Yaozh News Star Club Edu BBS TOP100 Customer Service APP
Iphone Download Android Download
  • English
  • 简体中文
Login Register
Search
Current Location： Home > Feedback Help Print

【结 构 式】

【分子编号】14005

【品名】2-Bromoacetyl bromide; Bromoacetyl bromide

【CA登记号】598-21-0

【 分 子 式 】C2H2Br2O

【 分 子 量 】201.84528

【元素组成】C 11.9% H 1% Br 79.17% O 7.93%
与该中间体有关的原料药合成路线共 28 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23合成路线24合成路线25合成路线26合成路线27合成路线28

合成路线1

该中间体在本合成路线中的序号：(IV)

The benzoylation of 1,3,5(10)-estratrien-3,17beta-diol (I) with benzoyl chloride (II) by means of NaOH in THF-water gives 3-benzoyloxy-1,3,5(10)-estratrien-17beta-ol (III), which is acylated with bromoacetyl bromide (IV) by means of pyridine in THF-CCl4 yielding 3-benzoyloxy-17beta-bromoacetoxy 1,3,5(10)-estratriene (V). Finally, this compound is condensed with silver 4-[4-[bis(2-chloroethyl)amino]phenyl]butyrate (VI) in DMSO.

参考文献 中间体
合成目标
【1】 Asano, K.; Tamura, H.; Tanaka, H.; Enomoto, S.; Novel estradiol compound, its preparation and anti-tumor agent containing the same. BE 0878186; JP 55027121 .
【2】 Castaner, J.; Serradell, M.N.; KM-2210. Drugs Fut 1984, 9, 5, 334.
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) 34210 (8R,9S,13S,14S,17S)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3,17-diol 50-28-2 C18H24O2 详情 详情
(II) 10643 (1S,2S,3R,4S,7S,8S,10R,13S)-10-(acetoxy)-1,7-bis(benzyloxy)-13-[[tert-butyl(dimethyl)silyl]oxy]-8,12,15,15-tetramethyl-5,9-dioxo-4-[(phenylsulfanyl)methyl]tricyclo[9.3.1.0(3,8)]pentadec-11-en-2-yl benzoate C55H66O9SSi 详情 详情
(III) 34211 (8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl benzoate C25H28O3 详情 详情
(IV) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(V) 34212 (8R,9S,13S,14S,17S)-17-[(2-bromoacetyl)oxy]-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl benzoate C27H29BrO4 详情 详情
(VI) 34213 silver(1+) 4-[4-[bis(2-chloroethyl)amino]phenyl]butanoate C14H18AgCl2NO2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(A)

The methylation of 2-amino-5-chlorobenzophenone (I) with dimethyl-sulfate affords the 5-chloro-2-methylaminobenzophenone (II), which is conden-sed with bromoacetyl bromide (A) to yieId 2-(2-bromo-N-methylacetamido)-5-chlorobenzophenone (III). The amonolysis of (III) with ammonia in methanol gives 2-(2-amino-N-methylacetamido)-5-chlorobenzophenone (IV), which is finally condensed with diketene (B) in refluxing acetone. This product can also be obtained by condensation of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (V) with acetyl chloride (C) and triethylamine in ether or with diketene (B) in acetone.

参考文献 中间体
合成目标
【1】 Szmuszkovicz, J.; et al.; Tetrahedron Lett 1971, 39, 39, 3665.
【2】 Szmuszkovicz, J.; Oxazinobenzodiazepine derivatives. DE 1947226; ES 371392; FR 2018432; GB 1222294 .
【3】 Szmuszkovicz, J.; Process for the preparation of 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d]benzodiazepine-4,7-6H-dione. CH 530414; JP 49025953B; NL 7014824; US 3575965 .
【4】 Castaner, J.; Chatterjee, S.S.; Ketazolam. Drugs Fut 1976, 1, 6, 293.
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) 11367 4-Methylene-2-oxetanone; Acetyl ketene 674-82-8 C4H4O2 详情 详情
(A) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(I) 10279 (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone 719-59-5 C13H10ClNO 详情 详情
(II) 33972 [5-chloro-2-(methylamino)phenyl](phenyl)methanone 1022-13-5 C14H12ClNO 详情 详情
(III) 33973 N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-methylacetamide C16H13BrClNO2 详情 详情
(IV) 33974 2-amino-N-(2-benzoyl-4-chlorophenyl)-N-methylacetamide C16H15ClN2O2 详情 详情
(V) 33975 7-chloro-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one C16H15ClN2O 详情 详情
(C) 19273 acetyl chloride 75-36-5 C2H3ClO 详情 详情

合成路线3

该中间体在本合成路线中的序号：(B)

1) The alkylation of 2-amino-5-chlorobenzophenone (I) with 2,2,2-trifluoroethyl trichloromethansulfonate (II) in refluxing xylene gives the N-trifluoroethyl derivative (III), which is then cyclized with glycine ethyl ester (A) in refluxing pyridine. 2) Compound (III) can also be bromoacetylated with bromoacetyl bromide (B) in refluxing benzene yielding the N-bromoacetyl compound (IV), which is then cyclized with ammonia in CHCl3. 3) By alkylation of 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IX) with NaOMe and 2,2,2-trifluoroethyl iodide in MeOH.

参考文献 中间体
合成目标
【1】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 .
【2】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 .
【3】 Topliss, J.G.; Verfahren zur Herstellung von neuen 1,4-benzodiazepinen bzw. ihren 4-Oxyden. CH 505842; DE 1793682; FR 1518382; GB 1179125 .
【4】 Castaner, J.; Thorpe, P.; Halazepam. Drugs Fut 1978, 3, 2, 109.
【5】 Topliss, J.G.; Steinman, M.; Alekel, R.; Wong, Y.S.; York, E.E.; 1-Polyfluoroalkylbenzodiazepines. J Med Chem 1973, 16, 12, 1354-60.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
18806 1,1,1-trifluoro-2-iodoethane 353-83-3 C2H2F3I 详情 详情
(A) 10309 ethyl 2-aminoacetate; Glycine ethyl ester 459-73-4 C4H9NO2 详情 详情
(B) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(I) 10279 (2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone 719-59-5 C13H10ClNO 详情 详情
(II) 33474 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate 23199-56-6 C3H2Cl3F3O3S 详情 详情
(III) 33848 [5-chloro-2-[(2,2,2-trifluoroethyl)amino]phenyl](phenyl)methanone C15H11ClF3NO 详情 详情
(IV) 33849 N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-(2,2,2-trifluoroethyl)acetamide C17H12BrClF3NO2 详情 详情
(IX) 10281 7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one; 1,4-benzdiazepin-2-one-5-phenyl-7-chloro 1088-11-5 C15H11ClN2O 详情 详情

合成路线4

该中间体在本合成路线中的序号：(B)

N-bromoacetyl compound (IV) can also be obtained by bromoacetylation of (XV) with bromoacetyl bromide (B) in refluxing benzene affording 4-chloro-N-bromoacetyl-N-(2,2,2-trifluoroethyl)aniline (XVI), followed by a Friedel-Crafts reaction with benzoyl chloride by means of AlCl3.

参考文献 中间体
合成目标
【1】 Topliss, J.G.; 2-Polyfluoroweralkyl benzophenones. US 3641147 .
【2】 Topliss, J.G.; 1-Polyhalogenoalkyl-2-oxo-1,3-dihydro-2H-14-benzodiazepines. US 3429874 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(B) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(IV) 33849 N-(2-benzoyl-4-chlorophenyl)-2-bromo-N-(2,2,2-trifluoroethyl)acetamide C17H12BrClF3NO2 详情 详情
(XV) 33475 N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)amine; 4-chloro-N-(2,2,2-trifluoroethyl)aniline C8H7ClF3N 详情 详情
(XVI) 33852 2-bromo-N-(4-chlorophenyl)-N-(2,2,2-trifluoroethyl)acetamide C10H8BrClF3NO 详情 详情

合成路线5

该中间体在本合成路线中的序号：(V)

Condensation of the chiral 2-chloro-3-(alpha-methylbenzyl)tetrahydro-2H-1,3,2-oxaazaphosphorine 2-oxide (I) with 2-chloroethylamine (II) afforded the 2-(chloroethylamino) derivative (III). The chiral auxiliary group of (III) was then removed by catalytic hydrogenation with H2 over -Pd/C yielding (R)-2-(2-chloroethylamino)tetrahydro-2H-1,3,2-oxaazaphosphorine 2-oxide (IV). Acylation of (IV) with bromoacetyl bromide (V) in the presence of triethylamine hydrobromide furnished bromoacetamide (VI). The amide carbonyl group of (VI) was finally reduced by treatment with NaBH4 and BF3·Et2O.

