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【结 构 式】

【分子编号】10355

【品名】Diethylenediamine; Piperazine

【CA登记号】110-85-0

【 分 子 式 】C4H10N2

【 分 子 量 】86.13688

【元素组成】C 55.78% H 11.7% N 32.52%
与该中间体有关的原料药合成路线共 69 条
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合成路线1

该中间体在本合成路线中的序号：(X)

The condensation of 2,4-dichloro-5-fluorobenzoyl chloride (I) with diethyl malonate (II) by means of magnesium ethoxide in ether gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate (III), which is partially hydrolyzed and decarboxylated with p-toluenesulfonic acid water yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate (IV). The condensation of (IV) with triethyl orthoformate (V) in refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate (VI), which is treated with cyclopropylamine (VII) in ethanol to give ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-cyclopropylaminoacrylate (VIII). The cyclization of (VIII) with NaH in refluxing dioxane yields 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IX), which is finally condensed with piperazine (X) in hot DMSO.

参考文献 中间体
合成目标
【1】 Reddy, P.G.; Baskaran, S.; Microwave assisted amination of quinolone carboxylic acids: An expeditious synthesis of fluoroquinolone antibacterials. Tetrahedron Lett 2001, 42, 38, 6775.
【2】 Grohe, K.; Zeiler, H. J.; Metzger, K.G. (Bayer AG); 1-Cyclopropyl-6-fluoro-1,4-dihidro-4-oxo-7-piperazino-quinoline-3-carboxilic acids, process for their preparation and antibacterial agents containing them. EP 0078362; JP 4253963; JP 58074667 .
【3】 Serradell, M.N.; Castaner, J.; Ciprofloxacin. Drugs Fut 1984, 9, 3, 179.
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) 22093 2,4-dichloro-5-fluorobenzoyl chloride 86393-34-2 C7H2Cl3FO 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(III) 22095 diethyl 2-(2,4-dichloro-5-fluorobenzoyl)malonate C14H13Cl2FO5 详情 详情
(IV) 22096 ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate C11H9Cl2FO3 详情 详情
(V) 21304 Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether 122-51-0 C7H16O3 详情 详情
(VI) 22098 ethyl (Z)-2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxy-2-propenoate C14H13Cl2FO4 详情 详情
(VII) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VIII) 22100 ethyl (E)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl)-2-propenoate C15H14Cl2FNO3 详情 详情
(IX) 30340 ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate 86483-54-7 C15H13ClFNO3 详情 详情
(X) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The reaction of cyclohexylamine (I) with chloroacetyl chloride (II) in water in the presence of sodium hydroxide gives N-cyclohexyl-2-chloro-acetamide (III), which by reaction with piperazine (IV) in water is converted to N-[(N-cyclohexylcarbamoyl)methyl]piperazine (V). This compound is then treated with one equivalent of HCl.

参考文献 中间体
合成目标
【1】 Corvi-Mora, C. (Camillo Corvi SpA); N-Cyclohexyl-piperazino acetamides and propionamides. US 4123530; US 4278796 .
【2】 de Angelis, L.; Esaprazole hydrochloride. Drugs Fut 1986, 11, 4, 263.
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) 17966 cyclohexanamine; cyclohexyl amine; cyclohexylamine 108-91-8 C6H13N 详情 详情
(II) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(III) 27377 2-chloro-N-cyclohexylacetamide C8H14ClNO 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 27378 N-cyclohexyl-2-(1-piperazinyl)acetamide C12H23N3O 详情 详情

合成路线3

该中间体在本合成路线中的序号：(V)

The earlier synthesis starts with the reaction of 4-chloro-7-(trifluoromethyl)quinoline (I) with 4-aminobenzoic acid (II) in ethanol-HCl giving 4-(4-carboxyphenylamino)-7-(trifluoromethyl)quinoline (III), which is converted to its acyl chloride (IV) by treatment with SOCl2. The reaction of (IV) with piperazine (V) yields 1-[4-[7-(trifluoromethyl)quinolin-4-ylamino]benzoyl]piperazine (VI), which is finally acylated with 4-fluorobenzenesulfonyl chloride (VII) to give U-54669 F. However, this method is not economically efficient, since the most expensive compound [quinoline (I)] is already used in the first step of the synthesis.

参考文献 中间体
合成目标
【1】 McCall, J.M. (Pharmacia Corp.); Aminoquinolines. GB 2021567 .
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) 20003 4-chloro-7-(trifluoromethyl)quinoline 346-55-4 C10H5ClF3N 详情 详情
(II) 20004 p-aminobenzoic acid; 4-aminobenzoic acid 150-13-0 C7H7NO2 详情 详情
(III) 20005 4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoic acid C17H11F3N2O2 详情 详情
(IV) 20006 4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl chloride C17H10ClF3N2O 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 20008 1-piperazinyl(4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl)methanone C21H19F3N4O 详情 详情
(VII) 12292 4-Fluorobenzenesulfonyl chloride 349-88-2 C6H4ClFO2S 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

The condensation of 4-nitrobenzoyl chloride (I) with piperazine (II) in water by means of KOH gives 4-nitrobenzoylpiperazine (III), which is reduced with H2 over Pd/C in methanol yielding 4-aminobenzoyl piperazine (IV). The condensation of (IV) with 4-chloro-7-trifluoromethylquinoline (V) by means of HCl in refluxing ethanol affords 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (VI), which is finally acylated with 4-fluorobenzenesulfonyl chloride (VII) by means of triethylamine in THF.

参考文献 中间体
合成目标
【1】 McCall, J.M. (Pharmacia Corp.); Aminoquinolines. GB 2021567 .
【2】 Castaner, J.; Serradell, M.N.; U-54669-F. Drugs Fut 1984, 9, 1, 36.
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) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 20011 (4-nitrophenyl)(1-piperazinyl)methanone C11H13N3O3 详情 详情
(IV) 20014 (4-aminophenyl)(1-piperazinyl)methanone C11H15N3O 详情 详情
(V) 20003 4-chloro-7-(trifluoromethyl)quinoline 346-55-4 C10H5ClF3N 详情 详情
(VI) 20008 1-piperazinyl(4-[[7-(trifluoromethyl)-4-quinolinyl]amino]phenyl)methanone C21H19F3N4O 详情 详情
(VII) 12292 4-Fluorobenzenesulfonyl chloride 349-88-2 C6H4ClFO2S 详情 详情

合成路线5

该中间体在本合成路线中的序号：(I)

The acylation of piperazine (I) with 1,4-benzodioxan-2-ylcarbonyl chloride (II) by means of sodium acetate in water-acetone gives N-(1,4-benzodioxan-2-carbonyl)piperazine (III), which is then condensed with 4-amino-2-chloro-6,7-dimethoxyquinazoline (IV) in refluxing butanol.

参考文献 中间体
合成目标
【1】 Campbell, S.F. (Pfizer Inc.); Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines. DE 2847623; FR 24079529; US 4188390 .
【2】 Serradell, M.N.; Castaner, J.; Blancafort, P.; Doxazosin. Drugs Fut 1982, 7, 12, 877.
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(II) 32160 2,3-dihydro-1,4-benzodioxine-2-carbonyl chloride C9H7ClO3 详情 详情
(III) 32161 2,3-dihydro-1,4-benzodioxin-2-yl(1-piperazinyl)methanone C13H16N2O3 详情 详情
(IV) 10443 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine 23680-84-4 C10H10ClN3O2 详情 详情

合成路线6

该中间体在本合成路线中的序号：(X)

The condensation of 2-amino-7-hydroxy-1,8-naphthyridine (I) with 5,6-dihydro-1,7-dithiin-2,3-dicarboxylic acid anhydride (II) in biphenyl-diphenyl ether at 230 C gives 5,7-dioxo-8-(7-hydroxy-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (III), which by reaction with POCl3 at 100 C is converted to the corresponding 7-chloro derivative (IV). Partial reduction of (IV) with KBH4 in methanol yields 6-(7-chloro-1,8-naphthyridin 2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (V), which is condensed with 4-chlorocarbonyl-1-(tert-butoxycarbonyl)piperazin (VI) by means of NaH in DMF affording 5-[(4-tert-butoxycarbonylpiperazin-1-yl)carbonyloxy]-6-(7-chloro-1,8-naphthyndin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (VII) Deprotection of (VII) by means of trifluoroacetic acid gives 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-[(piperazin-1-yl)carbonyloxy]-2,3,6,7-tetrahydro-5H-1,4-dithino[2,3-c]pyrrole (VIII), which is finally acetylated with propionic acid (IX) by means of dicyclohexylcarbodiimide in methylene chloride. The piperazine derivative (VI) is prepared as follows: The condensation of piperazine (X) with tert-butyl azidoformate (XI) in aqueous HCl gives 1-(tert-butoxycarbonyl)piperazine (XII), which is then condensed with phosgene in anhydrous toluene.

参考文献 中间体
合成目标
【1】 Cotrel, C.; Crisan, C.; Jeanmart, C.; Messer, M.N. (Aventis Pharma SA); Heterocyclic compounds. BE 0835325; DE 2550111; FR 2313060; FR 2322600; FR 2322601; FR 2322602; GB 1468497; JP 7670776; JP 7733685; JP 7998790; JP 8040671; JP 8051087; US 4220646 .
【2】 Serradell, M.N.; Castaner, J.; Suproclone. Drugs Fut 1985, 10, 1, 45.
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) 28994 7-amino[1,8]naphthyridin-2-ol C8H7N3O 详情 详情
(II) 28995 2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione C6H5NO2S2 详情 详情
(III) 28996 6-(7-hydroxy[1,8]naphthyridin-2-yl)-2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione C14H9N3O3S2 详情 详情
(IV) 28997 6-(7-chloro[1,8]naphthyridin-2-yl)-2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione C14H8ClN3O2S2 详情 详情
(V) 28998 6-(7-chloro[1,8]naphthyridin-2-yl)-7-hydroxy-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-one C14H10ClN3O2S2 详情 详情
(VI) 28999 tert-butyl 4-(chlorocarbonyl)-1-piperazinecarboxylate C10H17ClN2O3 详情 详情
(VII) 29000 1-(tert-butyl) 4-[6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-yl] 1,4-piperazinedicarboxylate C24H26ClN5O5S2 详情 详情
(VIII) 29001 6-(7-chloro[1,8]naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-[1,4]dithiino[2,3-c]pyrrol-5-yl 1-piperazinecarboxylate C19H18ClN5O3S2 详情 详情
(IX) 20178 propionic acid 79-09-4 C3H6O2 详情 详情
(X) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(XI) 29002 2-[(azidocarbonyl)oxy]-2-methylpropane C5H9N3O2 详情 详情
(XII) 13225 N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18N2O2 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

By condensation of 2-chloro-6-nitroquinoline (I) with piperazine in refluxing xylene.

参考文献 中间体
合成目标
【1】 Mebius, E.J. (Duphar International Research BV); Farmacologisch wekzame 2-(1-piperazinyl)-chinolinederivaten. NL 7904723 .
【2】 Castaner, J.; Serradell, M.N.; Owen, R.T.; DU-24565. Drugs Fut 1985, 10, 5, 385.
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) 29328 2-chloro-6-nitroquinoline C9H5ClN2O2 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线8

该中间体在本合成路线中的序号：(II)

The reaction of cyclopropylmethyl chloride or cyclopropylmethyl bromide (Ia-b) with piperazine (II) by means of Na2CO3 in anhydrous DMF gives N,N-dicyclopropylmethylpiperazine.

参考文献 中间体
合成目标
【1】 Robba, M.F.; Aurousseau, M.E. (Laboratoire Innothera SA); Cyclopropylmethyl piperazines, the process for preparing the same and their use in therapeutics. CA 1171085; EP 81401516; FR 8021527; JP 163681; US 4474783 .
【2】 Leclerc, G.; INO-2628 CZ. Drugs Fut 1985, 10, 11, 907.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Ib) 22277 Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane 7051-34-5 C4H7Br 详情 详情
(Ia) 29776 1-(chloromethyl)cyclopropane 5911-08-0 C4H7Cl 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

By condensation of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (I) with piperazine (II) by heating at 170 C in water in a pressure tube.

参考文献 中间体
合成目标
【1】 Blancafort, P.; Sweetman, A.J.; Castaner, J.; Serradell, M.N.; AM-715. Drugs Fut 1981, 6, 8, 462.
【2】 Irikura, T. (Kyorin Pharmaceutical Co., Ltd.); Piperazinyl derivs. of quinoline carboxylic acids. US 4146719 .
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) 32076 7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 68077-26-9 C12H9ClFNO3 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线10

该中间体在本合成路线中的序号：(I)

The total synthesis of picumast dihydrochloride has been described: The alkylation of piperazine (I) with 4-chlorobenzyl chloride (II) in ethanol gives 1-(4-chlorobenzyl)piperazine (III), which is alkylated again with 1-bromo-3-chloropropane (IV) by means of triethylamine in a suitable solvent to yield 1-(4-chlorobenzyl)-4-(3-chloropropyl)piperazine (V). Finally, this compound is condensed with 7-hydroxy-3,4-dimethylcoumarin (VI) by means of K2CO3 in refluxing butanone. Compound (VI) is obtained by cyclization of resorcinol (VII) with ethyl 2-methylacetoacetate (VIII) by means of refluxing acetic acid containing HCl.

参考文献 中间体
合成目标
【1】 Witte, E.-C.; Chemical synthesis of picumast dihydrochloride. Arzneim-Forsch Drug Res 1989, 39, 10a, 1309.
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(II) 10356 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride 104-83-6 C7H6Cl2 详情 详情
(III) 10357 1-(4-Chlorobenzyl)piperazine; N-(4-Chlorobenzyl)piperazine C11H15ClN2 详情 详情
(IV) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(V) 10359 1-(4-Chlorobenzyl)-4-(3-chloropropyl)piperazine C14H20Cl2N2 详情 详情
(VI) 10360 3,4-Dimethylumbelliferone; 7-Hydroxy-3,4-dimethyl-2H-chromen-2-one 2107-78-0 C11H10O3 详情 详情
(VII) 10361 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol 108-46-3 C6H6O2 详情 详情
(VIII) 10362 ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate 609-14-3 C7H12O3 详情 详情

合成路线11

该中间体在本合成路线中的序号：(A)

The condensation of 11-amino-2-chlorodibenzo[b,f][1,4]oxazepine (IV) with piperazine (A) by means of aluminum chloride at 100 C.

参考文献 中间体
合成目标
【1】 Howell, C.F.; et al.; Nouveau procédé pour la préparation des 11-tert-aminodibenz[b,f][1,4]oxazépines et thiazépines. DE 1645954; ES 335760; FR 1508536; US 3444169 .
【2】 Playle, A.C.; Castaner, J.; Amoxapine. Drugs Fut 1976, 1, 11, 511.
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(IV) 34090 2-chlorodibenzo[b,f][1,4]oxazepin-11-amine; 2-chlorodibenzo[b,f][1,4]oxazepin-11-ylamine C13H9ClN2O 详情 详情

合成路线12

该中间体在本合成路线中的序号：(II)

Condensation of bis(4-fluorophenyl)methyl 2-chloroethyl ether (I) with piperazine (II) in refluxing toluene afforded the monosubstituted piperazine (III). This was then alkylated with (3-bromopropyl)benzene (IV) in boiling EtOH to furnish the title compound.

参考文献 中间体
合成目标
【1】 Gootjes, J. (Gist-Brocades NV); Piperazine derivs., process for their preparation and their use. DE 2755752; US 4202896 .
【2】 Van der Zee, P.; et al.; Aryl 1,4-dialk(en)ylpiperazines as selective and very potent inhibitors of dopamine uptake. Eur J Med Chem 1980, 15, 4, 363.
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) 54931 1-[(2-chloroethoxy)(4-fluorophenyl)methyl]-4-fluorobenzene; bis(4-fluorophenyl)methyl 2-chloroethyl ether C15H13ClF2O 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 54932 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazine; bis(4-fluorophenyl)methyl 2-(1-piperazinyl)ethyl ether C19H22F2N2O 详情 详情
(IV) 20884 1-(3-bromopropyl)benzene 637-59-2 C9H11Br 详情 详情

合成路线13

该中间体在本合成路线中的序号：(II)

1-(3-Phenylpropyl)piperazine (III) has been obtained by condensation of 3-phenylpropyl bromide (I) with piperazine (II) in refluxing acetonitrile. The condensation of bis(4-fluorophenyl)methanol (IV) with 2-chloroethanol (V) by means of sulfuric acid gives the 2-chloroethyl bis(4-fluorophenyl)methyl ether (VI), which si treated with NaI to yield the corresponding iodo derivative (VII). Finally this compound is condensed with the intermediate piperazine (III) by means of aq. Na2CO3 to afford the target disubstituted piperazine.

