940; WO 9304061 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 16140 1-[[(E)-benzylidene]amino]-1H-imidazole-2,4(3H,5H)-dione C10H9N3O2 详情 详情
(II) 16141 1-bromo-4-chlorobutane 6940-78-9 C4H8BrCl 详情 详情
(III) 16142 3-(4-chlorobutyl)-1-[[(E)-benzylidene]amino]-1H-imidazole-2,4(3H,5H)-dione C14H16ClN3O2 详情 详情
(IV) 16143 3-(4-iodobutyl)-1-[[(E)-benzylidene]amino]-1H-imidazole-2,4(3H,5H)-dione C14H16IN3O2 详情 详情
(V) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(VI) 16145 3-[4-(4-methylpiperazino)butyl]-1-[[(E)-benzylidene]amino]-1H-imidazole-2,4(3H,5H)-dione C19H27N5O2 详情 详情
(VII) 16146 1-amino-3-[4-(4-methylpiperazino)butyl]-1H-imidazole-2,4(3H,5H)-dione C12H23N5O2 详情 详情
(VIII) 16147 5-(4-Chloro-phenyl)-furan-2-carbaldehyde; 5-(4-Chlorophenyl)-2-furaldehyde 34035-03-5 C11H7ClO2 详情 详情

合成路线28

该中间体在本合成路线中的序号：(IX)

Benzodioxan-6-amine (I) was protected as the corresponding acetanilide (II), which was subsequently subjected to Friedel-Crafts condensation with chloroacetyl chloride (III) in the presence of ZnCl2, yielding the chloro ketone (IV). Acidic hydrolysis of the acetamide function of (IV) provided amino ketone (V). Alternatively, intermediate (V) was prepared by direct acylation of aniline (I) employing chloroacetonitrile (VI) in the presence of BCl3. The 7-(chloromethyl)camptothecin derivative (VIII) was synthesized through a Friedlander condensation between amino ketone (V) and the known keto lactone (VII). Finally, displacement of the chloride of (VIII) with N-methylpiperazine (IX) gave rise to the title piperazinylmethyl camptothecin.

参考文献 中间体
合成目标
【1】 Luzzio, M.J.; et al.; Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem 1995, 38, 3, 395.
【2】 Luzzio, M.J.; Besterman, J.M.; Evans, M.G.; Myers, P.L. (GlaxoSmithKline plc); Water soluble camptothecin derivs.. EP 0540099; JP 1993222048; JP 2000109475; US 5559235 .
【3】 Sternbach, D.D.; Lackey, K. (GlaxoSmithKline Inc.); Preparation of water soluble camptothecin derivs.. US 5342947 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 54867 1,4-Benzodioxan-6-amine; 3,4-Ethylenedioxyaniline; 6-Amino-1,4-benzodioxane 22013-33-8 C8H9NO2 详情 详情
(II) 54868 N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide C10H11NO3 详情 详情
(III) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(IV) 54869 N-[7-(2-chloroacetyl)-2,3-dihydro-1,4-benzodioxin-6-yl]acetamide C12H12ClNO4 详情 详情
(V) 54870 1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone C10H10ClNO3 详情 详情
(VI) 14443 2-chloroacetonitrile; chloroacetonitrile 107-14-2 C2H2ClN 详情 详情
(VII) 10841 (4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione C13H13NO5 详情 详情
(VIII) 54871 (8S)-15-(chloromethyl)-8-ethyl-8-hydroxy-2,3-dihydro-11H-[1,4]dioxino[2,3-g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(8H,14H)-dione C23H19ClN2O6 详情 详情
(IX) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线29

该中间体在本合成路线中的序号：(IX)

In a different strategy, the dioxinoquinoline system (XII) was prepared by acylation of amino ketone (X) with methyl malonyl chloride (XI), followed by intramolecular Knoevenagel condensation of the intermediate keto malonamide. Chlorination of (XII) with POCl3 afforded the dichloro derivative (XIII), which was subsequently condensed with N-methylpiperazine (IX) to give (XIV). Reduction of the ester group of (XIV) by means of DIBAL provided alcohol (XV). Replacement of the 7-chloro of (XV) by an iodide group required previous oxidation of (XV) to the more reactive aldehyde (XVI). Treatment of (XVI) with NaI and HCl led to the corresponding iodo aldehyde, which was further reduced to alcohol (XVII) using NaBH4.

参考文献 中间体
合成目标
【1】 Fang, F.G.; Xie, S.; Lowery, M.W. (GlaxoSmithKline Inc.); Intermediates in pharmaceutical camptothecin preparation. WO 9529917 .
【2】 Huie, E.M.; Fang, F.G.; Xie, S.; Comins, D.L. (GlaxoSmithKline Inc.; North Carolina State University); Preparation of a camptothecin deriv. by intramolecular cyclisation. WO 9529919 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(X) 54870 1-(7-amino-2,3-dihydro-1,4-benzodioxin-6-yl)-2-chloro-1-ethanone C10H10ClNO3 详情 详情
(XI) 50272 Malonic acid monomethyl ester chloride; Methyl (chloroformyl)acetate; Methyl malonyl chloride ;Methyl 3-chloro-3-oxopropionate 37517-81-0 C4H5ClO3 详情 详情
(XII) 54872 methyl 9-(chloromethyl)-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate C14H12ClNO5 详情 详情
(XIII) 54873 methyl 7-chloro-9-(chloromethyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate C14H11Cl2NO4 详情 详情
(XIV) 54874 methyl 7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylate C19H22ClN3O4 详情 详情
(XV) 54875 {7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol C18H22ClN3O3 详情 详情
(XVI) 54876 7-chloro-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carbaldehyde C18H20ClN3O3 详情 详情
(XVII) 54877 {7-iodo-9-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro[1,4]dioxino[2,3-g]quinolin-8-yl}methanol C18H22IN3O3 详情 详情

合成路线30

该中间体在本合成路线中的序号：(IX)

The silylated pyranopyridine (XXXIV) was prepared by an analoguos route to that of Scheme 3 starting from 2-methoxy-6-(trimethylsilyl)pyridine (XXX). Halogenation-desilylation of (XXXIV) by means of ICl-furnished iodide (XXXV). Subsequent demethylation of (XXXV) to give lactam (XXXVI) was performed employing either aqueous HI or iodotrimethylsane. Alkylation of lactam (XXXVI) with 1,4-dichloro-2-butyne (XXXVII) to (XXXVIII), followed by reaction with piperazine (IX), yielded (XXXIX). The cascade radical cyclization of (XXXIX) with isonitrile (XL) under sunlamp irradiation in the presence of hexamethyldistannane led to an inseparable mixture of the title compound and its regioisomer (XLI).

参考文献 中间体
合成目标
【1】 Josien, H.; et al.; A general synthetic approach to the (20S)-camptothecin family of antitumor agents by a regiocontrolled cascade radical cyclization of aryl isonitriles. Chemistry (Weinheim) 1998, 4, 1, 67.
【2】 Curran, D.P.; et al.; Cascade radical reactions of isonitriles: A second-generation synthesis of (20S)-camptothecin, topotecan, irinotecan, and GI-147211C. Angew Chem. Int Ed 1995, 34, 23-24, 2683.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XIX) 54879 2-(dimethylamino)ethyl(methyl)formamide C6H14N2O 详情 详情
(XXII) 54882 2-Butene-1-ol; Crotyl Alcohol; trans-Propenylcarbinol 504-61-0 C4H8O 详情 详情
(XXX) 54890 methyl 6-(trimethylsilyl)-2-pyridinyl ether; 2-methoxy-6-(trimethylsilyl)pyridine C9H15NOSi 详情 详情
(XXXI) 54891 4-iodo-2-methoxy-6-(trimethylsilyl)nicotinaldehyde C10H14INO2Si 详情 详情
(XXXII) 54892 3-{[(E)-2-butenyloxy]methyl}-4-iodo-2-methoxy-6-(trimethylsilyl)pyridine; (E)-2-butenyl [4-iodo-2-methoxy-6-(trimethylsilyl)-3-pyridinyl]methyl ether C14H22INO2Si 详情 详情
(XXXIII) 35096 4-ethyl-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridin-8-yl methyl ether; 4-ethyl-8-methoxy-6-(trimethylsilyl)-1H-pyrano[3,4-c]pyridine C14H21NO2Si 详情 详情
(XXXIV) 54893 (4S)-4-ethyl-4-hydroxy-8-methoxy-6-(trimethylsilyl)-1,4-dihydro-3H-pyrano[3,4-c]pyridin-3-one C14H21NO4Si 详情 详情
(XXXV) 54894 (4S)-4-ethyl-4-hydroxy-6-iodo-8-methoxy-1,4-dihydro-3H-pyrano[3,4-c]pyridin-3-one C11H12INO4 详情 详情
(XXXVI) 49255 (4S)-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione C10H10INO4 详情 详情
(XXXVII) 50923 1,4-Dichloro-2-butyne 821-10-3 C4H4Cl2 详情 详情
(XXXVIII) 54895 (4S)-7-(4-chloro-2-butynyl)-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione C14H13ClINO4 详情 详情
(XXXIX) 54886 (4S)-4-ethyl-8-methoxy-3,4-dihydro-1H-pyrano[3,4-c]pyridine-3,4-diol C11H15NO4 详情 详情
(XL) 54898 　 C9H7NO2 详情 详情
(XLI) 54897 (9S)-9-ethyl-9-hydroxy-16-[(4-methyl-1-piperazinyl)methyl]-2,3-dihydro-12H-[1,4]dioxino[2,3-f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10,13(9H,15H)-dione C28H30N4O6 详情 详情

合成路线31

该中间体在本合成路线中的序号：(VI)

The condensation of 2,5-difluoronitrobenzene (I) with ethyl 2-amino-5-methylthiophene-3-carboxylate (II) by means of triethylamine in hot DMSO or 2-methoxyethanol giving ethyl 2-(4-fluoro-2-nitroanilino)-5-methylthiophene-3-carboxylate (III), which is reduced with H2 over Pd/C in ethanol to ethyl 2-(4-fluoro-2-aminoanilino)-5-methylthiophene-3-carboxylate (IV). The cyclization of (IV) by means of NaH in DMSO affords 9,10-dihydro-7-fluoro-2-methyl-4H-thieno[2,3b][1,5]benzodiazepin-2-one (V), which is finally condensed with N-methylpiperazine by means of TiCl4 in anisole at 120 C.

参考文献 中间体
合成目标
【1】 Chakrabarti, J.K.; Tupper, D.E.; Benzodiazepine derivatives. DE 2552403; FR 2292479; GB 1533235; JP 51076296 .
【2】 Pullar, I.A.; Chakrabarti, J.K.; Horsman, L.; Wright, F.C.; Tupper, D.E.; Hotten, T.M.; Heterooarenobenzodiazepines. 3. 4-Piperazinyl-10H-thieno[2,3-b][1,5]benzodiazepines as potential neuroleptics. J Med Chem 1980, 23, 8, 878-884.
【3】 Blancafort, P.; Castañer, J.; Serradell, M.N.; Flumezapine. Drugs Fut 1983, 8, 2, 110.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 32036 2,4-difluoro-1-nitrobenzene 446-35-5 C6H3F2NO2 详情 详情
(II) 35949 ethyl 2-amino-5-methyl-3-thiophenecarboxylate C8H11NO2S 详情 详情
(III) 35950 ethyl 2-(5-fluoro-2-nitroanilino)-5-methyl-3-thiophenecarboxylate C14H13FN2O4S 详情 详情
(IV) 35951 ethyl 2-(2-amino-5-fluoroanilino)-5-methyl-3-thiophenecarboxylate C14H15FN2O2S 详情 详情
(V) 35952 7-fluoro-2-methyl-5,10-dihydro-4H-thieno[2,3-b][1,5]benzodiazepin-4-one C12H9FN2OS 详情 详情
(VI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线32

该中间体在本合成路线中的序号：(XVI)

Treatment of 3,4-difluoroaniline (I) with CS2 and Et3N gives triethylammonium dithiocarbamate (II), which reacts with ethyl chloroformate in chloroform to yield (III). Isothiocyanate (III) is converted into the potassium salt (IV) by reaction with diethyl malonate and KOH in dioxane and then transformed into methoxymethyl thioether (VI) by means of reagent (V) and Et3N in toluene. Cyclization of (VI) by heating in diphenyl ether affords quinoline (VII), which then reacts with benzoyl chloride (VIII) in pyridine to furnish (IX). Benzoyloxy derivative (IX) is converted into (X) by means of HCl in EtOH, and its reaction with 1-bromo-2-fluoroethane (XI) and NaHCO3 yields compound (XII). Chlorination of (XII) with SO2Cl2 in hexane provides (XIII), which by simultaneous hydrolysis and intramolecular cyclization by means of Et3N /H2O in THF provides the mixture of isomers (XIV). (+)-(XV) is obtained by HPLC chromatography of (XIV) on a chiral stationary phase. Treatment of (+)-(XV) with 1-methylpiperazine (XVI) in DMF provides ethyl ester (+)-(XVII), which is finally hydrolyzed by means of H2SO4 in H2O.