参考文献 中间体
合成目标
【1】 Kinas, R.W.; Stec, W.J.; Kusnierczyk, H.; Misiura, K.; radzikowski, C.; (S)-(-)-Bromofosfamide (CBM-11): Synthesis and antitumor activity and cytotoxicity in mice. Anti-Cancer Drugs 2001, 12, 5, 453.
【2】 Kutner, A.; Grynkiewicz, G.; Stec, W.J.; Radzikowski, C.; Szelejeswki, W.; Kinas, R.; Misiura, K.; Grodner, J.; Kusnierczyk, H.; Pilichowska, S.; Process for the production of the derivs. of 1,3,2-oxazaphosphorinane. EP 0295576 .
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) 56222 2-chloro-3-[(1S)-1-phenylethyl]-1,3,2lambda~5~-oxazaphosphinan-2-one C11H15ClNO2P 详情 详情
(II) 33455 2-chloro-1-ethanamine; 2-chloroethylamine C2H6ClN 详情 详情
(III) 56223 2-[(2-chloroethyl)amino]-3-[(1S)-1-phenylethyl]-1,3,2lambda~5~-oxazaphosphinan-2-one C13H20ClN2O2P 详情 详情
(IV) 56224 2-[(2-chloroethyl)amino]-1,3,2lambda~5~-oxazaphosphinan-2-one C5H12ClN2O2P 详情 详情
(V) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(VI) 56225 3-(2-bromoacetyl)-2-[(2-chloroethyl)amino]-1,3,2lambda~5~-oxazaphosphinan-2-one C7H13BrClN2O3P 详情 详情

合成路线6

该中间体在本合成路线中的序号：(V)

2-Aminobenzophenone (I) is acylated with bromoacetyl bromide followed by reaction with ammonia to form the [1,4]benzodiazepine. N1-Methylation produces 1,3-dihydro-1-methyl-5-phenyl-2H-[1,4]benzodiazepin-2-one (II). Treatment with isoamyl nitrate and t-BuOK gives an oxime, which is reduced by catalytic hydrogenation to racemic 3-amino-benzodiazepine (III), which is isolated as the crystalline benzenesulfonic acid salt. Crystallization-induced asymmetric transformation yields 3(S)-(-)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-[1,4]benzodiazepin-2-one (IV). Acylation with indole-2-carbonylimidazolide produces MK-329.

参考文献 中间体
合成目标
【1】 Reider, P.J.; Davis, P.; Grabowski, E.J.J.; Hughes, D.L.; Crystallization-induced asymmetric transformation: Stereospecific synthesis of a potent peripheral CCK antagonis. J Org Chem 1987, 52, 955.
【2】 Freidinger, R.M.; Berlin, R.G.; MK-329. Drugs Fut 1989, 14, 9, 862.
【3】 Veber, D.F.; Freidinger, R.M.; Hirshfield, J.; Rittle, K.E.; Springer, J.P.; DiPardo, R.M.; Bock, M.G.; Evans, B.E.; Synthesis and resolution of 3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones. J Org Chem 1987, 52, 3232.
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) 21101 (2-aminophenyl)(phenyl)methanone; 2-Aminobenzophenone 2835-77-0 C13H11NO 详情 详情
(II) 21319 1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one C16H14N2O 详情 详情
(III) 21320 3-Amino-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one benzenesulfonate C22H21N3O4S 详情 详情
(IV) 21321 (3S)-3-amino-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one C16H15N3O 详情 详情
(V) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(VI) 21323 3,5-dichloro-2-hydroxybenzaldehyde; 3,5-Dichlorosalicylaldehyde 90-60-8 C7H4Cl2O2 详情 详情
(VII) 21324 1H-imidazol-1-yl(1H-indol-2-yl)methanone C12H9N3O 详情 详情

合成路线7

该中间体在本合成路线中的序号：(VIII)

Several novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), a key intermediate in the synthesis of losartan, have been described: 1) Treatment of glycine methyl ester hydrochloride (I) with NaOH in methanol, followed by reaction with methyl pentanimidate (II), gives 2-butyl-4,5-dihydro-1H-imidazol-5-one (III), which is treated with POCl3 to give the 2-butyl-5-chloro-1H-imidazole (IV). Reaction of (IV) with POCl3 and DMF yields the enamine (V), which is finally hydrolyzed with water to 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), the desired intemediate in the synthesis of losartan. 2) Imidazolinone (III) can also be obtained by cyclization of chloroacetic acid methyl ester (VI), chloroacetyl chloride (VII) or bromoacetyl bromide (VIII) with pentanamidine (IX) by means of NaOH in methanol. 3) Alternatively, imidazolinone (III) can be treated with dimethylformamide dimethylacetal in dichloromethane yielding the enamine (X), which is finally treated with POCl3 and hydrolyzed with water. 4) The reaction of glycine (XI) with methyl pentanimidate (II) in NaOH/MeOH gives amidine (XII), which, without isolation, is treated with POCl3 and DMF at 100 C for 2 h, and then hydrolyzed with water to give the desired 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde. Methyl pentanimidate (II) is obtained treating a solution of valeronitrile in MeOH with HCl gas followed by neutralization with aqueous KOH and extraction with Et2O.

参考文献 中间体
合成目标
【1】 Kohr, J.; Griffiths, G.J.; Imwinkelried, R.; Hauck, M.B.; Roten, C.A.; Stucky, G.C.; Novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde: A key intermediate for the synthesis of the angiotensin II antagonist losartan. J Org Chem 1999, 64, 22, 8084.
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) 17568 methyl 2-aminoacetate C3H7NO2 详情 详情
(II) 34050 methyl pentanimidoate C6H13NO 详情 详情
(III) 34051 2-butyl-3,5-dihydro-4H-imidazol-4-one C7H12N2O 详情 详情
(IV) 34052 2-butyl-5-chloro-1H-imidazole C7H11ClN2 详情 详情
(V) 34053 N-[(2-butyl-5-chloro-4H-imidazol-4-ylidene)methyl]-N,N-dimethylamine; (2-butyl-5-chloro-4H-imidazol-4-ylidene)-N,N-dimethylmethanamine C10H16ClN3 详情 详情
(VI) 10257 methyl 2-chloroacetate; methyl chloroacetate 96-34-4 C3H5ClO2 详情 详情
(VII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(VIII) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(IX) 14576 pentanimidamide 109-51-3 C5H12N2 详情 详情
(X) 34054 2-butyl-5-[(E)-(dimethylamino)methylidene]-3,5-dihydro-4H-imidazol-4-one C10H17N3O 详情 详情
(XI) 13925 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde 83857-96-9 C8H11ClN2O 详情 详情
(XII) 20436 glycine 56-40-6 C2H5NO2 详情 详情
(XIII) 34055 2-(pentanimidoylamino)acetic acid C7H14N2O2 详情 详情
(XIV) 13921 Pentanenitrile; n-Valeronitrile 110-59-8 C5H9N 详情 详情

合成路线8

该中间体在本合成路线中的序号：(VI)

The condensation of 2-chlorobenzoyl chloride (I) with cyanacetic acid (II) by means of butyllithium in THF gives 2-(2-chlorobenzoyl)acetonitrile (III), which is cyclized with N-(ethoxycarbonyl)piperidin-4-one (IV) by means of S and morpholine in refluxing methanol yielding the bicyclic ethyl ester (V). The acylation of (V) with bromoacetyl bromide (VI) in chloroform affords the corresponding 2-(bromoacetamido) derivative (VII), which by reaction with dry ammonia in THF is converted into the 2-glycinamido derivative (VIII). The cyclization of (VIII) in refluxing pyridine gives the tricyclic ethyl ester (IX), which by reaction with P2S5 in refluxing pyridine is converted into the corresponding thioketone (X). The reaction of (X) with hydrazine in methanol yields the 2-hydrazino derivative (XI), which is acylated with acetyl chloride (XII) and NaHCO3 in THF affording the 2-(acetylhydrazino) derivative (XIII). The cyclization of (XIII) in refluxing acetic acid gives the tetracyclic ethyl ester (XIV), which is decarboxylated with 30% HBr yielding the tetracyclic precursor (XV). The acylation of (XV) with 2-(3,4-dimethoxyphenylthio)acetic acid (XVI) by means of dicyclohexylcarbodiimide (DCC) in DMF affords the acylated compound (XVII), which is finally treated with P2S5 or Lawesson's reagent.