参考文献 中间体
合成目标
【1】 Zhang, J.; Ironside, M.D.; Sugathapala, P.M.; Robertson, J.; Darey, M.C.P.; Scale-up synthesis of the dopamine uptake inhibitor GBR-12909. Org Process Res Dev 2002, 6, 5, 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
(I) 20884 1-(3-bromopropyl)benzene 637-59-2 C9H11Br 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 38636 1-(3-phenylpropyl)piperazine C13H20N2 详情 详情
(IV) 41974 4,4'-Difluorobenzhydrol; bis(4-Fluorophenyl)methanol; alpha-(4-fluorophenyl)benzenemethanol; 4-fluoro-alpha-(4-fluorophenyl)benzenemethanol 365-24-2 C13H10F2O 详情 详情
(V) 10384 2-Chloro-1-ethanol; Ethylene chlorohydrin 107-07-3 C2H5ClO 详情 详情
(VI) 54931 1-[(2-chloroethoxy)(4-fluorophenyl)methyl]-4-fluorobenzene; bis(4-fluorophenyl)methyl 2-chloroethyl ether C15H13ClF2O 详情 详情
(VII) 56868 bis(4-fluorophenyl)methyl 2-iodoethyl ether; 1-fluoro-4-[(4-fluorophenyl)(2-iodoethoxy)methyl]benzene C15H13F2IO 详情 详情

合成路线14

该中间体在本合成路线中的序号：(IV)

1) The acylation of 2,6-dimethylaniline (II) with chloroacetyl chloride by means of triethylamine in dichloromethane gives N-(2,6-dimethylphenyl) chloroacetamide (III), which is condensed with piperidine (IV) in refluxing ethanol to yield N-(2,6-dimethylphenyl)-2-piperazinoacetamide IV). Finally, this compound is condensed with 3-(2-methoxyphenoxy)-12-epoxypropane (VI) in refluxing methanol toluene.

参考文献 中间体
合成目标
【1】 Ainsworth, A.T.; Smith, D.G. (SmithKline Beecham plc); Ethanamine derivs., their preparation and use in pharmaceutical compsns. EP 0023385 .
【2】 Prous, J.; Castaner, J.; RANOLAZINE < Rec INN; USAN >. Drugs Fut 1988, 13, 9, 837.
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(II) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(III) 24100 2-chloro-N-(2,6-dimethylphenyl)acetamide 2198-53-0 C10H12ClNO 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 24102 N-(2,6-dimethylphenyl)-2-(1-piperazinyl)acetamide C14H21N3O 详情 详情
(VI) 24103 2-[(2-methoxyphenoxy)methyl]oxirane C10H12O3 详情 详情

合成路线15

该中间体在本合成路线中的序号：(IV)

2) The condensation of epoxide (VI) with piperazine (IV) in refluxing isopropanol gives 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]piperazine (VII), which is then condensed with chloroacetamide (III) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Ainsworth, A.T.; Smith, D.G. (SmithKline Beecham plc); Ethanamine derivs., their preparation and use in pharmaceutical compsns. EP 0023385 .
【2】 Prous, J.; Castaner, J.; RANOLAZINE < Rec INN; USAN >. Drugs Fut 1988, 13, 9, 837.
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) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(II) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(III) 24100 2-chloro-N-(2,6-dimethylphenyl)acetamide 2198-53-0 C10H12ClNO 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 24103 2-[(2-methoxyphenoxy)methyl]oxirane C10H12O3 详情 详情
(VII) 24109 1-(2-methoxyphenoxy)-3-(1-piperazinyl)-2-propanol C14H22N2O3 详情 详情

合成路线16

该中间体在本合成路线中的序号：(VI)

Reaction of the dicarboxylic acid (I) with thionyl chloride in hot toluene gives the di-acid chloride (II). Treatment of (II) with Cl2 in CH2Cl2 gives the sulfenyl chloride (III), which upon reaction with NH4OH affords the benzisothiazole (IV). Chlorination of (IV) in heat POCl3 yields the chlorobenzisothiazole (V). Reaction of (V) and piperazine (VI) in excess molten pipeazine gives the monosubstituted piperazine (VII). Reaction of (VII) with the dibromide (VIII) in refluxing ethanol yields the spiroquaternary (IX). Finally, BMY-13859-1 is obtained by treatment of (IX) with the glutarimide (X) in refluxing xylene followed by treatment with HCl in isopropanol.

参考文献 中间体
合成目标
【1】 Eison, M.S.; Taylor, D.P.; New, J.S.; Minielli, J.L.; BMY-13859. Drugs Fut 1985, 10, 9, 731.
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) 10404 Ethyl vanillin; 3-Ethoxy-4-hydroxybenzaldehyde 121-32-4 C9H10O3 详情 详情
(II) 10405 2-Chloro-2-[3-ethoxy-4-(pentyloxy)phenyl]acetonitrile C15H20ClNO2 详情 详情
(III) 28018 2-(chlorosulfanyl)benzoyl chloride C7H4Cl2OS 详情 详情
(IV) 16278 1,2-benzisothiazol-3(2H)-one; 1,2-Benzisothiazolin-3-one 2634-33-5 C7H5NOS 详情 详情
(V) 16279 3-chloro-1,2-benzisothiazole C7H4ClNS 详情 详情
(VI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VII) 16280 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) 87691-87-0 C11H13N3S 详情 详情
(VIII) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(IX) 28019 8-(1,2-benzisothiazol-3-yl)-8-aza-5-azoniaspiro[4.5]decane bromide C15H20BrN3S 详情 详情
(X) 28020 8-azaspiro[4.5]decane-7,9-dione 1075-89-4 C9H13NO2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(I)

The condensation of piperazine (I) with [14C]-labeled 2-chloropyrimidine (II) in refluxing ethanol gives the labeled 1-(2-pyrimidinyl)piperazine (III), which is then condensed with the N-(4-bromobutyl)imide (IV) by means of K2CO3 and KI as before, affording SM-3997 labeled at the pyrimidine ring.

参考文献 中间体
合成目标
【1】 Kanamaru, H.; Nishioka, K.; 14C-labeling of a novel anxiolytic agent tandospirone. J Label Compd Radiopharm 1992, 31, 6, 427.
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(II) 11191 2-Chloropyrimidine 1722-12-9 C4H3ClN2 详情 详情
(II) 45056 2-chloropyrimidine C4H3ClN2 详情 详情
(III) 11175 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine 20980-22-7 C8H12N4 详情 详情
(III) 45057 2-(1-piperazinyl)pyrimidine C8H12N4 详情 详情
(IV) 11174 (1R,2S,6R,7S)-4-(4-Bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione C13H18BrNO2 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

The reaction of furoyl chloride (I) with piperazine (II) by means of NaOH in water gives N-(2-furoyl)piperazin (III), which is reduced with H2 over Raney-Ni in methanol to afford N-(tetrahydro-2-furoyl)piperazine (IV) . Finally, this compound is condensed with 2-chloro-4-amino-6,7-dimethoxyquinazoline (V) in refluxing methoxyethanol.

参考文献 中间体
合成目标
【1】 Winn, M.; Kyncl, J.; Dunnigan, D.A.; Jones, P.H. (Abbott Laboratories Inc.); Antihypertensive agents. CA 1057754; CH 602712; DE 2646186; FR 2327787; GB 1517403; JP 52048678; US 4026894; US 4112097 .
【2】 Roteman, R. (Abbott Laboratories Inc.); 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride dihydrate. CA 1081229; DE 2831112; FR 2399430; JP 54027588 .
【3】 Thorpe, P.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Terazosin Hydrochloride. Drugs Fut 1983, 8, 1, 45.
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) 26093 2-Furoyl chloride 527-69-5 C5H3ClO2 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 30751 2-furyl(1-piperazinyl)methanone; 2-Furoyl-1-piperazine 40172-95-0 C9H12N2O2 详情 详情
(IV) 30752 1-piperazinyl(tetrahydro-2-furanyl)methanone; 1-(Tetrahydro-2-furoyl)piperazine 63074-07-7 C9H16N2O2 详情 详情
(V) 10443 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine 23680-84-4 C10H10ClN3O2 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XI)

2) The condensation of quinoline (IX) with piperazine (XI) by heating at 140 C as before gives 1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-3-carboxylic acid (XII), which is finally treated with ethyl iodide and triethylamine in hot DMF.

参考文献 中间体
合成目标
【1】 Grohe, K.; Petersen, U.; Kuck, K.-H. (Bayer AG); Antimicrobial agent of quinolone-carboxylic acid b. DE 3248507; US 4563459 .
【2】 Grohe, K.; Klimetzek, V.; Metzger, K.G.; Stunkel, K.G.; Zeiler, H.-J. (Bayer AG); Immunostimulant agent. AU 8542762; DE 3420116; EP 0165474; ES 8607020; JP 1985258163; US 4659603 .
【3】 Castaner, J.; Prous, J.; Enrofloxacin. Drugs Fut 1988, 13, 4, 305.
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) 10925 Iodoethane;ethyl iod 75-03-6 C2H5I 详情 详情
(IX) 22101 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 86393-33-1 C13H9ClFNO3 详情 详情
(XI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(XII) 22103 1-cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-3-quinolinecarboxylic acid 85721-33-1 C17H18FN3O3 详情 详情

合成路线20

该中间体在本合成路线中的序号：(IX)

This compound can be prepared by two related ways: 1) The reaction of 2-nitrobenzoic acid (I) with PCl5 at 50 C gives the corresponding acyl chloride (II), which by a Friedel-Craft's condensation with benzene and AlCl3 yields 2-nitrobenzophenone (III). The reduction of (III) with H2 over Pd/C in ethanol affords 2-aminobenzophenone (IV), which is acylated with acetic anhydride sodium acetate to give 2-acetamidobenzophenone (V). The cyclization of (V) by means of sodium methoxide in refluxing ethanol yields 4-phenylquinoline-2(1H)-one (VI), which by reaction with SOCl2-DMF in hot CHCl3 is converted to 2-chloro-4-phenylquinoline (VII). Finally, this compound is condensed with N-ethylpiperazine (VIII) at 130 C. 2) Quinoline (VII) is condensed with piperazine (IX) as before to give 4-phenyl-2-(1-piperazinyl)quinoline (X), which is finally alkylated with ethyl iodide and sodium carbonate in refluxing butanone.

参考文献 中间体
合成目标
【1】 Uno, H.; Nagai, Y.; Karasawa, T.; Furukawa, K. (Dainippon Pharm. Co.; Ltd.); 2-(4-Ethyl-1-piperazinyl)-4-phenylquinoline and its salts with acids, process for their preparation and their use as antidepressant agents. DE 2912414 .
【2】 Uno, H.; Nagai, Y.; Hino, K.; Kawashima, K.; Oka, M.; Matsumoto, J.; A novel class of antiulcer agents. 4-Phenyl-2-(1-piperazinyl)quinolines. Chem Pharm Bull 1989, 37, 1, 110.
【3】 Prous, J.; Castaner, J.; AD-2646. Drugs Fut 1989, 14, 8, 735.
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) 20951 2-nitrobenzoic acid；o-Nitrobenzoic acid 552-16-9 C7H5NO4 详情 详情
(II) 21099 o-nitrobenzoyl chloride; 2-nitrobenzoyl chloride 610-14-0 C7H4ClNO3 详情 详情
(III) 21100 (2-nitrophenyl)(phenyl)methanone 2243-79-0 C13H9NO3 详情 详情
(IV) 21101 (2-aminophenyl)(phenyl)methanone; 2-Aminobenzophenone 2835-77-0 C13H11NO 详情 详情
(V) 21102 N-(2-benzoylphenyl)acetamide 85-99-4 C15H13NO2 详情 详情
(VI) 21103 4-phenyl-2(1H)-quinolinone C15H11NO 详情 详情
(VII) 21104 2-chloro-4-phenylquinoline C15H10ClN 详情 详情
(VIII) 14213 N-Ethylpiperazine; 1-Ethylpiperazine 5308-25-8 C6H14N2 详情 详情
(IX) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(X) 21107 4-phenyl-2-(1-piperazinyl)quinoline C19H19N3 详情 详情

合成路线21

该中间体在本合成路线中的序号：(III)

This compound has been obtained by two related ways: 1) The saponification of 2-(5-chloro-2-oxobenzothiazolin-3-yl)acetic acid methyl ester (I) with NaOH in methanol/water gives the corresponding free acid (II), which is condensed with piperazine (III) by means of TiCl4 in THF yielding the acyl piperazine (IV). The nitrosation of (IV) with isoamyl nitrite in dichloromethane affords the N-nitrosopiperazine (V), which is finally reduced with Zn and acetic acid to the target amino derivative. 2) The nitrosation of piperazine (III) with NaNO2 and acetic acid gives 1-nitrosopiperazine (VI), which is reduced with Zn and acetic acid to 1-aminopiperazine (VII). The reaction of (VII) with benzaldehyde affords 1-(benzylideneamino)piperazine (VIII), which is condensed with of 2-(5-chloro-2-oxobenzothiazolin-3-yl)acetic acid (II) by means of SOCl2 and triethylamine in dichloromethane yielding the acyl piperazine (IX). Finally, this compound is debenzylated with hydroxylamine and HCl in acetonitrile/water.

参考文献 中间体
合成目标
【1】 Matsuo, M.; Nakaguchi, O.; Okumura, H.; Tsuji, K.; Ueda, I. (Fujisawa Pharmaceutical Co., Ltd.); N-Containing fused heterocyclic cpds., processes for the preparation thereof and pharmaceutical compsn. comprising the same. EP 0232740; JP 1987181253; US 4797399 .
【2】 Zanka, A.; et al.; Process development of a platelet aggregation inhibitor. Org Process Res Dev 1998, 2, 6, 418.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(I) 35662 methyl 2-[5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl]acetate C10H8ClNO3S 详情 详情
(II) 35663 2-[5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl]acetic acid C9H6ClNO3S 详情 详情
(III) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(IV) 35664 5-chloro-3-[2-oxo-2-(1-piperazinyl)ethyl]-1,3-benzothiazol-2(3H)-one C13H14ClN3O2S 详情 详情
(V) 35665 5-chloro-3-[2-(4-nitroso-1-piperazinyl)-2-oxoethyl]-1,3-benzothiazol-2(3H)-one C13H13ClN4O3S 详情 详情
(VI) 17260 1-nitrosopiperazine C4H9N3O 详情 详情
(VII) 35666 1-piperazinylamine; 1-piperazinamine C4H11N3 详情 详情
(VIII) 35667 N-[(E)-benzylidene]-N-(1-piperazinyl)amine; N-[(E)-benzylidene]-1-piperazinamine C11H15N3 详情 详情
(IX) 35668 5-chloro-3-[2-oxo-2-(4-[[(E)-benzylidene]amino]-1-piperazinyl)ethyl]-1,3-benzothiazol-2(3H)-one C20H19ClN4O2S 详情 详情

合成路线22

该中间体在本合成路线中的序号：(XII)

The cyclization of ethyl cyanoacetate (I) with urea (II) in ethanolic NaOEt provided 6-aminouracil (III). Nitrosation of (III) with NaNO2 in aqueous AcOH, followed by reduction of the resulting nitroso compound (IV) using sodium hydrosulfite gave 5,6-diaminouracil, which was purified by conversion to its hydrochloride salt (V). Condensation of this diamine with melted oxalic acid produced tetrahydroxypteridine (VI). Subsequent reaction of (VI) with PCl5 and POCl3 afforded tetrachlorocompound (VII). The reaction of (VII) with pyrrolidine (VIII) in aqueous KHCO3/CHCl3 resulted in a mixture of 2-, 4-, 7- and 4,7-substituted compounds, from which the desired 4-pyrrolidino-2,6,7-trichloropteridine (IX) was isolated by column chromatography. Further treatment of (IX) with benzylamine (X) in dioxan at r.t. provided diamine (XI). Finally, substitution of the third chlorine atom for piperazine (XII) was accomplished in boiling dioxan.

