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【结 构 式】 
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【分子编号】31845 【品名】2-[3-[(tert-butoxycarbonyl)amino]phenyl]-2-[(trityloxy)imino]acetic acid 【CA登记号】 |
【 分 子 式 】C32H30N2O5 【 分 子 量 】522.60068 【元素组成】C 73.55% H 5.79% N 5.36% O 15.31% |
合成路线1
该中间体在本合成路线中的序号：(XII)The condensation of 1,3-dichloroacetone (I) with ethyl 3-sulfanylpropionate (II) by means of triethylamine in THF gives ethyl 3-(3-chloro-2-oxopropylsulfanyl)propionate (III), which is condensed with ethyl carbazate (IV) by means of Ts-OH in acetonitrile yielding the corresponding hydrazone (V). The cyclization of (V) with SOCl2 in DMF gives the 1,2,3-thiadiazole (VI), which is condensed with 2-aminoethanethiol (A) by means of NaI in dioxane/water afffording the bis thioether (VII). The protection of the amino group of (VII) with Boc2O yields the carbamate (VIII), which is treated with sodium methoxide in methanol to provide sodium thiolate (IX). The condensation of (IX) with the cephem derivative (X) in ethyl acetate/aqueous NaHCO3 gives the expected addition product (XI), which is further condensed with 2-(tert-butoxycarbonylamino)-2-(trityloxyimino)acetic acid (XII) by means of POCl3 in THF yielding the fully protected target compound (XIII). Finally, this compound is deprotected by treatment with TFA and triethylsilane.
| 【1】 Hecker, S.J.; Fan, A.T.; Ludwikow, M.; Wang, M.; Cho A.; Glinka, T.W.; New anti-MRSA cephalosporins with a basic aminopyridine at the C-7 position. Bioorg Med Chem Lett 2001, 11, 2, 137. |
| 【2】 Lee, V.J.; Price, M.; Zhang, Z.J.; Fan, A.; Glinka, T.; Chamberland, S.; Cho, A.; Ludwikow, M.; Hecker, S.J.; Liu, N.; Design, synthesis, and SAR of water-soluble dibasic cephalosporins active against resistant Gram-positive bacteria. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F392. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (I) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (II) | 31837 | ethyl 3-sulfanylpropanoate | 5466-06-8 | C5H10O2S | 详情 | 详情 |
| (III) | 31838 | ethyl 3-[(3-chloro-2-oxopropyl)sulfanyl]propanoate | C8H13ClO3S | 详情 | 详情 | |
| (IV) | 12556 | methyl 1-hydrazinecarboxylate; methyl carbazate | 6294-89-9 | C2H6N2O2 | 详情 | 详情 |
| (V) | 31839 | methyl 2-((E)-2-chloro-1-[[(3-ethoxy-3-oxopropyl)sulfanyl]methyl]ethylidene)-1-hydrazinecarboxylate | C10H17ClN2O4S | 详情 | 详情 | |
| (VI) | 31840 | ethyl 3-[[4-(chloromethyl)-1,2,3-thiadiazol-5-yl]sulfanyl]propanoate | C8H11ClN2O2S2 | 详情 | 详情 | |
| (VII) | 31841 | ethyl 3-[(4-[[(2-aminoethyl)sulfanyl]methyl]-1,2,3-thiadiazol-5-yl)sulfanyl]propanoate | C10H17N3O2S3 | 详情 | 详情 | |
| (VIII) | 31842 | ethyl 3-([4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,2,3-thiadiazol-5-yl]sulfanyl)propanoate | C15H25N3O4S3 | 详情 | 详情 | |
| (IX) | 31843 | sodium 4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,2,3-thiadiazole-5-thiolate | C10H16N3NaO2S3 | 详情 | 详情 | |
| (X) | 15892 | benzhydryl (6R,7R)-7-amino-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H24N2O4S2 | 详情 | 详情 | |
| (XI) | 31844 | benzhydryl (6R,7R)-7-amino-3-([4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,2,3-thiadiazol-5-yl]sulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C30H33N5O5S4 | 详情 | 详情 | |
| (XII) | 31845 | 2-[3-[(tert-butoxycarbonyl)amino]phenyl]-2-[(trityloxy)imino]acetic acid | C32H30N2O5 | 详情 | 详情 | |
| (XIII) | 31846 | benzhydryl (6R,7R)-3-([4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,2,3-thiadiazol-5-yl]sulfanyl)-7-([2-[3-[(tert-butoxycarbonyl)amino]phenyl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C62H61N7O9S4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)The cyclization of ethyl cyanoacetate (I) with carbon disulfide gives 5-sulfanylthiazole-4-carboxylic acid ethyl ester (II), which is reduced with LiAlH4 in THF to the corresponding carbinol (III). The condensation of (III) with 2-iodoethyl phenyl sulfone (IV) affords the thioether (V), which is treated with SOCl2 in DMF to afford the chloromethyl derivative (VI). The condensation of (VI) with 2-aminoethanethiol (A) by means of NaI in dioxane/water gives the bis thioether (VII), which is protected at the amino group with Boc2 to afford the carbamate (VIII), and treated with NaOMe in methanol to provide the sodium thiolate (IX). The condensation of (IX) with the cephem derivative (X) in ethyl acetate/aqueous NaHCO3 gives the expected addition product (XI), which is further condensed with 2-(tert-butoxycarbonylamino)-2-(trityloxyimino)acetic acid (XII) by means of POCl3 in THF yielding the fully protected target compound (XIII). Finally, this compound is deprotected by treatment with TFA and triethylsilane.
