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【结 构 式】 
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【分子编号】18349 【品名】(E)-1,4-dibromo-2-butene；trans-1,4-dibromo-2-butene 【CA登记号】821-06-7 |
【 分 子 式 】C4H6Br2 【 分 子 量 】213.89964 【元素组成】C 22.46% H 2.83% Br 74.71% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(XXIX)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 |
合成路线3
该中间体在本合成路线中的序号：(I)Substitution on dibromobutene (I) by potassium phthalimide (II) provided bromobutenyl phthalimide (III). Further treatment with sodium acetate afforded acetate (IV) which, after hydrolysis, gave phthalimidobutenol (V). Reaction with refluxing ethyl orthoacetate in the presence of a trace of butyric acid generated the intermediate ketene acetal (VI), which experienced a Claisen rearrangement to give pentenoate ester (VII). Ozonolysis of the olefinic double bond of (VII) yielded aldehyde (VIII). Then, Wittig reaction of aldehyde (VIII) with (isopropylidene)triphenylphosphorane in cold THF provided olefin (IX), which was hydrogenated in the presence of Pd/C to give the isobutyl compound (X). Finally, hydrolysis of both ester and phthalimide groups in refluxing 6 N HCl provided the GABA analogue.
| 【1】 Serfass, L.; Casara, P.J.; General synthesis of 3-substituted alkenyl GABA as potential anticonvulsants. Bioorg Med Chem Lett 1998, 8, 18, 2599. |
| 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) | 18349 | (E)-1,4-dibromo-2-butene；trans-1,4-dibromo-2-butene | 821-06-7 | C4H6Br2 | 详情 | 详情 |
| (II) | 10926 | (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)potassium | C8H4KNO2 | 详情 | 详情 | |
| (III) | 18351 | 2-[(E)-4-bromo-2-butenyl]-1H-isoindole-1,3(2H)-dione | C12H10BrNO2 | 详情 | 详情 | |
| (IV) | 18352 | (E)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-butenyl acetate | C14H13NO4 | 详情 | 详情 | |
| (V) | 18353 | 2-[(E)-4-hydroxy-2-butenyl]-1H-isoindole-1,3(2H)-dione | C12H11NO3 | 详情 | 详情 | |
| (VI) | 18354 | 2-[(E)-4-[(1-ethoxyvinyl)oxy]-2-butenyl]-1H-isoindole-1,3(2H)-dione | C16H17NO4 | 详情 | 详情 | |
| (VII) | 18355 | ethyl 3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-pentenoate | C16H17NO4 | 详情 | 详情 | |
| (VIII) | 18356 | ethyl 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-formylbutanoate | C15H15NO5 | 详情 | 详情 | |
| (IX) | 18357 | ethyl 3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-5-methyl-4-hexenoate | C18H21NO4 | 详情 | 详情 | |
| (X) | 18358 | ethyl 3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-5-methylhexanoate | C18H23NO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The intermediate phenylacetic acid allyl ester (IV) is prepared by two methods. Reaction of trans-1,4-dibromo-2-butene (I) with benzyl alcohol under phase-transfer conditions provides the benzyl ether (II). Subsequent DBU-mediated coupling of (II) with (4-methoxyphenyl)acetic acid (III) yields ester (IV).
| 【1】 Kottirsch, G.; et al.; beta-Aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme. J Med Chem 2002, 45, 11, 2289. |
| 【2】 Kottirsch, G.; Neumann, U. (Novartis AG); Hydroxamic acid derivs.. EP 0929517; JP 2000508338; US 2002003804; US 6500983; WO 9814424 . |
| 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) | 18349 | (E)-1,4-dibromo-2-butene；trans-1,4-dibromo-2-butene | 821-06-7 | C4H6Br2 | 详情 | 详情 |
| (II) | 61680 | benzyl (E)-4-bromo-2-butenyl ether; 1-({[(E)-4-bromo-2-butenyl]oxy}methyl)benzene | C11H13BrO | 详情 | 详情 | |
| (III) | 34794 | (E)-3-chloro-2,3-bis(4-methoxyphenyl)-2-propenal | C17H15ClO3 | 详情 | 详情 | |
| (IV) | 61681 | (E)-4-(benzyloxy)-2-butenyl 2-(4-methoxyphenyl)acetate | C20H22O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXV)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 |