参考文献 中间体
合成目标
【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 .
【2】 Kise, M.; Amimoto, I.; Kitano, M.; Segawa, J.; Tomii, Y.; Matsuoka, M.; Masui, Y.; Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives. Chem Pharm Bull 1999, 47, 12, 1765.
【3】 Segawa, J.; Kitano, M.; Kazuno, K.; Matsuoka, M.; Shirahase, I.; Ozaki, M.; Matsuda, M.; Tomii, Y.; Kise, M.; Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3, 2-a]quinoline-3-carboxylic acids. J Med Chem 1992, 35, 25, 4727.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13451 3,4-Difluoroaniline; 3,4-Difluorophenylamine 3863-11-4 C6H5F2N 详情 详情
(II) 42953 3,4-difluorophenylcarbamodithioic acid C7H5F2NS2 详情 详情
(III) 13453 1,2-Difluoro-4-isothiocyanatobenzene; 3,4-difluorophenyl isothiocyanate 113028-75-4 C7H3F2NS 详情 详情
(IV) 42954 potassium 1-(3,4-difluoroanilino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propene-1-thiolate C14H14F2KNO4S 详情 详情
(V) 18319 Chloro(methoxy)methane; Chloromethyl methyl ether 107-30-2 C2H5ClO 详情 详情
(VI) 13455 diethyl 2-[(3,4-difluoroanilino)[(methoxymethyl)sulfanyl]methylene]malonate C16H19F2NO5S 详情 详情
(VII) 13456 ethyl 6,7-difluoro-4-hydroxy-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate C14H13F2NO4S 详情 详情
(VIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(IX) 42955 ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate C21H17F2NO5S 详情 详情
(X) 42956 ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate C19H13F2NO4S 详情 详情
(XI) 28769 1-bromo-2-fluoroethane 762-49-2 C2H4BrF 详情 详情
(XII) 42957 ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(2-fluoroethyl)sulfanyl]-3-quinolinecarboxylate C21H16F3NO4S 详情 详情
(XIII) 42958 ethyl 4-(benzoyloxy)-2-[(1-chloro-2-fluoroethyl)sulfanyl]-6,7-difluoro-3-quinolinecarboxylate C21H15ClF3NO4S 详情 详情
(XIV) 42959 ethyl 6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H10F3NO3S 详情 详情
(XV) 42960 ethyl (1R)-6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H10F3NO3S 详情 详情
(XVI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XVII) 42961 ethyl (1R)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C19H21F2N3O3S 详情 详情

合成路线33

该中间体在本合成路线中的序号：(XVI)

Alternatively, (+)-(XVII) can be obtained as follows: Treatment of (X) with 1-acetoxy-2-bromoethane (XVIII) in DMF in the presence of NaHCO3 yields derivative (XIX), which is then chlorinated by means of SO2Cl2 in CH2Cl2 to provide (XX). Simultaneous hydrolysis and intramolecular cyclization of (XX) by means of Et3N /H2O in THF affords (XXI), which is then converted into butyl ester derivative (XXII) by treatment with refluxing butanol (B). Resolution of the racemic mixture (XXII) by treatment with Lipase PL in vinyl acetate followed by chromatographic separation provides alcohol (-)-(XXIII) and acetoxy (+)-(XXIV). Hydrolysis of (+)-(XXIV) with hot H2SO4/EtOH gives alcohol (+)-(XXV), which is then condensed with 1-methylpiperazine (XVI) in DMF to yield derivative (+)-(XXVI). Finally, treatment with (diethylamino)sulfur trifluoride (DAST) in CH2Cl2 provides fluoro derivative (+)-(XVII). Alternatively, (+)-(XXV) can be obtained by conversion of (XXI) into octyl ester (XXVII) by means of refluxing octanol (A), followed by its enantiomer enzymatic resolution with Liposyme IM in vinyl acetate and chromatographic separation to afford (-)-(XXVIII) and (+)-(XXIX). Finally, hydrolysis of (+)-(XXIX) with hot H2SO4/EtOH yields (+)-(XXV). An analogous procedure comprising enantiomer separation and subsequent hydrolysis can be performed from ethyl esters (XX) or (XXI) by treatment with the corresponding lipases in an appropriate solvent.

参考文献 中间体
合成目标
【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
24543 vinyl acetate 108-05-4 C4H6O2 详情 详情
(A) 12970 (8R,9S,10R,13S,14R)-14-Hydroxy-3-methoxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one C20H28O3 详情 详情
(B) 29766 butanol; n-butanol; 1-butanol 71-36-3 C4H10O 详情 详情
(X) 42956 ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate C19H13F2NO4S 详情 详情
(XVI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XVII) 42961 ethyl (1R)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C19H21F2N3O3S 详情 详情
(XVIII) 33463 2-bromoethyl acetate 927-68-4 C4H7BrO2 详情 详情
(XIX) 42962 ethyl 2-[[2-(acetoxy)ethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate C23H19F2NO6S 详情 详情
(XX) 42963 ethyl 2-[[2-(acetoxy)-1-chloroethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate C23H18ClF2NO6S 详情 详情
(XXI) 42964 ethyl 1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C16H13F2NO5S 详情 详情
(XXII) 42965 butyl 6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C16H15F2NO4S 详情 详情
(XXIII) 42966 butyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C16H15F2NO4S 详情 详情
(XXIV) 42967 butyl (1R)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C18H17F2NO5S 详情 详情
(XXV) 42968 ethyl (1R)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H11F2NO4S 详情 详情
(XXVI) 42969 ethyl (1R)-6-fluoro-1-(hydroxymethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C19H22FN3O4S 详情 详情
(XXVII) 42971 octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate C21H25F2NO4S 详情 详情
(XXVIII) 42972 octyl 2-[(1S)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate C23H27F2NO5S 详情 详情
(XXIX) 42973 octyl 2-[(1R)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate C21H25F2NO4S 详情 详情

合成路线34

该中间体在本合成路线中的序号：(XVI)

Treatment of 3,4-difluoroaniline (I) with CS2 and Et3N gives triethylammonium dithiocarbamate (II), which reacts with ethyl chloroformate in chloroform to yield (III). Isothiocyanate (III) is converted into the potassium salt (IV) by reaction with diethyl malonate and KOH in dioxane, and then transformed into methoxymethyl thioether (VI) by means of reagent (V) and Et3N in toluene. Cyclization of (VI) by heating in diphenyl ether affords quinoline (VII), which is then converted into (IX) by means of benzoyl chloride (VIII) in pyridine. Benzoyloxy derivative (IX) is converted into (X) by means of HCl in EtOH, and its reaction with 1-bromo-2-fluoroethane (XI) and NaHCO3 yields compound (XII). Chlorination of (XII) with SO2Cl2 in hexane provides (XIII), which by simultaneous hydrolysis and intramolecular cyclization by means of Et3N /H2O in THF provides the mixture of isomers (XIV). (-)-(XV) is then obtained by HPLC chromatography on a chiral stationary phase. Treatment of (-)-(XV) with 1-methylpiperazine (XVI) in DMF provides ethyl ester (-)-(XVII), which is finally hydrolyzed by means of H2SO4 in H2O.

参考文献 中间体
合成目标
【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 .
【2】 Kise, M.; Amimoto, I.; Kitano, M.; Segawa, J.; Tomii, Y.; Matsuoka, M.; Masui, Y.; Synthesis and antibacterial activity of novel 7-substituted-6-fluoro-1-fluoromethyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid derivatives. Chem Pharm Bull 1999, 47, 12, 1765.
【3】 Segawa, J.; Kitano, M.; Kazuno, K.; Matsuoka, M.; Shirahase, I.; Ozaki, M.; Matsuda, M.; Tomii, Y.; Kise, M.; Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3, 2-a]quinoline-3-carboxylic acids. J Med Chem 1992, 35, 25, 4727.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 13451 3,4-Difluoroaniline; 3,4-Difluorophenylamine 3863-11-4 C6H5F2N 详情 详情
(II) 42953 3,4-difluorophenylcarbamodithioic acid C7H5F2NS2 详情 详情
(III) 13453 1,2-Difluoro-4-isothiocyanatobenzene; 3,4-difluorophenyl isothiocyanate 113028-75-4 C7H3F2NS 详情 详情
(IV) 42954 potassium 1-(3,4-difluoroanilino)-3-ethoxy-2-(ethoxycarbonyl)-3-oxo-1-propene-1-thiolate C14H14F2KNO4S 详情 详情
(V) 18319 Chloro(methoxy)methane; Chloromethyl methyl ether 107-30-2 C2H5ClO 详情 详情
(VI) 13455 diethyl 2-[(3,4-difluoroanilino)[(methoxymethyl)sulfanyl]methylene]malonate C16H19F2NO5S 详情 详情
(VII) 13456 ethyl 6,7-difluoro-4-hydroxy-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate C14H13F2NO4S 详情 详情
(VIII) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(IX) 42955 ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate C21H17F2NO5S 详情 详情
(X) 42956 ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate C19H13F2NO4S 详情 详情
(XI) 28769 1-bromo-2-fluoroethane 762-49-2 C2H4BrF 详情 详情
(XII) 42957 ethyl 4-(benzoyloxy)-6,7-difluoro-2-[(2-fluoroethyl)sulfanyl]-3-quinolinecarboxylate C21H16F3NO4S 详情 详情
(XIII) 42958 ethyl 4-(benzoyloxy)-2-[(1-chloro-2-fluoroethyl)sulfanyl]-6,7-difluoro-3-quinolinecarboxylate C21H15ClF3NO4S 详情 详情
(XIV) 42959 ethyl 6,7-difluoro-1-(fluoromethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H10F3NO3S 详情 详情
(XV) 42971 octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate C21H25F2NO4S 详情 详情
(XVI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XVII) 42975 ethyl (1S)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C19H21F2N3O3S 详情 详情

合成路线35

该中间体在本合成路线中的序号：(XVI)

Alternatively, (-)-(XVII) can be obtained as follows: Treatment of (X) with 1-acetoxy-2-bromoethane (XVIII) in DMF in the presence of NaHCO3 yields derivative (XIX), which is then chlorinated by means of SO2Cl2 in CH2Cl2 to provide (XX). Simultaneous hydrolysis and intramolecular cyclization of (XX) by means of Et3N /H2O in THF affords (XXI), which is then converted into octyl ester derivative (XXII) by treatment with refluxing octanol (A). Resolution of the racemic mixture (XXII) by treatment with Liposyme IM in vinyl acetate followed by chromatographic separation provides alcohol (+)-(XXIII) and acetoxy (-)-(XXIV). Hydrolysis of (-)-(XXIV) with hot H2SO4/EtOH gives alcohol (-)-(XXV), which then reacts with 1-methylpiperazine (XVI) in DMF to yield derivative (-)-(XXVI). Finally, treatment with (diethylamino)sulfur trifluoride (DAST) in CH2Cl2 provides fluoro derivative (-)-(XVII). Alternatively, (-)-(XXV) can be obtained by conversion of (XXI) into butyl ester (XXVII) by means of refluxing butanol (B), followed by its enantiomer enzymatic resolution with Lipase PL in vinyl acetate and chromatographic separation to afford (+)-(XXVIII) and (-)-(XXIX). Finally, hydrolysis of (-)-(XXIX) with hot H2SO4/EtOH yields (-)-(XXV). An analogous procedure comprising enantiomer separation and subsequent hydrolysis can be performed from ethyl esters (XX) or (XXI) by treatment with the corresponding lipases in an appropriate solvent.

参考文献 中间体
合成目标
【1】 Segawa, J.; Matsuoka, M.; Tomii, Y. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid deriv. and process for producing the same. EP 0675127; WO 9414819 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
24543 vinyl acetate 108-05-4 C4H6O2 详情 详情
(A) 12970 (8R,9S,10R,13S,14R)-14-Hydroxy-3-methoxy-10,13-dimethyl-1,2,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthren-17-one C20H28O3 详情 详情
(B) 29766 butanol; n-butanol; 1-butanol 71-36-3 C4H10O 详情 详情
(X) 42956 ethyl 4-(benzoyloxy)-6,7-difluoro-2-sulfanyl-3-quinolinecarboxylate C19H13F2NO4S 详情 详情
(XVI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XVII) 42975 ethyl (1S)-6-fluoro-1-(fluoromethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C19H21F2N3O3S 详情 详情
(XVIII) 33463 2-bromoethyl acetate 927-68-4 C4H7BrO2 详情 详情
(XIX) 42962 ethyl 2-[[2-(acetoxy)ethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate C23H19F2NO6S 详情 详情
(XX) 42963 ethyl 2-[[2-(acetoxy)-1-chloroethyl]sulfanyl]-4-(benzoyloxy)-6,7-difluoro-3-quinolinecarboxylate C23H18ClF2NO6S 详情 详情
(XXI) 42964 ethyl 1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C16H13F2NO5S 详情 详情
(XXII) 42971 octyl 2-[6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate C21H25F2NO4S 详情 详情
(XXIII) 42973 octyl 2-[(1R)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate C21H25F2NO4S 详情 详情
(XXIV) 42972 octyl 2-[(1S)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinolin-3-yl]acetate C23H27F2NO5S 详情 详情
(XXV) 42976 ethyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H11F2NO4S 详情 详情
(XXVI) 42977 ethyl (1S)-6-fluoro-1-(hydroxymethyl)-7-(4-methyl-1-piperazinyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C19H22FN3O4S 详情 详情
(XXVII) 42965 butyl 6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C16H15F2NO4S 详情 详情
(XXVIII) 42967 butyl (1R)-1-[(acetoxy)methyl]-6,7-difluoro-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C18H17F2NO5S 详情 详情
(XXIX) 42966 butyl (1S)-6,7-difluoro-1-(hydroxymethyl)-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C16H15F2NO4S 详情 详情

合成路线36

该中间体在本合成路线中的序号：(XI)

Condensation of benzodiazepinone (IV) with 4-nitrobenzoyl chloride (V) afforded amide (VI), which was alkylated with ethyl bromoacetate in the presence of NaH to give (VII). The nitro group of (VII) was reduced to aniline (VIII) using Fe and AcOH. Subsequent coupling of (VIII) with the acid chloride generated from biphenyl carboxylic acid (III) and oxalyl chloride produced the corresponding amide (IX). The ester group of (IX) was then hydrolyzed with NaOH, and the resulting carboxylic acid (X) was finally condensed with N-methylpiperazine (XI) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole as the coupling reagents.

参考文献 中间体
合成目标
【1】 Hosogai, N.; Tanaka, H.; Tomita, M.; Ohkawa, T.; Hemmi, K.; Setoi, H.; Zenkoh, O.; Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists. Chem Pharm Bull 1999, 47, 4, 501.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(III) 16915 4'-methyl[1,1'-biphenyl]-2-carboxylic acid 7148-03-0 C14H12O2 详情 详情
(IV) 18498 1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one C9H10N2O 详情 详情
(V) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(VI) 27975 5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one C16H13N3O4 详情 详情
(VII) 27976 ethyl 2-[5-(4-nitrobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate C20H19N3O6 详情 详情
(VIII) 27977 ethyl 2-[5-(4-aminobenzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate C20H21N3O4 详情 详情
(IX) 27978 ethyl 2-[5-(4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetate C34H31N3O5 详情 详情
(X) 27979 2-[5-(4-[[(4'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]benzoyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl]acetic acid C32H27N3O5 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线37

该中间体在本合成路线中的序号：(IX)

The cyclization of 2,5-dimethoxy-1,3,4-trimethylbenzene (I) with 2-bromo-2-methylpropionyl bromide (II) by means of FeCl3 and NaOH in methanol/water gives 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-3-one (III), which is treated with benzyl bromide (IV) and K2CO3 to yield the benzyl ether (V). The reaction of (V) with methylmagnesium bromide, followed by dehydration of the intermediate carbinol affords the methylene derivative (VI), which is hydroxylated with borane / dimethylsulfide and NaOH/H2O2 to furnish the hydroxymethyl compound (VII). The reaction of (VII) with MsCl and TEA gives the mesylate (VIII), which is finally condensed with 1-methylpiperazine (IX) by means of K2CO3 and debenzylated by hydrogenation with H2 over Pd/C in ethanol/HOAc to afford the target compound as a racemic mixture.