参考文献 中间体
合成目标
【1】 Braquet, P.; Esanu, A.; Laurent, J.-P.; Pommier, J. (SCRAS (Societé de Conseils de Recherches et d'Applications Scientifiques)); Thieno-triazolo-diazepine derivs. and process for their preparation. BE 1004122; CH 681009; DE 4015137; FR 2646774; FR 2646851; GB 2231330; JP 1991005484; US 5049559 .
【2】 Braquet,P.; Castaner, J.; Duverger, D.; Koltai, M.; Spinnewyn, B.; Pirotzky, E.; Esanu, A.; BN 50739. Drugs Fut 1991, 16, 5, 413.
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) 14000 o-Chlorobenzoyl chloride; 2-Chlorobenzoyl chloride 609-65-4 C7H4Cl2O 详情 详情
(II) 12591 Cyanoacetic Acid; 2-Cyanoacetic acid 372-09-8 C3H3NO2 详情 详情
(III) 12923 3-(2-Chlorophenyl)-3-oxopropanenitrile 40018-25-5 C9H6ClNO 详情 详情
(IV) 13486 Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone 29976-53-2 C8H13NO3 详情 详情
(V) 14004 ethyl 2-amino-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate C17H17ClN2O3S 详情 详情
(VI) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(VII) 14006 ethyl 2-[(2-bromoacetyl)amino]-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate C19H18BrClN2O4S 详情 详情
(VIII) 14007 ethyl 2-[(2-aminoacetyl)amino]-3-(2-chlorobenzoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate C19H20ClN3O4S 详情 详情
(IX) 14008 ethyl 5-(2-chlorophenyl)-2-oxo-1,2,3,6,7,9-hexahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate C19H18ClN3O3S 详情 详情
(X) 14009 ethyl 5-(2-chlorophenyl)-2-thioxo-1,2,3,6,7,9-hexahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate C19H18ClN3O2S2 详情 详情
(XI) 14010 ethyl 5-(2-chlorophenyl)-2-hydrazino-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate C19H20ClN5O2S 详情 详情
(XII) 14011 1-(Chlorooxy)-1-oxoethane C2H3ClO2 详情 详情
(XIII) 14012 ethyl 2-(2-acetylhydrazino)-5-(2-chlorophenyl)-3,6,7,9-tetrahydro-8H-pyrido[4',3':4,5]thieno[2,3-e][1,4]diazepine-8-carboxylate C21H22ClN5O3S 详情 详情
(XIV) 14013 ethyl 6-(2-chlorophenyl)-1-methyl-7,10-dihydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-9(8H)-carboxylate C21H20ClN5O2S 详情 详情
(XV) 14014 6-(2-Chlorophenyl)-1-methyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine C18H16ClN5S 详情 详情
(XVI) 14015 2-[(3,4-Dimethoxyphenyl)sulfanyl]acetic acid 95735-63-0 C10H12O4S 详情 详情
(XVII) 14016 1-[6-(2-Chlorophenyl)-1-methyl-7,10-dihydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-9(8H)-yl]-2-[(3,4-dimethoxyphenyl)sulfanyl]-1-ethanone C28H26ClN5O3S2 详情 详情

合成路线9

该中间体在本合成路线中的序号：(IV)

Nitration of minocycline (I) with KNO3 and H2SO4 gives the 9-nitro derivative (II), which is reduced with H2 over Pd/C in 2-methoxyethanol/2N H2SO4 to provide 9-aminominocycline (III). Acylation of compound (III) with 2-bromoacetyl bromide (IV) in N,N-dimethylpropyleneurea (DMPU) affords 9-(2-bromoacetamido)minocycline (V). Finally, this compound is treated with tert-butylamine (VI) to yield, after purification, GAR-936.

参考文献 中间体
合成目标
【1】 Hunter, P.A.; Castaner, J.; GAR-936. Drugs Fut 2001, 26, 9, 851.
【2】 Sum, P.-E.; Petersen, P.; Synthesis and structure-activity relationship of novel glycylcline derivatives leading to the discovery of GAR-936. Bioorg Med Chem Lett 1999, 9, 10, 1459.
【3】 Sum, P.-E.; Lee, V.J. (American Cyanamid Co.); Method of producing 7-(substd.)-9-[(substd. glycyl)amidol]-6-demethyl-6-deoxytetracyclines. EP 0582790; US 5284963 .
【4】 Sum, P.-E.; Lee, V.J.; Testa, R.T.; Hlavka, J.J.; Ellestad, G.A.; Bloom, J.D.; Gluzman, Y.; Tally, F.P.; Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines. J Med Chem 1994, 37, 1, 184-8.
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) 16360 (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide 10118-90-8 C23H27N3O7 详情 详情
(II) 16361 (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide C23H26N4O9 详情 详情
(III) 16362 (4S,4aS,5aR,12aS)-9-amino-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide C23H28N4O7 详情 详情
(IV) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(V) 48570 (4S,4aS,5aR,12aS)-9-[(2-bromoacetyl)amino]-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamide C25H29BrN4O8 详情 详情
(VI) 17895 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine 75-64-9 C4H11N 详情 详情
(VII) 48571 2-(tert-butylamino)acetyl chloride C6H12ClNO 详情 详情

合成路线10

该中间体在本合成路线中的序号：(IX)

2) An improved procedure consisted of condensation of 5-nitroisatoic anhydride (I) with beta-alanine ethyl ester (V) to give amide (XIV). The amino group of (XIV) was protected with benzhydryl bromide (VII) yielding (XV), and then the nitro group of (XV) was reduced to aniline (XVI) by catalytic transfer hydrogenation. Protection of the amine of (XVI) as the tert-butyl carbamate (XVIII) was effected using 2-(tert-butoxycarbonyloxymino)-2-phenylacetonitrile (XVII). The sequence of condensation of (XVIII) with bromoacetyl bromide (IX), followed by cyclization of the intermediate bromoacetamide with DBU provided the benzodiazepinedione (XIX). Hydrogenolysis of the N-benzhydryl group of (XIX) in the presence of Pearlman's catalyst, followed by treatment with trimethylsilyl azide furnished the tetrazole (XX). The Boc group of (XX) was deprotected with trifluoroacetic acid, and subsequent coupling with 4-cyanobenzoyl chloride (III) gave amide (XXI). The cyano group was of (XXI) then converted to hydroxyamidine (XXII) with hydroxylamine. Catalytic hydrogenation of (XXII) in the presence of Ac2O and AcOH produced the corresponding amidine. Finally, the ester group was hydrolyzed with LiOH.

参考文献 中间体
合成目标
【1】 Robarge, K.D.; Dina, M.S.; Somers, T.C.; Lee, A.; Rawson, T.E.; Olivero, A.G.; Tischler, M.H.; Webb, R.R. II; Weese, K.J.; Aliagas, I.; Blackburn, B.K.; Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists. Bioorg Med Chem 1998, 6, 12, 2345.
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) 22347 5-Nitroisatoic anhydride; 6-nitro-2H-3,1-benzoxazine-2,4(1H)-dione 4693-02-1 C8H4N2O5 详情 详情
(III) 19280 4-cyanobenzoyl chloride 6068-72-0 C8H4ClNO 详情 详情
(VII) 17639 beta-Alanine, ethyl ester; ethyl 3-aminopropanoate 924-73-2 C5H11NO2 详情 详情
(IX) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XIV) 22360 ethyl 3-[(2-amino-5-nitrobenzoyl)amino]propanoate C12H15N3O5 详情 详情
(XV) 22361 ethyl 3-[[2-(benzhydrylamino)-5-nitrobenzoyl]amino]propanoate C25H25N3O5 详情 详情
(XVI) 22362 ethyl 3-[[5-amino-2-(benzhydrylamino)benzoyl]amino]propanoate C25H27N3O3 详情 详情
(XVII) 22363 2-[[(tert-butoxycarbonyl)oxy]imino]-2-phenylacetonitrile 58632-95-4 C13H14N2O3 详情 详情
(XVIII) 22364 ethyl 3-([2-(benzhydrylamino)-5-[(tert-butoxycarbonyl)amino]benzoyl]amino)propanoate C30H35N3O5 详情 详情
(XIX) 22365 ethyl 3-[1-benzhydryl-7-[(tert-butoxycarbonyl)amino]-2,5-dioxo-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl]propanoate C32H35N3O6 详情 详情
(XX) 22366 ethyl 3-[8-[(tert-butoxycarbonyl)amino]-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate C19H24N6O5 详情 详情
(XXI) 22357 ethyl 3-[8-[(4-cyanobenzoyl)amino]-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate C22H19N7O4 详情 详情
(XXII) 22368 ethyl 3-[8-([4-[amino(hydroxyimino)methyl]benzoyl]amino)-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate C22H22N8O5 详情 详情

合成路线11

该中间体在本合成路线中的序号：(V)

C1-C6 fragment.- The reaction of 3-methyl-2-butenylmagnesium chloride (I) with propanal (II) gives racemic 4,4-dimethyl-5-hexen-3-ol (III), which was submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme yielding the (R) enantiomer (IV). The esterification of (IV) with bromoacetyl bromide (V) and dimethylaniline yields the corresponding ester (VI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to afford chiral tetrahydropyran-2-one (VII). The reduction of (VII) with Red-Al, followed by cyclization with 2-methoxypropene (VIII) and PPTS yields the acetonide (IX), which is finally oxidized with N-methylmorpholine-N-oxide and PPTS in dichloromethane giving the target intermediate (X).