参考文献 中间体
合成目标
【1】 Merz, K.-H.; Marko, D.; Regiert, T.; Reiss, G.; Frank, W.; Eisenbrand, G.; Synthesis of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potent inhibitors of cAMP-specific phosphodiesterase and of malignant tumor cell growth. J Med Chem 1998, 41, 24, 4733.
【2】 Taylor, E.C. Jr.; Sherman, W.R.; Diaminouracil hydrochloride. Org Synth Coll 1957, 37, 15.
【3】 Schopf, C.; Reichert, R.; Zur kenntnis des leukopterins. Liebigs Ann Chem 1941, 548, 82.
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) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 详情 详情
(II) 19310 urea 57-13-6 CH4N2O 详情 详情
(III) 19311 6-amino-2,4(1H,3H)-pyrimidinedione 873-83-6 C4H5N3O2 详情 详情
(IV) 19312 6-amino-5-nitroso-2,4(1H,3H)-pyrimidinedione C4H4N4O3 详情 详情
(V) 19313 5,6-diamino-2,4(1H,3H)-pyrimidinedione 3240-72-0 C4H6N4O2 详情 详情
(VI) 19314 2,4,6,7-pteridinetetrol C6H4N4O4 详情 详情
(VII) 19315 2,4,6,7-tetrachloropteridine C6Cl4N4 详情 详情
(VIII) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(IX) 19317 2,6,7-trichloro-4-(1-pyrrolidinyl)pteridine C10H8Cl3N5 详情 详情
(X) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(XI) 19319 N-benzyl-N-[2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinyl]amine; N-benzyl-2,6-dichloro-4-(1-pyrrolidinyl)-7-pteridinamine C17H16Cl2N6 详情 详情
(XII) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线23

该中间体在本合成路线中的序号：(IV)

The reaction of 1-bromo-3-chloropropane (I) with thiophenol (II) by means of NaOH in refluxing water gives 1-(phenylthio)-3-chloropropane (III), which is condensed with piperazine (IV) by means of NaOH in refluxing ethanol-water yielding 1-(3-phenylthiopropyl)piperazine (V). Finally, this compound is condensed with 7-(2,3-epoxypropyl)theophylline (VI) in refluxing ethanol.

参考文献 中间体
合成目标
【1】 Favier, C.; Pinhas, H.; Beranger, S.; Pascal, J.-C. (Roche Bioscience); Piperazine derivatives of theophylline. EP 0033674; GB 2069487; JP 56120683; US 4374835 .
【2】 Castaner, R.M.; Castaner, J.; Serradell, M.N.; Tester-Dalderup, C.; Tazifylline Hydrochloride. Drugs Fut 1987, 12, 11, 1036.
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) 12951 Benzenethiol; Phenylmercaptan; Phenylhydrosulfide 108-98-5 C6H6S 详情 详情
(II) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(III) 27778 1-[(3-chloropropyl)sulfanyl]benzene C9H11ClS 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 27779 1-[3-(phenylsulfanyl)propyl]piperazine C13H20N2S 详情 详情
(VI) 27780 1,3-dimethyl-7-(2-oxiranylmethyl)-3,7-dihydro-1H-purine-2,6-dione C10H12N4O3 详情 详情

合成路线24

该中间体在本合成路线中的序号：(VI)

The cyclization of 2-(2,4-dichloro-5-fluorobenzoyl)acetic acid ethyl ester (I) with S-phenyl(cyclopropylimino)chlorothioformate (II) by means of NaH in DMF gives 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-2-(phenylsulfanyl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (III), which is oxidized with MCPBA in dichloromethane, yielding the sulfinyl derivative (IV). The cyclization of (IV) with NaSH and hydroxylamine-O-sulfonic acid in THF affords the isothiazoloquinoline (V), which is finally condensed with piperazine in pyridine to furnish the target compound.

参考文献 中间体
合成目标
【1】 Mohamadi, F.; Spees, M.M.; Grindey, G.B.; Antineoplastic bicyclic sulfonylureas. Bioorg Med Chem Lett 1992, 3, 987-992.
【2】 Chu, D.T.W.; Isothiazoloquinolones: Antibacterial and antineoplastic agents. Drugs Fut 1992, 17, 12, 1101.
【3】 Ehlhardt, W.J.; Woodland, J.M.; Worzalla, J.F.; Bewley, J.R.; Grindey, G.B.; Todd, G.C.; Toth, J.E.; Howbert, J.J.; Comparison of metabolism and toxicity to the structure of the anticancer agent sulofenur and related sulfonylureas. Chem Res Toxicol 1992, 5, 5, 667.
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) 22096 ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate C11H9Cl2FO3 详情 详情
(II) 43201 1-[[chloro(cyclopropylimino)methyl]sulfanyl]benzene C10H10ClNS 详情 详情
(III) 43208 ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-2-(phenylsulfanyl)-1,4-dihydro-3-quinolinecarboxylate C21H17ClFNO3S 详情 详情
(IV) 43209 ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-2-(phenylsulfinyl)-1,4-dihydro-3-quinolinecarboxylate C21H17ClFNO4S 详情 详情
(V) 43210 7-chloro-9-cyclopropyl-6-fluoroisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione C13H8ClFN2O2S 详情 详情
(VI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线25

该中间体在本合成路线中的序号：(X)

The condensation of 2-(2,4,5-trifluorobenzoyl)acetic acid ethyl ester (I) with cyclopropyl isothiocyanate (II) by means of NaH in DMF gives the sodium salt (IIIa-b), which is methylated with methyl iodide to afford the methylsulfanyl derivative (IVa-b). The cyclization of (IVa-b) by means of NaH in THF provides the methylsulfanyl quinolone (V), which is oxidized with MCPBA to the corresponding methylsulfinyl compound (VI). The reaction of (VI) with NaSH in THF furnishes 1-cyclopropyl-6,7-difluoro-4-oxo-2-sulfanyl-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (VII), which is cyclized with hydroxylamine-O-sulfonic acid and NaHCO3 through the intermediate (VIII), affording the isothiazoloquinoline (IX). Finally, this compound is condensed with piperazine (X) in pyridine to give the target compound.

参考文献 中间体
合成目标
【1】 Chu, D.T.W.; Isothiazoloquinolones: Antibacterial and antineoplastic agents. Drugs Fut 1992, 17, 12, 1101.
【2】 Aquilar-Bryan, L.; Bryan, J.; Boyd, A.E. III; et al.; Sulfonylurea signal transduction. Recent Prog Horm Res 1991, 47, 299-317.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IIIa) 43212 sodium (Z)-1-(cyclopropylamino)-3-ethoxy-3-oxo-2-(2,4,5-trifluorobenzoyl)-1-propene-1-thiolate C15H13F3NNaO3S 详情 详情
(IIIb) 43213 sodium (E)-1-(cyclopropylamino)-3-ethoxy-3-oxo-2-(2,4,5-trifluorobenzoyl)-1-propene-1-thiolate C15H13F3NNaO3S 详情 详情
(IVa) 43214 ethyl (Z)-3-(cyclopropylamino)-3-(methylsulfanyl)-2-(2,4,5-trifluorobenzoyl)-2-propenoate C16H16F3NO3S 详情 详情
(IVb) 43215 ethyl (E)-3-(cyclopropylamino)-3-(methylsulfanyl)-2-(2,4,5-trifluorobenzoyl)-2-propenoate C16H16F3NO3S 详情 详情
(I) 22096 ethyl 3-(2,4-dichloro-5-fluorophenyl)-3-oxopropanoate C11H9Cl2FO3 详情 详情
(II) 43211 1-isothiocyanatocyclopropane; cyclopropyl isothiocyanate 56601-42-4 C4H5NS 详情 详情
(V) 43216 ethyl 1-cyclopropyl-6,7-difluoro-2-(methylsulfanyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H15F2NO3S 详情 详情
(VI) 43217 ethyl 1-cyclopropyl-6,7-difluoro-2-(methylsulfinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H15F2NO4S 详情 详情
(VII) 43218 ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-2-sulfanyl-1,4-dihydro-3-quinolinecarboxylate C15H13F2NO3S 详情 详情
(VIII) 43219 ethyl 2-(aminosulfanyl)-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate C15H14F2N2O3S 详情 详情
(IX) 43220 9-cyclopropyl-6,7-difluoroisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione C13H8F2N2O2S 详情 详情
(X) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线26

该中间体在本合成路线中的序号：(IV)

The synthesis has been described by Bøgesø et al. and the absolute configuration has been determined by X-ray crystallography by Jensen.

参考文献 中间体
合成目标
【1】 Hyttel, J.; Bogeso, K.P.; Gundertofte, K.; Boeck, V.; Christensen, A.V.; Arnt, J.; Antihypertensive activity in a series of 1-piperazino-3-phenylindans with potent 5-HT2-antagonistic activity. J Med Chem 1988, 31, 12, 2247.
【2】 Jensen, B.; Structure of the (+)-tartrate of the selective 5-HT2 antagonist irindalon. Acta Cryst 1988, C44, 1602.
【3】 Boeck, V.; Bogeso, K.P.; Hyttel, J.; IRINDALONE TARTRATE < Rec INNM >. Drugs Fut 1989, 14, 9, 859.
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) 21325 1-chloro-3-(4-fluorophenyl)indane C15H12ClF 详情 详情
(II) 21326 1-[3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]piperazine C19H21FN2 详情 详情
(III) 21327 1-(2-[4-[3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]-1-piperazinyl]ethyl)-2-imidazolidinone C24H29FN4O 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 21329 1-(2-chloroethyl)-2-imidazolidinone 2387-20-4 C5H9ClN2O 详情 详情

合成路线27

该中间体在本合成路线中的序号：(IX)

The reaction of 3,4-difluoroaniline (I) with carbon disulfide and triethylamine gives triethylammonium N-(3,4-difluorophenyl)dithiocarbamate (II), which by reaction with ethyl chloroformate and triethylamine in chloroform is converted into 3,4-difluorophenyl isothiocyanate (III). The reaction of (III) with diethyl malonate and KOH in dioxane affords the potassium salt (IV), which is treated with chloromethyl methyl ether in DMF to give the corresponding methoxymethylsulfanyl compound (V). The cyclization of (V) at 240 C in diphenyl ether affords 6,7-difluoro-4-hydroxy-2-(methoxymethylsulfanyl)quinoline-3-carboxylic acid ethyl ester (VI), which by treatment with HCl in ethanol gives the corresponding mercapto compound (VII). The cyclization of (VII) with 1,1-dibromoethane by means of K2CO3 and KI in hot DMF yields 5,6-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl ester (VIII), which is condensed with piperazine (IX) in DMF to afford the corresponding piperazino-derivative (X). The hydrolysis of (X) with KOH in hot tert-butanol gives the corresponding free acid (XI) , which is finally condensed with 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (XII) by means of KHCO3 in DMF.

参考文献 中间体
合成目标
【1】 Tracy, M.; Castaner, J.; Prulifloxazin < Prop INN >. Drugs Fut 1996, 21, 8, 805.
【2】 Kise, M.; Kitano, M.; Ozaki, M.; Kazuno, K.; Matsuda, M.; Shirahase, I.; Segawa, J. (Nippon Shinyaku Co., Ltd.); Quinolinecarboxylic acid derivs. AU 8824673; EP 0315828; JP 1989294680 .
【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) 13452 N,N-diethyl-1-ethanaminium 3,4-difluorophenylcarbamodithioate C13H20F2N2S2 详情 详情
(III) 13453 1,2-Difluoro-4-isothiocyanatobenzene; 3,4-difluorophenyl isothiocyanate 113028-75-4 C7H3F2NS 详情 详情
(IV) 13454 2-(3,4-Difluorophenylamino)-2-sulfanylethylene-1,1-dicarboxylic acid diethyl ester potassium salt C14H14F2KNO4S 详情 详情
(V) 13455 diethyl 2-[(3,4-difluoroanilino)[(methoxymethyl)sulfanyl]methylene]malonate C16H19F2NO5S 详情 详情
(VI) 13456 ethyl 6,7-difluoro-4-hydroxy-2-[(methoxymethyl)sulfanyl]-3-quinolinecarboxylate C14H13F2NO4S 详情 详情
(VII) 13457 ethyl 6,7-difluoro-4-hydroxy-2-sulfanyl-3-quinolinecarboxylate C12H9F2NO3S 详情 详情
(VIII) 13458 ethyl 6,7-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C14H11F2NO3S 详情 详情
(IX) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(X) 13460 ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate C18H20FN3O3S 详情 详情
(XI) 13461 6-Fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid C16H16FN3O3S 详情 详情
(XII) 13462 4-(Bromomethyl)-5-methyl-1,3-dioxol-2-one 80715-22-6 C5H5BrO3 详情 详情

合成路线28

该中间体在本合成路线中的序号：(VI)

The cyclization of 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropionic acid ethyl ester (I) with S-phenyl(cyclopropylimino)chlorothioformate (II) by means of NaH in DMF gives 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-2-(phenylsulfanyl)-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (III), which is oxidized with MCPBA in dichloromethane, yielding the sulfinyl derivative (IV). The cyclization of (IV) with NaSH and hydroxylamine-O-sulfonic acid in THF affords the isothiazolonaphthyridine (V), which is finally condensed with piperazine in pyridine to furnish the target compound.

参考文献 中间体
合成目标
【1】 Aquilar-Bryan, L.; Bryan, J.; Boyd, A.E. III; et al.; Sulfonylurea signal transduction. Recent Prog Horm Res 1991, 47, 299-317.
【2】 Chu, D.T.W.; Isothiazoloquinolones: Antibacterial and antineoplastic agents. Drugs Fut 1992, 17, 12, 1101.
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) 15228 ethyl 3-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-oxopropanoate C10H8Cl2FNO3 详情 详情
(II) 43201 1-[[chloro(cyclopropylimino)methyl]sulfanyl]benzene C10H10ClNS 详情 详情
(III) 43205 ethyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-2-(phenylsulfanyl)-1,4-dihydro[1,8]naphthyridine-3-carboxylate C20H16ClFN2O3S 详情 详情
(IV) 42306 methyl 4-[5-(1,5-diisopropyl-1H-pyrazol-3-yl)-1H-pyrrol-2-yl]benzoate C21H25N3O2 详情 详情
(V) 43027 tert-butyl (1S)-1-isobutyl-3-methyl-2-oxo-3-butenylcarbamate C14H25NO3 详情 详情
(VI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线29

该中间体在本合成路线中的序号：(V)

This compound can be obtained by two related ways: 1) The reaction of cis-octahydroisobenzofuran-1,3-dione (I) with ammonia in water at 180-90 gives cis-octahydro-1H-isoindole-1,3-dione (II), which is alkylated with 1,4-dibromobutane (III) and K2CO3 in refluxing acetone to yield cis-2-(4-bromobutyl)octahydro-1H-isoindole-1,3-dione (IV). The condensation of (IV) with piperazine (V) in refluxing toluene affords cis-2-(4-piperazinobutyl)octahydro-1H-isoindole-1,3-dione (VI), which is finally condensed with 3-chloro-1,2-benzisothiazole (VII) and K2CO3 in refluxing toluene. 2) The condensation of benzisothiazole (VII) with piperazine (V) by heating at 120 C gives 3-piperazino-1,2-benzisothiazole (VIII), which is then condensed with isoindole (IV) by means of K2CO3 and KI in hot DMF. 3) The 3-chloro-1,2-benzisothiazole (VII) is obtained as follows: The reaction of 2,2'-dithiobenzoic acid (IX) with refluxing SOCl2 gives the corresponding acyl chloride (X), which by treatment with methylamine in THF is converted into the diamide (XI). The reaction of (XI) with PCl5 in refluxing benzene affords 3-chloro-2-methyl-1,2-benzisothiazolium chloride (XII), which is finally heated in refluxing 1,2-dichlorobenzene to give (VII).

参考文献 中间体
合成目标
【1】 Ishizumi, N.; Antoku, F.; Maruyama, I.; Kojima, A. (Sumitomo Pharmaceuticals Co., Ltd.); Imide derivs., their production and use. EP 0196096; ES 8800219; JP 1987123179; JP 1987277355; JP 1987277356; US 4745117 .
【2】 Prous, J.; Castaner, J.; SM-9018. Drugs Fut 1991, 16, 2, 122.
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) 27329 (3aR,7aS)hexahydro-2-benzofuran-1,3-dione 13149-00-3 C8H10O3 详情 详情
(II) 31245 (3aR,7aS)hexahydro-1H-isoindole-1,3(2H)-dione 7506-66-3 C8H11NO2 详情 详情
(III) 11883 1,4-Dibromobutane; 1,4-Butylene bromide 110-52-1 C4H8Br2 详情 详情
(IV) 31246 (3aR,7aS)-2-(4-bromobutyl)hexahydro-1H-isoindole-1,3(2H)-dione C12H18BrNO2 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 31247 (3aR,7aS)-2-[4-(1-piperazinyl)butyl]hexahydro-1H-isoindole-1,3(2H)-dione C16H27N3O2 详情 详情
(VII) 16279 3-chloro-1,2-benzisothiazole C7H4ClNS 详情 详情
(VIII) 16280 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) 87691-87-0 C11H13N3S 详情 详情
(IX) 20404 2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid 119-80-2 C14H10O4S2 详情 详情
(X) 20405 2-[[2-(chlorocarbonyl)phenyl]disulfanyl]benzoyl chloride C14H8Cl2O2S2 详情 详情
(XI) 31248 N-methyl-2-([2-[(methylamino)carbonyl]phenyl]disulfanyl)benzamide 2527-58-4 C16H16N2O2S2 详情 详情
(XII) 31249 3-chloro-2-methyl-1,2-benzisothiazol-2-ium chloride C8H7Cl2NS 详情 详情

合成路线30

该中间体在本合成路线中的序号：(B)

FG5803 is obtained in a three-step synthesis: In the first step 4-(4-fluorophenyl)-4,4-ethylenedioxybutylchloride (A) reacts with piperazine (B) to give 1-[4-(4-fluorophenyl)-4,4-ethylenedioxybutyl]piperazine (I), which is reacted with cyclohexylisocyanate (C) to form 4-[4-(4-fluorophenyl)-4,4-ethylenedioxybutyl]-N-cyclohexyl-1-piperazinecarboxamide (II). The protecting group is removed by HCl in ethanol and the final product is isolated, 4-[4-(4-fluorophenyl)-4-oxobutyl]-N-cyclohexyl-1-piperazinecarboxamide hydrochloride (III).