参考文献 中间体
合成目标
【1】 Petty, M.A.; Marciniak, G.; Design and biological evaluation of new antioxidants for use in cerebrovascular disorders. Drugs Fut 1996, 21, 10, 1037.
【2】 Ayers, T.A.; Schnettler, R.A.; Marciniak, G.; Krysan, D.J. (Hoechst Marion Roussel Inc.); Novel process for preparing derivatives of 2,2,4,6,7-pentaalkyl-2,2-dihydrobenzofuranols. EP 0813530 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 41220 1,4-dimethoxy-2,3,5-trimethylbenzene; 4-methoxy-2,3,5-trimethylphenyl methyl ether C11H16O2 详情 详情
(II) 19367 2-bromo-2-methylpropanoyl bromide 20769-85-1 C4H6Br2O 详情 详情
(III) 41221 5-hydroxy-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one C13H16O3 详情 详情
(IV) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(V) 41222 5-(benzyloxy)-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one C20H22O3 详情 详情
(VI) 41223 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-methylene-2,3-dihydro-1-benzofuran; benzyl 2,2,4,6,7-pentamethyl-3-methylene-2,3-dihydro-1-benzofuran-5-yl ether C21H24O2 详情 详情
(VII) 30773 [5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol C21H26O3 详情 详情
(VIII) 26455 5-(benzyloxy)-2,2,4,6,7-pentamethyl-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-2,3-dihydro-1-benzofuran C24H32O3S 详情 详情
(IX) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线38

该中间体在本合成路线中的序号：(IX)

The enantiomers of the title product have been obtained by optical resolution of the racemic hydroxymethyl compound (rac)-(VII) by means of "Candida cylindracea" and vinyl acetate to give (S)-(VII) and (R)-(VII). Finally both chiral intermediates are condensed with 1-methylpiperazine (IX) and debenzylated by hydrogenation with H2 over Pd/C in ethanol/HOAc for the racemic mixture (rac)-(VII).

参考文献 中间体
合成目标
【1】 Petty, M.A.; Marciniak, G.; Design and biological evaluation of new antioxidants for use in cerebrovascular disorders. Drugs Fut 1996, 21, 10, 1037.
【2】 Ayers, T.A.; Schnettler, R.A.; Marciniak, G.; Krysan, D.J. (Hoechst Marion Roussel Inc.); Novel process for preparing derivatives of 2,2,4,6,7-pentaalkyl-2,2-dihydrobenzofuranols. EP 0813530 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(rac)-(VII) 30773 [5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol C21H26O3 详情 详情
(S)-(VII) 41224 [(3S)-5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol C21H26O3 详情 详情
(R)-(VII) 41225 [(3R)-5-(benzyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-yl]methanol C21H26O3 详情 详情
(IX) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线39

该中间体在本合成路线中的序号：(VI)

Condensation of ethyl 2,4,5-trifluorobenzoylacetate (I) with triethyl orthoformate in refluxing Ac2O produced the benzoyl ethoxyacrylate (II), which was further condensed with 2-amino-5-fluoropyridine (III) to afford enamine (IV). Cyclization of (IV) in the presence of K2CO3 gave rise to the quinolone (V). The 7-fluoride group of (V) was then displaced by N-methylpiperazine (VI) in cold pyridine to furnish the piperazinyl quinolone (VII). Finally, ester hydrolysis in (VII) under acidic conditions yielded the target compound. In a closely related procedure, ester (V) was hydrolyzed to acid (VIII) using HCl. Subsequent displacement of the 7-fluoride of (VIII) with N-methylpiperazine (VI) provided the desired piperazinyl quinolone.

参考文献 中间体
合成目标
【1】 Yoon, S.J.; et al.; Synthesis, pharmacokinetics, and biological activity of a series of new pyridonecarboxylic acid antibacterial agents bearing a 5-fluoro-2-pyridyl group or a 3-fluoro-4-pyridyl group at N-1. J Heterocycl Chem 1997, 34, 3, 1021.
【2】 Skuballa, W.; Buchmann, B.; Heindl, J.; Frohlich, W.; Ekerdt, R.; Giesen, C. (Schering AG); Leukotriene B4 derivs., methods of preparing them and their use as drugs. EP 0741687; JP 1997511487; WO 9520564 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 55875 Ethyl 2,4,5-trifluorobenzoylacetate C11H9F3O3 详情 详情
(II) 55876 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluorobenzoyl)-2-propenoate C14H13F3O4 详情 详情
(III) 55877 5-fluoro-2-pyridinamine; 5-fluoro-2-pyridinylamine C5H5FN2 详情 详情
(IV) 55878 ethyl (Z)-3-[(5-fluoro-2-pyridinyl)amino]-2-(2,4,5-trifluorobenzoyl)-2-propenoate C17H12F4N2O3 详情 详情
(V) 55879 ethyl 6,7-difluoro-1-(5-fluoro-2-pyridinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C17H11F3N2O3 详情 详情
(VI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(VII) 55880 ethyl 6-fluoro-1-(5-fluoro-2-pyridinyl)-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C22H22F2N4O3 详情 详情
(VIII) 55881 6,7-difluoro-1-(5-fluoro-2-pyridinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C15H7F3N2O3 详情 详情

合成路线40

该中间体在本合成路线中的序号：(III)

The title compound has been prepared by treatment of carboxylic acid (I) with oxalyl chloride, followed by condensation of the resulting acid chloride (II) with N-methylpiperazine (III).

参考文献 中间体
合成目标
【1】 Doherty, J.B.; Finke, P.E.; Dorn, C.P.; Maccoss, M.; Durette, P.L.; Mills, S.G.; Shah, S.K.; Lanza, T.J.; Sahoo, S.P.; Hagmann, W.K.; Hale, J.J. (Merck & Co., Inc.); New substd. azetidinones as antiinflammatory and antidegenerative agents. EP 0595557; JP 1994263723; US 5591737; US 5747485; WO 9410142 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 53619 4-{[(2S)-1-({[(1R)-1-(1,3-benzodioxol-5-yl)butyl]amino}carbonyl)-3,3-diethyl-4-oxoazetidinyl]oxy}benzoic acid n/a C26H30N2O7 详情 详情
(II) 53620 4-{[(2S)-1-({[(1R)-1-(1,3-benzodioxol-5-yl)butyl]amino}carbonyl)-3,3-diethyl-4-oxoazetidinyl]oxy}benzoyl chloride n/a C26H29ClN2O6 详情 详情
(III) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线41

该中间体在本合成路线中的序号：(III)

In a different procedure, displacement of the propionate group of azetidinone (IV) by benzyl 4-hydroxybenzoate (V) in the presence of Cs2CO3 afforded the racemic adduct (VI). Subsequent transfer hydrogenolysis of (VI) with cyclohexene and Pd/C provided the carboxylic acid (VII), which was resolved employing (S)-alpha-methylbenzylamine. Alternatively, a kinetic enzymatic resolution of the benzyl ester (VI) was developed. Treatment of ester (VI) with lipase PS-800 provided the desired (S)-acid (VIII), while leaving the unchanged (R)-benzyl ester. Coupling of acid (VIII) with N-methylpiperazine (III) in the presence of DCC and HOBt furnished the corresponding amide (IX).

参考文献 中间体
合成目标
【1】 Cvetovich, R.J.; et al.; An asymmetric synthesis of L-694,458, a human leukocyte elastase inhibitor, via novel enzyme resolution of beta-lactam esters. J Org Chem 1996, 61, 19, 6575.
【2】 Li, H.-Y.; Fortunak, J.M.; Storace, L.; Sheeran, P.J.; Anzalone, L. (DuPont Pharmaceuticals Co.); An efficient process for the preparation of a human leukocyte elastase inhibitor. WO 0012474 .
【3】 Amato, J.S.; Cvetovich, R.; Hartner, F.W. (Merck & Co., Inc.); Process for preparing substd. azetidinones. WO 9716448 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IV) 53621 3,3-diethyl-4-oxo-2-azetidinyl propionate n/a C10H17NO3 详情 详情
(V) 53622 4-Hydroxybenzoic acid benzyl ester; Benzyl 4-hydroxybenzoate; Benzyl-p-Hydroxybenzoate; Benzylparaben 94-18-8 C14H12O3 详情 详情
(VI) 53623 benzyl 4-[(3,3-diethyl-4-oxo-2-azetidinyl)oxy]benzoate n/a C21H23NO4 详情 详情
(VII) 53624 4-[(3,3-diethyl-4-oxo-2-azetidinyl)oxy]benzoic acid n/a C14H17NO4 详情 详情
(VIII) 53625 4-{[(2S)-3,3-diethyl-4-oxoazetidinyl]oxy}benzoic acid n/a C14H17NO4 详情 详情
(IX) 53626 (4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone n/a C19H27N3O3 详情 详情

合成路线42

该中间体在本合成路线中的序号：(III)

In a further procedure, 4-hydroxybenzoic acid (XIX) was converted to amide (XXII) via formation of the mixed anhydride-ester (XX) with pivaloyl chloride, followed by coupling with N-methylpiperazine (III) and alcoholysis of the resultant amide-ester (XXI) or, alternatively, by direct coupling of acid (XIX) with piperazine (III) in the presence of DCC. The propionate group of azetidinone (IV) was then displaced by the 4-hydroxybenzamide (XXII) to give the racemic adduct (XXIII). Resolution of (XXIII) by means of (-)-diisopropylidene ketogulonic acid (DAG) provided the desired enantiomer (IX), which was finally converted into the title compound by condensation with isocyanate (XVIII) in the presence of DBU in acetonitrile.

参考文献 中间体
合成目标
【1】 Storace, L.; et al.; An efficient large-scale process for the human leukocyte elastase inhibitor, DMP 777. Org Process Res Dev 2002, 6, 1, 54.
【2】 Li, H.-Y.; Fortunak, J.M.; Storace, L.; Sheeran, P.J.; Anzalone, L. (DuPont Pharmaceuticals Co.); An efficient process for the preparation of a human leukocyte elastase inhibitor. WO 0012474 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(III) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IV) 53621 3,3-diethyl-4-oxo-2-azetidinyl propionate n/a C10H17NO3 详情 详情
(IX) 53626 (4S)-3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone n/a C19H27N3O3 详情 详情
(XVIII) 53632 5-[(1R)-1-isocyanatobutyl]-1,3-benzodioxole; (1R)-1-(1,3-benzodioxol-5-yl)butyl isocyanate n/a C12H13NO3 详情 详情
(XIX) 28205 4-hydroxybenzoic acid 99-96-7 C7H6O3 详情 详情
(XX) 53634 1,1-dimethylpropanoic 4-[(2,2-dimethylpropanoyl)oxy]-1-benzenecarboxylic anhydride n/a C17H22O5 详情 详情
(XXI) 53635 4-[(4-methyl-1-piperazinyl)carbonyl]phenyl pivalate n/a C17H24N2O3 详情 详情
(XXII) 53633 (4-hydroxyphenyl)(4-methyl-1-piperazinyl)methanone n/a C12H16N2O2 详情 详情
(XXIII) 53636 3,3-diethyl-4-{4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy}-2-azetidinone n/a C19H27N3O3 详情 详情

合成路线43

该中间体在本合成路线中的序号：(X)

Condensation of 2-chloronitrobenzene (I) with 2-hydroxy-4-methoxybenzaldehyde (II) by means of Cu/KOH in refluxing DMF provides derivative (III), which is then oxidized with KMnO4 in pyridine/H2O to afford carboxylic acid (IV). Reduction of the nitro moiety of (IV) by hydrogenation over Pd/C yields amine (V), which is then cyclized at high temperatures to furnish the dibenzo[b,f][1,4]oxazepinone intermediate (VI) (1). O-Demethylation of (VI) by treatment with AlCl3 in ethylmercaptan (EtSH) gives hydroxy derivative (VII), which then reacts with triflic anhydride in CH2Cl2 in the presence of Et3N to provide compound (VIII). Treatment of (VIII) with POCl3 in refluxing toluene in the presence of N,N-dimethylaniline yields chloro derivative (IX), which is finally condensed with N-methylpiperazine (X) in refluxing toluene to give the desired product.

参考文献 中间体
合成目标
【1】 Wikstrom, H.; Liao, Y.; Venhuis, B.J.; Rodenhuis, N.; Timmerman, W.; New (sulfonyloxy)piperazinyldibenzazepines as potential atypical antipsychotics: Chemistry and pharmacological evaluation. J Med Chem 1999, 42, 12, 2235.
【2】 De Boer, P.; Liao, Y.; Wikstrom, H.; New sulfone ester analogues of iso-clozapine and related structures: Atypical neuroleptics. WO 9629316 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15248 1-chloro-2-nitrobenzene 88-73-3 C6H4ClNO2 详情 详情
(II) 29301 2-hydroxy-5-methoxybenzaldehyde 672-13-9 C8H8O3 详情 详情
(III) 45965 5-methoxy-2-(2-nitrophenoxy)benzaldehyde C14H11NO5 详情 详情
(IV) 45966 5-methoxy-2-(2-nitrophenoxy)benzoic acid C14H11NO6 详情 详情
(V) 45967 2-(2-aminophenoxy)-5-methoxybenzoic acid C14H13NO4 详情 详情
(VI) 45968 2-methoxydibenzo[b,f][1,4]oxazepin-11(10H)-one C14H11NO3 详情 详情
(VII) 45969 2-hydroxydibenzo[b,f][1,4]oxazepin-11(10H)-one C13H9NO3 详情 详情
(VIII) 45970 11-oxo-10,11-dihydrodibenzo[b,f][1,4]oxazepin-2-yl trifluoromethanesulfonate C14H8F3NO5S 详情 详情
(IX) 45971 11-chlorodibenzo[b,f][1,4]oxazepin-2-yl trifluoromethanesulfonate C14H7ClF3NO4S 详情 详情
(X) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线44

该中间体在本合成路线中的序号：(III)

2-(2-Naphthyl)acetic acid (I) is activated as the corresponding acid chloride (II) upon refluxing with SOCl2. Subsequent condensation of acid chloride (II) with N-methyl piperazine (III) affords the title amide.

参考文献 中间体
合成目标
【1】 Hayes, E.S. (Cardiome Pharma Corp.); Serotonin ligands as pro-erectile cpds.. WO 0028993 .
【2】 Zolotoy, A.B.; Hayes, E.S. (Cardiome Pharma Corp.); Aroylpiperazines for modulating sexual activity. WO 9902159 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 50657 2-Naphthylacetic acid; beta-Naphthylacetic acid 581-96-4 C12H10O2 详情 详情
(II) 13970 2-(2-Naphthyl)acetyl chloride C12H9ClO 详情 详情
(III) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线45

该中间体在本合成路线中的序号：(XV)

The reaction of 4-bromothiophene-2-carbaldehyde (I) with triethyl orthoformate gives the corresponding acetal (II), which is treated with NaOMe, CuO and KI in hot methanol yielding 5-methoxythiophene-2-carbaldehyde diethylacetal (III). The hydrolysis of (III) with HCl in methanol affords the carbaldehyde (IV), which is condensed with the phosphonate (V) by means of NaH in THF to provide the ethyl acrylate (VI). The hydrolysis of (VI) with KOH in methanol gives the acrylic acid (VII), which is esterified with 4-nitrophenol, TEA and 2-chloro-1-methylpyridinium iodide in dichloromethane yielding the activate ester (VIII). The condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the adduct (XI), which is treated with HBr in acetonitrile to open the cyclopropane ring and provide the bromomethyl compound (XII). The aromatization of (XII) with p-nitrophenyl chloroformate (XIII) and TEA in dichloromethane affords the activated carbonate ester (XIV), which is finally treated with 1-methylpiperazine (XV) to furnish the target carbamate.

