|
【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% |
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 |