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【结 构 式】 
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【分子编号】69058 【品名】(1S,2R)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride 【CA登记号】 |
【 分 子 式 】C9H14N2O3S.HCl 【 分 子 量 】266.748 【元素组成】C 40.52% H 5.67% Cl 13.29% N 10.50% O 17.99% S 12.02% |
合成路线1
该中间体在本合成路线中的序号：(IV)In one method, intramolecular ring-closing metathesis of diene (I) using Neolyst-M1 or Zhan 1B catalysts in CH2Cl2 produces the macrocyclic triamide (II), which undergoes methyl ester hydrolysis with LiOH in THF/H2O at 40 °C, giving carboxylic acid (III). Subsequent coupling of acid (III) with the vinylcyclopropylamine derivative (IV) in the presence of HATU, DMAP and DIEA in CH2Cl2 at 40 °C yields the corresponding amide (V), which is finally reduced by catalytic hydrogenation over Pd/C in EtOAc .
In an alternative strategy, reduction of the macrocyclic alkene (II) by means of H2 and Pd/C in EtOAc yields the saturated macrocycle (VI), which by hydrolysis with LiOH in THF/MeOH/H2O furnishes carboxylic acid (VII). Finally, macrocyclic free acid (VII) is condensed with the ethylcyclopropylamine derivative (VIII) by means of HATU, DMAP and DIEA in DMF .
| 【1】 Holloway, M.K., Liverton, N.J., Ludmerer, S.W. et al. (Merck & Co., Inc.). HCV NS3 protease inhibitors. EP 1910404, EP 924593, JP 2009502793, US 2007027071, WO 2007015787, WO 2007015855. |
| 【2】 McCauley, J.A., McIntyre, C.J., Rudd, M.T. et al. Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor. J Med Chem 2010, 53(6): 2443-63. |
| 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) | 69055 | (3S,5R)-1-(2-((((2,2-dimethylhex-5-en-1-yl)oxy)carbonyl)amino)-3,3-dimethylbutanoyl)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinylisoindoline-2-carboxylate | C32H45N3O7 | 详情 | 详情 | |
| (II) | 69056 | C30H41N3O7 | 详情 | 详情 | ||
| (III) | 69057 | C29H39N3O7 | 详情 | 详情 | ||
| (IV) | 69058 | (1S,2R)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride | C9H14N2O3S.HCl | 详情 | 详情 | |
| (V) | 69060 | C38H51N5O9S | 详情 | 详情 | ||
| (VI) | 69061 | C30H43N3O7 | 详情 | 详情 | ||
| (VII) | 69062 | C29H39N3O7 | 详情 | 详情 | ||
| (VIII) | 69059 | (1S,2S)-1-amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamide hydrochloride | C9H16N2O3S.HCl | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Condensation of benzaldehyde (XXVI) with ethyl glycinate hydrochloride (XXVII) by means of Na2SO4 and Et3N in tert-butyl methyl ether gives 2-(benzylideneamino)acetic acid ethyl ester (XXVIII), which cyclizes with 1,4-dibromo-2(E)-butene (XXIX) in the presence of t-BuOLi in dry toluene to yield, after imine hydrolysis, the cyclopropylamine derivative (XXX). Protection of amine (XXX) with Boc2O furnishes the racemic N-Boc amino ester (XXXI), which is subjected to kinetic resolution by means of enzymes such as Acalase®, Savinase® or Esperase® in DMSO to afford unreacted (1R,2S)-isomer (XXXII). Saponification of ethyl ester (XXXII) using LiOH in THF/MeOH gives the cyclopropanecarboxylic acid derivative (XXXIII), which, after activation with CDI in refluxing THF, is coupled with cyclopropanesulfonamide (XXXIV) (prepared by treatment of cyclopropanesulfonyl chloride [XXXV] with NH3 in THF) in the presence of DBU to yield the N-acylsulfonamide (XXXVI). Alternatively, the sulfonamide intermediate (XXXIV) can be prepared by condensation of 3-chloropropanesulfonyl chloride (XXXVIII) with tert-butylamine in THF to give N-tert-butyl-(3-chloro)propylsulfonamide (XXXIX), which then cyclizes to the cyclopropyl derivative (XL) by treatment with n-BuLi in THF at –78 °C. Removal of the N-tert-butyl group in intermediate (XL) using CF3CO2H then furnishes cyclopropanesulfonamide (XXXIV). After N-Boc group cleavage in (XXXVI) by means of CF3CO2H in DCM, acidification with HCl in Et2O affords intermediate (IV) . Intermediate (VIII) can be obtained by vinyl group reduction in (IV) with H2 and Pd/C in EtOAc. Intermediate (VIII) can also be obtained by reduction of vinylcyclopropylamine derivative (XXXVI) with H2 over Ru/C in MeOH to yield N-Boc-ethylcyclopropylamine (XXXVII), which is finally N-deprotected by means of HCl in CH2Cl2 .