参考文献 中间体
合成目标
【1】 Saito, H.; Kobayashi, E.; Gomi, K.; Okamoto, A.; Nagamura, S.; Amishiro, N.; Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing 5-membered heteroarylacryloyl groups. Chem Pharm Bull 1999, 47, 10, 1393.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11236 4-Nitrophenol; p-Nitrophenol 100-02-7 C6H5NO3 详情 详情
(I) 24142 4-bromo-2-thiophenecarbaldehyde 18791-75-8 C5H3BrOS 详情 详情
(II) 38358 (4-bromo-2-thienyl)(ethoxy)methyl ethyl ether; 4-bromo-2-(diethoxymethyl)thiophene C9H13BrO2S 详情 详情
(III) 38359 5-(diethoxymethyl)-3-thienyl methyl ether; 2-(diethoxymethyl)-4-methoxythiophene C10H16O3S 详情 详情
(IV) 35360 　 C47H75N3O14 详情 详情
(V) 38361 ethyl 2-(dimethoxyphosphoryl)acetate C6H13O5P 详情 详情
(VI) 38362 ethyl (E)-3-(4-methoxy-2-thienyl)-2-propenoate C10H12O3S 详情 详情
(VII) 38363 (E)-3-(4-methoxy-2-thienyl)-2-propenoic acid C8H8O3S 详情 详情
(VIII) 38364 4-nitrophenyl (E)-3-(4-methoxy-2-thienyl)-2-propenoate C14H11NO5S 详情 详情
(IX) 38365 methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate C14H14N2O3 详情 详情
(X) 38366 methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate C26H25N3O8 详情 详情
(XI) 38367 methyl (3bR,4aS)-6-[(E)-3-(4-methoxy-2-thienyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate C22H20N2O5S 详情 详情
(XII) 38368 methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxy-2-thienyl)-2-propenoyl]-2-methyl-4-oxo-3,4,6,7,8,8a-hexahydropyrrolo[3,2-e]indole-1-carboxylate C22H21BrN2O5S 详情 详情
(XIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XIV) 38369 methyl (8S)-8-(bromomethyl)-6-[(E)-3-(4-methoxy-2-thienyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C29H24BrN3O9S 详情 详情
(XV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线46

该中间体在本合成路线中的序号：(XII)

Friedel-Crafts acetylation of 4-chlorothioanisole (I) gave acetophenone (II), which was then brominated to afford the corresponding bromoketone (III). Further reaction of (III) with hexamethylenetetramine, followed by acid hydrolysis yielded the aminoketone (IV). The Clauson-Kaas reaction of amine (IV) with 2,5-dimethoxytetrahydrofuran (V) in the presence of AcOH-AcONa provided pyrrole (VI), and then the thioether function of (VI) was oxidized to sulfoxide (VII) with sodium periodate. The subsequent Pummerer cyclization using trifluoroacetic anhydride produced an intermediate tricyclic sulfonium salt (VIII) that, upon losing a methyl group, yielded the pyrrolobenzothiazepine (IX). Reduction of the ketone function of (IX) to alcohol (X) with NaBH4, followed by treatment with PBr3, furnished bromide (XI). Finally, displacement of the bromide of (XI) at 130 C with N-methylpiperazine (XII) provided the title compound, which was isolated as the dihydrochloride salt on treating with methanolic HCl.

参考文献 中间体
合成目标
【1】 Campiani, G.; Nacci, V.; Bechelli, S.; Ciani, S.M.; Garofalo, A.; Fiorini, I.; Wikstrom, H.; de Boer, P.; Liao, Y.; Tepper, P.G.; Cagnotto, A.; Mennini, T.; New antipsychotic agents with serotonin and dopamine antagonist properties based on a pyrrolo[2,1-b][1,3]benzothiazepine structure. J Med Chem 1998, 41, 20, 3763.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 20423 4-chlorophenyl methyl sulfide; 1-chloro-4-(methylsulfanyl)benzene 123-09-1 C7H7ClS 详情 详情
(II) 20424 1-[5-chloro-2-(methylsulfanyl)phenyl]-1-ethanone C9H9ClOS 详情 详情
(III) 20425 2-bromo-1-[5-chloro-2-(methylsulfanyl)phenyl]-1-ethanone C9H8BrClOS 详情 详情
(IV) 20426 2-amino-1-[5-chloro-2-(methylsulfanyl)phenyl]-1-ethanone C9H10ClNOS 详情 详情
(V) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(VI) 20428 1-[5-chloro-2-(methylsulfanyl)phenyl]-2-(1H-pyrrol-1-yl)-1-ethanone C13H12ClNOS 详情 详情
(VII) 20429 1-[5-chloro-2-(methylsulfinyl)phenyl]-2-(1H-pyrrol-1-yl)-1-ethanone C13H12ClNO2S 详情 详情
(VIII) 20430 7-chloro-4-methyl-9-oxo-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-4-ium C13H11ClNOS 详情 详情
(IX) 20431 7-chloropyrrolo[2,1-b][1,3]benzothiazepin-9(10H)-one C12H8ClNOS 详情 详情
(X) 20432 7-chloro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepin-9-ol C12H10ClNOS 详情 详情
(XI) 20433 9-bromo-7-chloro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine C12H9BrClNS 详情 详情
(XII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线47

该中间体在本合成路线中的序号：(XV)

The reaction of 2-chloropyrimidine (I) with NaOMe in methanol gives 2-methoxypyrimidine (II), which is iodinated with N-iodosuccinimide (NIS) and trifluoroacetic anhydride in refluxing THF to yield 5-iodo-2-methoxypyrimidine (III). The condensation of (III) with methyl acrylate (IV) by means of Pd(OAc)2, K2CO3 and Bu4NCl at 120 C affords 3-(2-methoxypyrimidin-5-yl)acrylic acid methyl ester (V), which is hydrolyzed with KOH in methanol to provide the free acid (VI). The esterification of (VI) with p-nitrophenol (VII) by means of DCC and DMAP in dichloromethane gives the activate ester (VIII). The condensation of (VIII) with the tetracyclic ketone (IX) (obtained by treatment of the dimeric ketonic compound (X) with NaOMe in methanol) affords the adduct (XI), which is treated with HBr in acetonitrile to open the cyclopropane ring and provide the bromomethyl compound (XII). The aromatization of (XII) with p-nitrophenyl chloroformate (XIII) and TEA in dichloromethane affords the activated carbonate ester (XIV), which is finally treated with 1-methylpiperazine (XV) to furnish the target carbamate.

参考文献 中间体
合成目标
【1】 Nagamura, S.; et al.; Synthesis and antitumor activity of duocarmycin derivatives: Modification of affinity moiety to DNA minor groove. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 206.
【2】 Saito, H.; Nagamura, S.; Amishiro, N.; Kobayashi, E.; Gomi, K.; New water-soluble duocarmycin derivatives: Synthesis and antitumor activity of A-ring pyrrole compounds bearing beta-heteroarylacryloyl groups. J Med Chem 1999, 42, 4, 669.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11191 2-Chloropyrimidine 1722-12-9 C4H3ClN2 详情 详情
(II) 38398 methyl 2-pyrimidinyl ether; 2-methoxypyrimidine C5H6N2O 详情 详情
(III) 38394 5-iodo-2-methoxypyrimidine; 5-iodo-2-pyrimidinyl methyl ether C5H5IN2O 详情 详情
(IV) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(V) 38395 methyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate C9H10N2O3 详情 详情
(VI) 38396 (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoic acid C8H8N2O3 详情 详情
(VII) 11236 4-Nitrophenol; p-Nitrophenol 100-02-7 C6H5NO3 详情 详情
(VIII) 38397 4-nitrophenyl (E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoate C14H11N3O5 详情 详情
(IX) 38365 methyl (3bR,4aS)-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate C14H14N2O3 详情 详情
(X) 38366 methyl (2R,3bR,4aS)-2-methyl-3,8-dioxo-6-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2,3,4,4a,5,6,8-octahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carboxylate C26H25N3O8 详情 详情
(XI) 38399 methyl (3bR,4aS)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-8-oxo-1,4,4a,5,6,8-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-3-carboxylate C22H20N4O5 详情 详情
(XII) 38400 methyl (8S)-8-(bromomethyl)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-4-oxo-3,4,6,7,8,8a-hexahydropyrrolo[3,2-e]indole-1-carboxylate C22H21BrN4O5 详情 详情
(XIII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XIV) 38401 methyl (8S)-8-(bromomethyl)-6-[(E)-3-(2-methoxy-5-pyrimidinyl)-2-propenoyl]-2-methyl-4-[[(4-nitrophenoxy)carbonyl]oxy]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C29H24BrN5O9 详情 详情
(XV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线48

该中间体在本合成路线中的序号：(IX)

Catalytic hydrogenation of 1-acetyl-6-nitroindoline (V) afforded amine (VI). Condensation of (VI) with mechlorethamine hydrochloride (VIII) in the presence of K2CO3 in refluxing n-butanol produced piperazinylindoline (X). Alternatively, intermediate (X) was obtained by Sandmeyer reaction of amine (VI) in the presence of CuBr, followed by condensation of the resulting bromide (VII) with N-methylpiperazine (IX). Chlorination of (X) with N-chlorosuccinimide provided (XI). The acetamide function of (XI) was then hydrolyzed in refluxing 2M HCl to give amine (XII). Finally, coupling of (XII) with isocyanate (IV) gave rise to the corresponding urea.

参考文献 中间体
合成目标
【1】 Evans, M.; Gaster, L.M.; Gordon, l.; et al.; Mixed 5-HT1A/1B/1D receptor antagonists as novel antidepressants. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PB-77.
【2】 Gaster, L.M.; Rami, H.K.; Wyman, P.A. (SmithKline Beecham plc); Indole derivs. having combined 5HT1A, 5HT1B and 5HT1D receptor antagonist activity. EP 0975593; WO 9850358 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 44709 4-(4-pyridinyl)-1-naphthyl isocyanate; 4-(4-isocyanato-1-naphthyl)pyridine C16H10N2O 详情 详情
(V) 44710 1-(6-nitro-2,3-dihydro-1H-indol-1-yl)-1-ethanone C10H10N2O3 详情 详情
(VI) 44711 1-(6-amino-2,3-dihydro-1H-indol-1-yl)-1-ethanone C10H12N2O 详情 详情
(VII) 44712 1-(6-bromo-2,3-dihydro-1H-indol-1-yl)-1-ethanone C10H10BrNO 详情 详情
(VIII) 44713 2-chloro-N-(2-chloroethyl)-N-methyl-1-ethanamine; N,N-bis(2-chloroethyl)-N-methylamine C5H11Cl2N 详情 详情
(IX) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(X) 44714 1-[6-(4-methyl-1-piperazinyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone C15H21N3O 详情 详情
(XI) 44715 1-[5-chloro-6-(4-methyl-1-piperazinyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone C15H20ClN3O 详情 详情
(XII) 44716 5-chloro-6-(4-methyl-1-piperazinyl)indoline C13H18ClN3 详情 详情

合成路线49

该中间体在本合成路线中的序号：(II)

Title compound was synthesized by condensation of ethyl 6-fluoro-4-quinolone-3-carboxylate (I) with N-methylpiperazine (II) in pyridine at 120 C under pressure.

参考文献 中间体
合成目标
【1】 Srivastava S; Srivastava, S.K.; Shukla, A.; Chauhan, P.M.; Puri, S.K.; Bhaduri, A.P.; Pandey, V.C.; Synthesis and methemoglobin toxicity of the amides of 6/7 mono or disubstituted quinolone. Bioorg Med Chem Lett 1999, 9, 1, 25.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19903 ethyl 6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C12H10FNO3 详情 详情
(II) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线50

该中间体在本合成路线中的序号：(II)

Title compound was synthesized by condensation of ethyl 7-chloro-6-fluoro-4-quinolone-3-carboxylate (I) with N-methylpiperazine (II) in pyridine at 120 C under pressure.

参考文献 中间体
合成目标
【1】 Srivastava S; Srivastava, S.K.; Shukla, A.; Chauhan, P.M.; Puri, S.K.; Bhaduri, A.P.; Pandey, V.C.; Synthesis and methemoglobin toxicity of the amides of 6/7 mono or disubstituted quinolone. Bioorg Med Chem Lett 1999, 9, 1, 25.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19904 ethyl 7-chloro-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C12H9ClFNO3 详情 详情
(II) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线51

该中间体在本合成路线中的序号：(VI)

Friedel-Crafts acylation of chlorobenzene (I) with levulinic acid chloride (II) afforded diketone (III), which was converted to pyrrole (V) by condensation with 4-chloroaniline (IV) in the presence of a catalytic amount of HBr. Mannich reaction of (V) with formaldehyde and N-methylpiperazine (VI) then provided the target aminomethyl pyrrole.

参考文献 中间体
合成目标
【1】 Retico, A.; Cerreto, F.; Scalzo, M.; Villa, A.; Studies on anti-Candida agents with a pyrrole moiety. Synthesis and microbiological activity of some 3-aminomethyl-1,5-diaryl-2-methyl-pyrrole derivatives. Eur J Med Chem 1992, 27, 7, 701.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10190 1-Chlorobenzene 108-90-7 C6H5Cl 详情 详情
(II) 28526 4-oxopentanoyl chloride C5H7ClO2 详情 详情
(III) 28527 1-(4-chlorophenyl)-1,4-pentanedione C11H11ClO2 详情 详情
(IV) 12034 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline 106-47-8 C6H6ClN 详情 详情
(V) 28528 1,2-bis(4-chlorophenyl)-5-methyl-1H-pyrrole C17H13Cl2N 详情 详情
(VI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线52

该中间体在本合成路线中的序号：(IV)

The condensation of 4-chloro-2-(2-naphthyl)quinoline (I) with p-aminophenol (II) at 130 C provided the corresponding 4-anilinoquinoline (III). Then, Mannich reaction of (III) with N-methylpiperazine (IV) and formaldehyde furnished the title compound.

参考文献 中间体
合成目标
【1】 Kotecka, B.M.; Strekowski, L.; Say, M.; Manzel, L.; Henary, M.; Zegrocka, O.; Macfarlane, D.E.; Mokrosz, M.J.; Structure-activity relationship analysis of substituted 4-quinolinamines, antagonists of immunostimulatory CpG-oligodeoxynucleotides. Bioorg Med Chem Lett 1999, 9, 13, 1819.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 34398 4-chloro-2-(2-naphthyl)quinoline C19H12ClN 详情 详情
(II) 15715 4-Aminophenol 123-30-8 C6H7NO 详情 详情
(III) 34399 4-[[2-(2-naphthyl)-4-quinolinyl]amino]phenol C25H18N2O 详情 详情
(IV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线53

该中间体在本合成路线中的序号：(XI)

Horner-Emmons condensation of 1-naphthaldehyde (VI) with triethyl phosphonoacetate (VII) using DBU as the base afforded naphthylacrylate (VIII). This was reacted with tosylmethylisocyanide and potassium tert-butoxide to produce pyrrole (IX). Hydrolysis of the ester group of (IX) with KOH gave rise to the carboxylic acid (X), which was coupled with N-methylpiperazine (XI) employing EDC and HOBt or, alternatively, by previous conversion to the corresponding acid chloride with SOCl2. The resulting amide (XII) was finally alkylated at the pyrrole N atom with chloride (V) in the presence of NaH.

