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【结 构 式】 
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【分子编号】27616 【品名】7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid 2,2,2-trichloroethyl ester S,S-dioxide 【CA登记号】 |
【 分 子 式 】C17H20Cl3NO6S 【 分 子 量 】472.77304 【元素组成】C 43.19% H 4.26% Cl 22.5% N 2.96% O 20.3% S 6.78% |
合成路线1
该中间体在本合成路线中的序号：(IX)1) Treatment of 6-azopenicillanate (I) with boron trifluoroetherate in a mixture of methanol and methylene chloride gives 6alpha-methoxy penicillanate (II), which on oxidation with peracetic acid gives the corresponding 1beta-oxide (III). Ring opening of the oxide (III) by heating with 2-mercaptohenzothiazole in toluene gives the intermediate (IV), which on cyclization with bromine in methylene chloride gives 2beta-bromomethyl penicillanate (V). Rearrangement of (V) with pyridine in dimethyl sulfoxide gives the cephem intermediate (VI). The sulfone derivative (VII) is obtained by oxidizing (VI) with peracetic acid in methylene chloride. Introduction of the double bound at C-2 position of the sulfone (VII) is achieved by heating with dimethylamine hydrochloride in a mixture of tert-BuOH methylene chloride and formaldehyde. Reaction of the intermediate (VIII) with diazo cyclopentane, generated in situ by treatment of cyclopentyl hydrazono with silver (I) oxide, gives 2,2,2-tricholoroethyl-7alpha-methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (IX). Removal of the trichloroethyl group by treatment with Zn/glacial acetic acid gives the corresponding acid (X). Reaction of the acid (X) with oxalyl chloride in methylene chloride gives the acid chloride (XI), which is condensed with 4-(1-butoxycarbonylmethyl)piperazine to afford the product (XII). Deprotection of the tert-butyl group with formic acid gives the free acid (XIII). Finally, this compound is converted into the sodium salt (XIV) of Syn-1390 by treatment with sodium carbonate in water.
| 【1】 Maiti, S.N.; Woods, D.E.; Cantin, A.M.; 2-Spirocyclopropyl cephem sulfones: Human neutrophil elastase inhibitors Syn-1390 and Syn-1396. Drugs Fut 1998, 23, 6, 635. |
| 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) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (B) | 25055 | cyclopentanone hydrazone | C5H10N2 | 详情 | 详情 | |
| (I) | 27608 | 6-Diazo-2,2-dimethylpenam-3(R)-carboxylic acid 2,2,2-trichlloroethyl ester | C10H10Cl3N3O3S | 详情 | 详情 | |
| (II) | 27609 | 2,2,2-trichloroethyl (2S,6S)-6-methoxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H14Cl3NO4S | 详情 | 详情 | |
| (III) | 27610 | 2,2,2-trichloroethyl (2S,6S)-6-methoxy-3,3-dimethyl-4,7-dioxo-4lambda(4)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H14Cl3NO5S | 详情 | 详情 | |
| (IV) | 27611 | 2,2,2-trichloroethyl (2R)-2-[(3S)-2-(1,3-benzothiazol-2-yldisulfanyl)-3-methoxy-4-oxoazetidinyl]-3-methyl-3-butenoate | C18H17Cl3N2O4S3 | 详情 | 详情 | |
| (V) | 27612 | 2,2,2-trichloroethyl (2S,3R,6S)-3-(bromomethyl)-6-methoxy-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H13BrCl3NO4S | 详情 | 详情 | |
| (VI) | 27613 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C11H12Cl3NO4S | 详情 | 详情 | |
| (VII) | 27614 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C11H12Cl3NO6S | 详情 | 详情 | |
| (VIII) | 27615 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-4-methylene-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H12Cl3NO6S | 详情 | 详情 | |
| (IX) | 27616 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid 2,2,2-trichloroethyl ester S,S-dioxide | C17H20Cl3NO6S | 详情 | 详情 | |
| (X) | 27617 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid S,S-dioxide | C15H19NO6S | 详情 | 详情 | |
| (XI) | 27618 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carbonyl chloride S,S-dioxide | C15H18ClNO5S | 详情 | 详情 | |
| (XII) | 27619 | 2-[4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazin-1-yl]acetic acid tert-butyl ester S,S-dioxide | C25H37N3O7S | 详情 | 详情 | |