| 【1】 Lee, V.J.; Price, M.; Zhang, Z.J.; Fan, A.; Glinka, T.; Chamberland, S.; Cho, A.; Ludwikow, M.; Hecker, S.J.; Liu, N.; Design, synthesis, and SAR of water-soluble dibasic cephalosporins active against resistant Gram-positive bacteria. 39th Intersci Conf Antimicrob Agents Chemother (Sept 26 1999, San Francisco) 1999, Abst F392. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (I) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 31848 | ethyl 5-sulfanyl-1,3-thiazole-4-carboxylate | C6H7NO2S2 | 详情 | 详情 | |
| (III) | 31849 | (5-sulfanyl-1,3-thiazol-4-yl)methanol | C4H5NOS2 | 详情 | 详情 | |
| (IV) | 31850 | 2-iodoethyl phenyl sulfone; (2-iodoethyl)(dioxo)phenyl-lambda(6)-sulfane | C8H9IO2S | 详情 | 详情 | |
| (V) | 31851 | (5-[[2-(phenylsulfonyl)ethyl]sulfanyl]-1,3-thiazol-4-yl)methanol | C12H13NO3S3 | 详情 | 详情 | |
| (VI) | 31852 | 2-[[4-(chloromethyl)-1,3-thiazol-5-yl]sulfanyl]ethyl phenyl sulfone; 4-(chloromethyl)-5-[[2-(phenylsulfonyl)ethyl]sulfanyl]-1,3-thiazole | C12H12ClNO2S3 | 详情 | 详情 | |
| (VII) | 31853 | 2-[[(5-[[2-(phenylsulfonyl)ethyl]sulfanyl]-1,3-thiazol-4-yl)methyl]sulfanyl]ethylamine; 2-[[(5-[[2-(phenylsulfonyl)ethyl]sulfanyl]-1,3-thiazol-4-yl)methyl]sulfanyl]-1-ethanamine | C14H18N2O2S4 | 详情 | 详情 | |
| (VIII) | 31854 | tert-butyl 2-[[(5-[[2-(phenylsulfonyl)ethyl]sulfanyl]-1,3-thiazol-4-yl)methyl]sulfanyl]ethylcarbamate | C19H26N2O4S4 | 详情 | 详情 | |
| (IX) | 31855 | sodium 4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,3-thiazole-5-thiolate | C11H17N2NaO2S3 | 详情 | 详情 | |
| (X) | 15892 | benzhydryl (6R,7R)-7-amino-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C23H24N2O4S2 | 详情 | 详情 | |
| (XI) | 31856 | benzhydryl (6R,7R)-7-amino-3-([4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,3-thiazol-5-yl]sulfanyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C31H34N4O5S4 | 详情 | 详情 | |
| (XII) | 31845 | 2-[3-[(tert-butoxycarbonyl)amino]phenyl]-2-[(trityloxy)imino]acetic acid | C32H30N2O5 | 详情 | 详情 | |
| (XIII) | 31857 | benzhydryl (6R,7R)-3-([4-[([2-[(tert-butoxycarbonyl)amino]ethyl]sulfanyl)methyl]-1,3-thiazol-5-yl]sulfanyl)-7-([2-[3-[(tert-butoxycarbonyl)amino]phenyl]-2-[(trityloxy)imino]acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C63H62N6O9S4 | 详情 | 详情 |