参考文献 中间体
合成目标
【1】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580.
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) 27170 chloro(3-methyl-2-butenyl)magnesium C5H9ClMg 详情 详情
(II) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(III) 27171 4,4-dimethyl-5-hexen-3-ol C8H16O 详情 详情
(IV) 27172 (3R)-4,4-dimethyl-5-hexen-3-ol C8H16O 详情 详情
(V) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(VI) 27173 (1R)-1-ethyl-2,2-dimethyl-3-butenyl 2-bromoacetate C10H17BrO2 详情 详情
(VII) 27174 (4S,6R)-6-ethyl-4,5,5-trimethyltetrahydro-2H-pyran-2-one C10H18O2 详情 详情
(VIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(IX) 27175 (3R)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanol C12H24O3 详情 详情
(X) 27176 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone C12H22O3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XVIII)

Condensation of 1,3-benzodioxole-5-carbaldehyde (XV) with nitromethane by means of ammonium acetate in HOAc gives the nitrostyrene (I), which is condensed with ethyl 2-(4-methoxybenzoyl)acetate (II) [obtained by reaction of acetophenone (XVI), diethyl carbonate and potassium tert-amyloxide] by means of NaOEt in THF to yield the 4-nitrobutyrate (III). Reductive cyclization of (III) with H2 over Raney-Ni in THF affords the (cis, cis)-pyrrolidine (VI), which is isomerized to the (trans,trans)-isomer (V) by means of NaOEt in refluxing ethanol. This racemic ester (V) is submitted to optical resolution with (S)-(+)-mandelic acid to provide the pure chiral ester (XVII). This compound is condensed with 2-bromo-N,N-dibutylacetamide (XIII) [obtained by reaction of 2-bromoacetyl bromide (XVIII) with dibutylamine (XIX) in toluene] by means of DIEA in acetonitrile to give the ethyl ester (XX), which is finally hydrolyzed with NaOH in hot ethanol.

参考文献 中间体
合成目标
【1】 Leeson, P.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; Atrasentan. Drugs Fut 2001, 26, 10, 939.
【2】 Winn, M.; Boyd, S.A.; Hutchins, C.W.; Tasker, A.S.; Von Geldern, T.W.; Kester, J.A.; Sorensen, B.K.; Szczepankiewicz, B.G.; Henry, K.J. Jr.; Liu, G.; Wittenberger, S.J.; King, S.A. (Abbott Laboratories Inc.); Novel benzo-1,3-dioxolyl- and benzofuranyl substd. pyrrolidine derivs. as endothelin antagonists. EP 0885215; WO 9730045 .
【3】 Jae, H.-S.; Hutchins, C.W.; Szczepankiewicz, B.G.; King, S.A.; Winn, M.; Boyd, S.A.; Henry, K.J.; Geldern, T.W.; Wittenberger, S.J.; Tasker, A.S.; Sorensen, B.K.; Kester, J.A. (Abbott Laboratories Inc.); Endothelin antagonists. WO 9906397 .
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) 20675 5-[(E)-2-nitroethenyl]-1,3-benzodioxole 1485-00-3 C9H7NO4 详情 详情
(II) 20676 ethyl 3-(4-methoxyphenyl)-3-oxopropanoate C12H14O4 详情 详情
(III) 20677 ethyl 3-(1,3-benzodioxol-5-yl)-2-(4-methoxybenzoyl)-4-nitrobutanoate C21H21NO8 详情 详情
(VI) 20679 ethyl (2S,3R,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate C21H23NO5 详情 详情
(XIII) 20685 2-Bromo-N,N-dibutylacetamide; N,N-Dibutylbromoacetamide C10H20BrNO 详情 详情
(XV) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(XVI) 11041 4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone 100-06-1 C9H10O2 详情 详情
(XVII) 20680 ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate C21H23NO5 详情 详情
(XVIII) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XIX) 33492 N,N-dibutylamine; N-butyl-1-butanamine 111-92-2 C8H19N 详情 详情
(XX) 48687 ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)-3-pyrrolidinecarboxylate C31H42N2O6 详情 详情

合成路线13

该中间体在本合成路线中的序号：(IV)

The condensation of 2-methylaniline (I) with 2-fluorobenzonitrile (II) by means of BCl3 and AlCl3 gives 2-amino-2'-fluoro-3-methylbenzophenone (III), which is acylated at the amino group with bromoacetyl bromide (IV) in pyridine yielding the bromoacetamide (V). The cyclization of (V) with hydroxylamine and NaOH affords the benzodiazepinone-N-oxide (VI), which is treated with acetic anhydride to provide 3-acetoxy-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (VII). The reaction of (VII) with potassium phthalimide (VIII) and NaI gives the phthalimido derivative (IX), which by cleavage with hydrazine yields 3-amino-5-(2-fluorophenyl)-9-methyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (X). The protection of the amino group of (X) with Boc2O and TEA affords the carbamate (XI), which is alkylated with ethyl bromoacetate (XII) by means of NaH giving the ethoxycarbonylmethyl derivative (XIII). The hydrolysis of (XIII) with NaOH affords the corresponding carboxymethyl derivative (XIV), which is condensed with 3-azabicyclo[3,2,2]nonane (XV) by means of HOBT, WSCD and TEA to give the expected amide (XVI). The cleavage of the tert-butoxycarbonyl group of (XVI) with HCl yields the amine (XVII), which is finally condensed with the activated carbamate (XVIII) to furnish the title compound.

参考文献 中间体
合成目标
【1】 Toyoda, T.; Adachi, M.; Sugasawa, T.; et al.; Aminohaloborane in organic synthesis. I. Specific ortho substitution reaction of anilines. J Am Chem Soc 1978, 100, 4842.
【2】 Satoh, Y.; Tabuchi, S.; Mitsui, H.; Design of dual CCK-A and CCK-B receptor antagonists. Drugs Fut 1997, 22, 10, 1117.
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) 15511 o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine 95-53-4 C7H9N 详情 详情
(II) 41199 2-fluorobenzonitrile 394-47-8 C7H4FN 详情 详情
(III) 41200 (2-amino-3-methylphenyl)(2-fluorophenyl)methanone C14H12FNO 详情 详情
(IV) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(V) 41201 2-bromo-N-[2-(2-fluorobenzoyl)-6-methylphenyl]acetamide C16H13BrFNO2 详情 详情
(VI) 41202 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-4-ium-4-olate C16H13FN2O2 详情 详情
(VII) 41203 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl acetate C18H15FN2O3 详情 详情
(VIII) 27890 Potassium phthalimide 1074-82-4 C8H4KNO2 详情 详情
(IX) 41204 2-[5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]-1H-isoindole-1,3(2H)-dione C24H16FN3O3 详情 详情
(X) 41205 3-amino-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one C16H14FN3O 详情 详情
(XI) 41206 tert-butyl 5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate C21H22FN3O3 详情 详情
(XII) 16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(XIII) 41207 ethyl 2-[3-[(tert-butoxycarbonyl)amino]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetate C25H28FN3O5 详情 详情
(XIV) 41208 2-[3-[(tert-butoxycarbonyl)amino]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-1-yl]acetic acid C23H24FN3O5 详情 详情
(XV) 41209 3-azabicyclo[3.2.2]nonane C8H15N 详情 详情
(XVI) 41210 tert-butyl 1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-ylcarbamate C31H37FN4O4 详情 详情
(XVII) 41211 3-amino-1-[2-(3-azabicyclo[3.2.2]non-3-yl)-2-oxoethyl]-5-(2-fluorophenyl)-9-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one C26H29FN4O2 详情 详情
(XVIII) 41212 4-nitrophenyl 3-(1H-1,2,3,4-tetraazol-5-yl)phenylcarbamate C14H10N6O4 详情 详情

合成路线14

该中间体在本合成路线中的序号：

Condensation of piperonal (I) with nitromethane in the presence of ammonium acetate in AcOH provided nitrostyrene (II). Ketoester (IV) was prepared by carbethoxylation of 4'-propoxyacetophenone (III) with diethyl carbonate. Subsequent conjugate addition of ketoester (IV) to nitrostyrene (II) using DBU provided adduct (V). Hydrogenation of the nitro group of (V) over Raney Nickel, with concomitant ring closure formed the cyclic imine (VI), and further reduction of (VI) with NaBH3CN yielded the corresponding pyrrolidine as a diastereomeric mixture. Chromatographic separation removed the cis,cis isomer, affording a mixture of trans,trans and cis,trans pyrrolidines (VIIa, VIIb). 2,6-Diethylbromoacetanilide (IX) was prepared by acylation of 2,6-diethylaniline (VIII) with bromoacetyl bromide. N-Alkylation of the mixture of pyrrolidines (VIIa, VIIb) with bromoacetanilide (IX) furnished (Xa, Xb).

