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【结 构 式】 
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【分子编号】46020 【品名】2-[[4-((E)-3-[[2-(tert-butoxy)-2-oxoethyl]amino]-3-oxo-1-propenyl)-2,5-dichlorophenyl]sulfanyl]acetic acid 【CA登记号】 |
【 分 子 式 】C17H19Cl2NO5S 【 分 子 量 】420.313 【元素组成】C 48.58% H 4.56% Cl 16.87% N 3.33% O 19.03% S 7.63% |
合成路线1
该中间体在本合成路线中的序号：(XVI)The iodination of trichloroaniline (VIII) via diazotization produced iodide (IX). Subsequent Heck reaction of iodide (IX) with tert-butyl acrylate (X) furnished tert-butyl trichlorocinnamate (XI), which was condensed with the sodium salt of methyl mercaptoacetate (XII), yielding thioether (XIII). After acid cleavage of the tert-butyl ester of (XIII), the resulting carboxylic acid (XIV) was coupled with glycine tert-butyl ester via activation as the corresponding N-hydroxysuccinimidyl ester. Then, saponification of the methyl ester group of (XV) afforded the intermediate acid (XVI).
| 【1】 Singh, J.; et al.; A practical synthesis of an anti-methicillin resistant Staphylococcus aureus cephalosporin BMS-247243. Org Process Res Dev 2000, 4, 6, 488. |
| 【2】 Springer, D.M.; Luh, B.Y.; D'Andrea, S.V.; Hudyma, T.W.; Kim, O.K. (Bristol-Myers Squibb Co.); Cephalosporin derivs.. EP 0966472; WO 9823621 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 46013 | 2,4,5-trichlorophenylamine; 2,4,5-trichloroaniline | 636-30-6 | C6H4Cl3N | 详情 | 详情 |
| (IX) | 46014 | 1-Iodo-2,4,5-trichlorobenzene; 2,4,5-Trichloroiodobenzene; 1,2,4-trichloro-5-iodobenzene | 7145-82-6 | C6H2Cl3I | 详情 | 详情 |
| (X) | 12760 | tert-butyl acrylate | 1663-39-4 | C7H12O2 | 详情 | 详情 |
| (XI) | 46015 | tert-butyl (E)-3-(2,4,5-trichlorophenyl)-2-propenoate | C13H13Cl3O2 | 详情 | 详情 | |
| (XII) | 46016 | sodium 2-methoxy-2-oxo-1-ethanethiolate | C3H5NaO2S | 详情 | 详情 | |
| (XIII) | 46017 | tert-butyl (E)-3-[2,5-dichloro-4-[(2-methoxy-2-oxoethyl)sulfanyl]phenyl]-2-propenoate | C16H18Cl2O4S | 详情 | 详情 | |
| (XIV) | 46018 | (E)-3-[2,5-dichloro-4-[(2-methoxy-2-oxoethyl)sulfanyl]phenyl]-2-propenoic acid | C12H10Cl2O4S | 详情 | 详情 | |
| (XV) | 46019 | methyl 2-[[4-((E)-3-[[2-(tert-butoxy)-2-oxoethyl]amino]-3-oxo-1-propenyl)-2,5-dichlorophenyl]sulfanyl]acetate | C18H21Cl2NO5S | 详情 | 详情 | |
| (XVI) | 46020 | 2-[[4-((E)-3-[[2-(tert-butoxy)-2-oxoethyl]amino]-3-oxo-1-propenyl)-2,5-dichlorophenyl]sulfanyl]acetic acid | C17H19Cl2NO5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)An improved procedure for the synthesis of intermediate (XVI) was further developed. Heck coupling of iodide (IX) with acrylic acid formed cinnamic acid (XVIII). This was converted to the corresponding acid chloride upon treatment with Vilsmeier reagent, and subsequent coupling with glycine tert-butyl ester gave amide (XIX). Selective chlorine displacement in (XIX) by means of the lithium salt of methyl mercaptoacetate, followed by in situ hydrolysis with LiOH, afforded acid (XVI).
| 【1】 Singh, J.; et al.; A practical synthesis of an anti-methicillin resistant Staphylococcus aureus cephalosporin BMS-247243. Org Process Res Dev 2000, 4, 6, 488. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 46014 | 1-Iodo-2,4,5-trichlorobenzene; 2,4,5-Trichloroiodobenzene; 1,2,4-trichloro-5-iodobenzene | 7145-82-6 | C6H2Cl3I | 详情 | 详情 |
| (XVI) | 46020 | 2-[[4-((E)-3-[[2-(tert-butoxy)-2-oxoethyl]amino]-3-oxo-1-propenyl)-2,5-dichlorophenyl]sulfanyl]acetic acid | C17H19Cl2NO5S | 详情 | 详情 | |
| (XVII) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (XVIII) | 46021 | (E)-3-(2,4,5-trichlorophenyl)-2-propenoic acid | C9H5Cl3O2 | 详情 | 详情 | |
| (XIX) | 46022 | tert-butyl 2-[[(E)-3-(2,4,5-trichlorophenyl)-2-propenoyl]amino]acetate | C15H16Cl3NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVI)Acylation of the cephem nucleus (XX) with the intermediate acid (XVI) via activation with either DCC or the Vilsmeier reagent provided amide (XXI). The ester groups of (XXI) were then cleaved with trifluoroacetic acid to give acid (XXII). Finally, condensation of (XXII) with pyridine thione (VII) furnished the title compound.
| 【1】 Singh, J.; et al.; A practical synthesis of an anti-methicillin resistant Staphylococcus aureus cephalosporin BMS-247243. Org Process Res Dev 2000, 4, 6, 488. |
| 【3】 Springer, D.M.; Luh, B.Y.; D'Andrea, S.V.; Hudyma, T.W.; Kim, O.K. (Bristol-Myers Squibb Co.); Cephalosporin derivs.. EP 0966472; WO 9823621 . |
| 【2】 Kim, O.; et al.; Discovery, synthesis and SAR of BMS-247243, a novel cephalosporin active against methicillin-resistant Staphylococcus aureus (MRSA) and susceptible Staphylococcus aureus (MSSA). 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2000, Abst F-1062. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 46012 | 4-[3-[2,6-dimethyl-4-thioxo-1(4H)-pyridinyl]propyl]-4-methylmorpholin-4-ium iodide | C15H25IN2OS | 详情 | 详情 | |
| (XVI) | 46020 | 2-[[4-((E)-3-[[2-(tert-butoxy)-2-oxoethyl]amino]-3-oxo-1-propenyl)-2,5-dichlorophenyl]sulfanyl]acetic acid | C17H19Cl2NO5S | 详情 | 详情 | |
| (XX) | 31135 | benzhydryl (6R,7R)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C21H19ClN2O3S | 详情 | 详情 | |
| (XXI) | 46023 | benzhydryl (6R,7R)-7-[(2-[[4-((E)-3-[[2-(tert-butoxy)-2-oxoethyl]amino]-3-oxo-1-propenyl)-2,5-dichlorophenyl]sulfanyl]acetyl)amino]-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C38H36Cl3N3O7S2 | 详情 | 详情 | |
| (XXII) | 46024 | (6R,7R)-7-([2-[(4-[(E)-3-[(carboxymethyl)amino]-3-oxo-1-propenyl]-2,5-dichlorophenyl)sulfanyl]acetyl]amino)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C21H18Cl3N3O7S2 | 详情 | 详情 |