| (XIII) | 27620 | 2-[4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazin-1-yl]acetic acid S,S-dioxide | C21H29N3O7S | 详情 | 详情 | |
| (C) | 25056 | tert-butyl 2-(1-piperazinyl)acetate | C10H20N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)1) Treatment of 6-azopenicillanate (I) with boron trifluoroetherate in a mixture of methanol and methylene chloride gives 6alpha-methoxy penicillanate (II), which on oxidation with peracetic acid gives the corresponding 1beta-oxide (III). Ring opening of the oxide (III) by heating with 2-mercaptohenzothiazole in toluene gives the intermediate (IV), which on cyclization with bromine in methylene chloride gives 2beta-bromomethyl penicillanate (V). Rearrangement of (V) with pyridine in dimethyl sulfoxide gives the cephem intermediate (VI). The sulfone derivative (VII) is obtained by oxidizing (VI) with peracetic acid in methylene chloride. Introduction of the double bound at C-2 position of the sulfone (VII) is achieved by heating with dimethylamine hydrochloride in a mixture of tert-BuOH methylene chloride and formaldehyde. Reaction of the intermediate (VIII) with diazo cyclopentane, generated in situ by treatment of cyclopentyl hydrazono with silver (I) oxide, gives 2,2,2-tricholoroethyl-7alpha-methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (IX). Removal of the trichloroethyl group by treatment with Zn/glacial acetic acid gives the corresponding acid (X). Reaction of the acid (X) with oxalyl chloride followed by treatment with 4-tert-butoxycarbonyl piperidine in methylene chloride gives the intermediate (XV). Hydrolysis of the tert-butyl ester with formic acid gives the free acid (XVI). Treatment with sodium carbonate in water gives the corresponding sodium salt of Syn-1396 (XVII).
| 【1】 Maiti, S.N.; Woods, D.E.; Cantin, A.M.; 2-Spirocyclopropyl cephem sulfones: Human neutrophil elastase inhibitors Syn-1390 and Syn-1396. Drugs Fut 1998, 23, 6, 635. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 | |
| (A) | 24677 | 1,3-benzothiazol-2-ylhydrosulfide | 149-30-4 | C7H5NS2 | 详情 | 详情 |
| (B) | 25055 | cyclopentanone hydrazone | C5H10N2 | 详情 | 详情 | |
| (I) | 27608 | 6-Diazo-2,2-dimethylpenam-3(R)-carboxylic acid 2,2,2-trichlloroethyl ester | C10H10Cl3N3O3S | 详情 | 详情 | |
| (II) | 27609 | 2,2,2-trichloroethyl (2S,6S)-6-methoxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H14Cl3NO4S | 详情 | 详情 | |
| (III) | 27610 | 2,2,2-trichloroethyl (2S,6S)-6-methoxy-3,3-dimethyl-4,7-dioxo-4lambda(4)-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H14Cl3NO5S | 详情 | 详情 | |
| (IV) | 27611 | 2,2,2-trichloroethyl (2R)-2-[(3S)-2-(1,3-benzothiazol-2-yldisulfanyl)-3-methoxy-4-oxoazetidinyl]-3-methyl-3-butenoate | C18H17Cl3N2O4S3 | 详情 | 详情 | |
| (V) | 27612 | 2,2,2-trichloroethyl (2S,3R,6S)-3-(bromomethyl)-6-methoxy-3-methyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate | C11H13BrCl3NO4S | 详情 | 详情 | |
| (VI) | 27613 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C11H12Cl3NO4S | 详情 | 详情 | |
| (VII) | 27614 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C11H12Cl3NO6S | 详情 | 详情 | |
| (VIII) | 27615 | 2,2,2-trichloroethyl (7S)-7-methoxy-3-methyl-4-methylene-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H12Cl3NO6S | 详情 | 详情 | |
| (IX) | 27616 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid 2,2,2-trichloroethyl ester S,S-dioxide | C17H20Cl3NO6S | 详情 | 详情 | |
| (X) | 27617 | 7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-ene]-2''-carboxylic acid S,S-dioxide | C15H19NO6S | 详情 | 详情 | |
| (XV) | 27627 | 4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazine-1-carboxylic acid tert-butyl ester S,S-dioxide | C24H35N3O7S | 详情 | 详情 | |
| (XVI) | 27628 | 4-[7''-Methoxy-3''-methyl-8''-oxodispiro[cyclopentane-1,1'-cyclopropane-2'',4''-[5'']thia[1'']azabicyclo[4,1,0]oct-2''-en]-2''-ylcarbonyl]piperazine-1-carboxylic acid S,S-dioxide | C20H27N3O7S | 详情 | 详情 |