参考文献 中间体
合成目标
【1】 Sorensen, B.K.; Tasker, A.S.; von Geldern, T.W.; et al.; Pyrrolide-3-carboxylic acids as endothelin antagonists. 4. Side chain conformational restriction leads to ETB selectivity. J Med Chem 1999, 42, 18, 3668.
【2】 Tasker, A.S.; Boyd, S.A.; Sorensen, B.K.; Winn, M.; Jae, H.-S.; Von Geldern, T.W.; Henry, K.J. (Abbott Laboratories Inc.); 4-(Benzo-1,3-dioxolyl)-pyrrolidine-3-carboxylic acid derivs. as endothelin antagonists. EP 0888340; JP 2000504727; WO 9730046 .
【3】 Tasker, A.S.; Henry, K.J.; Boyd, S.A.; Von Geldern, T.W.; Sorensen, B.K.; Jae, H.-S.; Winn, M. (Abbott Laboratories Inc.); Pyrrolidine carboxylic acid derivs. as endothelin antagonists. EP 0991620; WO 9857933 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
17470 diethyl carbonate; diethylcarbonate 105-58-8 C5H10O3 详情 详情
39563 nitromethane 75-52-5 CH3NO2 详情 详情
(VIIa) 35056 ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate C23H27NO5 详情 详情
(VIIb) 35057 ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate C23H27NO5 详情 详情
(Xa) 35060 ethyl (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate C35H42N2O6 详情 详情
(Xb),(XI) 35061 ethyl (2S,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(2,6-diethylanilino)-2-oxoethyl]-2-(4-propoxyphenyl)-3-pyrrolidinecarboxylate C35H42N2O6 详情 详情
(I) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(II) 20675 5-[(E)-2-nitroethenyl]-1,3-benzodioxole 1485-00-3 C9H7NO4 详情 详情
(III) 35052 1-(4-propoxyphenyl)-1-ethanone C11H14O2 详情 详情
(IV) 35053 ethyl 3-oxo-3-(4-propoxyphenyl)propanoate C14H18O4 详情 详情
(V) 35054 ethyl 3-(1,3-benzodioxol-5-yl)-4-nitro-2-(4-propoxybenzoyl)butanoate C23H25NO8 详情 详情
(VI) 35055 ethyl 3-(1,3-benzodioxol-5-yl)-5-(4-propoxyphenyl)-3,4-dihydro-2H-pyrrole-4-carboxylate C23H25NO5 详情 详情
(VIII) 35058 2,6-diethylphenylamine; 2,6-diethylaniline 579-66-8 C10H15N 详情 详情
(IX) 35059 2-bromo-N-(2,6-diethylphenyl)acetamide C12H16BrNO 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XI)

The deprotection of the resin (I) with piperidine in DMF gives the amino-resin (II), which is condensed with N-Fmoc-L-proline (III) by means of diisopropylcarbodiimide (DIC) in DMF to yield the anchored proline (IV). The deprotection of (IV) with piperidine in DMF affords compound (V) with a free NH group, which is condensed with 2-bromoacetic acid (VI) by means of DIC DMF to provide the bromoacetyl proline resin (VII). The condensation of (VII) with 6-(2-aminoethylamino)pyridine-3-carbonitrile (VIII) in DMSO to give the resin anchored precursor (IX), which is finally cleaved by means of trifluoroacetic anhydride (TFAA) in THF to furnish the target pyrrolidine-carbonitrile. Alternatively, the acylation of L-prolinamide (X) with 2-bromoacetyl bromide (XI) by means of TEA and DMAP in dichloromethane gives the 1-(2-bromoacetyl)-L-prolinamide (XII), which is dehydrated by means of TFAA in dichloromethane to yield the pyrrolidine-carbonitrile (XIII). Finally, this compound is condensed with 6-(2-aminoethylamino)pyridine-3-carbonitrile (VIII) in THF to furnish the target pyrrolidine-carbonitrile.

参考文献 中间体
合成目标
【1】 Mangold, B.L.; Mone, M.D.; Dunning, B.E.; Russell, M.E.; Brinkman, J.A.; Weldon, S.C.; Hughes, T.E.; Naderi, G.B.; Villhauer, E.B.; 1-[2-[(5-Cyanopyridin-2-yl)amino]-ethylamino]acetyl-2-(S)-pyrrolidine-carbonitrile: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2002, 45, 12, 2362.
【2】 Villhauer, E.B. (Novartis AG); N-Substd. 2-cyanopyrrolidines. JP 2000511559; WO 9819998 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V),(X) 36137 (2S)-2-pyrrolidinecarboxamide;L-prolinamide 7531-52-4 C5H10N2O 详情 详情
(VII),(XII) 54331 (2S)-1-(2-bromoacetyl)-2-pyrrolidinecarboxamide n/a C7H11BrN2O2 详情 详情
(I) 28722 9H-fluoren-9-ylmethyl carbamate 84418-43-9 C15H13NO2 详情 详情
(III) 34762 (2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid 71989-31-6 C20H19NO4 详情 详情
(IV) 42841 9H-fluoren-9-ylmethyl (2R)-2-(aminocarbonyl)-1-pyrrolidinecarboxylate C20H20N2O3 详情 详情
(VI) 23660 2-Bromoacetic acid 79-08-3 C2H3BrO2 详情 详情
(VIII) 54332 6-[(2-aminoethyl)amino]nicotinonitrile n/a C8H10N4 详情 详情
(IX) 54333 (2S)-1-[2-({2-[(5-cyano-2-pyridinyl)amino]ethyl}amino)acetyl]-2-pyrrolidinecarboxamide n/a C15H20N6O2 详情 详情
(XI) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XIII) 54334 (2S)-1-(2-bromoacetyl)-2-pyrrolidinecarbonitrile n/a C7H9BrN2O 详情 详情

合成路线16

该中间体在本合成路线中的序号：(XX)

The reaction of 3-methyl-2-butenylmagnesium bromide (XVI) with propanal (XVII) gives racemic hexenol (XVIII), which is submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme, yielding the R-enantiomer (XIX). The esterification of (XIX) with bromoacetyl bromide (XX) and dimethylaniline (DMA) affords the corresponding ester (XXI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to provide the chiral tetrahydropyranone (XXII). The reduction of (XXII) with Red-Al, followed by cyclization with 2-methoxypropene (XXIII) and PPTS, gives the acetonide (XXIV), which is oxidized with PPTS and NMO to provide the protected dihydroxyketone (XXV). The condensation of the ketone (XXV) with 2(S)-methyl-6-heptenal (XXVI) by means of LDA in THF gives the hydroxyundecenone (XXVII), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (XXVIII). The silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (XXIX), which is selectively monodesilylated with CSA to provide the primary alcohol (XXX). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the target tridecenoic acid intermediate (XII).

参考文献 中间体
合成目标
【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523.
【2】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 27170 chloro(3-methyl-2-butenyl)magnesium C5H9ClMg 详情 详情
(XVII) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(XVIII) 27171 4,4-dimethyl-5-hexen-3-ol C8H16O 详情 详情
(XIX) 27172 (3R)-4,4-dimethyl-5-hexen-3-ol C8H16O 详情 详情
(XX) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XXI) 27173 (1R)-1-ethyl-2,2-dimethyl-3-butenyl 2-bromoacetate C10H17BrO2 详情 详情
(XXII) 27174 (4S,6R)-6-ethyl-4,5,5-trimethyltetrahydro-2H-pyran-2-one C10H18O2 详情 详情
(XXIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XXIV) 27175 (3R)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanol C12H24O3 详情 详情
(XXV) 27176 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone C12H22O3 详情 详情
(XXVI) 27185 (2S)-2-methyl-6-heptenal C8H14O 详情 详情
(XXVII) 44434 (4R,5S,6S)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one C20H36O4 详情 详情
(XXVIII) 44435 (3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one C17H32O4 详情 详情
(XXIX) 44436 (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one C35H74O4Si3 详情 详情
(XXX) 44437 (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one C29H60O4Si2 详情 详情
(XXX) 44438 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid C29H58O5Si2 详情 详情

合成路线17

该中间体在本合成路线中的序号：

Selective acylation of the silyl ester of prostaglandin E2 (V) at C-15 hydroxyl group with bromoacetyl bromide in the presence of pyridine at -25 C afforded bromoacetate ester (VI). Then, displacement of the halogen atom with thiol (IV) in aqueous dioxan furnished the correspondig desilylated sulfide. This was finally converted into the title disodium phosphonate salt by treatment with cation exchange resin.

