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【结 构 式】

【分子编号】67915

【品名】cyclopropanesulfonyl chloride;Cyclopropylsulfonylchloride;Cyclopropylsulphonyl chloride

【CA登记号】139631-62-2

【 分 子 式 】C3H5ClO2S

【 分 子 量 】140.59

【元素组成】C 25.63% H 3.58% Cl 25.22% O 22.76% S 22.81%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号: (XV)

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:(XXXV)

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:(XIII)

Condensation of 1,2,3,5-tetrafluoro-4-nitrobenzene (I) with 2-fluoro-4-iodoaniline (II) by means of LiHMDS in THF gives diaryl amine (III),which undergoes selective fluoride substitution with NaOMe in THF to yield 5-methoxy-6-nitroaniline derivative (IV). Nitro group reduction in intermediate (IV) by means of Fe and NH4Cl in refluxing EtOH provides the corresponding diamine (V), which is then condensed with 1-allylcyclopropanesulfonyl chloride (VI) in the presence of pyridine at 40 °C to produce the sulfonamide (VII). Dihydroxylation of the allyl group of compound (VII) with OsO4 and NMMO in THF affords racemic refametinib, which is finally resolved using chiral HPLC .
In an alternative method, coupling of the primary amine (V) with the chiral sulfonyl chloride (VIII) in the presence of pyridine yields the corresponding sulfonamide (IX), which is finally hydrolyzed at the acetonide moiety with HCl in THF .
1-Allylcyclopropanesulfonyl chloride intermediate (VI) is prepared as follows. Treatment of 3-chloro-1-propanesulfonyl chloride (X) with BuOH affords butyl 3-chloro-1-propanesulfonate (XI), which cyclizes in the presence of BuLi to yield butyl cyclopropanesulfonate (XII),which can also be obtained by treatment of cyclopropanesulfonyl chloride (XIII) with BuOH in the presence of pyridine. Alkylation of butyl cyclopropanesulfonate (XII) with allyl iodide (XIV) using BuLi in THF at –78 °C yields butyl 1-allylcyclopropanesulfonate (XV), which is hydrolyzed by treatment with KSCN in DME/H2O at reflux producing potassium 1-allylcyclopropanesulfonate (XVI). Finally, the potassium sulfonate (XVI) is chlorinated with refluxing SOCl2 in the presence of a catalytic amount of DMF .

1 Maderna, A., Vernier, J., Barawkar, D., Chamakura, V., El Abdellaoui, H., Hong, Z. (Ardea Biosciences, Inc.). Derivatives of N-(arylamino)sulfonamides as inhibitors of MEK. US 2008058340, US 8101799.
3 Maderna, A., Vernier, J.-M. (Ardea Biosciences, Inc.). Preparation of (R)-and (S)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2, 3-dihydroxypropyl)cyclopropane-1-sulfonamide and protected derivatives thereof. EP 2462111, JP 2013500242, KR 2012032536, WO 2011009541.
2 Maderna, A., Vernier, J.-M., Barawkar, D., Chamakura, V., Abdellaoui, H.E., Hong, Z. (Ardea Biosciences, Inc.). N-(Arylamino)-sulfonamide inhibitors of MEK. EP 1912636, US 2012022076, WO 2007014011
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) 67905 1,2,3,5-tetrafluoro-4-nitrobenzene 314-41-0 C6HF4NO2 详情 详情
(II) 63342 2-fluoro-4-iodoaniline; 2-fluoro-4-iodophenylamine 29632-74-4 C6H5FIN 详情 详情
(III) 67906 2,3,5-trifluoro-N-(2-fluoro-4-iodophenyl)-6-nitroaniline   C12H5F4IN2O2 详情 详情
(IV) 67907 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-5-methoxy-6-nitroaniline   C13H8F3IN2O3 详情 详情
(V) 67908 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine   C13H10F3IN2O 详情 详情
(VI) 67909 1-allylcyclopropanesulfonyl chloride 923032-59-1 C6H9ClO2S 详情 详情
(VII) 67910 1-allyl-N-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxyphenyl)cyclopropane-1-sulfonamide   C19H18F3IN2O3S 详情 详情
(VIII) 67911 (S)-1-((5,5-dimethyltetrahydrofuran-2-yl)methyl)cyclopropane-1-sulfonyl chloride   C10H17ClO3S 详情 详情
(IX) 67912 (S)-N-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxyphenyl)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)cyclopropane-1-sulfonamide   C22H24F3IN2O5S 详情 详情
(X) 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
(XI) 67913 butyl 3-chloro-1-propanesulfonate;3-Chloro-propane-1-sulfonic acid butyl ester 146475-47-0 C7H15ClO3S 详情 详情
(XII) 67914 butyl cyclopropanesulfonate 83635-12-5 C7H14O3S 详情 详情
(XIII) 67915 cyclopropanesulfonyl chloride;Cyclopropylsulfonylchloride;Cyclopropylsulphonyl chloride 139631-62-2 C3H5ClO2S 详情 详情
(XIV) 32112 3-iodo-1-propene;3-iodo-propen;allyl iodide 556-56-9 C3H5I 详情 详情
(XV) 67917 butyl 1-allylcyclopropane-1-sulfonate   C10H18O3S 详情 详情
(XVI) 67916 potassium 1-allylcyclopropanesulfonate 923032-57-9 C6H9KO3S 详情 详情
Extended Information