参考文献 中间体
合成目标
【1】 Bjork, A.; Fex, T.; Olsson, K.; Abramo, A.; Gustafsson, B.; Christensson, E. (Ferrosan AB); Novel 1-piperazinecarboxamide derivs.. EP 0136274; ES 8704917; ES 8705411; ES 8802039; JP 1985501956; US 4935419; WO 8500811 .
【2】 Lundstedt, T.; Bjork, A.; Pettersson, G.; Svartengren, J.; Christensson, E.; Gustavsson, B.; FG5803. Drugs Fut 1990, 15, 12, 1176.
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(A) 28203 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane 3308-94-9 C12H14ClFO2 详情 详情
(I) 31226 1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]piperazine C16H23FN2O2 详情 详情
(II) 31227 N-cyclohexyl-4-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-1-piperazinecarboxamide C23H34FN3O3 详情 详情
(C) 18108 1-isocyanatocyclohexane; cyclohexyl isocyanate 3173-53-3 C7H11NO 详情 详情

合成路线31

该中间体在本合成路线中的序号：(IV)

The benzoxazinorifamycin (III) was obtained by oxidative condensation of rifamycin S (I) with 2-aminoresorcinol (II). 1-Isobutylpiperazine (V), prepared by alkylation of piperazine (IV) with isobutyl bromide, was then coupled to the benzoxazine ring of (III) in the presence of MnO2 as the oxidant to afford the target piperazinyl derivative. In an improved procedure, 2-aminoresorcinol (II) was protected as the mono-silyl ether (VI) and subsequently coupled to rifamycin S (I) in the presence of MnO2, yielding (VII). Oxidative coupling of the benzoxazino derivative (VII) with 1-isobutylpiperazine (V) proceeded with simultaneous desilylation to furnish the title compound.

参考文献 中间体
合成目标
【1】 Yamane, T.; Hashizume, T.; Yamashita, K.; Hosoe, K.; Kuze, F.; Watanabe, K. (Kaneka Corp.); 3'-Hydroxybenzoxazinorifamycin deriv., process for preparing the same and antibacterial agent containing them. EP 0366914; JP 1991007291; US 4983602 .
【2】 Yamane, T.; et al.; Synthesis and biological activity of 3'-hydroxy-5'-aminobenzoxazinorifamycin derivatives. Chem Pharm Bull 1993, 41, 1, 148.
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) 58522 (7S,11S,12R,13S,14R,15R,16R,17S,18S)-2,15,17-trihydroxy-11-methoxy-3,7,12,14,16,18-hexamethyl-6,23,27,29-tetraoxo-8,30-dioxa-24-azatetracyclo[23.3.1.1~4,7~.0~5,28~]triaconta-1(28),2,4,9,19,21,25-heptaen-13-yl acetate C36H43NO12 详情 详情
(II) 58101 2-amino-1,3-benzenediol C6H7NO2 详情 详情
(III) 58523 (7S,11S,12R,13S,14R,15R,16R,17S,18S)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18-hexamethyl-6,23,37-trioxo-8,27,38-trioxa-24,34-diazahexacyclo[23.11.1.1~4,7~.0~5,36~.0~26,35~.0~28,33~]octatriaconta-1(36),2,4,9,19,21,25,28,30,32,34-undecaen-13-yl acetate C42H46N2O13 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 58524 N-Isobutyl piperazine 5308-28-1 C8H18N2 详情 详情
(VI) 58102 2-amino-3-{[tert-butyl(dimethyl)silyl]oxy}phenol C12H21NO2Si 详情 详情
(VII) 58525 (7S,11S,12R,13S,14R,15R,16R,17S,18S)-32-{[tert-butyl(dimethyl)silyl]oxy}-2,15,17-trihydroxy-11-methoxy-3,7,12,14,16,18-hexamethyl-6,23,37-trioxo-8,27,38-trioxa-24,34-diazahexacyclo[23.11.1.1~4,7~.0~5,36~.0~26,35~.0~28,33~]octatriaconta-1(36),2,4,9,19,21,25,28,30,32,34-undecaen-13-yl acetate C48H60N2O13Si 详情 详情

合成路线32

该中间体在本合成路线中的序号：(II)

The title compound was obtained by condensation between 2-fluoro-5-methylbenzenesulfonic acid (I) and piperazine (II) in the presence of copper powder and cuprous iodide in a sealed tube at 160 C. It was converted to the more stable monohydrate form by suspension of the anhydrous crystals in cold water.

参考文献 中间体
合成目标
【1】 Okushima, H.; Narimatsu, A.; Kobayashi, M.; Satoh, N.; Morita, M. (Mitsubishi Chemical Corp.); Aminobenzenesulfonic acid deriv.. EP 0390654; JP 1991007263; US 5053409 .
【2】 Yamazaki, C.; Sato, T.; Nagano, T. (Mitsubishi Chemical Corp.); Monohydrates of aminobenzenesulfonic acid derivs. and method for preparation thereof. EP 0779283; JP 2001316381; US 5990113; US 6245767 .
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) 59240 2-fluoro-5-methylbenzenesulfonic acid C7H7FO3S 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线33

该中间体在本合成路线中的序号：(II)

By condensation of 2-chloro-4-(2-fluorophenyl)-6-methylthieno[2,3-d]pyrimidine (I) with piperazine (II) in refluxing chloroform or ethanol.

参考文献 中间体
合成目标
【1】 Ninomiya, K.; Nitta, I.; Tobe, A.; Egawa, S. (Mitsubishi Chem. Ind., Ltd.); Antidepressant and cerebral function improving agents. JP 8700042 .
【2】 Ninomiya, K.; Nitta, I.; Tobe, A.; Egawa, M.; Kikumoto, R. (Mitsubishi Chemical Corp.); Thieno[2,3-d]pyrimidine derivs. And salts thereof. EP 0150469; JP 1985146891 .
【3】 Ninomiya, K.; Nitta, K.; Tobe, A.; Egawa, M. (Mitsubishi Chemical Corp.); Antidepressant and cerebral function improving agent. JP 1987000427 .
【4】 Prous, J.; Castaner, J.; MCI-225. Drugs Fut 1992, 17, 5, 380.
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) 14760 2-chloro-4-(2-fluorophenyl)-6-methylthieno[2,3-d]pyrimidine C13H8ClFN2S 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线34

该中间体在本合成路线中的序号：(II)

The preparation of KW-3196 is as follows: Reaction of 1,4:3,6-dianhydro-D-glucitol 5-methanesulfonate (I) (1) with piperazine (II) afforded (III), which was nitrated with fuming HNO3 to give the nitrate ester (IV). Nicotynoylation of (IV) gave KW-319).

参考文献 中间体
合成目标
【1】 Klessing, K.; Chatterjee, S.S. (Dr. Willmar Schwabe); Alkylaminodeoxy-1,4:3,6-dianhydrohexitol nitrates substituted by purine bases and their pharmaceutical compositions. EP 0044927 .
【2】 Suzuki, F.; Hayashi, H.; Kuroda, T.; Kubo, K.; Ikeda, J. (Kyowa Hakko Kogyo Co., Ltd.); Hexitol derivatives having vasodilative activity. EP 0393574; JP 1991218381; US 5053408 .
【3】 Ueno, H.; Hayashi, H.; Suzuki, F.; Synthesis of stereoisomers of 1,4:3,6-dianhydrohexitol nitrate derivative, KF14124. Bioorg Med Chem Lett 1992, 2, 1187-92.
【4】 Suzuki, F.; KW-3196. Drugs Fut 1992, 17, 11, 995.
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) 14844 (3R,3aS,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl methanesulfonate C7H12O6S 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 14845 (3S,3aR,6S,6aR)-6-piperazinohexahydrofuro[3,2-b]furan-3-ol C10H18N2O3 详情 详情
(IV) 14846 1-[(3S,3aR,6S,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl]piperazine C10H17N3O5 详情 详情
(V) 10753 Nicotinoyl chloride C6H4ClNO 详情 详情

合成路线35

该中间体在本合成路线中的序号：(I)

Nucleophilic aromatic substitution of 2-chloro-3-nitropyridine (II) with excess piperazine (I) in acetonitrile at room temperature produces 1-(3-nitro-2-pyridyl)piperazine. Protection of the free piperazine nitrogen by treatment with di-tert-butyldicarbonate affords nitropyridine (III). Reduction of the nitro group to the amine is accomplished via hydrogenation (40 psi) over palladium on carbon. Treatment of the aminopyridine with acetaldehyde and sodium cyanoborohydride in methanol affords the (ethylamino)pyridine (IV). Removal of the BOC protecting group with trifluoroacetic acid and coupling of the resulting 1-[3-(ethylamino)pyridyl]piperazine with 5-methoxyindole-2-carboxylic acid using 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) or 1,1'-carbonyldiimidazole (CDI) affords U-87201 (V). Dissolution of (V) in methanol, treatment with 1 eq of methanesulfonic acid, and the addition of diethyl ether results in the precipitation of atevirdine mesylate.

参考文献 中间体
合成目标
【1】 Richman, D.D.; Fischl, M.A.; Grieco, M.H.; et al.; The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. New Engl J Med 1987, 317, 4, 192-7.
【2】 Tan, C.-K.; Busso, M.; Romero, D.L.; et al.; Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proc Natl Acad Sci USA 1991, 88, 19, 8806-10.
【3】 Romero, D.L.; Atevirdine Mesylate. Drugs Fut 1994, 19, 1, 9.
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(II) 10321 2-Chloro-3-nitropyridine 5470-18-8 C5H3ClN2O2 详情 详情
(III) 16159 tert-butyl 4-(3-nitro-2-pyridinyl)tetrahydro-1(2H)-pyrazinecarboxylate C14H20N4O4 详情 详情
(IV) 14880 tert-butyl 4-[3-(ethylamino)-2-pyridinyl]tetrahydro-1(2H)-pyrazinecarboxylate C16H26N4O2 详情 详情
(V) 63849 {4-[3-(ethylamino)-2-pyridinyl]-1-piperazinyl}(1H-indol-2-yl)methanone C20H23N5O 详情 详情

合成路线36

该中间体在本合成路线中的序号：(V)

The reaction of 3-amino-2-chloropyridine (I) with triethyl orthoacetate (II) catalyzed by TsOH gives the acetimidate (III), which is reduced to 3-(ethylamino)-2-chloropyridine (IV) by means of DIBAL in toluene. The reaction of (IV) with piperazine (V) by means of Na2CO3 by heating at 144 C affords 3-(ethylamino)-2-(1-piperazinyl)pyridine (VI), which is finally condensed with 5-methoxy-1H-indole-2-carboxylic acid (II) by means of CDI in dichloromethane and treated with CH3SO3H in methanol to provide the target mesylate.

参考文献 中间体
合成目标
【1】 Perrault, W.R.; et al.; Production scale synthesis of the non-nucleoside recverse transcriptase inhibitor atervirdine mesylate (U-87,201E). Org Process Res Dev 1997, 1, 2, 106.
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) 11160 2-Chloro-3-pyridinamine; 2-Chloro-3-pyridinylamine; 3-Amino-2-chloropyridine; 2-Chloro-3-aminopyridine 6298-19-7 C5H5ClN2 详情 详情
(II) 36531 1,1,1-trimethoxypropane; 1,1-dimethoxypropyl methyl ether C6H14O3 详情 详情
(III) 36532 methyl N-(2-chloro-3-pyridinyl)ethanimidoate C8H9ClN2O 详情 详情
(IV) 36533 N-(2-chloro-3-pyridinyl)-N-ethylamine; 2-chloro-N-ethyl-3-pyridinamine C7H9ClN2 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 36534 N-ethyl-N-[2-(1-piperazinyl)-3-pyridinyl]amine; N-ethyl-2-(1-piperazinyl)-3-pyridinamine C11H18N4 详情 详情
(VII) 28885 5-methoxy-1H-indole-2-carboxylic acid 4382-54-1 C10H9NO3 详情 详情

合成路线37

该中间体在本合成路线中的序号：(VI)

The cyclization of 2-(2,4-dichloro-3,5-difluorobenzoyl)acetic acid ethyl ester (I) with S-phenyl(cyclopropylimino)chlorothioformate (II) by means of NaH in DMF gives 7-chloro-1-cyclopropyl-6,8-difluoro-4-oxo-2-(phenylsulfanyl)-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (III), which is oxidized with MCPBA in dichloromethane, yielding the sulfinyl derivative (IV). The cyclization of (IV) with NaSH and hydroxylamine-O-sulfonic acid in THF affords the isothiazoloquinoline (V), which is finally condensed with piperazine in pyridine to furnish the target compound.

参考文献 中间体
合成目标
【1】 Aquilar-Bryan, L.; Bryan, J.; Boyd, A.E. III; et al.; Sulfonylurea signal transduction. Recent Prog Horm Res 1991, 47, 299-317.
【2】 Chu, D.T.W.; Isothiazoloquinolones: Antibacterial and antineoplastic agents. Drugs Fut 1992, 17, 12, 1101.
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) 43200 ethyl 3-(2,4-dichloro-3,5-difluorophenyl)-3-oxopropanoate C11H8Cl2F2O3 详情 详情
(II) 43201 1-[[chloro(cyclopropylimino)methyl]sulfanyl]benzene C10H10ClNS 详情 详情
(III) 43202 ethyl 7-chloro-1-cyclopropyl-6,8-difluoro-4-oxo-2-(phenylsulfanyl)-1,4-dihydro-3-quinolinecarboxylate C21H16ClF2NO3S 详情 详情
(IV) 43203 ethyl 7-chloro-1-cyclopropyl-6,8-difluoro-4-oxo-2-(phenylsulfinyl)-1,4-dihydro-3-quinolinecarboxylate C21H16ClF2NO4S 详情 详情
(V) 43204 7-chloro-9-cyclopropyl-6,8-difluoroisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione C13H7ClF2N2O2S 详情 详情
(VI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线38

该中间体在本合成路线中的序号：(V)

The synthesis of some metabolites of olanzapine have been described: 1) Synthesis of 4'-N-desmethyl olanzapine: 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). Finally, this compound is condensed with piperazine (V) in toluene/DMSO affording the metabolite 2-methyl-4-(1-piperazinyl)-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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线39

该中间体在本合成路线中的序号：(IV)

N-Alkylation of 2-chlorobenzimidazole (I) with benzyl bromide (II) by means of NaH in DMF provides benzylated derivative (III), which is converted into the desired compound by heating with piperazine (IV).

