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【结 构 式】

【分子编号】68234

【品名】ethyl glycinate hydrochloride;Glycine ethyl ester hydrochloride

【CA登记号】623-33-6

【 分 子 式 】C4H9NO2.HCl

【 分 子 量 】139.582

【元素组成】C 34.42% H 7.22% Cl 25.40% N 15.03% O 22.92%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(I)

Condensation of ethyl glycinate hydrochloride (I) with benzaldehyde in the presence of Na2SO4 and Et3N in tert-butyl methyl ether gives ethyl N-benzylideneglycinate (II), which is then cyclocondensed with trans-1,4-dibromo-2-butene (III) by means of t-BuOLi in toluene to yield ethyl 1-amino-2-vinylcyclopropanecarboxylate (IV). Alternatively, condensation of ethyl N-(diphenylmethylene)glycinate (V) also with trans-1,4-dibromo-2-butene (III) by means of t-BuOK in THF affords cyclopropanecarboxylate (IV), which is then N-protected with Boc2O at reflux to generate N-Boc derivative (VI). Enzymatic resolution of the racemate (VI) by means of acalase or savinase (proteases from Bacillus clausii) or esperase (protease from Bacillus halodurans) in DMSO at 40 °C leads to the desired ethyl (1R,2S)-N-Boc-cyclopropanecarboxylate diastereomer (VII). Hydrolysis of ethyl ester (VII) with LiOH in THF/MeOH leads to the carboxylic acid (VIII), which is then coupled with cyclopropanesulfonamide (IX) using CDI and DBU in THF to provide the sulfonamide (X). N-Deprotection of this compound by means of TFA in CH2Cl2 followed by treatment with HCl in Et2O gives amine hydrochloride (XI) .
Cyclopropanesulfonamide (IX) is prepared by amination of 3-chloropropane-1-sulfonyl chloride (XII) with t-BuNH2 in THF to provide N-tert-butyl-3-chloropropane-1-sulfonamide (XIII), which is then cyclocondensed in the presence of BuLi in THF to yield N-tert-butylcyclopropanesulfonamide (XIV). Finally, the tert-butyl group of intermediate (XIV) is removed with TFA, affording cyclopropanesulfonamide (IX), which can also be prepared by direct amination of cyclopropanesulfonyl chloride (XV) with NH3 in THF .

1 Campbell, J.A., Wang, X.A., Sin, N. et al. (Bristol-Myers Squibb Co.). Hepatitis C virus inhibitors. EP 1505963, EP 2340830, JP 2005533028, KR 2010093140, US 200410659, US 6995174, US 2011311482, WO 200309974.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 68241 tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate   C14H22N2O5S 详情 详情
(XV) 67915 cyclopropanesulfonyl chloride;Cyclopropylsulfonylchloride;Cyclopropylsulphonyl chloride 139631-62-2 C3H5ClO2S 详情 详情
(I) 68234 ethyl glycinate hydrochloride;Glycine ethyl ester hydrochloride 623-33-6 C4H9NO2.HCl 详情 详情
(II) 68235 (E)-ethyl 2-(benzylideneamino)acetate;2-(benzylideneamino)acetic acid ethyl ester;ethyl N-benzylideneglycinate;Benzylideneglycine ethyl ester;N-Benzylideneglycineethyl ester;ethyl(benzylideneamino)acetate 40682-54-0 C11H13NO2 详情 详情
(III) 18349 (E)-1,4-dibromo-2-butene;trans-1,4-dibromo-2-butene 821-06-7 C4H6Br2 详情 详情
(IV) 68236 ethyl 1-amino-2-vinylcyclopropanecarboxylate 787548-29-2 C8H13NO2 详情 详情
(V) 68237 ethyl N-(diphenylmethylene)glycinate;(Benzhydrylideneamino)aceticacid methyl ester;Benzophenoneimine glycine methyl ester;Methyl2-[(diphenylmethylene)amino]acetate;Methyl 3-aza-4,4-diphenylbut-3-enoate;Methyl N-(diphenylmethylene)glycinate;Methyl[(diphenylmethylene)amino]acetate;N-(Diphenylmethylene)glycine methyl ester;N-Diphenylmethylideneglycine methyl ester 81167-39-7 C16H15NO2 详情 详情
(VI) 68238 ethyl 1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate 681807-59-0 C13H21NO4 详情 详情
(VII) 68239 ethyl (1R,2S)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate 213316-49-5 C13H21NO4 详情 详情
(VIII) 68240 (1R,2S)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylic acid 213316-50-8 C11H17NO4 详情 详情
(IX) 68242 cyclopropanesulfonamide;Cyclopropanesulfonyl amide 154350-29-5 C3H7NO2S 详情 详情
(XI) 68243 tert-butyl ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate hydrochloride   C14H22N2O5S.HCl 详情 详情
(XII) 39225 g-Chloropropanesulfonyl chloride;3-Chloropropansulfonyl chloride;1-Chloro-3-propanesulfonylchloride;3-Chloropropanesulfonyl chloride;3-chloro-1-propanesulfonyl chloride;3-chloropropane-1-sulfonyl chloride 1633-82-5 C3H6Cl2O2S 详情 详情
(XIII) 68244 N-tert-butyl-(3-chloro)propylsulfonamide;N-tert-butyl-3-chloropropane-1-sulfonamide;3-Chloro-N-(1,1-dimethylethyl)-1-propanesulfonamide;1-Propanesulfonamide,3-chloro-N-(1,1-dimethylethyl)- 63132-85-4 C7H16ClNO2S 详情 详情
(XIV) 68245 N-(tert-butyl)cyclopropanesulfonamide;N-tert-butylcyclopropanesulfonamide;N-(tert-butyl)cyclopropanesulfonamide   C7H15NO2S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XXIII)