参考文献 中间体
合成目标
【1】 Lee, J.; Lee, H.; Shin, Y.; et al.; Synthesis and structure-activity relationships of 1-(1(3)H-imidazole-5(4)-yl)-methylpyrroles as farnesyl protein transferase inhibitors (FTPI). 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 210.
【2】 Lee, J.H.; Yoo, J.K.; Koh, J.S.; Choi, T.S.; Shin, Y.S.; Kim, K.H.; Jung, W.H.; Kim, J.H.; Lee, S.H.; Ahn, I.A.; Ro, S.G.; Lee, H.I.; Kim, H.S.; Chung, H.H.; Jeong, S.W.; Kwak, T.H. (LG Chem Ltd.); Imidazole derivs. having an inhibitory activity for farnesyl transferase and process for preparation thereof. WO 9928315 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 33672 1-(1,3-benzodioxol-5-ylmethyl)-5-(chloromethyl)-1H-imidazole C12H11ClN2O2 详情 详情
(VI) 12314 1-Naphthaldehyde 66-77-3 C11H8O 详情 详情
(VII) 10019 Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate 867-13-0 C8H17O5P 详情 详情
(VIII) 25405 ethyl (E)-3-(1-naphthyl)-2-propenoate C15H14O2 详情 详情
(IX) 33673 ethyl 4-(1-naphthyl)-1H-pyrrole-3-carboxylate C17H15NO2 详情 详情
(X) 33674 4-(1-naphthyl)-1H-pyrrole-3-carboxylic acid C15H11NO2 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XII) 33675 (4-methyl-1-piperazinyl)[4-(1-naphthyl)-1H-pyrrol-3-yl]methanone C20H21N3O 详情 详情

合成路线54

该中间体在本合成路线中的序号：(IV)

The esterification of (rac)-6-(5-chloro-3-pyridyl)-5-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-7-one rac-(I) with vinyl chloroformate (II) in pyridine gives the racemic carbonate rac-(III), which is submitted to an enantioselective hydrolysis with Candida antarctica (SP 435L) lipase in dioxane/benzyl alcohol yielding a mixture of rac-(I), which is recycled, and enantiomerically pure (95% e.e.) (S)-(III). Finally, this compound is condensed with 1-methylpiperazine (IV) in acetone.

参考文献 中间体
合成目标
【1】 Culy, C.; Castañer, J.; Bayes, M.; Eszopiclone. Drugs Fut 2003, 28, 7, 640.
【2】 Cotrel, C.; Roussel, G. (Aventis Pharma SA); Optically active deriv. of 5H-pyrrolo[3,4-b]pyrazine, its preparation and pharmaceutical compsns. containing it. EP 0495717; EP 0609210; FR 2671800; JP 1994504548; WO 9212980 .
【3】 Gotor, V.; et al.; Enzymic resolution of (±)-6-(5-chloropyridin-2-yl)-7-vinyloxycarbonyloxy-6,7-dihydro[5H] pyrrolo[3,4-b]pyrazin-5-one. Synthesis of (+)-zopiclone. Tetrahedron Asymmetry 1997, 8, 7, 995.
【4】 Bayod Jasanada, M.S.; Brieva Collado, R.; Linares López, F.J.; García Campos, R.; Gotor Santamaría, V. (Asturpharma SA); (+)-6-(5-Chloropyrid-2-yl)-7-oxo-vinylcarbonyloxy-5,6-dihydropyrrolo[3,4b]pyrazine and their use in a process for the preparation of (+)-6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)-carbonyloxy-7-oxo-5,6-dihydropyrrolo[3,4b]pyrazine. ES 2101653 .
【5】 Cotrel, C.; et al. (Aventis Pharma SA); Pyrrolo-[3,4,b]pyrazine derivatives. DE 2300491; GB 1358680; JP 52048687; US 3862149 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(I) 32796 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one C11H7ClN4O2 详情 详情
(S)-(III) 32797 6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl vinyl carbonate C14H9ClN4O4 详情 详情
rac-(III) 32798 (5S)-6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl vinyl carbonate C14H9ClN4O4 详情 详情
(II) 28068 1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate 5130-24-5 C3H3ClO2 详情 详情
(IV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线55

该中间体在本合成路线中的序号：(IV)

The esterification of (rac)-6-(5-chloro-3-pyridyl)-5-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-7-one rac-(I) with chloromethyl chloroformate (V) in pyridine gives the racemic carbonate rac-(III), which is submitted to an enantioselective hydrolysis with Candida antarctica (SP 435L) lipase in dioxane/benzyl alcohol yielding a mixture of rac-(I), which is recycled, and enantiomerically pure (96% e.e.) (S)-(III). Finally, this compound is condensed with 1-methylpiperazine (IV) in acetone.

参考文献 中间体
合成目标
【1】 Culy, C.; Castañer, J.; Bayes, M.; Eszopiclone. Drugs Fut 2003, 28, 7, 640.
【2】 Solares, L.F.; Diaz, M.; Brieva, R.; Sanchez, V.M.; Bayod, M.; Gotor, V.; Enzymatic resolution of new carbonate intermediates for the synthesis of (S)-(+)-zopiclone. Tetrahedron Asymmetry 2002, 13, 23, 2577.
【3】 Gotor, V.; et al.; Enzymic resolution of (±)-6-(5-chloropyridin-2-yl)-7-vinyloxycarbonyloxy-6,7-dihydro[5H] pyrrolo[3,4-b]pyrazin-5-one. Synthesis of (+)-zopiclone. Tetrahedron Asymmetry 1997, 8, 7, 995.
【4】 Cotrel, C.; et al. (Aventis Pharma SA); Pyrrolo-[3,4,b]pyrazine derivatives. DE 2300491; GB 1358680; JP 52048687; US 3862149 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(I) 32796 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one C11H7ClN4O2 详情 详情
rac-(III) 62951 chloromethyl 6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl carbonate C13H8Cl2N4O4 详情 详情
(S)-(III) 62952 chloromethyl (5S)-6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl carbonate C13H8Cl2N4O4 详情 详情
(IV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(V) 19249 Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane 22128-62-7 C2H2Cl2O2 详情 详情

合成路线56

该中间体在本合成路线中的序号：(V)

The condensation of ethyl 2-aminobenzo[b]thiophene-3-carboxylate (I) with 2,4-difluoronitrobenzene (II) afforded the diaryl amine (III). The nitro group of (III) was then reduced to amine (IV) by catalytic hydrogenation over Pd/C. Then, cyclization of amino ester (IV) with N-methylpiperazine (V) using TiCl4 in hot anisole produced the target benzothienobenzodiazepine, which was finally isolated as the corresponding maleate salt.

参考文献 中间体
合成目标
【1】 Fujimura, M.; Horiuchi, H.; Tanaka, H.; Kohara, T.; Hashimoto, K.; Kimura, K.; Seio, K.; Yasumatsu, H. (Welfide Corporation); Fused thiophene cpds. and medicinal use thereof. EP 1016664; JP 2001072684; WO 9911647 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 46396 ethyl 2-amino-1-benzothiophene-3-carboxylate C11H11NO2S 详情 详情
(II) 32036 2,4-difluoro-1-nitrobenzene 446-35-5 C6H3F2NO2 详情 详情
(III) 46397 ethyl 2-(5-fluoro-2-nitroanilino)-1-benzothiophene-3-carboxylate C17H13FN2O4S 详情 详情
(IV) 46398 ethyl 2-(2-amino-5-fluoroanilino)-1-benzothiophene-3-carboxylate C17H15FN2O2S 详情 详情
(V) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线57

该中间体在本合成路线中的序号：(V)

In a related procedure, the condensation of 2-aminobenzo[b]thiophene-3-carbonitrile (VI) with 2,4-difluoronitrobenzene (II) produced the diaryl amine (VII). Reduction of the nitro group of (VII) using sodium hydrosulfite yielded diamine (VIII). Subsequent cyclization of amino nitrile (VIII) upon acidic treatment gave rise to the tetracyclic system (IX). This was then treated with refluxing N-methylpiperazine (V) to provide the title compound.

参考文献 中间体
合成目标
【2】 Fujimura, M.; Horiuchi, H.; Tanaka, H.; Kohara, T.; Hashimoto, K.; Kimura, K.; Seio, K.; Yasumatsu, H. (Welfide Corporation); Fused thiophene cpds. and medicinal use thereof. EP 1016664; JP 2001072684; WO 9911647 .
【1】 Horiuchi, H.; Kimura, K.; Tanaka, H.; et al.; Y-931, a novel antipsychotic with potential anti-NRH (NMDA receptor-hypofunction) activity: Synthesis and structure-activity relationships of 6H-[1]benzothieno[2,3-b][1,5]benzodiazepines. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PB-128.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 32036 2,4-difluoro-1-nitrobenzene 446-35-5 C6H3F2NO2 详情 详情
(V) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(VI) 46399 2-amino-1-benzothiophene-3-carbonitrile C9H6N2S 详情 详情
(VII) 46400 2-(5-fluoro-2-nitroanilino)-1-benzothiophene-3-carbonitrile C15H8FN3O2S 详情 详情
(VIII) 46401 2-(2-amino-5-fluoroanilino)-1-benzothiophene-3-carbonitrile C15H10FN3S 详情 详情
(IX) 46402 8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12-ylamine; 8-fluoro-6H-[1]benzothieno[2,3-b][1,5]benzodiazepin-12-amine C15H10FN3S 详情 详情

合成路线58

该中间体在本合成路线中的序号：(XVI)

Displacement of the mesylate group of (XV) with N-methylpiperazine (XVI) produced the disubstituted piperazine (XVII). The tert-butyl ester of (XVII) was cleaved to the corresponding carboxylic acid (XVIII) by means of trifluoroacetic acid in CH2Cl2. Then coupling of (XVIII) with 3-(aminomethyl)pyridine (XIX) gave rise to the title amide.

参考文献 中间体
合成目标
【1】 Bavetsias, V.; et al.; The design and synthesis of water-soluble analogues of CB30865, a quinazolin-4-one-based antitumor agent. J Med Chem 2002, 45, 17, 3692.
【2】 Bavetsias, V.; Jackman, A.; Skelton, L. (Cancer Research Campaign Technology Ltd.); Anti-cancer dihydroquinazoline derivs.. WO 0050417 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XV) 46871 tert-butyl 4-[[(7-chloro-3-methyl-2-[[(methylsulfonyl)oxy]methyl]-4-oxo-3,4-dihydro-6-quinazolinyl)methyl](2-propynyl)amino]benzoate C26H28ClN3O6S 详情 详情
(XVI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XVII) 46872 tert-butyl 4-[([7-chloro-3-methyl-2-[(4-methyl-1-piperazinyl)methyl]-4-oxo-3,4-dihydro-6-quinazolinyl]methyl)(2-propynyl)amino]benzoate C30H36ClN5O3 详情 详情
(XVIII) 46873 4-[([7-chloro-3-methyl-2-[(4-methyl-1-piperazinyl)methyl]-4-oxo-3,4-dihydro-6-quinazolinyl]methyl)(2-propynyl)amino]benzoic acid C26H28ClN5O3 详情 详情
(XIX) 18731 3-pyridinylmethanamine; 3-pyridinylmethylamine 3731-52-0 C6H8N2 详情 详情

合成路线59

该中间体在本合成路线中的序号：(IV)

3-Phenylisoquinolinone (II) was synthesized by addition of benzonitrile to the dilithium derivative of N-methyltoluamide (I). Conversion of (II) to the 1-chloroisoquinoline (III) was achieved by heating with POCl3. Then, displacement of the chlorine atom of (III) with N-methylpiperazine (IV) in refluxing DMF furnished the title compound.

参考文献 中间体
合成目标
【1】 Park, M.-J.; Chung, B.-H.; Cho, W.-J.; Lee, C.-O.; Yo, S.-J.; Synthesis and antitumor activity of 3-arylisoquinoline derivatives. Arch Pharmacal Res 1997, 20, 3, 264.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 47428 N,2-dimethylbenzamide 2170-09-4 C9H11NO 详情 详情
(II) 47429 3-phenyl-1(2H)-isoquinolinone C15H11NO 详情 详情
(III) 47430 1-chloro-3-phenylisoquinoline C15H10ClN 详情 详情
(IV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线60

该中间体在本合成路线中的序号：(XIII)

Alkylation of 4-hydroxy-5-methoxy benzoic acid methyl ester (I) with 3-chloropropyl p-toluene sulfonate (III) by means of K2CO3 and methyl-tricapryl ammonium chloride (Aliquat 128) in refluxing acetone affords compound (III), which is then nitrated by means of HNO3 in HOAc to furnish 2-nitro derivative (IV). Reduction of the nitro moiety of (IV) by means of Fe in H2O/MeOH in the presence of ammonium chloride yields 2-amino compound (V), which is subjected to reaction with refluxing dimethylformamide dimethylacetal (VI) to provide amidine (VII). Condensation of (VII) with acetonitrile by means of n-BuLi in hexane/THF/HOAc gives substituted quinoline-carbonitrile (IX), whose hydroxyl group is replaced by a chlorine by treatment of (IX) with refluxing POCl3 to afford compound (X). Coupling of (X) with 2,4-dichloro-5-methoxyaniline (XI) in 2-ethoxyethanol in the presence of pyridine hydrochloride yields compound (XII), which is finally converted into the desired compound by condensation with 1-methylpiperazine (XII) by means of NaI in refluxing ethylene glycol dimethyl ether.

参考文献 中间体
合成目标
【1】 Boschelli, D.H.; Ye, F.; Wang, Y.D.; Dutia, M.; Johnson, S.L.; Wu, B.; Miller, K.; Powell, D.W.; Yaczko, D.; Young, M.; Tischler, M.; Arndt, K.; Discafani, C.; Etienne, C.; Gibbons, J.; Grod, J.; Lucas, J.; Weber, J.M.; Boschelli, F.; Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem 2001, 44, 23, 3965.
【2】 Boschelli, D.H.; Dutia, M.; Ye, F.; et al.; Inhibition of SRC kinase activity by 4-phenylamino-3-quinolinecarbonitriles Part 2: Optimization of the side chain at C-7. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 145.
【3】 Boschelli, D.H.; Wang, Y.D.; Ye, F.; et al.; Synthesis and Src kinase inhibitory activity of a series of 4-phenylamino-3-quinolinecarbonitriles. J Med Chem 2001, 44, 5, 822.
【4】 Tsou, H.-R.; Wissner, A.; Johnson, B.D.; Reich, M.F.; Floyd, M.B. Jr.; Kitchen, D.B. (American Cyanamid Co.); Substituted 3-cyano quinolines. US 6002008 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 29176 methyl 4-hydroxy-3-methoxybenzoate 3943-74-6 C9H10O4 详情 详情
(II) 19490 3-chloro-1-propanol 627-30-5 C3H7ClO 详情 详情
(III) 50008 methyl 4-(3-chloropropoxy)-3-methoxybenzoate C12H15ClO4 详情 详情
(IV) 50009 methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate C12H14ClNO6 详情 详情
(V) 50010 methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate C12H16ClNO4 详情 详情
(VI) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(VII) 50011 methyl 4-(3-chloropropoxy)-2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxybenzoate C15H21ClN2O4 详情 详情
(VIII) 37210 acetonitrile 75-05-8 C2H3N 详情 详情
(IX) 50012 7-(3-chloropropoxy)-4-hydroxy-6-methoxy-3-quinolinecarbonitrile C14H13ClN2O3 详情 详情
(X) 48519 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile C14H12Cl2N2O2 详情 详情
(XI) 50013 2,4-dichloro-5-methoxyphenylamine; 2,4-dichloro-5-methoxyaniline C7H7Cl2NO 详情 详情
(XII) 50014 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrile C21H18Cl3N3O3 详情 详情
(XIII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线61

该中间体在本合成路线中的序号：(II)

The condensation of 4-fluoro-3-nitrobenzoic acid (I) with 1-methylpiperazine (II) by means of oxalyl chloride in dichloromethane gives the expected acyl derivative (III), which is reduced with BH3/THF to yield the benzyl piperazine (IV). The condensation of (IV) with 2(R)-hydroxy-2-phenylethylamine (V) by means of DIEA in NMP affords the secondary amine (VI), which is reduced with H2 over Pd/C in ethanol, providing the phenylenediamine (VII). Finally, this compound is cyclized with 4-methoxybenzoyl isothiocyanate (VIII) by means of EDC in DMF to furnish the target benzimidazole.

