【结 构 式】 |
【分子编号】27623 【品名】tert-butyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C13H19NO6S 【 分 子 量 】317.363 【元素组成】C 49.2% H 6.03% N 4.41% O 30.25% S 10.1% |
合成路线1
该中间体在本合成路线中的序号:(XXI)2) 7-ADCA (XVIII) is reacted with isobutylene and concentrated H2SO4 in DME to afford the corresponding tert-butyl ester (XIX), which on oxidation with Na2WO4 in presence of H2O2 gives the sulfone (XX). The sulfone (XX) on treatment with NaNO2 and 2.5 (N) H2SO4 in the presence of MeOH gives the 7alpha-methoxy cephem intermediate (XXI). Heating of compound (XXI) with dimethylamine hydrochloride and formaldehyde in a mixture of DMF and dioxane gives the 2-exomethylene cephem intermediate (XXII). Cycloaddition of (XXII) with diazo cyclopentane generated in situ by treatment of cyclopentyl hydrazone with silver (I) oxide, gives 7alpha-methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl cephem derivative (XXIII). Deprotection of the tert-butyl ester group with formic acid gives the free acid (X). From the intermediate acid (X), the target molecule Syn-1390 and its corresponding sodium salt can be prepared, as described in Scheme 26506201a.
【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 |
---|---|---|---|---|---|---|
(D) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
(B) | 25055 | cyclopentanone hydrazone | C5H10N2 | 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 | |
(XVIII) | 27626 | (7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C8H10N2O3S | 详情 | 详情 | |
(XIX) | 27621 | tert-butyl (7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H18N2O3S | 详情 | 详情 | |
(XX) | 27622 | tert-butyl (7R)-7-amino-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H18N2O5S | 详情 | 详情 | |
(XXI) | 27623 | tert-butyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C13H19NO6S | 详情 | 详情 | |
(XXII) | 27624 | tert-butyl (7S)-7-methoxy-3-methyl-4-methylene-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H19NO6S | 详情 | 详情 | |
(XXIII) | 27625 | 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 tert-butyl ester S,S-dioxide | C19H27NO6S | 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:(XXI)2) 7-ADCA (XVIII) is reacted with isobutylene and concentrated H2SO4 in DME to afford the corresponding tert-butyl ester (XIX), which on oxidation with Na2WO4 in presence of H2O2 gives the sulfone (XX). The sulfone (XX) on treatment with NaNO2 and 2.5 (N) H2SO4 in the presence of MeOH gives the 7alpha-methoxy cephem intermediate (XXI). Heating of compound (XXI) with dimethylamine hydrochloride and formaldehyde in a mixture of DMF and dioxane gives the 2-exomethylene cephem intermediate (XXII). Cycloaddition of (XXII) with diazo cyclopentane generated in situ by treatment of cyclopentyl hydrazone with silver (I) oxide, gives 7alpha-methoxy-2-spiro-(2'-spirocyclopentyl)cyclopropyl cephem derivative (XXIII). Deprotection of the tert-butyl ester group with formic acid gives the free acid (X). From the intermediate acid (X), the target molecule Syn-1396 and its corresponding sodium salt can be prepared, as described in Scheme 26506301a.
【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 | |
(D) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
(B) | 25055 | cyclopentanone hydrazone | C5H10N2 | 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 | |
(XVIII) | 27626 | (7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | C8H10N2O3S | 详情 | 详情 | |
(XIX) | 27621 | tert-butyl (7R)-7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H18N2O3S | 详情 | 详情 | |
(XX) | 27622 | tert-butyl (7R)-7-amino-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C12H18N2O5S | 详情 | 详情 | |
(XXI) | 27623 | tert-butyl (7S)-7-methoxy-3-methyl-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C13H19NO6S | 详情 | 详情 | |
(XXII) | 27624 | tert-butyl (7S)-7-methoxy-3-methyl-4-methylene-5,5,8-trioxo-5lambda(6)-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C14H19NO6S | 详情 | 详情 | |
(XXIII) | 27625 | 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 tert-butyl ester S,S-dioxide | C19H27NO6S | 详情 | 详情 |