参考文献 中间体
合成目标
【1】 Gil, L.; et al.; Prostaglandin E2-bisphosphonate conjugates: Potential agents for treatment of osteoporosis. Bioorg Med Chem 1999, 7, 5, 901.
【2】 Gil, L.; Young, R.N.; Ruel, R.; Han, Y. (Merck Frosst Canada Inc.); Prostaglandin conjugates for treating or preventing bone disease. US 6121253; WO 0031084 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(IV) 27983 1-phosphono-4-sulfanylbutylphosphonic acid C4H12O6P2S 详情 详情
(V) 27984 tert-butyl(diphenyl)silyl (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-1-octenyl]-5-oxocyclopentyl]-5-heptenoate C36H50O5Si 详情 详情
(VI) 27985 tert-butyl(diphenyl)silyl (Z)-7-((1R,2R,3R)-2-[(E,3S)-3-[(2-bromoacetyl)oxy]-1-octenyl]-3-hydroxy-5-oxocyclopentyl)-5-heptenoate C38H51BrO6Si 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 acylation of m-difluorobenzene (I) with 2-bromoacetyl bromide (II) by means of AlCl3 gives the phenacyl bromide (III), which is treated with ethylmercaptan (IV) and K2CO3 to yield the sulfanyl derivative (V). The fluorination of (V) with N-fluoro-4-methylpyridinium-2-sulfonate affords the difluoroacetyl derivative (VI). The methylenation of the carbonyl group of (VI) with trimethylsulfoxonium iodide provides the oxiranyl derivative (VII), which is opened with 1,2,4-triazole (VIII) and K2CO3, furnishing the propanol derivative (IX). The oxidation of the sulfanyl group of (IX) by means of H2O2 or MCPBA gives the corresponding sulfonyl derivative (X). Finally, the racemic mixture (X) is submitted to optical resolution by crystallization of the (+)-3-bromocamphorsulfonic acid. Alternatively, intermediate (VI) can be obtained as follows: The reaction of 2-chloro-2,2-difluoroacetic acid ethyl ester (XI) with ethylmercaptan (IV) by means of NaH gives the sulfanyl derivative (XII), which is finally condensed with 2,4-difluorobromobenzene (XIII) by means of BuLi to afford the desired intermediate (VI).

参考文献 中间体
合成目标
【1】 Kaneko, Y.; Takeda, S.; Eto, H.; et al.; New antifungal 1,2,4-triazoles with difluoro(substituted sulfonyl)methyl moiety. Chem Pharm Bull 2001, 49, 2, 173.
【2】 Sato, S.; Kaneko, Y.; Takeda, S.; Eto, H.; Tokizawa, M.; SS750, a new triazole agent: Structure-activity relationship of novel triazole-containing gem-difluoromethylsulfonyl moiety. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1080.
【3】 Matsumoto, M.; Kaneko, Y.; Maebashi, K.; Takeda, S.; Sato, S.; Tokizawa, M.; Ishida, K.; Eto, H.; Asaoka, T. (SSP Co., Ltd.); Triazole deriv. or salt thereof, preparation process thereof as well as pharmaceutical containing said cpd.. CA 2256060; EP 0927719; JP 1999240871; US 6083968 .
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) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(II) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(III) 47646 2-bromo-1-(2,4-difluorophenyl)-1-ethanone C8H5BrF2O 详情 详情
(IV) 23712 1-ethanethiol; ethylhydrosulfide 75-08-1 C2H6S 详情 详情
(V) 47647 1-(2,4-difluorophenyl)-2-(ethylsulfanyl)-1-ethanone C10H10F2OS 详情 详情
(VI) 47648 1-(2,4-difluorophenyl)-2-(ethylsulfanyl)-2,2-difluoro-1-ethanone C10H8F4OS 详情 详情
(VII) 47649 2-(2,4-difluorophenyl)-2-[(ethylsulfanyl)(difluoro)methyl]oxirane; [2-(2,4-difluorophenyl)-2-oxiranyl](difluoro)methyl ethyl sulfide C11H10F4OS 详情 详情
(VIII) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(IX) 47650 2-(2,4-difluorophenyl)-1-(ethylsulfanyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol C13H13F4N3OS 详情 详情
(X) 47651 2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol C13H13F4N3O3S 详情 详情
(XI) 47652 Chlorodifluoroacetic acid ethyl ester; Difluorochloroacetic acid ethyl ester; Ethyl chlorodifluoroacetate; ethyl 2-chloro-2,2-difluoroacetate 383-62-0 C4H5ClF2O2 详情 详情
(XII) 47653 ethyl 2-(ethylsulfanyl)-2,2-difluoroacetate C6H10F2O2S 详情 详情
(XIII) 15488 1-bromo-2,4-difluorobenzene 348-57-2 C6H3BrF2 详情 详情

合成路线19

该中间体在本合成路线中的序号：(IV)

Treatment of 2,2'-dimethylbenzophenone (I) with hydroxylamine afforded oxime (II), which was reduced to the benzhydryl amine (III) with sodium metal in liquid ammonia. Condensation of (III) with bromoacetyl bromide (IV) then produced the target amide (V).

参考文献 中间体
合成目标
【1】 Chiou, W.J.; Liu, G.; Kozmina, N.S.; Opgenorth, T.J.; Winn, M.; Dixon, D.B.; Nguyen, B.; von geldern, T.W.; Marsh, K.C.; Design, synthesis, and activity of a series of pyrrolidine-3-carboxylic acid-based, highly specific, orally active ETB antagonists containing a diphenylmethylamine acetamide side chain. J Med Chem 1999, 42, 18, 3679.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
32201 Hydroxylamine 7803-49-8 H3NO 详情 详情
(I) 35192 bis(2-methylphenyl)methanone C15H14O 详情 详情
(II) 35193 bis(2-methylphenyl)methanone oxime C15H15NO 详情 详情
(III) 35194 bis(2-methylphenyl)methanamine; bis(2-methylphenyl)methylamine C15H17N 详情 详情
(IV) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(V) 35195 N-[bis(2-methylphenyl)methyl]-2-bromoacetamide C17H18BrNO 详情 详情

合成路线20

该中间体在本合成路线中的序号：

3-Aminobenzoic acid (I) was protected as the trifluoroacetamide (II) using trifluoroacetic anhydride and then converted to acid chloride (III) by means of SOCl2. Subsequent condensation of (III) with urea provided 3-(trifluoroacetamido)benzoylurea (IV). After cleavage of the trifluoroacetamido group of (IV) by treatment with methanolic n-butylamine, the deprotected aniline (V) was coupled with bromoacetyl bromide in DMA to furnish the title bromoacetamide.

参考文献 中间体
合成目标
【1】 Bekesi, J.G.; Holland, J.F.; Jiang, J.-D.; Ma, L.; Roboz, J.; Deng, L.; Weisz, I.; Synthesis, cancericidal and antimicrotubule activities of 3-(haloacetamido)-benzoylureas. Anti-Cancer Drug Des 1998, 13, 7, 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
14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
19310 urea 57-13-6 CH4N2O 详情 详情
(I) 26638 3-Aminobenzoic acid 99-05-8 C7H7NO2 详情 详情
(II) 26639 3-[(2,2,2-trifluoroacetyl)amino]benzoic acid C9H6F3NO3 详情 详情
(III) 26640 3-[(2,2,2-trifluoroacetyl)amino]benzoyl chloride C9H5ClF3NO2 详情 详情
(IV) 26641 N-(3-[[(aminocarbonyl)amino]carbonyl]phenyl)-2,2,2-trifluoroacetamide C10H8F3N3O3 详情 详情
(V) 26642 N-(3-aminobenzoyl)urea C8H9N3O2 详情 详情

合成路线21

该中间体在本合成路线中的序号：(XI)

Regioselective coupling of the 2-arylpiperazine (IV) with 3,5-dimethylbenzoic acid (IX) at the less hindered N atom by means of EDC and HOBt afforded the 4-benzoyl piperazine (X). This was subsequently acylated with bromoacetyl bromide (XI) to yield the bromo amide (XII). Bromide displacement in (XII) with 4-amino-1-benzylpiperidine (XIII) then gave the title compound.

参考文献 中间体
合成目标
【1】 Shue, H.-J.; Shih, N.-Y.; Blythin, D.J.; Chen, X.; Tom, W.C.; Piwinski, J.J.; McCormick, K.D. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0823906; US 5719156; WO 9634864 .
【2】 Piwinski, J.J.; McCormick, K.D.; Shue, H.-J.; Chen, X.; Shih, N.-Y.; Blythin, D.J. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0850236; JP 2000344766; US 5795894; US 5892039; WO 9708166 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 47946 2-(3,4-dichlorophenyl)piperazine C10H12Cl2N2 详情 详情
(IX) 26775 3,5-dimethylbenzoic acid 499-06-9 C9H10O2 详情 详情
(X) 47950 [3-(3,4-dichlorophenyl)-1-piperazinyl](3,5-dimethylphenyl)methanone C19H20Cl2N2O 详情 详情
(XI) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XIII) 34808 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine 50541-93-0 C12H18N2 详情 详情

合成路线22

该中间体在本合成路线中的序号：(XI)

In a related method, the 2-arylpiperazine (IV) was first protected as the 4-tert-butyl carbamate (XIV) upon treatment with di-tert-butyl dicarbonate in MeOH at -78 C. Subsequent acylation of (XIV) with bromoacetyl bromide (XI) produced the bromo amide (XV), which was then condensed with the aminopiperidine (XIII), yielding the glycinamide derivative (XVI). Acidic cleavage of the Boc group of (XVI) afforded the 1-acyl piperazine (XVII). This was finally coupled with 3,5-dimethylbenzoic acid using EDC and HOBt.

