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【结 构 式】

【分子编号】50598

【品名】allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate

【CA登记号】

【 分 子 式 】C13H22N2O7S2

【 分 子 量 】382.45896

【元素组成】C 40.83% H 5.8% N 7.32% O 29.28% S 16.77%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XIV)

The reaction of 4(R)-hydroxy-L-proline (I) with allyl chloroformate (II) and NaOH gives the protected proline (III), which is esterified with MeOH and sulfuric acid to yield the methyl prolinate (IV). The reaction of (IV) with Ms-Cl and TEA affords the mesylate (V), which is reduced with NaBH4 to provide the prolinol derivative (VI). The Swern oxidation of alcohol (VI) gives the carbaldehyde (VII), which is condensed with the phosphorane (VIII) by means of NaOMe, yielding the acrylate (IX). The reduction of (IX) with DIBAL affords the substituted allyl alcohol (X), which is condensed with phthalimide (XI) by means of PPh3 and DIAD to provide the adduct (XII). The cleavage of the phthalimido group of (XII) with hydrazine gives the amino derivative (XIII), which is treated with Ms-Cl and TEA to yield the sulfonamide (XIV). The reaction of (XIV) with potassium thioacetate affords the acetylsulfanyl pyrrolidine (XV), which is hydrolyzed with HCl to provide the thiol (XVI). The condensation of the thiol (XVI) with the carbapenem derivative (XVII) by means of DIEA gives the protected adduct (XVIII), which is finally treated with Pd(II) and Bu3SnH in order to eliminate the allyl protecting groups. The intermediate carbapenem derivative (XVII) has been obtained from azetidinone (XIX) by known methods as indicated in the scheme.

1 Kwon, J.W.; Kim, W.B.; Kim, S.H.; Lee, M.G.; DA-1131. Drugs Fut 2001, 26, 11, 1040.
2 Shin, H.C.; Kim, J.Y.; Kim, G.W.; Lee, C.W.; Lim, J.I.; Chang, M.S.; Kim, N.S.; Kim, D.S.; Im, W.B.; Rhee, J.K. (Dong-A Pharmaceutical Co., Ltd.); Carbapenem derivs. and processes for preparing the same. WO 9514692 .
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) 14489 (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 51-35-4 C5H9NO3 详情 详情
(II) 38115 3-[(chlorocarbonyl)oxy]-1-propene 2937-50-0 C4H5ClO2 详情 详情
(III) 47730 (2S,4R)-1-[(allyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid C9H13NO5 详情 详情
(IV) 42200 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate C10H15NO5 详情 详情
(V) 42201 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate C11H17NO7S 详情 详情
(VI) 42202 allyl (2S,4R)-2-(hydroxymethyl)-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C10H17NO6S 详情 详情
(VII) 49446 allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C10H15NO6S 详情 详情
(VIII) 14689 Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane;Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate 2605-67-6 C21H19O2P 详情 详情
(IX) 49447 allyl (2S,4R)-2-[(E)-3-methoxy-3-oxo-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C13H19NO7S 详情 详情
(X) 49448 allyl (2S,4R)-2-[(E)-3-hydroxy-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C12H19NO6S 详情 详情
(XI) 12376 Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione 85-41-6 C8H5NO2 详情 详情
(XII) 49449 allyl (2S,4R)-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C20H22N2O7S 详情 详情
(XIII) 49450 allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C12H20N2O5S 详情 详情
(XIV) 50598 allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C13H22N2O7S2 详情 详情
(XV) 49451 allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate C14H22N2O5S2 详情 详情
(XVI) 49452 allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate C12H20N2O4S2 详情 详情
(XVII) 32617 allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C25H26NO8P 详情 详情
(XVIII) 49454 allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C25H35N3O8S2 详情 详情
(XIX) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(XX) 50599   C17H27N3O6Si 详情 详情
(XXI) 16074 Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate 2524-64-3 C12H10ClO3P 详情 详情

合成路线2

该中间体在本合成路线中的序号:(X)

The condensation of the formyl pyrrolidine (I) with ethyl (triphenylphosphoranylidene)acetate (II) in dichloromethane gives acrylate (III), which is reduced with DIBAL in THF to yield the substituted allyl alcohol (IV). The condensation of (IV) with phthalimide (V) by means of PPh3 and DEAD in THF affords the adduct (VI), which is treated with hydrazine ethanol to provide the amino derivative (VII). The reaction of (VII) with Ms-Cl and TEA in dichloromethane gives the sulfonamide (VIII), which is desilylated by means of TBAF in THF, yielding the pyrrolidinol (IX). The reaction of (IX) with Ms-Cl and TEA in dichloromethane affords the sulfonate (X), which is treated with potassium thioacetate in refluxing acetonitrile to provide the acetylsulfanylpyrrolidine (XI). The hydrolysis of (XI) with NaOH in methanol gives the thiol (XII), which is condensed with the carbapenem derivative (XIII) by means of DIEA in acetonitrile to yield the protected adduct (XIV). Finally, this compound is treated with PdCl2(PPh3)2 and Bu3SnH in dichloromethane in order to eliminate the allyl protecting groups.

