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【结 构 式】 
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【药物名称】MK-7009;Vaniprevir 【化学名称】(5R,7S,10S)-10-tert-Butyl-N-[1(R)-[N-(cyclopropylsulfonyl)carbamoyl]-2(R)-ethylcyclopropyl]-15,15-dimethyl-3,9,12-trioxo-3,5,6,7,9,10,11,12,14,15,16,17,18,19-tetradecahydro-1H-2,23:5,8-dimethano-4,13,2,8,11-benzodioxatriazacyclohenicosine-7-carboxamide 【CA登记号】 【 分 子 式 】C38H55N5O9S 【 分 子 量 】757.936 |
【开发单位】Merck & Co., Inc. (US) 【药理作用】HCV NS3/4A Protease Inhibitor；Treatment of Hepatitis C |
合成路线1
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
Benzylic bromination of 3-bromo-o-xylene (IX) with NBS in the presence of benzoyl peroxide in refluxing CCl4 or chlorobenzene at 80 °C gives 1-bromo-2,3-bis(bromomethyl)benzene (X), which then cyclizes with benzylamine in the presence of KHCO3 in acetonitrile to yield 2-benzyl-4-bromoisoindoline (XI). Alkenylation of compound (XI) with tributyl(vinyl)tin (XII) by means of Pd(PPh3)4 in toluene provides the isoindoline (XIII), which is then deprotected by means of 1-chloroethyl chloroformate (ACE-Cl) in refluxing 1,2-dichloroethane to afford 4-vinylisoindoline (XIV). Finally, coupling of 4-vinylisoindoline (XIV) with N-Boc-trans-4-hydroxyproline methyl ester (XV), previously activated with CDI, in DMF at 60 °C results in carbamate (XVI) .
Alternatively, debenzylation of 2-benzyl-4-bromoisoindoline (XI) by means of ACE-Cl in chlorobenzene at 90 °C, followed by condensation of the deprotected isoindoline (XVII) with N-Boc-trans-4-hydroxyproline methyl ester (XV), previously treated with CDI, by means of DIEA in DMF at 50 °C furnishes carbamate (XVIII). Then, alkenylation of the aryl bromide (XVIII) with potassium vinyltrifluoroborate (XIX) and Et3N in refluxing EtOH affords the vinyl isoindoline derivative (XVI) .
Finally, Boc-deprotection of proline derivative (XVI) by means of HCl in dioxane gives the corresponding amine (XX), which is then coupled with the L-tert-leucine carbamate derivative (XXI) in the presence of EDC, DIEA and HOAt or HOBt in DMF to yield the building block diene (I) .
The L-tert-leucine carbamate (XXI) is prepared by alkylation of ethyl isobutyrate (XXII) with 4-bromo-1-butene (XXIII) and LDA in HMPA, followed by ester group reduction with LiAlH4 in Et2O, affording 2,2-dimethyl-5-hexen-1-ol (XXIV) . After treatment of hexenol (XXIV) with triphosgene by means of DIEA and NaOH in 1,4-dioxane, the resulting chloroformate is condensed with L-tert-leucine (XXV) to give carbamate (XXI) .
| 【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 | |
| (IX) | 69063 | 3-bromo-o-xylene;2,3-Dimethylbromobenzene;3-Bromo-1,2-dimethylbenzene | 576-23-8 | C8H9Br | 详情 | 详情 |
| (X) | 69064 | 1-bromo-2,3-bis(bromomethyl)benzene | C8H7Br3 | 详情 | 详情 | |
| (XI) | 69065 | 2-benzyl-4-bromoisoindoline | C15H14BrN | 详情 | 详情 | |
| (XII) | 24920 | tributyl(vinyl)stannane；Tributylvinylstannane;Vinyltributylstannane | 7486-35-3 | C14H30Sn | 详情 | 详情 |
| (XIII) | 69066 | 2-benzyl-4-vinylisoindoline | C17H17N | 详情 | 详情 | |
| (XIV) | 69067 | 4-vinylisoindoline | C10H11N | 详情 | 详情 | |
| (XV) | 15780 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (XVI) | 69070 | (2S,4S)-1-tert-butyl 2-methyl 4-((4-vinylisoindoline-2-carbonyl)oxy)pyrrolidine-1,2-dicarboxylate | C22H28N2O6 | 详情 | 详情 | |
| (XVII) | 69068 | 4-bromoisoindoline hydrochloride;3-Bromo-1H-isoindoline Hydrochloride;4-Bromo-1H-isoindoline hydrochloride;4-Bromo-2,3-dihydro-1H-isoindole hydrochloride | 923590-95-8 | C8H8BrN.HCl | 详情 | 详情 |
| (XVIII) | 69071 | (2S,4S)-1-tert-butyl 2-methyl 4-((4-bromoisoindoline-2-carbonyl)oxy)pyrrolidine-1,2-dicarboxylate | C20H25BrN2O6 | 详情 | 详情 | |
| (XIX) | 69072 | potassium vinyltrifluoroborate;potassium trifluoro(vinyl)borate | C2H3BF3K | 详情 | 详情 | |
| (XX) | 69069 | (3S,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinylisoindoline-2-carboxylate hydrochloride | C17H20N2O4.HCl | 详情 | 详情 | |
| (XXI) | 69073 | 2-((((2,2-dimethylhex-5-en-1-yl)oxy)carbonyl)amino)-3,3-dimethylbutanoic acid | C15H27NO4 | 详情 | 详情 | |
| (XXII) | 28650 | ethyl 2-methylpropanoate；ethyl isobutyrate | 97-62-1 | C6H12O2 | 详情 | 详情 |
| (XXIII) | 11720 | 4-Bromo-1-butene | 5162-44-7 | C4H7Br | 详情 | 详情 |
| (XXIV) | 69074 | 2,2-dimethyl-5-hexen-1-ol | C8H16O | 详情 | 详情 | |
| (XXV) | 69075 | (S)-2-amino-3,3-dimethylbutanoic acid;L-tert-leucine;L-2-Amino-3,3-dimethylbutanoic acid | 20859-02-3 | C6H13NO2 | 详情 | 详情 |
合成路线3
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 |