参考文献 中间体
合成目标
【1】 Heyer, D.; et al.; 2-Aminobenzimidazoles: A class of orally bioavailable and brain permeable neuropeptide YY5 antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 284.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 46937 4-fluoro-3-nitrobenzoic acid 453-71-4 C7H4FNO4 详情 详情
(II) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(III) 54041 (4-fluoro-3-nitrophenyl)(4-methyl-1-piperazinyl)methanone C12H14FN3O3 详情 详情
(IV) 54042 1-(4-fluoro-3-nitrobenzyl)-4-methylpiperazine C12H16FN3O2 详情 详情
(V) 10173 (1R)-2-Amino-1-phenyl-1-ethanol 2549-14-6 C8H11NO 详情 详情
(VI) 54043 (1R)-2-{4-[(4-methyl-1-piperazinyl)methyl]-2-nitroanilino}-1-phenyl-1-ethanol C20H26N4O3 详情 详情
(VII) 54044 (1R)-2-{2-amino-4-[(4-methyl-1-piperazinyl)methyl]anilino}-1-phenyl-1-ethanol C20H28N4O 详情 详情
(VIII) 54045 4-Methoxybenzoyl isothiocyanate 16778-84-0 C9H7NO2S 详情 详情

合成路线62

该中间体在本合成路线中的序号：(II)

Alternatively, the reduction of 4-fluoro-3-nitrobenzoic acid (I) with BH3/THF gives the benzyl alcohol (IX), which is treated with PBr3 in ethyl ether to yield the benzyl bromide (X). Finally, this compound is condensed with 1-methylpiperazine (II) by means of DIEA in THF to afford the already reported benzyl piperazine intermediate (IV).

参考文献 中间体
合成目标
【1】 Heyer, D.; et al.; 2-Aminobenzimidazoles: A class of orally bioavailable and brain permeable neuropeptide YY5 antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 284.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 46937 4-fluoro-3-nitrobenzoic acid 453-71-4 C7H4FNO4 详情 详情
(II) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IV) 54042 1-(4-fluoro-3-nitrobenzyl)-4-methylpiperazine C12H16FN3O2 详情 详情
(IX) 54046 (4-fluoro-3-nitrophenyl)methanol C7H6FNO3 详情 详情
(X) 47038 4-(bromomethyl)-1-fluoro-2-nitrobenzene C7H5BrFNO2 详情 详情

合成路线63

该中间体在本合成路线中的序号：(II)

The reduction of 4-fluoro-3-nitrobenzoic acid (I) with BH3/THF gives the benzyl alcohol (IX), which is condensed with 2(R)-hydroxy-2-phenylethylamine (V) by means of DIEA in NMP to yield nitro compound (XI). Derivative (XI) is then converted into secondary amine (XII) by reduction either with H2 over Pd/C in EtOH or with Na2S·9H2O in dioxane/H2O or by treatment with Na2S2O4 in dioxane/NH4OH. Cyclization of (XI) with 4-methoxybenzoyl isothiocyanate (VIII) by means of EDC in DMF affords the benzimidazole (XIII), which is oxidized at the carbinol group by means of MnO2 in THF to provide the corresponding carbaldehyde (XIV). Finally, this compound is reductocondensed with 1-methylpiperazine (II) by means of NaBH(OAc)3 to furnish the target benzimidazole.

参考文献 中间体
合成目标
【1】 Heyer, D.; et al.; 2-Aminobenzimidazoles: A class of orally bioavailable and brain permeable neuropeptide YY5 antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 284.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 46937 4-fluoro-3-nitrobenzoic acid 453-71-4 C7H4FNO4 详情 详情
(II) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(V) 10173 (1R)-2-Amino-1-phenyl-1-ethanol 2549-14-6 C8H11NO 详情 详情
(VIII) 54045 4-Methoxybenzoyl isothiocyanate 16778-84-0 C9H7NO2S 详情 详情
(IX) 54046 (4-fluoro-3-nitrophenyl)methanol C7H6FNO3 详情 详情
(XI) 54047 (1R)-2-[4-(hydroxymethyl)-2-nitroanilino]-1-phenyl-1-ethanol C15H16N2O4 详情 详情
(XII) 54048 (1R)-2-[2-amino-4-(hydroxymethyl)anilino]-1-phenyl-1-ethanol C15H18N2O2 详情 详情
(XIII) 54049 N-{5-(hydroxymethyl)-1-[(2R)-2-hydroxy-2-phenylethyl]-1H-benzimidazol-2-yl}-4-methoxybenzamide C24H23N3O4 详情 详情
(XIV) 54050 N-{5-formyl-1-[(2R)-2-hydroxy-2-phenylethyl]-1H-benzimidazol-2-yl}-4-methoxybenzamide C24H21N3O4 详情 详情

合成路线64

该中间体在本合成路线中的序号：(II)

Pyridazinylpiperazine (III) was prepared from 3,6-dichloropyridazine (I) and N-methylpiperazine (II) according to a literature method. Subsequent quaternization of piperazine (III) with methyl iodide gave the title ammonium salt.

参考文献 中间体
合成目标
【1】 Romanelli, M.N.; et al.; Structure-affinity relationships of a unique nicotinic ligand: N1-dimethyl-N4-phenylpiperazinium iodide (DMPP). J Med Chem 2001, 44, 23, 3946.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11292 3,6-Dichloropyridazine 141-30-0 C4H2Cl2N2 详情 详情
(II) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(III) 53381 3-chloro-6-(4-methyl-1-piperazinyl)pyridazine 27464-17-1 C9H13ClN4 详情 详情

合成路线65

该中间体在本合成路线中的序号：(XII)

The phenolic hydroxyl group of (IX) is acylated by 4-nitrophenyl chloroformate (X), producing carbonate (XI). Then, displacement of the 4-nitrophenoxy group of (XI) with N-methylpiperazine (XII) yields carbamate (XIII). Finally, nitro group reduction in (XIII) gives rise to the title compound

参考文献 中间体
合成目标
【1】 McGee, D.P.C.; Saunders, O.L.; Martichonok, V.; Wu, G.; Ng, H.P.; Li, Z.; Yarranton, G.T. (Medarex, Inc.); Cytotoxic agents. US 2003050331; WO 0296910 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 63445 methyl 8-(chloromethyl)-4-hydroxy-2-methyl-6-[(5-{[(7-nitro-1H-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C32H24ClN5O8 详情 详情
(X) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(XI) 63446 methyl 8-(chloromethyl)-2-methyl-6-[(5-{[(7-nitro-1H-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-4-({[(4-nitrophenyl)oxy]carbonyl}oxy)-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C39H27ClN6O12 详情 详情
(XII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XIII) 63447 methyl 8-(chloromethyl)-2-methyl-4-{[(4-methyl-1-piperazinyl)carbonyl]oxy}-6-[(5-{[(7-nitro-1H-indol-2-yl)carbonyl]amino}-1-benzofuran-2-yl)carbonyl]-3,6,7,8-tetrahydropyrrolo[3,2-e]indole-1-carboxylate C38H34ClN7O9 详情 详情

合成路线66

该中间体在本合成路线中的序号：(VIII)

Acylation of the anilino ester (I) with 4-nitrobenzoyl chloride (II) affords amide (III). After reduction of the 4-nitrobenzamide (III) by catalytic hydrogenation, the resultant amine (IV) is condensed with (2-ethyl-1-imidazolyl)benzoyl chloride (V) to furnish diamide (VI). Subsequent ester group saponification in (VI) gives acid (VII). This is finally coupled with N-methylpiperazine (VIII) in the presence of EDC and HOBt to produce the title compound.

参考文献 中间体
合成目标
【1】 Kakefuda, A.; Kusayama, T.; Tahara, A.; Tsukamoto, S.-I.; Tsukada, J.; N-Methylbenzanilide derivatives as a novel class of selective V1A receptor antagonists. Bioorg Med Chem Lett 2002, 12, 2, 229.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 57789 ethyl 6-[5-methyl-2-(methylamino)phenoxy]hexanoate C16H25NO3 详情 详情
(II) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(III) 57790 ethyl 6-{5-methyl-2-[methyl(4-nitrobenzoyl)amino]phenoxy}hexanoate C23H28N2O6 详情 详情
(IV) 57791 ethyl 6-{2-[(4-aminobenzoyl)(methyl)amino]-5-methylphenoxy}hexanoate C23H30N2O4 详情 详情
(V) 57792 2-(2-ethyl-1H-imidazol-1-yl)benzoyl chloride C12H11ClN2O 详情 详情
(VI) 57793 ethyl 6-{2-[(4-{[2-(2-ethyl-1H-imidazol-1-yl)benzoyl]amino}benzoyl)(methyl)amino]-5-methylphenoxy}hexanoate C35H40N4O5 详情 详情
(VII) 57794 6-{2-[(4-{[2-(2-ethyl-1H-imidazol-1-yl)benzoyl]amino}benzoyl)(methyl)amino]-5-methylphenoxy}hexanoic acid C33H36N4O5 详情 详情
(VIII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线67

该中间体在本合成路线中的序号：(XI)

Acid hydrolysis of the ethylene ketal function of (IX) afforded ketone (X). This was subjected to a reductive amination with N-methylpiperazine (XI) in the presence of sodium triacetoxyborohydride to produce the corresponding disubstituted cyclohexane compound as a 3:1 mixture of cis- and trans-isomers. The desired trans-compound (XII) was then isolated by column chromatography. Finally, acylation of (XII) with 2,3-dichlorobenzenesulfonyl chloride (XIII) provided the title sulfonamide.

参考文献 中间体
合成目标
【1】 Wishart, N.; Barlozzari, T.; Arnold, L.D.; et al.; Structure activity relationships for a novel series of pyrrolo[2,3-d]pyrimidine Tie-2 inhibitors. Proc Am Assoc Cancer Res 2002, 43, Abst 4205.
【2】 Hirst, G.C.; Ritter, K.; Arnold, L.D.; Wishart, N.; Calderwood, D. (BASF AG); Pyrrolopyrimidines as protein kinase inhibitors. EP 1114053; WO 0017203 .
【3】 Hirst, G.C.; Rafferty, P.; Arnold, L.D.; Johnston, D.N.; Calderwood, D.; Munschaufer, R. (BASF AG); Pyrrolopyrimidines as tyrosine kinase inhibitors. WO 0172751 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 53567 5-(4-amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylamine n/a C20H22FN5O2 详情 详情
(X) 53568 4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone n/a C18H18FN5O 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XII) 53569 5-(4-amino-3-fluorophenyl)-7-[4-(4-methyl-1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-amino-3-fluorophenyl)-7-[4-(4-methyl-1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine n/a C23H30FN7 详情 详情
(XIII) 53570 2,3-Dichlorobenzenesulfonyl chloride 82417-45-6 C6H3Cl3O2S 详情 详情

合成路线68

该中间体在本合成路线中的序号：(VII)

The condensation of 3-aminobenzoic acid (I) with 3-nitro-1,8-naphthalic anhydride (II) in hot DMSO/pyridine gives the corresponding cyclic naphthalmide (III), which is condensed with diethylenetriamine (IV) by means of CDI in DMF to yield the benzamide (V). The reaction of (V) with CDI in DMF affords the imidazolylcarbonyl derivative (VI), which is condensed with 1-methylpiperazine (VII) in THF to provide the piperazinocarbonyl compound (VIII). Finally, the amino group of (VIII) is condensed with 3-nitro-1,8-naphthalic anhydride (II) in DMSO/pyridine to give the target bis-cyclic imide.

参考文献 中间体
合成目标
【1】 Suzuki, K.; Yamada, Y.; Asao, T.; Noguchi, K.; Wakida, M. (Taiho Pharmaceutical Co., Ltd.); Naphthalimidobenzamide derivs.. EP 1020446; US 6300331; WO 0001672 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 26638 3-Aminobenzoic acid 99-05-8 C7H7NO2 详情 详情
(II) 15864 5-nitro-1H,3H-benzo[de]isochromene-1,3-dione; 3-Nitro-1,8-naphthalic anhydride 3027-38-1 C12H5NO5 详情 详情
(III) 55382 3-[5-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]benzoic acid C19H10N2O6 详情 详情
(IV) 55379 2,2'-Diaminodiethylamine; 2,2'-Iminodiethylamine; Bis(beta-Aminoethyl)amine; Diethylentriamine; N-(2-Aminoethyl)-1,2-ethanediamine 111-40-0 C4H13N3 详情 详情
(V) 55383 N-{2-[(2-aminoethyl)amino]ethyl}-3-[5-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]benzamide C23H21N5O5 详情 详情
(VI) 55384 N-{2-[(2-aminoethyl)amino]ethyl}-3-(1H-imidazol-1-ylcarbonyl)-5-[5-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]benzamide C27H23N7O6 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(VIII) 55385 N-{2-[(2-aminoethyl)amino]ethyl}-3-[(4-methyl-1-piperazinyl)carbonyl]-5-[5-nitro-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl]benzamide C29H31N7O6 详情 详情

合成路线69

该中间体在本合成路线中的序号：(XI)

Acetylation of o-aminophenol (I) gives o-hydroxy acetanilide (II), which is then protected as the benzyl ether (III) with benzyl bromide and K2CO3. Treatment of acetamide (III) with P2S5 affords the corresponding thioamide (IV), and subsequent S-methylation of (IV) gives rise to the thioimidate (V). Cyclization of thioimidate (V) with 4-biphenylcarboxylic acid hydrazide (VI) in hot DMF leads to the triazole derivative (VII). After benzyl group hydrogenolysis in (VII), the resultant phenol (VIII) is alkylated with 1,6-dibromohexane (IX) to produce the bromohexyl ether (X). Finally, condensation of bromide (X) with N-methylpiperazine (XI) furnishes the title compound.