| 【1】 Sun, L.-Q., Sit, S.-Y., Scola, P.M. et al. (Bristol-Myers Squibb Co.). Hepatitis C virus inhibitors. EP 1505963, JP 2005533028, US 2004106559, US 6995174, WO 2003099274. |
| 【2】 Holloway, M.K., Liverton, N.J., McCauley, J.A., Rudd, M.T., Vacca, J.P., Ludmerer, S.W., Olsen, D.B. (Merck & Co., Inc.). Macrocyclic peptides as HCV NS3 protease inhibitors. EP 1913016, JP 2009503080, WO 200701641. |
| 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) | 69058 | (1S,2R)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride | C9H14N2O3S.HCl | 详情 | 详情 | |
| (VIII) | 69059 | (1S,2S)-1-amino-N-(cyclopropylsulfonyl)-2-ethylcyclopropanecarboxamide hydrochloride | C9H16N2O3S.HCl | 详情 | 详情 | |
| (XXVI) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (XXVII) | 67884 | methyl glycinate hydrochloride | 5680-79-5 | C3H7NO2.HCl | 详情 | 详情 |
| (XXVIII) | 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 |
| (XXIX) | 18349 | (E)-1,4-dibromo-2-butene；trans-1,4-dibromo-2-butene | 821-06-7 | C4H6Br2 | 详情 | 详情 |
| (XXX) | 68236 | ethyl 1-amino-2-vinylcyclopropanecarboxylate | 787548-29-2 | C8H13NO2 | 详情 | 详情 |
| (XXXI) | 68238 | ethyl 1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate | 681807-59-0 | C13H21NO4 | 详情 | 详情 |
| (XXXII) | 69076 | (1R,2R)-ethyl 1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylate | C13H21NO4 | 详情 | 详情 | |
| (XXXIII) | 69077 | (1R,2R)-1-((tert-butoxycarbonyl)amino)-2-vinylcyclopropanecarboxylic acid | C11H17NO4 | 详情 | 详情 | |
| (XXXIV) | 68242 | cyclopropanesulfonamide；Cyclopropanesulfonyl amide | 154350-29-5 | C3H7NO2S | 详情 | 详情 |
| (XXXV) | 67915 | cyclopropanesulfonyl chloride;Cyclopropylsulfonylchloride;Cyclopropylsulphonyl chloride | 139631-62-2 | C3H5ClO2S | 详情 | 详情 |
| (XXXVI) | 69078 | tert-butyl ((1R,2R)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamate | C14H22N2O5S | 详情 | 详情 | |
| (XXXVII) | 69079 | tert-butyl ((1R,2R)-1-((cyclopropylsulfonyl)carbamoyl)-2-ethylcyclopropyl)carbamate | C14H24N2O5S | 详情 | 详情 | |
| (XXXVIII) | 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 |
| (XXXIX) | 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 |
| (XL) | 68245 | N-(tert-butyl)cyclopropanesulfonamide;N-tert-butylcyclopropanesulfonamide;N-(tert-butyl)cyclopropanesulfonamide | C7H15NO2S | 详情 | 详情 |