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【结 构 式】

【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%

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:(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
Extended Information