|
【结 构 式】 
|
【分子编号】26619 【品名】4-ethylbenzenesulfonyl chloride 【CA登记号】16712-69-9 |
【 分 子 式 】C8H9ClO2S 【 分 子 量 】204.67696 【元素组成】C 46.95% H 4.43% Cl 17.32% O 15.63% S 15.67% |
合成路线1
该中间体在本合成路线中的序号：(I)Thiol (II) was prepared by reduction of 4-ethylbenzenesulfonyl chloride (I) with LiAlH4. Subsequent alkylation of (II) with ethyl 4-chloroacetoacetate (III) provided sulfide (IV), which was cyclized to the required benzothiophene (V) on heating with polyphosphoric acid in toluene. Basic hydrolysis of the ester group of (V) gave carboxylic acid (IV). After conversion of (VI) to the corresponding acid chloride with SOCl2, treatment with NH4OH yielded amide (VII). This was dehydrated to nitrile (VIII) using trifluoroacetic anhydride and triethylamine. Reduction of the nitrile function of (VIII) by means of LiAlH4 and AlCl3 gave rise to the corresponding primary amine, which was isolated as the hydrochloride salt (IX). Finally, acylation with acetyl chloride furnished the title acetamide.
| 【1】 Lesieur, D.; Fourmaintraux, E.; Depreux, P.; Delagrange, P.; Renard, P.; Guardiola-Lemaître, B. (ADIR et Cie.); Alkyl(hetero)cyclic cpds., process for their preparation and pharmaceutical compsns. containing them. CA 2167039; CA 2167040; EP 0721938; EP 0721947; FR 2729147; JP 1996231530; JP 1996239353; US 5693665; US 5703121; US 5780512 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| (I) | 26619 | 4-ethylbenzenesulfonyl chloride | 16712-69-9 | C8H9ClO2S | 详情 | 详情 |
| (II) | 32934 | 4-ethylbenzenethiol; 4-ethylphenylhydrosulfide | 4946-13-8 | C8H10S | 详情 | 详情 |
| (III) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (IV) | 32935 | ethyl 4-[(4-ethylphenyl)sulfanyl]-3-oxobutanoate | C14H18O3S | 详情 | 详情 | |
| (V) | 32936 | ethyl 2-(5-ethyl-1-benzothiophen-3-yl)acetate | C14H16O2S | 详情 | 详情 | |
| (VI) | 32937 | 2-(5-ethyl-1-benzothiophen-3-yl)acetic acid | C12H12O2S | 详情 | 详情 | |
| (VII) | 32938 | 2-(5-ethyl-1-benzothiophen-3-yl)acetamide | C12H13NOS | 详情 | 详情 | |
| (VIII) | 32939 | 2-(5-ethyl-1-benzothiophen-3-yl)acetonitrile | C12H11NS | 详情 | 详情 | |
| (IX) | 32940 | 2-(5-ethyl-1-benzothiophen-3-yl)ethylamine; 2-(5-ethyl-1-benzothiophen-3-yl)-1-ethanamine | C12H15NS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The reaction of N-(benzyloxycarbonyl)-L-asparagine (I) with bis(trifluoroacetyl)iodobenzene (BTI) in DMF/water gives 3-amino-2(S)-(benzyloxycarbonylamino)propionic acid (II), wehich is protected at the amino group with tert-butoxycarbonyl anhydride yielding carbamate (III). The esterification of (III) with ethanol WSC and DMAP affords the expected ethyl ester (IV), which is selectively deprotected with methanesulfonic acid in acetonitrile providing 3-amino-2-(benzyloxycarbonylamino)propionic acid ethyl ester (V). The condensation of (V) with N-(tert-butoxycarbonyl)-beta-alanine (VI) by means of HOBT, WSC and triethylamine in DMF gives the protected propionamidopropionic ester (VII), which is selectively deprotected by hydrogenation with H2 over Pd/C in ethanol/ethyl acetate giving the 2-aminopropionic ester (VIII). The condensation of (VIII) with 4-ethylbenzenesulfonyl chloride (IX) by means of triethylamine in dichloromethane yields the sulfonamide (X), which is deprotected with methanesulfonic acid as before afording intermediate (XI) with a free amino group, which is condensed with 4-(tert-butoxycarbonylamino)benzoic acid (XII) by means of HOBT and WSC in DMF providing the fully protected target compound (XIII).
| 【1】 Ikeda, Y.; Ueki, Y.; Kishimoto, H.; Nishihara, T.; Kamikawa, Y. (Sumitomo Pharmaceuticals Co., Ltd.); 2,3-Diaminopropionic acid deriv.. US 5707994; US 6048854; WO 9511228 . |
| 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) | 14529 | (2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid | 2304-96-3 | C12H14N2O5 | 详情 | 详情 |
| (II) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (III) | 26613 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propionic acid | C16H22N2O6 | 详情 | 详情 | |
| (IV) | 26614 | ethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C18H26N2O6 | 详情 | 详情 | |
| (V) | 26615 | ethyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C13H18N2O4 | 详情 | 详情 | |
| (VI) | 26616 | N-(tert-butoxycarbonyl)-beta-alanine | 3303-84-2 | C8H15NO4 | 详情 | 详情 |
| (VII) | 26617 | ethyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)propanoate | C21H31N3O7 | 详情 | 详情 | |
| (VIII) | 26618 | ethyl (2S)-2-amino-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)propanoate | C13H25N3O5 | 详情 | 详情 | |
| (IX) | 26619 | 4-ethylbenzenesulfonyl chloride | 16712-69-9 | C8H9ClO2S | 详情 | 详情 |
| (X) | 26620 | ethyl (2S)-3-([3-[(tert-butoxycarbonyl)amino]propanoyl]amino)-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C21H33N3O7S | 详情 | 详情 | |
| (XI) | 26621 | ethyl (2S)-3-[(3-aminopropanoyl)amino]-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C16H25N3O5S | 详情 | 详情 | |
| (XII) | 26622 | 4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoic acid | C13H16N2O4 | 详情 | 详情 | |
| (XIII) | 26623 | ethyl (2S)-3-[[3-([4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoyl]amino)propanoyl]amino]-2-[[(4-ethylphenyl)sulfonyl]amino]propanoate | C29H39N5O8S | 详情 | 详情 |