参考文献 中间体
合成目标
【1】 Parihar, H.S.; et al.; 5-HT3R binding of lerisetron: An interdisciplinary approach to drug-receptor interactions. Bioorg Med Chem Lett 2001, 11, 16, 2133.
【2】 Orjales, A.; et al.; New 2-piperazinylbenzimidazole derivatives as 5-HT3 antagonists. Synthesis and pharmacological evaluation. J Med Chem 1997, 40, 4, 586.
【3】 Orjales-Venero, A.; Garcia-Dominguez, N.; Rubio-Royo, V.; Rodes-Solanes, R. (FAES); New 2-piperazinylbenzimidazole derivs.. EP 0512939; JP 1995002795; US 5256665 .
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) 26761 2-chloroimidazo[1,2-a]pyridine; 2-chlorobenzimidazole; 2-Amino-4'-chlorodiphenylether; 2-Aminodiphenylether; 2-chloro-1H-benzimidazole 4857-06-1 C7H5ClN2 详情 详情
(II) 12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(III) 49687 1-Benzyl-2-chloro-1H-benzoimidazole C14H11ClN2 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线40

该中间体在本合成路线中的序号：(I)

The synthesis of delavirdine mesylate is depicted in Scheme 19654001a: The first three chemical steps are the same as those used for the synthesis of atevirdine mesylate (ATV, U-87201E) (2, 3). Nucleophilic aromatic substitution of 2-chloro-3-nitropyridine (II) with excess piperazine in acetonitrile at room temperature produces 1-(3-nitro-2-pyridyl)piperazine. Protection of the free piperazine nitrogen by treatment with di-tert-butyldicarbonate affords nitropyridine (III). Reduction of the nitro group to the amine is accomplished via hydrogenation (40 psi) over palladium on carbon. Treatment of the aminopyridine with acetone and sodium cyanoborohydride in methanol affords the 3-(1-methylethylamino)pyridine (IV). Removal of the BOC protecting group with trifluoroacetic acid and coupling of the resulting 1-[3-(1-methylethylamino)pyridyl]piperazine with 5-nitroindole-2-carboxylic acid using 1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) or 1,1'-carbonyldiimidazole (CDI) affords (V). Catalytic reduction of the nitro group and treatment of the resulting amine with methanesulfonyl chloride provides U-90152. Dissolution of U-90152 in acetonitrile and treatment with 1 eq of methanesulfonic acid results in the precipitation of delavirdine mesylate.

参考文献 中间体
合成目标
【1】 Romero, D.L.; Atevirdine mesylate (U-87201E). Drugs Fut 1994, 19, 1, 7-12.
【2】 Aristoff, P.A.; Romero, D.L.; Palmer, J.R.; Thomas, R.C.; Smith, H.W. (Pharmacia Corp.); Diaromatic substd. cpds. as anti-HIV-1 agents. US 5563142 .
【3】 Busso, M.; Romero, D.L.; Biles, C.; Genin, M.J.; Tarpley, W.G.; Morge, R.A.; Reusser, F.; Althaus, I.W.; Thomas, R.C.; Resnick, L.; Bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: Structure-activity relationships of novel substituted indole analogues and the identification oF (U-90152S), a second-generation clinical candidate. J Med Chem 1993, 36, 10, 1505-8.
【4】 Romero, D.L.; Delavirdine Mesylate. Drugs Fut 1994, 19, 3, 238.
【5】 Tan, C.-K.; Busso, M.; Romero, D.L.; et al.; Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type 1 replication. Proc Natl Acad Sci USA 1991, 88, 19, 8806-10.
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(II) 10321 2-Chloro-3-nitropyridine 5470-18-8 C5H3ClN2O2 详情 详情
(III) 16159 tert-butyl 4-(3-nitro-2-pyridinyl)tetrahydro-1(2H)-pyrazinecarboxylate C14H20N4O4 详情 详情
(IV) 16160 tert-butyl 4-[3-(isopropylamino)-2-pyridinyl]tetrahydro-1(2H)-pyrazinecarboxylate C17H28N4O2 详情 详情
(V) 16161 [4-[3-(isopropylamino)-2-pyridinyl]piperazino](5-nitro-1H-indol-2-yl)methanone C21H24N6O3 详情 详情

合成路线41

该中间体在本合成路线中的序号：

Wolff-Kishner reduction of 6-chloroisatin (I) gives 6-chlorooxindole (II), which is treated with chloroacetyl chloride under Friedel-Crafts conditions to yield 5-chloroacetyl-6-chlorooxindole (III). The ketone (III) is reduced using triethylsilane in trifluoroacetic acid to produce 6-chloro-5-(2-chloroethyl)oxindole (IV). 1,2-Benzisothiazolin-3-one (V) is converted to 3-chloro-1,2-benzisothiazole (VI) using phosphorus oxychloride and is then condensed with piperazine to provide 1-(1,2-benzisothiazol-3-yl)piperazine (VII). Finally, intermediate (VII) is alkylated by compound (IV) in the presence of sodium carbonate in water and is converted to the salt with aqueous hydrochloric acid.

参考文献 中间体
合成目标
【1】 Lowe, J.A. III; Nagel, A.A. (Pfizer Inc.); Piperazinyl-heterocyclic cpds. US 4831031 .
【2】 Bowles, P. (Pfizer Inc.); Process for preparing aryl piperazinyl-heterocyclic cpds. EP 1029861; JP 1994184143; US 5206366 .
【3】 Howard, H.R. Jr.; Busch, F.R.; Grobin, A.W.; Leeman, K.R. (Pfizer Products Inc.); Controlled synthesis of ziprasidone and compsns. thereof. WO 0370246 .
【4】 Seeger, T.F.; Prakash, C.; Howard, H.R.; Ziprasidone Hydrochloride. Drugs Fut 1994, 19, 6, 560.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(I) 16274 6-chloro-1H-indole-2,3-dione; 6-Chloroisatin 6341-92-0 C8H4ClNO2 详情 详情
(II) 16275 6-chloro-1,3-dihydro-2H-indol-2-one 56341-37-8 C8H6ClNO 详情 详情
(III) 16276 6-chloro-5-(2-chloroacetyl)-1,3-dihydro-2H-indol-2-one C10H7Cl2NO2 详情 详情
(IV) 16277 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one; 5-chloroethyl-6-chloro-1,3-dihydro-1H-indol-2-one- C10H9Cl2NO 详情 详情
(V) 16278 1,2-benzisothiazol-3(2H)-one; 1,2-Benzisothiazolin-3-one 2634-33-5 C7H5NOS 详情 详情
(VI) 16279 3-chloro-1,2-benzisothiazole C7H4ClNS 详情 详情
(VII) 16280 3-piperazino-1,2-benzisothiazole; 1,2-Benzisothiazole-3-(1-piperazinyl) 87691-87-0 C11H13N3S 详情 详情

合成路线42

该中间体在本合成路线中的序号：(II)

A new, one-step commercial process for the preparation of 3-(1-piperazinyl)-1,2-benzisothiazole, a key intermediate in the synthesis of ziprasidone has been developed: The reaction of 2-cyanophenyl disulfide (I) with piperazine (II) by means of DMSO and isopropanol at 120-5 C.

参考文献 中间体
合成目标
【1】 Sinay, T.G.; Fox, D.E.; Walinsky, S.W.; Lambert, J.F.; New disulfide route to 3-(1-piperazinyl)-1,2-benzisothiazole. Nucleus for atypical antipsychotic drugs. Org Process Res Dev 1999, 3, 2, 126.
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) 37621 2-[(2-cyanophenyl)disulfanyl]benzonitrile 33174-74-2 C14H8N2S2 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线43

该中间体在本合成路线中的序号：(IV)

The bromination of 3-chloro-1,2-benzoisothiazole (I) with Br2 in AcOH using FeCl3 as catalyst gives a mixture of 3,5-dibromo-1,2-benzoisothiazole (II) and 3,7-dibromo-1,2-benzoisothiazole (III) that are separated by flash chromatography. The desired isomer (III) is condensed with piperazine (IV) in refluxing diglyme to yield 7-bromo-3-(1-piperazinyl)-1,2-benzoisothiazole (V), which is condensed with 6-chloro-5-(2-chloroethyl)indolin-2-one (VI) by means of Na2CO3 in refluxing water to afford the brominated adduct (VII). Finally, this compound is debrominated with tritium gas over a Pd/BaSO4 catalyst in THF to provide the target radiolabeled compound.

参考文献 中间体
合成目标
【1】 Howard, H.R.; Shenk, K.D.; Smolarek, T.A.; Marx, M.H.; Windels, J.H.; Roth, R.W.; Synthesis of H-3- and C-14-labelled CP-88,059: A potent atypical antipsychotic agent. J Label Compd Radiopharm 1994, 34, 2, 117.
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) 16279 3-chloro-1,2-benzisothiazole C7H4ClNS 详情 详情
(II) 62886 3,5-dibromo-1,2-benzisothiazole C7H3Br2NS 详情 详情
(III) 62887 3,7-dibromo-1,2-benzisothiazole C7H3Br2NS 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 62888 7-bromo-3-(1-piperazinyl)-1,2-benzisothiazole C11H12BrN3S 详情 详情
(VI) 16277 6-chloro-5-(2-chloroethyl)-1,3-dihydro-2H-indol-2-one; 5-chloroethyl-6-chloro-1,3-dihydro-1H-indol-2-one- C10H9Cl2NO 详情 详情
(VII) 62889 5-{2-[4-(7-bromo-1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-6-chloro-1,3-dihydro-2H-indol-2-one C21H20BrClN4OS 详情 详情

合成路线44

该中间体在本合成路线中的序号：(VIII)

A synthesis for the 18F-labeled compound has also been reported. The piperazinylquinoxaline (IX) was obtained from chloroquinoxaline (VI) and excess piperazine (VIII) at 160 C. This was then alkylated with 4-[18F]fluorobenzyl iodide (X) in refluxing CH2Cl2 to provide the labeled product.

参考文献 中间体
合成目标
【1】 Katounina, T.; et al.; Synthesis and biological investigations of [18F]MR. Bioorg Med Chem 1998, 6, 6, 789.
【2】 Lancelot, J.-C.; Prunier, H.; Rault, S.; et al.; Novel and selective partial agonists of 5-HT3 rece. J Med Chem 1997, 40, 12, 1808.
【3】 Katounina, T.; et al.; Synthesis of [18F]MR 18445 and its in vivo evaluat. J Label Compd Radiopharm 1997, 40, 542.
【4】 Rault, S.; Lancelot, J.-C.; Prunier, H.; Robba, M.; Delagrange, P.; Renard, P.; Adam, G. (ADIR et Cie.); Pyrrolopyrazine derivs. with 5-HT3 activity. CA 2122890; EP 0623620; FR 2704547; JP 1994340666; US 5599812 .
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) 23597 4-chloropyrrolo[1,2-a]quinoxalin-7-yl methyl ether; 4-chloro-7-methoxypyrrolo[1,2-a]quinoxaline C12H9ClN2O 详情 详情
(VIII) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(IX) 23600 7-methoxy-4-(1-piperazinyl)pyrrolo[1,2-a]quinoxaline; methyl 4-(1-piperazinyl)pyrrolo[1,2-a]quinoxalin-7-yl ether C16H18N4O 详情 详情
(X) 23601 1-fluoro-4-(iodomethyl)benzene C7H6FI 详情 详情
(X) 45316 1-fluoro-4-(iodomethyl)benzene C7H6FI 详情 详情

合成路线45

该中间体在本合成路线中的序号：(XVI)

Condensation of the anti-bromo derivative (XII) with piperazine (XVI) in refluxing acetonitrile provides 1-[10,11-(difluoromethano)dibenzosuber-5-yl]piperazine as a mixture of syn- and anti-isomers (XVII), which is separated by crystallization. Finally, the desired anti-isomer (VIII) is condensed with 5-[2(R),3-epoxypropoxy]quinoline (IX) in hot ethanol.

参考文献 中间体
合成目标
【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; Bayes, M.; Zosuquidar Trihydrochloride.. Drugs Fut 2003, 28, 2, 125-136.
【2】 Barnett, C.J.; Wilson, T.M.; Astleford, B.A.; Kobierski, M.E. (Eli Lilly and Company); Process for preparing a 10,11-methanodibenzosuberane deriv.. WO 0075132 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 56207 1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazine C20H20F2N2 详情 详情
(IX) 56211 (2R)oxiranylmethyl 5-quinolinyl ether; 5-[(2R)oxiranylmethoxy]quinoline C12H11NO2 详情 详情
(XII) 56208 (1aR,10bS)-6-bromo-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cycloheptene C16H11BrF2 详情 详情
(XVI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(XVII) 59523 1-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]piperazine C20H20F2N2 详情 详情

合成路线46

该中间体在本合成路线中的序号：(IV)

Ketone (I) was reduced with sodium borohydride in methanol to alcohol (II), which was then converted into chloride (III) on treatment with thionyl chloride in cooled toluene. Alkylation of piperazine (IV) with chloride (III) in the presence of triethylamine gave V. Finally, piperazine (V) was condensed with 4-pyridylacetic acid (VI) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (DEC), 1-hydroxybenzotriazole (HOBt), and N-methylmorpholine in DMF to afford the target amide.

参考文献 中间体
合成目标
【1】 Lesur, B.; et al.; New deoxynojirimycin derivatives as potent inhibitors of intestinal alpha-glucohydrolases. Bioorg Med Chem Lett 1997, 7, 3, 355-360.
【2】 Lesur, B.; Ducep, J.-B.; Danzin, C. (Merrell Pharmaceuticals, Inc.); Novel nojirimycin derivs.. EP 0453692; EP 0454580; JP 1993086072; US 5252587; US 5536732 .
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) 16504 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one; 8-Chloro-10,11-dihydro-4-aza-5H-dibenzo[a,d]cycloheptan-5-one 31251-41-9 C14H10ClNO 详情 详情
(II) 17935 8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol C14H12ClNO 详情 详情
(III) 17936 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine C14H11Cl2N 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 17938 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine C18H20ClN3 详情 详情
(VI) 17883 2-(4-pyridinyl)acetic acid 28356-58-3 C7H7NO2 详情 详情

合成路线47

该中间体在本合成路线中的序号：(IV)

The condensation of 4-chlorophenylsulfonate (I) with 4-bromophenol (II) by means of K2CO3 in hot DMF gives the aryl ether (III), which is condensed with piperazine (IV) by means of Pdo to yield the monosubstituted piperazine (V). Finally, this compound is condensed with the 4-bromophenyltriazolone (VI) by means of K2CO3 in hot DMSO to afford the target disubstituted piperazine

参考文献 中间体
合成目标
【1】 Hepperle, M.; Eckert, J.; Gala, D.; Shen, L.; Evans, C.A.; Goodman, A.; Mono N-arylation of piperazine(III): Metal-catalyzed N-arylation and its application to the novel preparations of the antifungal posaconazole and its advanced intermediate. Tetrahedron Lett 2002, 43, 18, 3359.
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) 17109 [(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-chlorobenzenesulfonate C20H18ClF2N3O4S 详情 详情
(II) 25313 4-bromophenol 106-41-2 C6H5BrO 详情 详情
(III) 64328 1-{[(2R,4R)-4-[(4-bromophenoxy)methyl]-2-(2,4-difluorophenyl)tetrahydro-2-furanyl]methyl}-1H-1,2,4-triazole; 4-bromophenyl [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl ether C20H18BrF2N3O2 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(V) 64329 1-(4-{[(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methoxy}phenyl)piperazine; [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl 4-(1-piperazinyl)phenyl ether C24H27F2N5O2 详情 详情
(VI) 64326 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-(4-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one C20H22BrN3O2 详情 详情

合成路线48

该中间体在本合成路线中的序号：(IV)

Alternatively, the condensation of with the 4-bromophenyltriazolone (VI) with piperazine (IV) by means of Pd2(dba)3, BINAP and t-BuONa in hot toluene gives the monosubstituted piperazine (VII), which is then condensed with the already reported aryl ether (III) by means of Pd2(dba)3, BINAP and t-BuONa in hot toluene, and debenzylated with Pd/C and formic acid to afford the target disubstituted piperazine.

参考文献 中间体
合成目标
【1】 Hepperle, M.; Eckert, J.; Gala, D.; Shen, L.; Evans, C.A.; Goodman, A.; Mono N-arylation of piperazine(III): Metal-catalyzed N-arylation and its application to the novel preparations of the antifungal posaconazole and its advanced intermediate. Tetrahedron Lett 2002, 43, 18, 3359.
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) 64328 1-{[(2R,4R)-4-[(4-bromophenoxy)methyl]-2-(2,4-difluorophenyl)tetrahydro-2-furanyl]methyl}-1H-1,2,4-triazole; 4-bromophenyl [(3R,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)tetrahydro-3-furanyl]methyl ether C20H18BrF2N3O2 详情 详情
(IV) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 64326 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-(4-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one C20H22BrN3O2 详情 详情
(VII) 64327 2-[(1S,2S)-2-(benzyloxy)-1-ethylpropyl]-4-[4-(1-piperazinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one C24H31N5O2 详情 详情

合成路线49

该中间体在本合成路线中的序号：(II)

The intermediate 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) has been obtained by several related ways: 1.- The condensation of 4-bromonitrobenzene (I) with piperazine (II) gives 1-(4-nitrophenyl)piperazine (III), which is condensed with 4-bromoanisole (IV) by means of Pdo to yield 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V). Alternatively, (V) can also be obtained by condensation of (III) with 4-methoxyphenylboronic acid (VI) by means of Cu(OAc)2 in DMSO. The demethylation of (V) with HBr yields 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol (VII), which is finally reduced with H2 over Pd/C to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). 2.- The condensation of piperazine (II) with 4-bromoanisole (IV) by means of Pdo gives 1-(4-methoxyphenyl)piperazine (IX), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and tetrabutylammonium iodide (TBAI) in hot DMSO to yield intermediate 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V), already reported. 3.- The condensation of piperazine (II) with 4-(benzyloxy)phenyl bromide (X) by means of Pdo gives 1-(4-benzyloxyphenyl)piperazine (XI), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and TBAI in hot DMSO to yield 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII). The nitro group of (XII) is reduced by means of H2 (50 psi) over Pd/C in wet THF at 50? C to afford 4-[4-(4-benzyloxyphenyl)piperazin-1-yl]aniline (XIII), which is finally debenzylated with H2 (80 psi) over Pd/C in wet THF at 70? C or other drastic conditions to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). Alternatively, 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII) can also be reduced directly to the target intermediate (VIII) with H2 over Pd/C under a variety of drastic conditions.