Condensation of benzaldehyde (XXII) with ethyl glycinate hydrochloride (XXIII) in the presence of Na2SO4 and Et3N in tert-butyl methyl ether gives ethyl[(benzylidene)amino]acetate (XXIV), which upon reaction with 1,4-dibromo-2-butene (XXV) in the presence of t-BuOLi in toluene yields racemic ethyl 1-amino-2-vinylcyclopropanecarboxylate (rac-[XXVI]). Resolution of rac-(XXVI) by treatment with (+)-dibenzoyltartaric acid in EtOAc gives ethyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate (+)-dibenzoyltartrate (XXVII) salt, which is finally treated with HCl in Et2O .
Alternatively, amino ester (rac-[XXVI]) can be prepared by condensation of ethyl ester (XXVIII) with 1,4-dibromo-2-butene (XXV) in the presence of t-BuOK in THF, followed by treatment of the resulting imine (rac-[XXIX]) with HCl in Et2O and then with NaHCO3 .

1 Llinas-Brunet, M., Bailey, M.D., Cameron, D. et al. (Boehringer Ingelheim [Canada] Ltd.). Hepatitis C inhibitor tri-peptides. CA 2338946, EP 1105413, EP 2028186, JP 2002522554, US 6323180, WO 2000009543.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
rac-(XXVI) 69285 racemic ethyl 1-amino-2-vinylcyclopropanecarboxylate   C8H13NO2 详情 详情
rac-(XXIX) 69287 racemic ethyl 1-((diphenylmethylene)amino)-2-vinylcyclopropanecarboxylate   C21H21NO2 详情 详情
(IX) 69270 (1R,2S)-ethyl 1-amino-2-vinylcyclopropanecarboxylate 746657-36-3 C8H13NO2 详情 详情
(XXII) 10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(XXIII) 68234 ethyl glycinate hydrochloride;Glycine ethyl ester hydrochloride 623-33-6 C4H9NO2.HCl 详情 详情
(XXIV) 68235 (E)-ethyl 2-(benzylideneamino)acetate;2-(benzylideneamino)acetic acid ethyl ester;ethyl N-benzylideneglycinate;Benzylideneglycine ethyl ester;N-Benzylideneglycineethyl ester;ethyl(benzylideneamino)acetate 40682-54-0 C11H13NO2 详情 详情
(XXV) 18349 (E)-1,4-dibromo-2-butene;trans-1,4-dibromo-2-butene 821-06-7 C4H6Br2 详情 详情
(XXVII) 69286 ethyl 1(R)-amino-2(S)-vinylcyclopropanecarboxylate (+)-dibenzoyltartrate 213316-32-6 C8H13NO2 详情 详情
(XXVIII) 26772 ethyl 2-((diphenylmethylene)amino)acetate;N-(Diphenylmethylene)glycine ethyl ester;Ethyl N-(diphenylmethylene)glycinate;ethyl 2-[(dibenzylene)amino]acetate 69555-14-2 C17H17NO2 详情 详情
Extended Information