参考文献 中间体
合成目标
【1】 Kakefuda, A.; et al.; Synthesis and pharmacological evaluation of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives as a novel class of selective antagonists for the human vasopressin V1A receptor. J Med Chem 2002, 45, 12, 2589.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 18663 o-aminophenol; 2-aminophenol 95-55-6 C6H7NO 详情 详情
(II) 56976 2-Acetamidophenol; 2-Hydroxyacetanilide; o-Acetamidophenol; o-Hydroxyacetanilide 614-80-2 C8H9NO2 详情 详情
(III) 56977 N-[2-(benzyloxy)phenyl]acetamide C15H15NO2 详情 详情
(IV) 56978 N-[2-(benzyloxy)phenyl]ethanethioamide C15H15NOS 详情 详情
(V) 56979 methyl N-[2-(benzyloxy)phenyl]ethanimidothioate C16H17NOS 详情 详情
(VI) 56980 4-Biphenylcarboxylic acid hydrazide; 4-Phenylbenzhydrazide 18622-23-6 C13H12N2O 详情 详情
(VII) 56981 benzyl 2-(3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazol-4-yl)phenyl ether; 4-[2-(benzyloxy)phenyl]-3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazole C28H23N3O 详情 详情
(VIII) 56982 2-(3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazol-4-yl)phenol C21H17N3O 详情 详情
(IX) 24786 1,6-dibromohexane 629-03-8 C6H12Br2 详情 详情
(X) 56983 3-[1,1'-biphenyl]-4-yl-4-{2-[(6-bromohexyl)oxy]phenyl}-5-methyl-4H-1,2,4-triazole; 2-(3-[1,1'-biphenyl]-4-yl-5-methyl-4H-1,2,4-triazol-4-yl)phenyl 6-bromohexyl ether C27H28BrN3O 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线70

该中间体在本合成路线中的序号：(XIV)

Attachment of the sulfonylpyrimidine (X) to a Merrifield thiol resin in the presence of NaH in DMF provides resin-bounded compound (XI). Then, saponification of the methyl ester group of (XI) yields carboxylic acid (XII). After formation of the corresponding acid chloride (XIII), coupling with N-methylpiperazine (XIV) gives rise to amide (XV). Sulfide group oxidation in (XV) leads to the sulfonylpyrimidine resin (XVI). Finally, cleavage from the resin in the presence of cyclopropylmethylamine (XVII) in hot NMP affords the target 2-aminopyrimidine derivative

参考文献 中间体
合成目标
【1】 McKenna, J.M.; Halley, F.; Souness, J.E.; McLay, I.M.; Pickett, S.D.; Collis, A.J.; Page, K.; Ahmed, I.; An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors. J Med Chem 2002, 45, 11, 2173.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 62740 methyl 2-{4-(4-fluorophenyl)-5-[2-(methylsulfonyl)-4-pyrimidinyl]-1H-imidazol-2-yl}-5-methyl-1,3-dioxane-5-carboxylate C21H21FN4O6S 详情 详情
(XI) 62741 methyl 2-[4-(4-fluorophenyl)-5-(2-sulfanyl-4-pyrimidinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylate C20H19FN4O4S 详情 详情
(XII) 62742 2-[4-(4-fluorophenyl)-5-(2-sulfanyl-4-pyrimidinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylic acid C19H17FN4O4S 详情 详情
(XIII) 62743 2-[4-(4-fluorophenyl)-5-(2-sulfanyl-4-pyrimidinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carbonyl chloride C19H16ClFN4O3S 详情 详情
(XIV) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(XV) 62744 {2-[4-(4-fluorophenyl)-5-(2-sulfanyl-4-pyrimidinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxan-5-yl}(4-methyl-1-piperazinyl)methanone C24H27FN6O3S 详情 详情
(XVI) 62745 {2-[5-[2-(dioxo-lambda~6~-sulfanyl)-4-pyrimidinyl]-4-(4-fluorophenyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxan-5-yl}(4-methyl-1-piperazinyl)methanone C24H27FN6O5S 详情 详情
(XVII) 59524 Aminomethylcyclopropane; Cyclopropanemethylamine 2516-47-4 C4H9N 详情 详情

合成路线71

该中间体在本合成路线中的序号：(VII)

Sulfonylation of methyl 5-bromo-3-methylanthranilate (I) with acid chloride (II) affords sulfonamide (III). Subsequent alkylation of the sulfonamide N of (III) with iodomethane and K2CO3 yields (IV). After protection of the phenolic hydroxyl group of (IV) as the silyl ether (V), benzylic halogenation with N-bromosuccinimide furnishes bromide (VI). Displacement of its benzylic bromide with 1-methylpiperazine (VII) occurs with concomitant desilylation to give (VIII). Mitsunobu coupling of phenol (VIII) with 2-butyn-1-ol (IX) leads to the propargyl ether (X). The methyl ester group of (X) is then hydrolyzed under alkaline conditions to furnish the carboxylic acid (XI).

参考文献 中间体
合成目标
【1】 Levin, J.I.; Chen, J.M.; Du, M.T.; Nelson, F.C.; Killar, L.M.; Skala, S.; Sung, A.; Jin, G.; Cowling, R.; Barone, D.; March, C.J.; Mohler, K.M.; Black, R.A.; Skotnicki, J.S.; Anthranilate sulfonamide hydroxamate TACE inhibitors. Part 2: SAR of the acetylenic P1' group. Bioorg Med Chem Lett 2002, 12, 8, 1199.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 60447 methyl 2-amino-5-bromo-3-methylbenzoate C9H10BrNO2 详情 详情
(II) 54660 4-hydroxybenzenesulfonyl chloride C6H5ClO3S 详情 详情
(III) 60448 methyl 5-bromo-2-{[(4-hydroxyphenyl)sulfonyl]amino}-3-methylbenzoate C15H14BrNO5S 详情 详情
(IV) 60449 methyl 5-bromo-2-[[(4-hydroxyphenyl)sulfonyl](methyl)amino]-3-methylbenzoate C16H16BrNO5S 详情 详情
(V) 60450 methyl 5-bromo-2-[[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)sulfonyl](methyl)amino]-3-methylbenzoate C22H30BrNO5SSi 详情 详情
(VI) 60451 methyl 5-bromo-3-(bromomethyl)-2-[[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)sulfonyl](methyl)amino]benzoate C22H29Br2NO5SSi 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(VIII) 60452 methyl 5-bromo-2-[[(4-hydroxyphenyl)sulfonyl](methyl)amino]-3-[(4-methyl-1-piperazinyl)methyl]benzoate C21H26BrN3O5S 详情 详情
(IX) 42514 2-butyn-1-ol 764-01-2 C4H6O 详情 详情
(X) 60453 methyl 5-bromo-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-3-[(4-methyl-1-piperazinyl)methyl]benzoate C25H30BrN3O5S 详情 详情
(XI) 60454 5-bromo-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-3-[(4-methyl-1-piperazinyl)methyl]benzoic acid C24H28BrN3O5S 详情 详情

合成路线72

该中间体在本合成路线中的序号：(V)

Acylation of ethyl 2-amino-4-thiazolylacetate (I) with 3-chloro-2-methylbenzenesulfonyl chloride (II) in pyridine affords sulfonamide (III). After alkaline hydrolysis of the ethyl ester group of (III), the resultant carboxylic acid (IV) is coupled to N-methylpiperazine (V) by means of EDC to furnish the target amide.

参考文献 中间体
合成目标
【1】 Barf, T.; Vallgarda, J.; Emond, R.; Haggstrom, C.; Kurz, G.; Nygren, A.; Larwood, V.; Mosialou, E.; Axelsson, K.; Olsson, R.; Engblom, L.; Edling, N.; Ronquist-Nii, Y.; Ohman, B.; Alberts, P.; Abrahmsen, L.; Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of potent and selective inhibitors of the 11beta-hydroxysteroid dehydrogenase type 1. J Med Chem 2002, 45, 18, 3813.
【2】 Emond, R.; Barf, T.; Kurz, G.; Nilsson, M.; Vallgarda, J. (Biovitrum AB); Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1. EP 1283831; WO 0190090 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 61407 Ethyl 2-amino-4-thiazoleacetate; Ethyl 2-aminothiazole-4-acetate; Ethyl-2-(2-Aminothiazole-4-Yl)acetate; (2-Amino-4-thiazolyl)acetic Acid Ethyl Ester; Ethyl (2-Amino-4-thiazolyl)acetate; Ethyl 2-(2-aminothiazol-4-yl)acetate; Ethyl 2-aminothiazol-4-yl-acetate 53266-94-7 C7H10N2O2S 详情 详情
(II) 61408 3-Chloro-2-methylbenzenesulfonyl chloride; 3-Chloro-2-methylbenzenesulphonyl chloride 80563-86-6 C7H6Cl2O2S 详情 详情
(III) 61409 ethyl 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetate C14H15ClN2O4S2 详情 详情
(IV) 61410 2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)acetic acid C12H11ClN2O4S2 详情 详情
(V) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线73

该中间体在本合成路线中的序号：(XI)

Reduction of 1,4-cyclohexanedione mono-ethylene ketal (VII) with NaBH4 gives alcohol (VIII). This is then coupled with the pyrazolopyrimidine (VI) under Mitsunobu conditions to afford adduct (IX). Subsequent acidic ketal hydrolysis in (IX) leads to ketone (X). Finally, reductive condensation of (X) with N-methylpiperazine (XI) in the presence of NaBH(OAc)3 produces a mixture of cis and trans disubstituted cyclohexanes, from which the title trans isomer is isolated by flash column chromatography.

参考文献 中间体
合成目标
【1】 Hirst, G.C.; Rafferty, P.; Ritter, K.; Arnold, L.D.; Wishart, N.; Calderwood, D.; Friedman, M.M. (BASF AG); Pyrazolopyrimidines as therapeutic agents. EP 1212327; WO 0119829 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 57048 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine C17H13N5O 详情 详情
(VII) 11377 1,4-Dioxaspiro[4.5]decan-8-one 4746-97-8 C8H12O3 详情 详情
(VIII) 53564 1,4-dioxaspiro[4.5]decan-8-ol 22428-87-1 C8H14O3 详情 详情
(IX) 57049 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine C25H25N5O3 详情 详情
(X) 57050 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanone C23H21N5O2 详情 详情
(XI) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线74

该中间体在本合成路线中的序号：(VII)

In an alternative synthetic route, cyclization of the aminopyrazole (I) with formamide gives the pyrazolopyrimidine (II), which is then iodinated to (III) by means of N-iodosuccinimide. Mitsunobu coupling of (III) with 4,4-(ethylenedioxy)cyclohexanol (IV) produces the cyclohexyl pyrazolopyrimidine derivative (V), and further ketal hydrolysis leads to ketone (VI). This is subjected to reductive amination with N-methylpiperazine (VII) in the presence of NaBH(OAc)3 to yield (VIII). Finally, Suzuki coupling of iodopyrazolopyrimidine (VIII) with 4-phenoxyphenylboronic acid (IX) gives rise to the title compound.

参考文献 中间体
合成目标
【1】 Burchat, A.F.; et al.; Pyrazolo[3,4-d]pyrimidines containing an extended 3-substituent as potent inhibitors of Lck - A selective insight. Bioorg Med Chem Lett 2002, 12, 12, 1687.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 57051 5-Amino-4-pyrazolecarbonitrile C4H4N4 详情 详情
(II) 41249 4-amine-1H-pyrazolo[3,4-d]pyrimidine; 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1H-pyrazolo[3,4-d]pyrimidin-4-amine 2380-63-4 C5H5N5 详情 详情
(III) 41250 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine C5H4IN5 详情 详情
(IV) 53564 1,4-dioxaspiro[4.5]decan-8-ol 22428-87-1 C8H14O3 详情 详情
(V) 57052 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine C13H16IN5O2 详情 详情
(VI) 57053 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone C11H12IN5O 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(VIII) 57054 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine C16H24IN7 详情 详情
(IX) 57055 4-Phenoxyphenylboronic acid 51067-38-0 C12H11BO3 详情 详情

合成路线75

该中间体在本合成路线中的序号：(VIII)

Treatment of 3-aminopyrazole-4-carbonitrile (I) with formamide at 180 C gives rise to the pyrazolopyrimidinyl amine (II). Subsequent iodination of (II) with N-iodosuccinimide in hot DMF affords 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (III). Reduction of 1,4-cyclohexanedione mono-ethylene ketal (IV) with NaBH4 furnishes alcohol (V). This is then subjected to Mitsunobu coupling with the pyrazolopyrimidine (III) to produce adduct (VI). Acidic hydrolysis of the ethylene ketal (VI) leads to the cyclohexanone (VII). The reductive amination of ketone (VII) with N-methylpiperazine (VIII), either employing NaBH(OAc)3 or via condensation in hot NMP, and then reduction of the resultant enamine with formic acid, produces a mixture of trans- (IX) and cis- (X) disubstituted cyclohexanes, with different ratios in each case.

参考文献 中间体
合成目标
【1】 Ferraris, D.; et al.; Design, synthesis and SAR of PARP-1 inhibitors. Drugs Fut 2002, 27, Suppl. A.
【2】 Hirst, G.C.; Rafferty, P.; Ritter, K.; Arnold, L.D.; Wishart, N.; Calderwood, D.; Friedman, M.M. (BASF AG); Pyrazolopyrimidines as therapeutic agents. EP 1212327; WO 0119829 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 57051 5-Amino-4-pyrazolecarbonitrile C4H4N4 详情 详情
(II) 41249 4-amine-1H-pyrazolo[3,4-d]pyrimidine; 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1H-pyrazolo[3,4-d]pyrimidin-4-amine 2380-63-4 C5H5N5 详情 详情
(III) 41250 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine C5H4IN5 详情 详情
(IV) 11377 1,4-Dioxaspiro[4.5]decan-8-one 4746-97-8 C8H12O3 详情 详情
(V) 53564 1,4-dioxaspiro[4.5]decan-8-ol 22428-87-1 C8H14O3 详情 详情
(VI) 57052 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine C13H16IN5O2 详情 详情
(VII) 57053 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone C11H12IN5O 详情 详情
(VIII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IX) 57054 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine C16H24IN7 详情 详情
(X) 58340 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine C16H24IN7 详情 详情

合成路线76

该中间体在本合成路线中的序号：(VII)

The oxidation of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (I) with MCPBA in dichloromethane gives 4,6-dichloro-2-(methylsulfonyl)pyrimidine (II), which is condensed with N-(4-sulfanylphenyl)cyclopropanecarboxamide (III) in hot butanol to yield the diaryl thioether (IV). The reaction of (IV) with 3-methyl-1H-pyrazol-5-amine (V) by means of DIEA in hot DMF affords the secondary amine (VI), which is finally condensed with 1-methylpiperazine (VII) by heating at 110 ºC to provide the target compound (1). Scheme 1.