参考文献 中间体
合成目标
【1】 Anthes, J.C.; McPhail, A.T.; Blythin, D.J.; Shue, H.-J.; Chen, X.; Piwinski, J.J.; shih, N.-Y.; Discovery of Sch 62373 and analogs, of novel series of 2-phenylpiperazines exhibiting potent dual NK1/NK2 antagonist activity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 244.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 47946 2-(3,4-dichlorophenyl)piperazine C10H12Cl2N2 详情 详情
(IX) 26775 3,5-dimethylbenzoic acid 499-06-9 C9H10O2 详情 详情
(XI) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XIII) 34808 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine 50541-93-0 C12H18N2 详情 详情
(XIV) 47952 tert-butyl 3-(3,4-dichlorophenyl)-1-piperazinecarboxylate C15H20Cl2N2O2 详情 详情
(XV) 47953 tert-butyl 4-(2-bromoacetyl)-3-(3,4-dichlorophenyl)-1-piperazinecarboxylate C17H21BrCl2N2O3 详情 详情
(XVI) 47954 tert-butyl 4-[2-[(1-benzyl-4-piperidinyl)amino]acetyl]-3-(3,4-dichlorophenyl)-1-piperazinecarboxylate C29H38Cl2N4O3 详情 详情
(XVII) 47955 2-[(1-benzyl-4-piperidinyl)amino]-1-[2-(3,4-dichlorophenyl)-1-piperazinyl]-1-ethanone C24H30Cl2N4O 详情 详情

合成路线23

该中间体在本合成路线中的序号：(XV)

An alternative route to the intermediate bromide (IX) has been reported. Condensation of phenol (XII) with 1,1,1-trichloro-2-methyl-2-propanol (V) led to 2-phenoxyisobutyric acid (XIII), which was further esterified by treatment with SOCl2 in EtOH to yield (XIV). Friedel-Crafts acylation of (XIV) with bromoacetyl bromide (XV) in the presence of AlCl3 provided the phenacyl bromide (XVI). The corresponding phenethyl bromide (IX) was then obtained by reduction of ketone (XVI) with triethylsilane in trifluoroacetic acid.

参考文献 中间体
合成目标
【1】 Hirabayashi, A.; Tamai, T.; Muranaka, H.; Tanaka, N.; Ishikawa, T.; Mukaiyama, H.; Akahane, M.; Akahane, S.; beta(3)- Adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[1S,2R)-2- hydroxy-2-(4- hydroxyphenyl)-1-methylethyl]ethyl) phenoxy]-2-methylpropionic acid. Bioorg Med Chem 2001, 9, 12, 3265.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 25975 1,1,1-trichloro-2-methyl-2-propanol 57-15-8 C4H7Cl3O 详情 详情
(IX) 56067 ethyl 2-[4-(2-bromoethyl)phenoxy]-2-methylpropanoate C14H19BrO3 详情 详情
(XII) 23540 Phenol 108-95-2 C6H6O 详情 详情
(XIII) 56069 2-methyl-2-phenoxypropanoic acid C10H12O3 详情 详情
(XIV) 56070 ethyl 2-methyl-2-phenoxypropanoate C12H16O3 详情 详情
(XV) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XVI) 56071 ethyl 2-[4-(2-bromoacetyl)phenoxy]-2-methylpropanoate C14H17BrO4 详情 详情

合成路线24

该中间体在本合成路线中的序号：(II)

The acylation of N-[4-(4-aminophenyl)-2-thiazolyl]carbamic acid tert-butyl ester (I) with bromoacetyl bromide (II) gives the bromoacetamide (III), which is then condensed with (S)-alpha-methylbenzylamine (IV) to yield the glycinamide derivative (V). The acylation of (V) with 4-pyridylcarbonyl chloride affords the protected precursor (VI), which is finally deprotected to provide the target BILS 179 BS.

参考文献 中间体
合成目标
【1】 Crute, J.J.; et al.; Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat Med 2002, 8, 4, 386.
【2】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 .
【3】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Crute, J.J.; Thavonekham, B.; Grygon, C. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Antiherpes virus cpds. and methods for their preparation and use. US 6288091 .
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) 54066 tert-butyl 4-(4-aminophenyl)-1,3-thiazol-2-ylcarbamate n/a C14H17N3O2S 详情 详情
(II) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(III) 54067 tert-butyl 4-{4-[(2-bromoacetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate n/a C16H18BrN3O3S 详情 详情
(IV) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(V) 54068 tert-butyl 4-{4-[(2-{[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate n/a C24H28N4O3S 详情 详情
(VI) 27850 isonicotinoyl chloride 39178-35-3 C6H4ClNO 详情 详情
(VII) 54069 tert-butyl 4-{4-[(2-{isonicotinoyl[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate n/a C30H31N5O4S 详情 详情

合成路线25

该中间体在本合成路线中的序号：(II)

The acylation of N-[4-(4-aminophenyl)-2-thiazolyl]carbamic acid tert-butyl ester (I) with bromoacetyl bromide (II) gives the bromoacetamide (III), which is then condensed with 4-pyridylmethylamine (IV) to yield the glycinamide derivative (V). The acylation of (V) with cyclohexanecarbonyl chloride affords the protected precursor (VI), which is finally deprotected to provide the target BILS 103 BS.

参考文献 中间体
合成目标
【1】 Crute, J.J.; et al.; Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease. Nat Med 2002, 8, 4, 386.
【2】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Thavonekham, B.; Grygon, C.A.; Crute, J.J. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Phenyl thiazole derivs. with anti-herpes virus properties. EP 0871619; JP 2000502702; US 6057451; WO 9724343 .
【3】 Hargrave, K.D.; Simoneau, B.; Faucher, A.-M.; Crute, J.J.; Thavonekham, B.; Grygon, C. (Boehringer Ingelheim (Canada) Ltd.; Boehringer Ingelheim Pharmaceuticals Inc.); Antiherpes virus cpds. and methods for their preparation and use. US 6288091 .
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) 54066 tert-butyl 4-(4-aminophenyl)-1,3-thiazol-2-ylcarbamate n/a C14H17N3O2S 详情 详情
(II) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(III) 54067 tert-butyl 4-{4-[(2-bromoacetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate n/a C16H18BrN3O3S 详情 详情
(IV) 20042 (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine C8H11N 详情 详情
(V) 54068 tert-butyl 4-{4-[(2-{[(1S)-1-phenylethyl]amino}acetyl)amino]phenyl}-1,3-thiazol-2-ylcarbamate n/a C24H28N4O3S 详情 详情
(VI) 17220 cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride 2719-27-9 C7H11ClO 详情 详情
(VII) 54070 tert-butyl 4-[4-({2-[(cyclohexylcarbonyl)(4-pyridinylmethyl)amino]acetyl}amino)phenyl]-1,3-thiazol-2-ylcarbamate n/a C29H35N5O4S 详情 详情

合成路线26

该中间体在本合成路线中的序号：(II)

Acylation of the 2-aminobenzophenone (I) with bromoacetyl bromide (II) provides the bromoacetamide (III). Subsequent treatment of (III) with ammonia leads to the benzodiazepinone (IV). Methylation of the lactam N with iodomethane in the presence of K2CO3 gives rise to (V). The potassium enolate of benzodiazepinone (V) is then alkylated by 2-(bromomethyl)naphthalene (VI) to furnish the naphthylmethyl derivative (VII). Finally, methyl ether cleavage using AlBr3 in ethanethiol provides the target phenolic compound

参考文献 中间体
合成目标
【1】 Kim, K.; Volkman, S.K.; Ellman, J.A.; Synthesis of 3-substituted 1,4-benzodiazepin-2-ones. J Braz Chem Soc 1998, 9, 4, 375.
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) 63044 　 C14H12ClNO2 详情 详情
(II) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(III) 63045 　 C16H13BrClNO3 详情 详情
(IV) 63046 　 C16H13ClN2O2 详情 详情
(V) 63043 　 C17H15ClN2O2 详情 详情
(VI) 35612 2-(bromomethyl)naphthalene 939-26-4 C11H9Br 详情 详情
(VII) 63042 　 C28H23ClN2O2 详情 详情

合成路线27

该中间体在本合成路线中的序号：(XII)

Lithiationof 5-fluoro-2-methoxybenzoic acid (I) with sec-BuLi in the presence of TMEDA in THF, followed by methylation of the resulting anion with methyliodide, gives 3-fluoro-6-methoxy-2-methylben methyl benzoic acid (II). Chlorination of carboxylic acid (II) with (COCl)2 in the presence of DMF in CH2Cl2 and subsequent reaction of the resulting acid chloride with PhOH by means of Et3N and DMAP in CH2Cl2 provides the corresponding phenyl ester (III). O-Demethylation of ether (III) by means of BBr3 in CH2Cl2 at −78° Cyields the 6-hydroxybenzoate (IV),which is then protected with Boc2O and DMAP in CH2Cl2 to generate the tert-butyl carbonate (V). Treatment of compound (V) with LDA and TMEDA in THF at −78°C, followed by coupling with enone (VI) in THF, produces the tetraceno[2,3-d] isoxazole derivative (VII),which is subsequently deprotected with HF and TFA in acetonitrile to give the octa hydrotetracene derivative (VIII). Reductive cleavage of the isoxazolering of tetracycline (VIII) with H2 over Pd/Cin methanol/dioxane affords the 2-hydroxyamide (IX),which by nitration with HNO3 and H2SO4 affords the 9-nitro-tetracycline derivative (X). Reduction of the nitro group of compound(X) with H2 over Pd/Cin methanol/dioxane gives the corresponding amine(XI).Then, reaction of amine (XI) with bromoacetyl bromide(XII) in the presence of Na2CO3 in DMPU/acetonitrile provides the bromoacetamide(XIII), which is finally condensed with pyrrolidine(XIV). Alternatively,amine(XI) is directly condensed withp yrrolidin-1-ylacetyl chloride(XV) orits hydrochloride salt in DMF.