1 Shin, H.C.; Kim, J.Y.; Kim, G.W.; Lee, C.W.; Lim, J.I.; Chang, M.S.; Kim, N.S.; Kim, D.S.; Im, W.B.; Rhee, J.K. (Dong-A Pharmaceutical Co., Ltd.); Carbapenem derivs. and processes for preparing the same. WO 9514692 .
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) 50600 allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-pyrrolidinecarboxylate C15H27NO4Si 详情 详情
(II) 14182 ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane 1099-45-2 C22H21O2P 详情 详情
(III) 50601 allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-ethoxy-3-oxo-1-propenyl]-1-pyrrolidinecarboxylate C19H33NO5Si 详情 详情
(IV) 50602 allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-hydroxy-1-propenyl]-1-pyrrolidinecarboxylate C17H31NO4Si 详情 详情
(V) 12376 Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione 85-41-6 C8H5NO2 详情 详情
(VI) 50603 allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-1-pyrrolidinecarboxylate C25H34N2O5Si 详情 详情
(VII) 50604 allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[[tert-butyl(dimethyl)silyl]oxy]-1-pyrrolidinecarboxylate C17H32N2O3Si 详情 详情
(VIII) 50605 allyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate C18H34N2O5SSi 详情 详情
(IX) 50606 allyl (2S,4R)-4-hydroxy-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate C12H20N2O5S 详情 详情
(X) 50598 allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C13H22N2O7S2 详情 详情
(XI) 49451 allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate C14H22N2O5S2 详情 详情
(XII) 49452 allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate C12H20N2O4S2 详情 详情
(XIII) 32617 allyl (4R,5R,6S)-3-[(diphenoxyphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C25H26NO8P 详情 详情
(XIV) 49454 allyl (4R,5S,6S)-3-[((3S,5S)-1-[(allyloxy)carbonyl]-5-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]pyrrolidinyl)sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate C25H35N3O8S2 详情 详情

合成路线3

该中间体在本合成路线中的序号:(X)

The chiral pyrrolidinethiol (XII), a key intermediate in the synthesis of 235904 (see scheme 23590401a intermediate (XVI) and scheme 23590402a intermediate (XII)), has been obtained as follows: The reaction of the N-protected hydroxyproline (I) with Ms-Cl and TEA in dichloromethane gives the mesylate (II), which is reduced with DIBAL in toluene to yield the carbaldehyde (III). The Horner-Emmons-Wadsworth condensation of (III) with triethyl phosphonoacetate (IV) by means of Na-OEt in THF affords the unsaturated ester (V), which is reduced with DIBAL in THF to provide the allyl alcohol derivative (VI) (1). The condensation of (VI) with phthalimide (VII) by means of PPh3 and DIAD furnishes the adduct (VIII). The cleavage of the phthalimido group of (VIII) with hydrazine gives the allylamino derivative (IX), which is treated with Ms-Cl and TEA to yield the methanesulfonamide (X). The reaction of (X) with potassium thioacetate yields the acetylsulfanyl pyrrolidine (XI), which is hydrolyzed with HCl to provide the target thiol intermediate (XII).

1 Im, W.B.; Lim, J.I.; Lee, C.W.; Choi, S.H.; Cho, J.H; Rhee, J.K.; Synthetic study of met-SH (hydroxy proline derivative), side chain of DA-1131. Korean J Med Chem 1988, 8, 1, 2-5.
2 Shin, H.C.; Kim, J.Y.; Kim, G.W.; Lee, C.W.; Lim, J.I.; Chang, M.S.; Kim, N.S.; Kim, D.S.; Im, W.B.; Rhee, J.K. (Dong-A Pharmaceutical Co., Ltd.); Carbapenem derivs. and processes for preparing the same. WO 9514692 .
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) 42200 1-allyl 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate C10H15NO5 详情 详情
(II) 42201 1-allyl 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1,2-pyrrolidinedicarboxylate C11H17NO7S 详情 详情
(III) 49446 allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C10H15NO6S 详情 详情
(IV) 38361 ethyl 2-(dimethoxyphosphoryl)acetate C6H13O5P 详情 详情
(V) 50607 allyl (2S,4R)-2-[(E)-3-ethoxy-3-oxo-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C14H21NO7S 详情 详情
(VI) 49448 allyl (2S,4R)-2-[(E)-3-hydroxy-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C12H19NO6S 详情 详情
(VII) 12376 Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione 85-41-6 C8H5NO2 详情 详情
(VIII) 49449 allyl (2S,4R)-2-[(E)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C20H22N2O7S 详情 详情
(IX) 49450 allyl (2S,4R)-2-[(E)-3-amino-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C12H20N2O5S 详情 详情
(X) 50598 allyl (2S,4R)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate C13H22N2O7S2 详情 详情
(XI) 49451 allyl (2S,4S)-4-(acetylsulfanyl)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-1-pyrrolidinecarboxylate C14H22N2O5S2 详情 详情
(XII) 49452 allyl (2S,4S)-2-[(E)-3-[(methylsulfonyl)amino]-1-propenyl]-4-sulfanyl-1-pyrrolidinecarboxylate C12H20N2O4S2 详情 详情
Extended Information