参考文献 中间体
合成目标
【1】 Charrier, J.-D., Kay, D., Mazzei, F., Miller, A. (Vertex Pharmaceuticals, Inc.). Processes for preparing substd. pyrimidines and pyrimidine derivs. as inhibitors of protein kinase. EP 1517905, EP 1746093, JP 2005320351, JP 2006501176, US 2004049032, WO 2004000833.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 65246 4,6-Dichloro-2-(methylthio)pyrimidine；4,6-dichloro-2-(methylsulfanyl)pyrimidine 6299-25-8 C5H4Cl2N2S 详情 详情
(II) 65247 4,6-Dichloro-2-(methylsulfonyl)pyrimidine; 2-(Methylsulfonyl)-4,6-Dichloropyrimidine; NSC 45040 4489-34-3 C5H4Cl2N2O2S 详情 详情
(III) 65248 N-(4-mercaptophenyl)cyclopropanecarboxamide 639090-54-3 C10H11NOS 详情 详情
(IV) 65249 　 　 C13H11Cl2N3OS 详情 详情
(V) 65250 5-amino-3-methyl-1H-pyrazole 　 C4H7N3 详情 详情
(VI) 65251 　 　 C17H17ClN6OS 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线77

该中间体在本合成路线中的序号：(VIII)

　

参考文献 中间体
合成目标
【1】 Kompella A, Bhujanga Rao AKS, Venkaiah Chowdary N, et aL 2004. Process for the preparation of the anti-cancer drug imatinib and its analogs via aminolysis of a (chloromethyl benzamide intermediate. WO 2004108699(本专利申请人为: Natco Pharma Limited, India)
【2】 Szczepek W, Luniewski W, Kaczmarek L, et aL 2006.A process for preparation of imatinib base. W0 2006071130(本专利申请人为: Instytut Farmaceutyczny, Pol)
【3】 Szakacs Z,Beni S,VargaZ,et aL 2005. Acid-base profiling of imatinib(gleevec) and its fragments. J Med Chem,8(1): 249一255
【4】 Zimmermann J.Buchdunger E, Mett H, et aL 1997. Potent and selective inhibitors of the abl-kinase: phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett,7(2): 187～191
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 47518 2-Amino-4-nitrotoluene; 5-Nitro-o-toluidine; 4-Nitro-2-aminotoluene; 2-methyl-5-nitrophenylamine; 2-methyl-5-nitroaniline 99-55-8 C7H8N2O2 详情 详情
(II) 47517 N-(2-methyl-5-nitrophenyl)guanidine 152460-07-6 C8H10N4O2 详情 详情
(III) 47516 (E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one 123367-26-0 C10H12N2O 详情 详情
(IV) 47519 N-(2-methyl-5-nitrophenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine; N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidinamine 152460-09-8 C16H13N5O2 详情 详情
(V) 47520 4-methyl-N(3)-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine; N-(5-amino-2-methylphenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine 152460-10-1 C16H15N5 详情 详情
(VI) 49112 4-(Chloromethyl)benzoyl chloride; p-(Chloromethyl)benzoyl chloride 876-08-4 C8H6Cl2O 详情 详情
(VII) 66476 4-(chloromethyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide 404844-11-7 C24H20ClN5O 详情 详情
(VIII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线78

该中间体在本合成路线中的序号：(III)

Reaction of 2,4-difluoronitrobenzene (I) with liquid ammonia gives 5-fluoro-2-nitroaniline (IIa) , which by subsequent displacement of the remaining fluoride group with N-methylpiperazine (III) in the presence of Et3N in NMP at 100 °C provides the piperazinyl aniline (IV) . Alternatively, nitroaniline (IV) can be prepared by condensation of 5-chloro-2-nitroaniline (IIb) with N-methylpiperazine (III) in hot EtOH , ethylene glycol or aqueous NaCl, optionally in the presence of NaOH . Catalytic hydrogenation of nitroaniline (IV) over Pd/C in EtOH at 40-45 °C yields the phenyldiamine (V) , wh ich by condensa t ion with ethyl 3-ethoxy-3-iminopropionate hydrochloride (VI) at reflux produces benzimidazole (VII) . Cyclocondensation of ethyl ester (VII) with 2-amino-6-fluorobenzonitrile (VIII) by means of LiHMDS , KHMDS or t-BuOK in THF or toluene furnishes dovitinib (IX ) , which is finally treated with racemic lactic acid in EtOH/H2O .

参考文献 中间体
合成目标
【1】 Machajewski, T., Shafer, C., McCrea, B. et al. (Novartis Vaccines and Diagnostics, Inc.). Quinolone derivatives. EP 1317442, EP 1650203, EP 1849782, JP 2004509112, US 2002107392, US 6605617, WO 2002022598.
【2】 Harrison, S.D., Shafer, C.M., Pecchi, S. et al. (Novartis Vaccines and Diagnostics, Inc.). Benzimidazole quinolines and uses thereof. EP 1539754, JP 2006503919, JP 2011162563, US 200409235, US 2013018058, WO 2004018419.
【3】 Renhowe, P.A., Pecchi, S., Machajewski, T.D. (Novartis Vaccines and Diagnostics, Inc.). Quinolone derivatives. JP 2005527587, US 2003028018, WO 2003087095.
【4】 Cai, S., Chou, J., Harwood, E., Machajewski, T.D., Ryckman, D., Shang, X., Zhu, S. (Novartis Vaccines and Diagnostics, Inc.). Pharmaceutically acceptable salts of quinolinone compounds having improved pharmaceutical properties. CN 102225926, EP 1699421, JP 2007522098, JP 2011042687, WO 2005046589.
【5】 Renhowe, P.A., Pecchi, S., Shafer, C.M. et al. Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: A novel class of receptor tyrosine kinase inhibitors. J Med Chem 2009, 52(2): 278-92.
【6】 Calvin, G., Harwood, E., Ryckman, D., Zhu, S. (Novartis AG). Methods for synthesizing heterocyclic compounds. EP 1888556, EP 2465857, JP 2008540675, US 2011046376, US 8222413, WO 2006125130.
【7】 Okhamafe, A., Chou, J., Gullapalli, R., Harwood, E., Ryckman, D., Zhu, S.,Shang, X. (Novartis Corp.). Crystalline and other forms of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one lactic acid salts. CN 102070614, EP 1904480, EP 2266974, EP 2270000, JP 200854289, US 2011178097, US 2012208825, WO 2006127926.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIa) 67969 5-fluoro-2-nitroaniline 2369-11-1 C6H5FN2O2 详情 详情
(IIb) 15709 5-chloro-2-nitrophenylamine; 5-chloro-2-nitroaniline 1635-61-6 C6H5ClN2O2 详情 详情
(I) 32036 2,4-difluoro-1-nitrobenzene 446-35-5 C6H3F2NO2 详情 详情
(III) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IV) 67970 5-(4-methylpiperazin-1-yl)-2-nitroaniline 　 C11H16N4O2 详情 详情
(V) 31430 2-amino-4-(4-methyl-1-piperazinyl)phenylamine; 4-(4-methyl-1-piperazinyl)-1,2-benzenediamine 54998-08-2 C11H18N4 详情 详情
(VI) 67971 ethyl 3-ethoxy-3-iminopropionate hydrochloride 2318-25-4 C7H13NO3.HCl 详情 详情
(VII) 67972 ethyl 2-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)acetate 　 C16H22N4O2 详情 详情
(VIII) 13857 5-Amino-2-fluorobenzonitrile; 2-Amino-6-fluorobenzonitrile 77326-36-4 C7H5FN2 详情 详情
(IX) 67973 4-amino-5-fluoro-3-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)quinolin-2(1H)-one 405169-16-6 C21H21FN6O 详情 详情

合成路线79

该中间体在本合成路线中的序号：(VII)

Oxidation of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (I) with 3-chlorobenzoyl peroxide in CH2Cl2 gives the sulfonyl derivative (II), which is alkynylated with phenylacetylenyl magnesium bromide (III) in THF to provide 4,6-dichloro-2-(phenylethynyl)pyrimidine (IV). Condensation of the dichloropyrimidine derivative (IV) with 5-methyl-3-aminopyrazole (V) by means of NaI and DIEA in DMA at 90 °C affords amine (VI), which is coupled with N-methylpiperazine (VII) in the presence of DMAP and DIEA in 1,4-dioxane at 100 °C to furnish the piperazinyl derivative (VIII). Reduction of alkyne (VIII) by means of LiAlH4 in THF gives alkene (IX), which is finally treated with sodium potassium tartrate .

参考文献 中间体
合成目标
【1】 Xiao, X.-Y., Patel, D.V., Ward, J.S., Bray, M.R., Agoston, G.E., Treston, A.M.(Miikana Therapeutics, Inc.). Substituted pyrazole compounds. EP 1928456, JP 2009510107, US 2007142368, WO 2007041358.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 65246 4,6-Dichloro-2-(methylthio)pyrimidine；4,6-dichloro-2-(methylsulfanyl)pyrimidine 6299-25-8 C5H4Cl2N2S 详情 详情
(II) 65247 4,6-Dichloro-2-(methylsulfonyl)pyrimidine; 2-(Methylsulfonyl)-4,6-Dichloropyrimidine; NSC 45040 4489-34-3 C5H4Cl2N2O2S 详情 详情
(III) 32758 bromo(2-phenylethynyl)magnesium；phenylacetylenyl magnesium bromide;(phenylethynyl)magnesium bromide C8H5BrMg 详情 详情
(IV) 68677 4,6-dichloro-2-(phenylethynyl)pyrimidine 　 C12H6Cl2N2 详情 详情
(V) 68679 5-methyl-3-aminopyrazole;3-Amino-5-methylpyrazole;3-Methyl-1H-pyrazol-5-amine 31230-17-8 C4H7N3 详情 详情
(VI) 68678 6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-2-(phenylethynyl)pyrimidin-4-amine 　 C16H12ClN5 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(VIII) 68680 N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-(phenylethynyl)pyrimidin-4-amine 　 C21H23N7 详情 详情
(IX) 68681 N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine;6-(4-Methyl-1-piperazinyl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(1E)-2-phenylethenyl]-4-pyrimidinamine 934353-76-1 C21H25N7 详情 详情

合成路线80

该中间体在本合成路线中的序号：(VII)

Treatment of cinnamonitrile (X) with HCl in toluene/EtOH gives the O-ethyl imidate.HCl (XI), which is aminated by means of methanolic ammonia in EtOH to provide amidine (XII). Cyclization of compound (XII) with dimethylmalonate (XIII) in the presence of NaOMe in MeOH at 90 °C affords the pyrimidindione (XIV), which is chlorinated with POCl3 to generate the dichloro derivative (XV). Coupling of dichloro compound (XV) with 5-methyl-3-aminopyrazole (V) by means of NaI and DIEA in DMA at 90 °C affords the secondary amine (XVI), which is finally condensed with Nmethylpiperazine (VII) to give the free base (IX) .

参考文献 中间体
合成目标
【1】 Xiao, X.-Y., Patel, D.V., Ward, J.S., Bray, M.R., Agoston, G.E., Treston, A.M.(Miikana Therapeutics, Inc.). Substituted pyrazole compounds. EP 1928456, JP 2009510107, US 2007142368, WO 2007041358.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 68679 5-methyl-3-aminopyrazole;3-Amino-5-methylpyrazole;3-Methyl-1H-pyrazol-5-amine 31230-17-8 C4H7N3 详情 详情
(VII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IX) 68681 N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine;6-(4-Methyl-1-piperazinyl)-N-(5-methyl-1H-pyrazol-3-yl)-2-[(1E)-2-phenylethenyl]-4-pyrimidinamine 934353-76-1 C21H25N7 详情 详情
(X) 68682 Cinnamonitrile;E-3-Phenyl-2-propenenitriletrans-Cinnamonitrile 1885-38-7 C9H7N 详情 详情
(XI) 68683 ethyl cinnamimidate hydrochloride 　 C11H13NO.HCl 详情 详情
(XII) 68684 cinnamimidamide 　 C9H10N2 详情 详情
(XIII) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(XIV) 68685 (E)-2-styrylpyrimidine-4,6(1H,5H)-dione 　 C12H10N2O2 详情 详情
(XV) 68686 (E)-4,6-dichloro-2-styrylpyrimidine 　 C12H8Cl2N2 详情 详情
(XVI) 68687 (E)-6-chloro-N-(5-methyl-1H-pyrazol-3-yl)-2-styrylpyrimidin-4-amine 　 C16H14ClN5 详情 详情

合成路线81

该中间体在本合成路线中的序号：(III)

Bromination of 1-methyl-4-nitro-2-(trifluoromethyl)benzene (I) with NBS in the presence of AIBN in refluxing CCl4 gives the corresponding bromomethyl derivative (II), which is condensed with 1-methylpiperazine (III) by means of Et3N in CH2Cl2 to afford 1-methyl-4-[4-nitro-2-(trifluoromethyl)benzyl]piperazine (IV). Reduction of compound (IV) with Na2S2O4 in refluxing acetone/H2O yields the aniline (V), which by coupling with 3-iodo-4-methylbenzoyl chloride (VI) (prepared by chlorinating acid [VII] with SOCl2 at reflux) in the presence of DIEA and DMAP in THF provides the corresponding amide (VIII). Finally, the iodobenzene derivative (VIII) is submitted to Sonogashira coupling with 3-ethynylimidazo[1,2-b]pyridazine (IX) by means of CuI, Pd(PPh3)4 and DIEA in DMF .
Intermediate (IX) is prepared by Sonogashira coupling of 3-bromoimidazo[1,2-b]pyridazine (X) with trimethylsilyl acetylene (XI) in the presence of CuI, PdCl2(PPh3)4 and DCHA in acetonitrile at 80 °C or CuI, Pd(PPh3)4 and DIEA in DMF to give 3-[(trimethylsilyl)ethynyl]imidazo[1,2-b]pyridazine (XII), which is deprotected by cleaving the trimethylsilyl moiety by means of TBAF in THF .

参考文献 中间体
合成目标
【1】 Huang, W.S., Metcalf, C., Sundaramoorthi, R. et al. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-Abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem 2010, 53(12): 4701-19.
【2】 Zou, D., Huang, W.-S., Thomas, R.M. et al. (Ariad Pharmaceuticals, Inc.).Bicyclic heteroaryl compounds. EP 1973545, JP 2009521462, US 2007191376, WO 2007075869.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 68863 1-methyl-4-nitro-2-(trifluoromethyl)benzene 　 C8H6F3NO2 详情 详情
(II) 68864 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene 　 C8H5BrF3NO2 详情 详情
(III) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情
(IV) 68865 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine 　 C13H16F3N3O2 详情 详情
(V) 68866 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline 694499-26-8 C13H18F3N3 详情 详情
(VI) 68867 3-iodo-4-methylbenzoyl chloride 　 C8H6ClIO 详情 详情
(VII) 68868 3-iodo-4-methylbenzoic acid 　 C8H7IO2 详情 详情
(VIII) 68869 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide 　 C21H23F3IN3O 详情 详情
(IX) 68870 3-ethynylimidazo[1,2-b]pyridazine 　 C8H5N3 详情 详情
(X) 68871 3-bromoimidazo[1,2-b]pyridazine 18087-73-5 C6H4BrN3 详情 详情
(XI) 23897 ethynyl(trimethyl)silane；trimethylsilyl acetylene 1066-54-2 C5H10Si 详情 详情
(XII) 68872 3-[(trimethylsilyl)ethynyl]imidazo[1,2-b]pyridazine 　　 C11H13N3Si 详情 详情
Extended Information