参考文献 中间体
合成目标
【1】 Zhou,J.,Xiao,X.-Y.,Plamondon,L.,Hunt,D.K.,Clark,R.B.,Zahler,R.B. (TetraphasePharmaceuticals, Inc.). CA2732883, CN102177134, EP 2323972,EP2682387, JP2011530534, KR2011058800, US2010105671, US2012302527, US2013109657, US8501716,WO 2010017470.
【2】 Xiao,X.Y.,Hunt,D.K.,Zhou,J. etal.Fluorocyclines.1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: A potent, broad spectrum antibacterial agent. JMed Chem 2012, 55(2):597-605.
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) 67727 phenyl 3-fluoro-6-methoxy-2-methylbenzoate 　 C15H13FO3 详情 详情
（V) 67729 phenyl 6-((tert-butoxycarbonyl)oxy)-3-fluoro-2-methylbenzoate 　 C19H19FO5 详情 详情
(I) 67725 5-fluoro-2-methoxybenzoic acid；2-Methoxy-5-fluorobenzoic acid 394-04-7 C8H7FO3 详情 详情
(II) 67726 3-fluoro-6-methoxy-2-methylbenzoic acid 　 C9H9FO3 详情 详情
(IV) 67728 phenyl 3-fluoro-6-hydroxy-2-methylbenzoate 　 C14H11FO3 详情 详情
(VI) 67730 (4aR,8aR,9R)-3-(benzyloxy)-4a-((tert- butyldimethylsilyl)oxy)-9-(dimethylamino)-8,8a,9,9a- tetrahydronaphtho[2,3-d]isoxazole-4,5(3aH,4aH)-dione 　 C26H34N2O5Si 详情 详情
(VII) 67731 (4aR,11aS,12aR,13R)-3-(benzyloxy)-4a-((tert- butyldimethylsilyl)oxy)-13-(dimethylamino)-10- fluoro-5-hydroxy-4,6-dioxo- 3a,4,4a,6,11,11a,12,12a,13,13a-decahydrotetraceno [2,3-d]isoxazol-7-yl tert-butyl carbonate 　 C39H47FN2O9Si 详情 详情
(VIII) 67732 (4aR,11aS,12aR,13R)-3-(benzyloxy)-13- (dimethylamino)-10-fluoro-4a,5,7-trihydroxy- 11,11a,12,12a,13,13a-hexahydrotetraceno[2,3-d] isoxazole-4,6(3aH,4aH)-dione 　 C28H25FN2O7 详情 详情
(IX) 67733 (4R,4aR,5aS,12aR)-4-(dimethylamino)-7-fluoro- 3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2- carboxamide 　 C21H23FN2O7 详情 详情
(X) 67734 (4R,4aR,5aS,12aR)-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-9-nitro-1,11-dioxo-1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2-carboxamide 　 C21H22FN3O9 详情 详情
(XI) 67735 (4R,4aR,5aS,12aR)-9-amino-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2-carboxamide 　 C21H24FN3O7 详情 详情
(XII) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XIII) 67736 (4R,4aR,5aS,12aR)-9-(2-bromoacetamido)-4-(dimethylamino)-7-fluoro-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,2,3,4,4a,5,5a,6,11,12a-decahydrotetracene-2-carboxamide 　 C23H25BrFN3O8 详情 详情
(XIV) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(XV) 67737 2-(pyrrolidin-1-yl)acetyl chloride 　 C6H10ClNO 详情 详情

合成路线28

该中间体在本合成路线中的序号：(I)

Reaction of bromoacetyl bromide (I) with phenol at 80 °C gives the phenyl ester (II) , which by cyclization with (S)-(+)-phenylglycinol (III), previously treated with DIEA, in acetonitrile provides 5(S)-phenylmorpholin-2-one (IV) . Treatment of compound (IV) with HCl affords the corresponding HCl salt (V), which is reacted with NaHCO3 followed by coupling with benzodioxane-6-carboxaldehyde (VI) in refluxing EtOAc/toluene to yield the oxazine adduct (VII). Oxazine derivative (VII) can also be obtained by direct coupling of 5(S)-phenylmorpholin-2-one (IV) with aldehyde (VI) in refluxing toluene. Opening of adduct (VII) with pyrrolidine (VIII) in CH2Cl2, CHCl3 or refluxing THF followed by addition of HCl in refluxing MeOH leads to 3-(1,4-benzodioxan-6-yl)-3(R)-hydroxy-2(R)-(2-hydroxy-1-phenylethylamino)-1-(pyrrolidin-1-yl)propanone (IX), which is reduced with LiAlH4 in refluxing THF to give diol (X). Cleavage of diol (X) by means of H2 and Pd(OH)2 in the presence of either CF3COOH or HCl in MeOH or EtOH/H2O provides amine (XI), which is finally coupled with octanoic acid N-hydroxysuccinimide ester (XII) in CH2Cl2 . Ester (XII) is prepared by condensation of octanoyl chloride (XIII) with N-hydroxysuccinimide (XIV) by means of Et3N in CH2Cl2 .

参考文献 中间体
合成目标
【1】 Dellaria, J.F. Jr., Santarsiero, B.D. Enantioselective synthesis of alphaamino acid derivatives via the stereoselective alkylation of a homochiral glycine enolate synthon. J Org Chem 1989, 54(16): 3916-26.
【2】 Siegel, C., Hirth, B.H. (Genzyme Corp.). Synthesis of UDP-glucose:N-acylsphingosine glucosyltransferase inhibitors. CA 2453978, EP 1409467, EP 2067775, JP 2005255686, JP 2005502635, JP 2010095546, US 2003050299, US 6855830, WO 2003008399.
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) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(II) 69187 phenyl 2-bromoacetate;Phenyl bromoacetate;alpha-Phenyl Bromoacetate;Phenyl a-bromoacetate;bromoacetic acidphenyl ester 620-72-4 C8H7BrO2 详情 详情
(III) 10973 (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol 20989-17-7 C8H11NO 详情 详情
(IV) 61798 (5S)-5-phenyl-2-morpholinone;5(S)-phenylmorpholin-2-one;(5S)-3,4,5,6-Tetrahydro-5-phenyl-4(H)-1,4-oxazin-2-one 144896-92-4 C10H11NO2 详情 详情
(V) 69188 5(S)-phenylmorpholin-2-one hydrochloride 　 C10H11NO2.HCl 详情 详情
(VI) 61797 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde; 1,4-Benzodioxan-6-carboxaldehyde; 3,4-ethylenedioxybenzaldehyde ;benzodioxane-6-carboxaldehyde 29668-44-8 C9H8O3 详情 详情
(VII) 61799 (1S,3S,5S)-1,3-di(2,3-dihydro-1,4-benzodioxin-6-yl)-5-phenyltetrahydro-8H-[1,3]oxazolo[4,3-c][1,4]oxazin-8-one C28H25NO7 详情 详情
(VIII) 11376 Pyrrolidine 123-75-1 C4H9N 详情 详情
(IX) 61800 (2R,3R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-2-[(2-hydroxy-1-phenylethyl)amino]-1-(1-pyrrolidinyl)-1-propanone C23H28N2O5 详情 详情
(X) 61801 (1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-3-(1-pyrrolidinyl)-1-propanol C23H30N2O4 详情 详情
(XI) 61802 (1R,2R)-2-amino-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1-pyrrolidinyl)-1-propanol C15H22N2O3 详情 详情
(XII) 69189 octanoic acid N-hydroxysuccinimide ester;2,5-Dioxopyrrolidin-1-yl octanoate;Caprylic acid N-hydroxysuccinimide ester;N-(Octanoyloxy)succinimide;N-Hydroxysuccinimidyl caprylate 14464-30-3 C12H19NO4 详情 详情
(XIII) 11123 Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride 111-64-8 C8H15ClO 详情 详情
(XIV) 10264 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione 6066-82-6 C4H5NO3 详情 详情
Extended Information