参考文献 中间体
合成目标
【1】 Hepperle, M.; Eckert, J.; Gala, D.; Shen, L.; Evans, C.A.; Goodman, A.; Mono N-arylation of piperazine(III): Metal-catalyzed N-arylation and its application to the novel preparations of the antifungal posaconazole and its advanced intermediate. Tetrahedron Lett 2002, 43, 18, 3359.
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) 26628 1-bromo-4-nitrobenzene 99-99-0 C6H4BrNO2 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 20299 1-(4-nitrophenyl)piperazine 6269-89-2 C10H13N3O2 详情 详情
(IV) 63436 1-bromo-4-methoxybenzene; 4-bromophenyl methyl ether C7H7BrO 详情 详情
(V) 16314 methyl 4-[4-(4-nitrophenyl)piperazino]phenyl ether; 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine C17H19N3O3 详情 详情
(VI) 39246 4-methoxyphenylboronic acid 5720-07-0 C7H9BO3 详情 详情
(VII) 16345 4-[4-(4-nitrophenyl)piperazino]phenol C16H17N3O3 详情 详情
(VIII) 17110 4-[4-(4-aminophenyl)piperazino]phenol; 1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine; 1-(4-Hydroxyphenyl)-4-(4-aminophenyl)piperazine 74853-08-0 C16H19N3O 详情 详情
(IX) 16312 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether 38212-30-5 C11H16N2O 详情 详情
(X) 43156 1-(benzyloxy)-4-bromobenzene; benzyl 4-bromophenyl ether 6793-92-6 C13H11BrO 详情 详情
(XI) 64373 1-[4-(benzyloxy)phenyl]piperazine; benzyl 4-(1-piperazinyl)phenyl ether C17H20N2O 详情 详情
(XII) 64372 benzyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether; 1-[4-(benzyloxy)phenyl]-4-(4-nitrophenyl)piperazine C23H23N3O3 详情 详情
(XIII) 64371 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}aniline; 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}phenylamine C23H25N3O 详情 详情

合成路线50

该中间体在本合成路线中的序号：(V)

This compound can be obtained by two different ways: 1) The acetylation of 1-nitrosopiperazine (I) with acetyl chloride and pyridine in dioxane gives 1-acetyl-4-nitrosopiperazine (II), which is reduced with Zn and acetic acid/water to 1-acetyl-4-aminopiperazine (III). Finally, this compound is acylated with 4-fluorobenzoyl chloride (IV) by means of triethylamine in dichloromethane. 2) The nitrosation of piperazine (V) with NaNO2/HCl in water, followed by condensation with benzyloxycarbonyl chloride (VI) by means of NaOH yields 1-(benzyloxycarbonyl)-4-nitrosopiperazine (VII), which is reduced with Zn and acetic acid/water as before to the corresponding amino derivative (VIII). The acylation of (VIII) with 4-fluorobenzoyl chloride and triethylamine in dichloromethane affords N-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-fluorobenzamide (IX), which is deprotected with HBr in acetic acid to yield N-(1-piperazinyl)-4-fluorobenzamide (X). Finally, this compound is acetylated with acetic anhydride/NaOH in water.

参考文献 中间体
合成目标
【1】 Graul, A.; Tracy, M.; Castañer, J.; FK-960. Drugs Fut 1997, 22, 8, 830.
【2】 Oku, T.; Todo, E.; Yokota, Y.; Kayakiri, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); New aminopiperazine derivs. EP 0436734; JP 1991510050; US 5250528; WO 9101979 .
【3】 Oku, T.; Kayakiri, H.; Tanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Novel intermediate for synthetic use and process for producing aminopiperazine derivs. WO 9500502 .
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) 17260 1-nitrosopiperazine C4H9N3O 详情 详情
(II) 17261 1-(4-nitrosopiperazino)-1-ethanone C6H11N3O2 详情 详情
(III) 17262 1-(4-aminopiperazino)-1-ethanone C6H13N3O 详情 详情
(IV) 17263 4-fluorobenzoyl chloride 403-43-0 C7H4ClFO 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(VII) 17266 benzyl 4-nitrosotetrahydro-1(2H)-pyrazinecarboxylate C12H15N3O3 详情 详情
(VIII) 17267 benzyl 4-aminotetrahydro-1(2H)-pyrazinecarboxylate C12H17N3O2 详情 详情
(IX) 17268 benzyl 4-[(4-fluorobenzoyl)amino]tetrahydro-1(2H)-pyrazinecarboxylate C19H20FN3O3 详情 详情
(X) 17269 4-fluoro-N-piperazinobenzamide C11H14FN3O 详情 详情

合成路线51

该中间体在本合成路线中的序号：(II)

Condensation of 3,4-difluoronitrobenzene (I) with an excess of piperazine (II) in refluxing acetonitrile yielded the 4-nitrophenylpiperazine (III), which was reduced to aniline (IV) by hydrogenation in the presence of Pd/C. Reaction with benzyl chloroformate provided the bis(carbamate) (V). This was treated with butyllithium at -78 C, and the resulting lithium salt was reacted with (R)-glycidyl butyrate (VI) to give chiral (R)-oxazolidinone (VII). Subsequent reaction with methanesulfonyl chloride, followed by displacement of the resulting mesylate with potassium phthalimide afforded the substituted phthalimide (VIII), which was deblocked with aqueous methylamine to give primary amine (IX). Further acetylation with Ac2O in pyridine yielded amide (IX) from which the N-carbobenzoxy group was removed by hydrogenolysis in the presence of Pd/C, providing the piperazine salt (XI). Alkylation of piperazine (XI) with 3,6-dichloropyridazine (XII) in DMF then gave the chloropyridazine derivative (XIII) and final hydrogenolysis of the halogen atom in the presence of palladium black yielded the title compound.

参考文献 中间体
合成目标
【1】 Brickner, S.J.; Hutchinson, D.K.; Barbachyn, M.R.; et al.; Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant Gram-positive bacterial infections. J Med Chem 1996, 39, 3, 673.
【2】 Tucker, J.A.; Allwine, D.A.; Grega, K.C.; Barbachyn, M.R.; Klock, J.L.; Adamski, J.L.; Brickner, S.J.; Hutchinson, D.K.; Ford, C.W.; Zurenko, G.E.; Conradi, R.A.; Burton, P.S.; Jensen, R.M.; Piperazinyl oxazolidinone antibacterial agents containing a pyridine, diazene, or triazene heteroaromatic ring. J Med Chem 1998, 41, 19, 3727.
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) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 18382 1-(2-fluoro-4-nitrophenyl)piperazine C10H12FN3O2 详情 详情
(IV) 18383 3-fluoro-4-(1-piperazinyl)phenylamine; 3-fluoro-4-(1-piperazinyl)aniline C10H14FN3 详情 详情
(V) 18384 benzyl 4-(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenyl)-1-piperazinecarboxylate C26H26FN3O4 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 18386 benzyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]-1-piperazinecarboxylate C22H24FN3O5 详情 详情
(VIII) 18387 benzyl 4-(4-[(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1-piperazinecarboxylate C30H27FN4O6 详情 详情
(IX) 18388 benzyl 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]-1-piperazinecarboxylate C22H25FN4O4 详情 详情
(X) 18389 benzyl 4-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1-piperazinecarboxylate C24H27FN4O5 详情 详情
(XI) 18390 N-([(5S)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide C16H21FN4O3 详情 详情
(XIII) 18393 N-[((5S)-3-[4-[4-(6-chloro-3-pyridazinyl)-1-piperazinyl]-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide C20H22ClFN6O3 详情 详情

合成路线52

该中间体在本合成路线中的序号：(II)

Condensation of 3,4-difluoronitrobenzene (I) with an excess of piperazine (II) in refluxing acetonitrile yielded the 4-nitrophenylpiperazine (III), which was reduced to aniline (IV) by hydrogenation in the presence of Pd/C. Reaction with benzyl chloroformate provided the bis(carbamate) (V). This was treated with butyllithium at -78 C, and the resulting lithium salt was reacted with (R)-glycidyl butyrate (VI) to give chiral (R)-oxazolidinone (VII). Subsequent reaction with methanesulfonyl chloride, followed by displacement of the resulting mesylate with potassium phthalimide afforded the substituted phthalimide (VIII), which was deblocked with aqueous methylamine to give primary amine (IX). Further acetylation with Ac2O in pyridine yielded amide (IX) from which the N-carbobenzoxy group was removed by hydrogenolysis in the presence of Pd/C, providing the piperazine salt (XI). Then, alkylation of piperazine (XI) with 3-chloro-6-methylpyridazine (XII) in dimethylpropyleneurea (DMPU) at 90 C yielded the title compound.

参考文献 中间体
合成目标
【1】 Brickner, S.J.; Hutchinson, D.K.; Barbachyn, M.R.; et al.; Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant Gram-positive bacterial infections. J Med Chem 1996, 39, 3, 673.
【2】 Tucker, J.A.; Allwine, D.A.; Grega, K.C.; Barbachyn, M.R.; Klock, J.L.; Adamski, J.L.; Brickner, S.J.; Hutchinson, D.K.; Ford, C.W.; Zurenko, G.E.; Conradi, R.A.; Burton, P.S.; Jensen, R.M.; Piperazinyl oxazolidinone antibacterial agents containing a pyridine, diazene, or triazene heteroaromatic ring. J Med Chem 1998, 41, 19, 3727.
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) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 18382 1-(2-fluoro-4-nitrophenyl)piperazine C10H12FN3O2 详情 详情
(IV) 18383 3-fluoro-4-(1-piperazinyl)phenylamine; 3-fluoro-4-(1-piperazinyl)aniline C10H14FN3 详情 详情
(V) 18384 benzyl 4-(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenyl)-1-piperazinecarboxylate C26H26FN3O4 详情 详情
(VI) 18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
(VII) 18386 benzyl 4-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]-1-piperazinecarboxylate C22H24FN3O5 详情 详情
(VIII) 18387 benzyl 4-(4-[(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1-piperazinecarboxylate C30H27FN4O6 详情 详情
(IX) 18388 benzyl 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl]-1-piperazinecarboxylate C22H25FN4O4 详情 详情
(X) 18389 benzyl 4-(4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)-1-piperazinecarboxylate C24H27FN4O5 详情 详情
(XI) 18390 N-([(5S)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide C16H21FN4O3 详情 详情
(XII) 13485 2,8-Dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane C11H19NO 详情 详情

合成路线53

该中间体在本合成路线中的序号：(XI)

The Knoevenagel condensation between methyl acetoacetate (I) and 3,4-difluorobenzaldehyde (II) afforded the benzylidene derivative (III), which was cyclized with O-methylisourea hemisulfate (IV), yielding the dihydropyrimidine (V). This compound, upon reaction with 4-nitrophenyl chloroformate, regioselectively produced the carbamate ester (VI) (1,2). Treatment of (VI) with aqueous HCl gave the dihydropyrimidinone (VII), which was subsequently coupled with 3-bromopropylamine·HBr (VIII) to give the bromopropyl amide (IX) (1). The intermediate N-(2-carboxamidophenyl)piperazine (XIII) was obtained by condensation of 2-bromobenzonitrile (X) with piperazine (XI), followed by partial hydrolysis of the nitrile group with H2SO4. The title compound was finally obtained by condensation between piperazine (XIII) and bromide (IX) in the presence of KI and K2CO3 in refluxing acetone.

参考文献 中间体
合成目标
【1】 Lagu, B.; Nagarathnam, D.; Miao, S.W.; et al.; Design and synthesis of novel alpha1a adrenoceptor-selective antagonists. 1. Structure-activity relationship in dihydropyrimidinones. J Med Chem 1999, 42, 23, 4764.
【2】 Marzabadi, M.R.; Murali Dhar, T.G.; Nagarathnam, D.; et al.; Design and synthesis of novel alpha1a adrenoceptor-selective antagonists. 2. Approaches to eliminate opioid agonist metabolites via modification of linker and 4-methoxycarbonyl-4-phenylpiperidine moiety. J Med Chem 1999, 42, 23, 4778.
【3】 Wong, W.C.; Lagu, B.; Nagarathnam, D.; Marzabadi, M.R.; Gluchowski, C. (Synaptic Pharmaceutical Corp.); Dihydropyrimidines and uses thereof. EP 1021185; JP 2000506904; WO 9742956 .
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) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情
(II) 26654 3,4-difluorobenzaldehyde 34036-07-2 C7H4F2O 详情 详情
(III) 38075 methyl (Z)-2-acetyl-3-(3,4-difluorophenyl)-2-propenoate C12H10F2O3 详情 详情
(IV) 26657 O-methyl isourea; [Amino(imino)methoxy]methane 52328-05-9 C2H6N2O 详情 详情
(V) 38076 methyl 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,6-dihydro-5-pyrimidinecarboxylate C14H14F2N2O3 详情 详情
(VI) 43072 5-benzyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate C27H21F2N3O7 详情 详情
(VII) 43073 5-benzyl 1-(4-nitrophenyl) 6-(3,4-difluorophenyl)-4-methyl-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate C26H19F2N3O7 详情 详情
(VIII) 25449 3-bromo-1-propanamine; 3-bromopropylamine 18370-81-5 C3H8BrN 详情 详情
(IX) 43074 benzyl 3-[[(3-bromopropyl)amino]carbonyl]-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate C23H22BrF2N3O4 详情 详情
(X) 15541 o-bromobenzonitrile; 2-bromobenzonitrile 2042-37-7 C7H4BrN 详情 详情
(XI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(XII) 43075 2-(1-piperazinyl)benzonitrile C11H13N3 详情 详情
(XIII) 43076 2-(1-piperazinyl)benzamide C11H15N3O 详情 详情

合成路线54

该中间体在本合成路线中的序号：(V)

Condensation of trimethylhydroquinone (I) with 4-chloro-1-butanol (II) in the presence of phosphomolybdic acid in refluxing toluene yielded the chlorobutyl ether (III). Benzhydrylpiperazine (VI), (prepared from chlorodiphenylmethane (IV) and piperazine (V)), was then condensed with chloride (III) to give the target compound, which was isolated as the dihydrochloride salt.

参考文献 中间体
合成目标
【1】 Kawasaki, N.; Satoh, T.; Nagai, H.; Nishiki, M.; Matsumoto, H.; Inagaki, N.; Miyataka, H.; Synthesis of trimethylhydroquinone derivatives as anti-allergic agents with anti-oxidative actions. Chem Pharm Bull 1999, 47, 2, 177.
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) 26357 2,3,5-trimethyl-1,4-benzenediol 700-13-0 C9H12O2 详情 详情
(II) 22336 4-chloro-1-butanol 928-51-8 C4H9ClO 详情 详情
(III) 27973 4-(4-chlorobutoxy)-2,3,6-trimethylphenol C13H19ClO2 详情 详情
(IV) 27974 Benzhydrylchloride; 1,1-Diphenylchloromethane; Dibenzyl chloride; Alpha-Chlorodiphenylmethane; Chlorodiphenylmethane; Diphenylchloromethane; 1-[chloro(phenyl)methyl]benzene 90-99-3 C13H11Cl 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 20796 N-(Benzhydryl)piperazine; 1-Benzhydrylpiperazine; 1-(dibenzyl)piperazine 841-77-0 C17H20N2 详情 详情

合成路线55

该中间体在本合成路线中的序号：(VII)

This compound has been obtained by two different ways: 1) The condensation of 2-bromobenzyl alcohol (I) with cyclohexane-1,4-dione monoethyleneketal (II) by means of BuLi in THF gives the expected adduct (III), which is cyclized and deprotected with TFA yielding the spirocyclohexanone (IV). The reduction of (IV) with NaBH4 in ethanol affords the cis-spirocyclohexanol (V), which by reaction with MsCl and TEA in dichloromethane is converted into the mesylate (VI). The condensation of (VI) with piperazine (VII) in refluxing isopropanol provides the trans-intermediate (VIII), which is finally condensed with 2,4-difluorobenzonitrile (IX) by means of K2CO3 in refluxing acetonitrile. 2) The condensation of piperazine (VII) with 2,4-difluorobenzonitrile (IX) by means of K2CO3 in acetonitrile gives 2-fluoro-4-(1-piperazinyl)benzonitrile (X), which is then reductocondensed with spirocyclohexanone (IV) by means of NaBH4 and 2-ethylhexanoic acid in CH2Cl2 to afford the target compound.

参考文献 中间体
合成目标
【1】 Urban, F.J.; et al.; Synthesis of a spiro[cyclohex-1,1'-isobenzofuranyl]dopamine receptor antagonist. Org Process Res Dev 1999, 3, 6, 460.
【2】 Butler, T.W.; Fliri, A.F.J. (Pfizer Inc.); Spirocyclic dopamine receptor subtype ligands. EP 0925291; JP 2000502360; WO 9808835 .
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) 36939 (2-bromophenyl)methanol 18982-54-2 C7H7BrO 详情 详情
(II) 16775 3,3-Dimethyl-1,5-dioxaspiro[5.5]undecan-9-one; 1,4-Cyclohexanedione mono-2,2-dimethyltrimethylene ketal 69225-59-8 C11H18O3 详情 详情
(III) 36940 9-[2-(hydroxymethyl)phenyl]-3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-ol C18H26O4 详情 详情
(IV) 36941 　 C13H14O2 详情 详情
(V) 36942 　 C13H16O2 详情 详情
(VI) 36943 　 C14H18O4S 详情 详情
(VII) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VIII) 36944 　 C17H24N2O 详情 详情
(IX) 36945 2,4-difluorobenzonitrile 64248-64-2 C7H3F2N 详情 详情
(X) 36946 2-fluoro-4-(1-piperazinyl)benzonitrile C11H12FN3 详情 详情

合成路线56

该中间体在本合成路线中的序号：(VI)

Chemoselective protection of the amino group of 2,3,5-trimethyl-4-aminophenol (I) with di-tert-butyl dicarbonate (Boc)2O in THF gives compound (II), which is then treated with NaH and (S)-glycidyl 3-nitrobenzenesulfonate (III) to yield epoxypropane (IV). On the other hand, treatment of 4,4'-difluorobenzophenone (V) with piperazine (VI) in acetonitrile in the presence of Et3N gives derivative (VII), which is reduced with Et3siH in the presence of H2SO4 and TFA to afford piperazine (VIII). Condensation of epoxypropane (IV) with piperazine (VIII) in refluxing 2-propanol furnishes compound (IX), which is finally converted into the desired product by first removal of the Boc group by exposure to TFA in CH2Cl2, followed by treatment with methanesulfonic acid (MeSO3H).

参考文献 中间体
合成目标
【2】 Nakanishi, K.; Annoura, H.; Tamura, S. (Suntory Ltd.); Arylpiperidinopropanol and arylpiperazinopropanol derivs. and pharmaceuticals containing the same. CA 2276373; EP 0958280; WO 9923072 .
【1】 Tamura-Horikawa, Y.; Miyajima, A.; Tamura, S.; Annoura, H.; Imajo, S.; Toba, T.; Takemoto, N.; Nakanishi, K.; Discovery of (2S)-1-(4-amino-2,3,5-trimethylphenoxy)-3-(4-[4-(4-fluorobenzyl)phenyl)-1-piperazinyl)-2-propanol dimethanesulfonate (SUN N8075): A dual Na+ and Ca2+ channel blocker with antioxidant activity. J Med Chem 2000, 43, 18, 3372.
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) 45629 4-amino-2,3,5-trimethylphenol C9H13NO 详情 详情
(II) 45630 tert-butyl 4-hydroxy-2,3,6-trimethylphenylcarbamate C14H21NO3 详情 详情
(III) 45631 (2S)oxiranylmethyl 4-nitrobenzenesulfonate C9H9NO6S 详情 详情
(IV) 45632 tert-butyl 2,3,6-trimethyl-4-[(2S)oxiranylmethoxy]phenylcarbamate C17H25NO4 详情 详情
(V) 45633 bis(4-fluorophenyl)methanone; 4,4'-Difluorobenzophenone 345-92-6 C13H8F2O 详情 详情
(VI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VII) 45634 (4-fluorophenyl)[4-(1-piperazinyl)phenyl]methanone C17H17FN2O 详情 详情
(VIII) 45635 1-[4-(4-fluorobenzyl)phenyl]piperazine C17H19FN2 详情 详情
(IX) 45636 tert-butyl 4-[((2S)-3-[4-[4-(4-fluorobenzyl)phenyl]-1-piperazinyl]-2-hydroxypropyl)oxy]-2,3,6-trimethylphenylcarbamate C34H44FN3O4 详情 详情

合成路线57

该中间体在本合成路线中的序号：(V)

Condensation of ethyl cyclopentanone-2-carboxylate (I) with pyrazolyl amine (II) in boiling AcOH produced pyrazolopyrimidinol (III), which was then chlorinated by means of POCl3 to give (IV). Finally, displacement of the chlorine atom of (IV) with piperazine in hot DMF furnished the title compound.

参考文献 中间体
合成目标
【1】 Stadler, H.; Boes, M.; Riemer, C. (F. Hoffmann-La Roche AG); Pyrazolopyrimidines and pyrazolotriazines with 5-HT6 receptor affinity. EP 0941994; JP 2000186090 .
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) 29947 ethyl 2-oxocyclopentanecarboxylate 611-10-9 C8H12O3 详情 详情
(II) 33690 3-(methylsulfanyl)-4-(phenylsulfonyl)-1H-pyrazol-5-ylamine; 3-(methylsulfanyl)-4-(phenylsulfonyl)-1H-pyrazol-5-amine C10H11N3O2S2 详情 详情
(III) 33691 2-(methylsulfanyl)-3-(phenylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-8-ol C16H15N3O3S2 详情 详情
(IV) 33692 8-chloro-2-(methylsulfanyl)-3-(phenylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine; 8-chloro-2-(methylsulfanyl)-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-3-yl phenyl sulfone C16H14ClN3O2S2 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线58

该中间体在本合成路线中的序号：(II)

The acylation of piperazine (II) with 4-nitrobenzoyl chloride (I) afforded a mixture of monoacylated (III) and diacylated (IV) products, which were separated by chromatography. Subsequent alkylation of monosubstituted piperazine (III) with 4-nitrophenethyl bromide (V) in the presence of K2CO3 and NaI yielded the title compound.

参考文献 中间体
合成目标
【1】 Kanojia, R.M.; Kauffman, J.; Salata, J.J.; Synthesis and class III type antiarrhythmic activity of 4-aroyl (and aryl)-1-aralkylpiperazines. Bioorg Med Chem Lett 2000, 10, 24, 2819.
【2】 Kanojia, R.M.; et al.; Synthesis and selective class III type antiarrhythmic activity of 4-aroyl (and aryl)-1-aralkylpiperazines. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 204.
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) 18941 p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride 122-04-3 C7H4ClNO3 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 20011 (4-nitrophenyl)(1-piperazinyl)methanone C11H13N3O3 详情 详情
(IV) 40947 [4-(4-nitrobenzoyl)-1-piperazinyl](4-nitrophenyl)methanone C18H16N4O6 详情 详情
(V) 19191 1-(2-bromoethyl)-4-nitrobenzene 5339-26-4 C8H8BrNO2 详情 详情

合成路线59

该中间体在本合成路线中的序号：(V)

8-Bromoquinoline (I) is treated with sec-BuLi in THF to afford lithium derivative (II), which then reacts with carbaldehyde (III) in THF to provide alcohol (IV). Finally, (IV) is converted into the desired compound by chlorination with SOCl2 in CH2Cl2 followed by reaction with piperazine (V) in refluxing acetonitrile.

参考文献 中间体
合成目标
【1】 Delorme, D.; Wei, Z.-Y.; Plobeck, N.; et al.; New diarylmethylpiperazines as potent and selective nonpeptide delta opioid receptor agonists with increased in vitro metabolic stability. J Med Chem 2000, 43, 21, 3878.
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) 45930 8-bromoquinoline 16567-18-3 C9H6BrN 详情 详情
(II) 45931 8-quinolinyllithium C9H6LiN 详情 详情
(III) 45932 N,N-diethyl-4-formylbenzamide C12H15NO2 详情 详情
(IV) 45933 N,N-diethyl-4-[hydroxy(8-quinolinyl)methyl]benzamide C21H22N2O2 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情

合成路线60

该中间体在本合成路线中的序号：(VI)

Nitration of quinazolone (I) by reaction with HNO3/H2SO4 affords 7-chloro-6-nitro-4-quinazolone (II), which is then chlorinated with phosphorus oxychloride (POCl3) to provide quinazoline (III). Selective amination of the quinazoline ring of (III) by reaction with 4-chlorophenethylamine (IV) in isopropanol in the presence of Et3N yields compound (V), which is finally converted into the desired compound by condensation with piperazine (VI) in refluxing butanol in the presence of DIEA. Alternatively the target product can be obtained by the following procedure: Condensation of quinazolone derivative (II) with piperazine (VI) in refluxing butanol in the presence of DIEA affords compound (VII), which is treated with POCl3 and finally subjected to condensation with 4-chlorophenethylamine (IV) in isopropanol in the presence of Et3N.

参考文献 中间体
合成目标
【1】 Matsumoto, M.; Hayashi, H.; Tomizawa, H.; Obara, F.; Nagasaki, T.; Tobe, M.; Isoba, Y.; Structure-activity relationships of quinazoline derivatives: Dual-acting compounds with inhibitory activities toward both TNF-alpha production and T cell proliferation. Bioorg Med Chem Lett 2001, 11, 4, 545.
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) 50077 7-chloro-4(3H)-quinazolinone C8H5ClN2O 详情 详情
(II) 50078 7-chloro-6-nitro-4(3H)-quinazolinone C8H4ClN3O3 详情 详情
(III) 50079 4,7-dichloro-6-nitroquinazoline C8H3Cl2N3O2 详情 详情
(IV) 38459 methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate C13H16N2O2 详情 详情
(V) 50080 N-(7-chloro-6-nitro-4-quinazolinyl)-N-(4-chlorophenethyl)amine; 7-chloro-N-(4-chlorophenethyl)-6-nitro-4-quinazolinamine C16H12Cl2N4O2 详情 详情
(VI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VII) 50081 6-nitro-7-(1-piperazinyl)-4(3H)-quinazolinone C12H13N5O3 详情 详情

合成路线61

该中间体在本合成路线中的序号：(V)

Intramolecular cyclization of p-hydroxy-4-chlorobutyrophenone (I) under alkaline conditions yields cyclopropyl(4-hydroxyphenyl) ketone (II). The phenolic hydroxyl group is then alkylated by 1-bromo-3-chloropropane (III) to furnish the chloropropyl ether (IV). Subsequent condensation of alkyl chloride (IV) with piperazine (V) gives rise to the N-substituted piperazine (VI). This is then coupled with N-Boc-L-alanine (VII) in the presence of EDC/DMAP to afford amide (VIII) (1, 2). After acidic cleavage of the N-Boc protecting group, the resultant monosubstituted piperazine (IX) is acylated by furanoyl chloride (X) to furnish the target furamide derivative

参考文献 中间体
合成目标
【1】 Black, L.A.; Faghih, R.; Liu, H.; et al.; Acyl-D-alanine amides: Selective histamine H3 receptor antagonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 323.
【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 .
【3】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. US 2001049367; US 6559140 .
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) 62995 　 C10H11ClO2 详情 详情
(II) 27425 cyclopropyl(4-hydroxyphenyl)methanone C10H10O2 详情 详情
(III) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(IV) 62988 5-bromo-N-(1H-imidazol-2-yl)-6-quinoxalinamine; N-(5-bromo-6-quinoxalinyl)-N-(1H-imidazol-2-yl)amine C11H8BrN5 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 62996 　 C17H24N2O2 详情 详情
(VII) 15859 Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid 7764-95-6 C8H15NO4 详情 详情
(VIII) 63042 　 C28H23ClN2O2 详情 详情
(IX) 63043 　 C17H15ClN2O2 详情 详情
(X) 26093 2-Furoyl chloride 527-69-5 C5H3ClO2 详情 详情

合成路线62

该中间体在本合成路线中的序号：(V)

Cyclization of 4-chloro-4'-hydroxybutyrophenone (I) in the presence of 50% aqueous NaOH produces cyclopropyl (4-hydroxyphenyl) ketone (II). This is then alkylated with 1-bromo-3-chloropropane (III) to afford the chloropropyl ether (IV). Chloride displacement in (IV) with an excess of piperazine (V) in the presence of KI and K2CO3 furnishes the monosubstituted piperazine (VI). Subsequent coupling of piperazine (VI) with N-Boc-L-alanine (VII) leads to amide (VIII). Finally, Boc group cleavage in (VIII) employing trifluoroacetic acid yields the title compound (1-3).

参考文献 中间体
合成目标
【1】 Faghih, R.; Dwight, W.; Black, L.; Liu, H.; Gentles, R.; Phelan, K.; Esbenshade, T.A.; Ireland, L.; Miller, T.R.; Kang, C.-H.; Krueger, K.M.; Fox, G.B.; Hancock; Bennani, Y.L.; Structure-activity relationships of non-imidazole H(3) receptor ligands. Part 2: Binding preference for D-amino acids motifs. Bioorg Med Chem Lett 2002, 12, 15, 2035.
【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 .
【3】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. US 2001049367; US 6559140 .
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) 62995 　 C10H11ClO2 详情 详情
(II) 27425 cyclopropyl(4-hydroxyphenyl)methanone C10H10O2 详情 详情
(III) 10358 1-Bromo-3-chloropropane 109-70-6 C3H6BrCl 详情 详情
(IV) 62998 [4-(3-chloropropoxy)phenyl](cyclopropyl)methanone C13H15ClO2 详情 详情
(V) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VI) 62996 　 C17H24N2O2 详情 详情
(VII) 15859 Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid 7764-95-6 C8H15NO4 详情 详情
(VIII) 64059 tert-butyl (1R)-2-(4-{3-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1-piperazinyl)-1-methyl-2-oxoethylcarbamate C25H37N3O5 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 condensation of 3,6-dichloropyridazine (I) with piperazine (II) by means of TEA in refluxing toluene gives 3-chloro-6-(1-piperazinyl)pyridazine (III), which is methylated with HCHO/ HCOOH at 110 C, yielding 3-chloro-6-(4-methylpiperazin-1-yl)pyridazine (IV). Finally, this compound is quaternized with methyl iodide in ethyl ether to provide the target dimethylpiperidinium salt.

参考文献 中间体
合成目标
【1】 Toma, L.; et al.; 6-Chloropyridazin-3-yl derivatives active as nicotinic agents: Synthesis, binding, and modeling studies. J Med Chem 2002, 45, 18, 4011.
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 57015 3-chloro-6-(1-piperazinyl)pyridazine C8H11ClN4 详情 详情
(IV) 53381 3-chloro-6-(4-methyl-1-piperazinyl)pyridazine 27464-17-1 C9H13ClN4 详情 详情

合成路线64

该中间体在本合成路线中的序号：

The antibacterial activity of RBx-7644 is due to the 5(S)-acetamidomethyl configuration at the oxazolidinone ring, and thus, asymmetric synthesis of only the 5(S)-enantiomer was desirable: 3,4-Difluoronitrobenzene (I) is condensed with piperazine in acetonitrile to give 4-(2-fluoro-4-nitrophenyl)-piperazine (II) as a light yellow compound. Compound (II) is dissolved in dichloromethane and triethylamine, followed by the addition of Boc-anhydride, to provide compound (III). 4-(tert-Butoxycarbonyl)-1-(2-fluoro-4-nitrophenyl)piperazine (III), upon hydrogenation with H2 over Pd/C in methanol at 50 psi, yields 4-(tert-butoxycarbonyl)-1-(2-fluoro-4-aminophenyl)piperazine (IV) as a dark solid. Compound (IV) reacts with benzylchloroformate in dry THF in the presence of solid sodium bicarbonate to afford the desired compound (V). 4-(tert-Butoxycarbonyl)-1-[2-fluoro-4-(benzyloxycarbonylamino)phenyl]piperazine (V), upon treatment with n-BuLi and (R)-glycidyl butyrate at -78 °C, gives the desired (R)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-5-(hydroxymethyl)-2-oxazolidinone (VI). The hydroxymethyl compound (VI) is treated with methanesulfonyl chloride in dichloromethane in the presence of triethylamine to give (R)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl]-5-(methylsulfonyloxymethyl)-2-oxazolidinone (VII). The sulfonyl derivative (VII) is treated with sodium azide in dimethylformamide to provide the azide (VIII) as a white solid. (R)-(-)-3-[3-Fluoro-4-[4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl]-5-(azidomethyl)-2-oxazolidinone (VIII), upon hydrogenation with H2 over Pd/C at 45 psi, gives (S)-(-)-3-[3-fluoro-4-[4-(tert-butoxycarbonyl)-piperazin-1-yl]phenyl]-5-(aminomethyl)-2-oxazolidinone (IX). The aminomethyl compound (IX), upon treatment with acetic anhydride in dichloromethane in the presence of triethylamine, affords the acetamide derivative (X). The acetamidomethyl-oxazolidinone derivative (X), upon treatment with trifluoroacetic acid, gives (S)-(-)-3-[3-fluoro-4-(1-piperazinyl)phenyl]-5-(acetamidomethyl)-2-oxazolidinone, which, without isolation, is treated with 5-nitro-2-furaldehyde in the presence of sodium triacetoxy borohydride to provide compound (XI). Compound (XI), upon treatment with ethanolic HCl, affords RBx-7644 as a light yellow crystalline solid.

参考文献 中间体
合成目标
【1】 Rattan, A.; RBx-7644. Drugs Fut 2003, 28, 11, 1070.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
18385 (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate 60456-26-0 C7H12O3 详情 详情
51375 5-Nitro-2-furaldehyde; 5-Nitrofurfural 698-63-5 C5H3NO4 详情 详情
(I) 17013 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene 369-34-6 C6H3F2NO2 详情 详情
(II) 18382 1-(2-fluoro-4-nitrophenyl)piperazine C10H12FN3O2 详情 详情
(III) 63060 tert-butyl 4-(2-fluoro-4-nitrophenyl)-1-piperazinecarboxylate C15H20FN3O4 详情 详情
(IV) 63061 tert-butyl 4-(4-amino-2-fluorophenyl)-1-piperazinecarboxylate C15H22FN3O2 详情 详情
(V) 63062 tert-butyl 4-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)-1-piperazinecarboxylate C23H28FN3O4 详情 详情
(VI) 63063 tert-butyl 4-{2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-1-piperazinecarboxylate C19H26FN3O5 详情 详情
(VII) 63064 tert-butyl 4-[2-fluoro-4-((5R)-5-{[(methylsulfonyl)oxy]methyl}-2-oxo-1,3-oxazolidin-3-yl)phenyl]-1-piperazinecarboxylate C20H28FN3O7S 详情 详情
(X) 63067 tert-butyl 4-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-oxazolidin-3-yl}-2-fluorophenyl)-1-piperazinecarboxylate C21H29FN4O5 详情 详情
(XI) 63068 N-{[(5S)-3-(3-fluoro-4-{4-[(5-nitro-2-furyl)methyl]-1-piperazinyl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide C21H24FN5O6 详情 详情

合成路线65

该中间体在本合成路线中的序号：(II)

Condensation of 4-fluorobenzonitrile (I) with piperazine (II) in hot DMSO gives rise to the dinitrile adduct (III). This is then converted into imidate (IV) with HCl/EtOH. Treatment of imidate (IV) with ethanolic ammonia furnishes the corresponding bis-amidine derivative, which is finally isolated as the dihydrochloride salt. (1,2)

参考文献 中间体
合成目标
【1】 Tao, B.; Huang, T.L.; Zhang, Q.; Jackson, L.; Queener, S.F.; Donkor, I.O.; Synthesis and anti-Pneumocystis carinii activity of conformationally restricted analogues of pentamidine. Eur J Med Chem 1999, 34, 6, 531.
【2】 Donkor, I.O.; Huang, T.L.; Tao, B.; Rattendi, D.; Lane, S.; Vargas, M.; Goldberg, B.; Bacchi, C.; Trypanocidal activity of conformationally restricted pentamidine congeners. J Med Chem 2003, 46, 6, 1041.
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) 14144 4-Fluorobenzonitrile 1194-02-1 C7H4FN 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 64041 4-[4-(4-cyanophenyl)-1-piperazinyl]benzonitrile C18H16N4 详情 详情
(IV) 64042 ethyl 4-(4-{4-[ethoxy(imino)methyl]phenyl}-1-piperazinyl)benzenecarboximidoate C22H28N4O2 详情 详情

合成路线66

该中间体在本合成路线中的序号：(II)

Reductive amination of 6-methoxy-1-indanone (I) with piperazine (II) in the presence of titanium isopropoxide and NaBH4 furnishes the indanyl piperazine (III). Racemic amine (III) is then resolved employing (S)-10-camphorsulfonic acid to provide the (R)-enantiomer (IV). Condensation of the optically active piperazine (IV) with ethyl isocyanate then affords the target urea (1-3).

参考文献 中间体
合成目标
【1】 Mattson, R.J.; Catt, J.D.; Keavy, D.; Sloan, C.P.; Epperson, J.; Gao, Q.; Hodges, D.B.; Iben, L.; Mahle, C.D.; Ryan, E.; Yocca, F.D.; Indanyl piperazines as melatonergic MT2 selective agents. Bioorg Med Chem Lett 2003, 13, 6, 1199.
【2】 Mattson, R.J.; Sloan, C.P.; Catt, J.D. (Bristol-Myers Squibb Co.); Novel melatonergic indanyl piperazines or homopiperazines. CA 2175395; EP 0745597 .
【3】 Mattson, R.J.; Catt, J.D. (Bristol-Myers Squibb Co.); Melatonergic indanyl piperazines. US 5780470 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
64586 1-nitrosoethane C2H5NO 详情 详情
(I) 34514 6-methoxy-1-indanone 13623-25-1 C10H10O2 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 64353 1-(6-methoxy-2,3-dihydro-1H-inden-1-yl)piperazine; methyl 3-(1-piperazinyl)-2,3-dihydro-1H-inden-5-yl ether C14H20N2O 详情 详情
(IV) 64354 1-[(1R)-6-methoxy-2,3-dihydro-1H-inden-1-yl]piperazine; methyl (3R)-3-(1-piperazinyl)-2,3-dihydro-1H-inden-5-yl ether C14H20N2O 详情 详情

合成路线67

该中间体在本合成路线中的序号：(XI)

Reaction of 2-carboxybenzaldehye (I) with dimethyl phosphite in the presence of MeONa in MeOH affords the isobenzofuranylphosphonate (II), which is condensed with 2-fluoro-5-formylbenzonitrile (III) by means of triethylamine in THF to give the benzylidene-isobenzofuranone (IV). Basic hydrolysis of the nitrile group of compound (IV) followed by treatment with hydrazine hydrate leads to the phthalazinone-carboxylic acid (V) (1-3), which can also be obtained by treatment of isobenzofuranone (IV) first with hydrazine hydrate in THF, followed by hydrolysis of the resulting phthalazinone nitrile (VI) with aqueous NaOH (2). Coupling of carboxylic acid (V) with N-Boc-piperazine (VII) by means of HBTU and DIEA in dimethylacetamide yields the Boc-protected amide (VIII), which is then deprotected to compound (IX) by treatment with HCl in EtOH or MeOH. Finally, piperazine-phthalazinone (IX) is acylated with cyclopropanecarbonyl chloride (X) in the presence of triethylamine or DIEA in CH2Cl2 (1, 2). Alternatively, condensation of piperazine (XI) with cyclopropanecarbonyl chloride (X) in AcOH solution gives N-(cyclopropylcarbonyl)piperazine (XII) (2), which is then coupled with the phthalazinone-carboxylic acid (V) by means of HBTU and DIEA in acetonitrile or dimethylacetamide (2, 3). Scheme 1.

参考文献 中间体
合成目标
【1】 Martin, N.M.B., Smith, G.C.M., Jackson, S.P. et al. (KuDOS Pharmaceuticals Ltd.; Maybridge Ltd.). Phthalazinone derivatives. CA 2517629, EP 1633724, GB 2415430, JP 2006519837, JP 2008001718, US 2005059663, US 2006149059, US 2008200469, US 7449464, WO 2004080976.
【2】 Menear, K.A., Ottridge, A.P., Londesbrough, D.J. et al. (KuDOS Pharmaceuticals Ltd.). Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one. US 2008146575, WO 2008047082.
【3】 Menear, K.A., Adcock, C., Boulter, R. et al. 4-[3-(4-Cyclopropanecarbonyl piperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A novel bioavailable inhibitor of poly (ADP-ribose) polymerase-1. J Med Chem 2008, 51(20): 6581-91.
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) 65828 3-hydroxy-2-benzofuran-1(3H)-one 　 C8H6O3 详情 详情
(II) 65829 Dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate; (3-Oxo-1,3-dihydroisobenzofuran-1-yl)phosphonic acid dimethyl ester 61260-15-9 C10H11O5P 详情 详情
(III) 65830 3-Cyano-4-fluorobenzaldehyde; 2-Fluoro-5-formylbenzonitrile 218301-22-5 C8H4FNO 详情 详情
(IV) 65831 2-Fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile 763114-25-6 C16H8FNO2 详情 详情
(V) 65832 2-Fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid 763114-26-7 C16H11FN2O3 详情 详情
(VI) 65833 　 　 C16H10FN3O 详情 详情
(VII) 13225 N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18N2O2 详情 详情
(VIII) 65834 　 　 C25H27FN4O4 详情 详情
(IX) 65835 1-[5-[(3,4-Dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine 763111-47-3 C20H19FN4O2 详情 详情
(X) 14061 Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride 4023-34-1 C4H5ClO 详情 详情
(XI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(XII) 65836 1-(Cyclopropylcarbonyl)piperazine 59878-57-8 C8H14N2O 详情 详情

合成路线68

该中间体在本合成路线中的序号：(I)

　

参考文献 中间体
合成目标
【1】 Deshpande PB, Chauhan AJ. 2006. Crystalline and amorphous form of ranolazine and the process for manufacturing them. WO 2006008753
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) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(II) 24103 2-[(2-methoxyphenoxy)methyl]oxirane C10H12O3 详情 详情
(III) 24109 1-(2-methoxyphenoxy)-3-(1-piperazinyl)-2-propanol C14H22N2O3 详情 详情
(IV) 24100 2-chloro-N-(2,6-dimethylphenyl)acetamide 2198-53-0 C10H12ClNO 详情 详情

合成路线69

该中间体在本合成路线中的序号：(VI)

Condensation of 2-bromoiodobenzene (I) with 2,4-dimethylthiophenol (II) by means of either Pd2(dba)3 or Pd(dba)2, t-BuOK and DPEphos or Pd(dba)2, BINAP and t-BuONa in toluene yields 1-(2-bromophenylsulfanyl)-2,4-dimethylbenzene (III) , which alternatively can be prepared by reaction of either 1-iodo- or 1-bromo-2,4-dimethylbenzene (IVa or IVb) with 2-bromobenzenethiol (V) in the presence of Pd2(dba)3 and DPEphos . Then, aryl bromide (III) is condensed with piperazine (VI) in the presence of Pd(dba)2, BINAP and t-BuONa in toluene to give the free base (VII) , which is finally treated with HBr in MeOH , EtOAc or toluene .
The free base (VII) can be alternatively prepared in a one-pot procedure by reaction of 2-bromoiodobenzene (I) with 2,4-dimethylthiophenol (II) and piperazine (VI) in the presence of Pd(dba)2, BINAP and t-BuONa .
Reaction of 2-bromoiodobenzene (I) with N-Boc-piperazine (VIII) by means of Pd2(dba)3 and xantphos affords the arylpiperazine (IX) , which is then condensed with 2,4-dimethylthiophenol (II) in the presence of Pd2(dba)3, t-BuOK and DPEphos in toluene at 100 °C to give the thioether (X) . Finally, compound (X) is submitted to N-deprotection with HBr in refluxing H2O .
Alternatively, reaction of thioether (III) with N-Boc-piperazine (VIII) in the presence of Pd(dba)2 or Pd2(dba)3, BINAP , and optionally, t-BuONa in toluene , provides the N-Boc-protected arylpiperazine (X), which is then N-deprotected with HCl in refluxing MeOH to give the free base (VII) .
In a solid-phase method, binding of piperazine (VI) to the p-nitrophenyl carbonate resin (XI) in the presence of NMM in DMF results in the 4-[(1-piperazinyl)carboxymethyl]phenoxymethyl polystyrene (XII), which is then condensed with [η6-1,2-dichloro-benzene][η5-cyclopentadienyl] iron hexafluorophosphate (XIII) in the presence of K2CO3 in THF to afford the N,N’-disubstituted piperazine (XIV). Finally, the resin-bound piperazine (XIV) is condensed with 2,4-dimethylthiophenol (II) (previously treated with NaH), and subsequently subjected to photolytic decomplexation, and further acidic cleavage from the resin (TFA/CH2Cl2), leading to the free base (VII) .

参考文献 中间体
合成目标
【1】 Bang-Andersen, B., Faldt, A., Moerk, A. et al. (H. Lundbeck A/S). 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of cognitive impairment. EP 2044043, JP 2009541216, JP 2010090165, US 2010297240, WO 2007144005.
【2】 Bang-Andersen, B., Ruhland, T., Smith, G. et al. Discovery of Lu AA21004: A novel compound for the treatment of mood disorders. 237th ACS Natl Meet (March 22-2, Salt Lake City) 2009, Abst MEDI 103.
【3】 Moore, N., Stensboel, T.B. (H. Lundbeck A/S). 1-[2-(2,4-Dimethylphenylsulfanyl)-phenyl]piperazine as a compound with combined serotonin reuptake, 5-HT3 and 5-HT1A activity for the treatment of pain or residual symptoms in depression relating to sleep and cognition. CA 2684571, EP 2142193, JP 201052501, US 2011009422, WO 2008113359.
【4】 Nicolajsen, H.V., Lopez de Diego, H., Rock, M.H. (H. Lundbeck A/S). Purification of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine. WO 2010094285.
【5】 Bang-Andersen, B., Ruhland, T., Jorgensen, M. et al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (LU AA21004): A novel multimodal compound for the treatment of major depressive disorder. J Med Chem 2011 54(9): 3206-21.
【6】 Smith, G.P., Pueschl, A., Moltzen, E.K., Ruhland, T., Bang-Andersen, B., Andersen, K. (H. Lundbeck A/S). Phenyl-piperazine derivatives as serotonin reuptake inhibitors. EP 1436271, EP 1749818, JP 2005505585, JP 2007031447, JP 2007051149, US 2006084662, US 2006089368, US 7138407, US 7144884, US 7148238, US 2007060574, US 7683053, US 2011009423, WO 2003029232.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IVa) 68826 1-iodo-2,4-dimethylbenzene;2,4-Dimethyliodobenzene;1,3-Dimethyl-4-iodobenzene;4-Iodo-m-xylene 4214-28-2 C8H9I 详情 详情
(IVb) 68827 1-bromo-2,4-dimethylbenzene;2,4-Dimethylbromobenzene;4-Bromo-1,3-dimethylbenzene;4-Bromo-m-xylene 583-70-0 C8H9Br 详情 详情
(I) 68823 2-bromoiodobenzene;o-Iodobromobenzene;o-Bromophenyl iodide;o-Bromoiodobenzene;2-Iodobromobenzene;2-Bromophenyliodide;2-Bromo-1-iodobenzene;1-Iodo-2-bromobenzene;1-Bromo-2-iodobenzene 583-55-1 C6H4BrI 详情 详情
(II) 68824 2,4-dimethylthiophenol;2,4-Dimethylbenzenethiol 13616-82-5 C8H10S 详情 详情
(III) 68825 1-(2-bromophenylsulfanyl)-2,4-dimethylbenzene;(2-bromophenyl)(2,4-dimethylphenyl)sulfane C14H13BrS 详情 详情
(V) 52030 2-Bromobenzenethiol; 2-Bromothiophenol;2-bromo-benzenethio;2-Bromo thiophenol 6320-02-1 C6H5BrS 详情 详情
(VI) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(VII) 68828 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine 　 C18H22N2S 详情 详情
(VIII) 13225 N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18N2O2 详情 详情
(IX) 68829 tert-butyl 4-(2-bromophenyl)piperazine-1-carboxylate;1-BOC-4-(2-Bromophenyl)piperazine;4-(2-BROMO-PHENYL)-PIPERAZINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER 494773-35-2 C15H21BrN2O2 详情 详情
(X) 68830 tert-butyl 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carboxylate 　 C23H30N2O2S 详情 详情
(XII) 68831 4-[(1-piperazinyl)carboxymethyl]phenoxymethyl polystyrene 　 　 详情 详情
(XIII) 68832 [η6-1,2-dichloro-benzene][η5-cyclopentadienyl]iron hexafluorophosphate 　 　 详情 详情
Extended Information