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【结 构 式】 
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【分子编号】49446 【品名】allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C10H15NO6S 【 分 子 量 】277.29824 【元素组成】C 43.31% H 5.45% N 5.05% O 34.62% S 11.56% |
合成路线1
该中间体在本合成路线中的序号：(VII)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：(III)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 |
合成路线3
该中间体在本合成路线中的序号：(IX)Propargyl alcohol (I) is oxidized with CrO3 under reduced pressure to give propynal (II), which is treated with sodium thiosulfate to afford the aldehyde dithionite (III). Subsequent cyclization of (III) in liquid ammonia gives rise to isothiazole (IV). The lithiated derivative of (IV) is formylated by means of DMF to provide aldehyde (V), which is further reduced to alcohol (VI) employing NaBH4 in THF (1). Bromination of alcohol (VI) in the presence of CBr4/PPh3 leads to 5-bromomethylisothiazole (VII). This is then converted into the phosphonium salt (VIII) upon treatment with triphenylphosphine in refluxing acetonitrile. Wittig condensation of (VIII) with the formyl pyrrolidine (IX) produces the ethenylpyrrolidine derivative (X). The mesylate group of (X) is displaced with potassium thioacetate to produce thioester (XI), which is subsequently hydrolyzed to thiol (XII) with methanolic NaOH. Condensation of thiol (XII) with the enol phosphate (XIII) in the presence of diisopropylethylamine affords the protected carbapenem derivative (XIV). This is finally deprotected with Bu3SnH and palladium catalyst to furnish the title compound (1,2)
| 【1】 Kang, Y.-K.; Lee, K.-S.; Yoo, K.-H.; Shin, K.-J.; Kim, D.-C.; Lee, C.-S.; Kong, J.Y.; Kim, D.J.; Synthesis and biological evaluation of novel 1beta-methylcarbapenems with isothiazoloethenyl side chains. Bioorg Med Chem Lett 2003, 13, 3, 463. |
| 【2】 Kim, D.J.; Yoo, K.H.; Kang, Y.K.; Park, S.W.; Shin, K.J.; Seo, K.J. (Korea Institute of Science and Technology); Novel 1beta-methylcarbapenem derivs. and process for preparation thereof. WO 0202561 . |
| 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) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (II) | 23544 | propiolaldehyde | C3H2O | 详情 | 详情 | |
| (III) | 63457 | sodium 1-{[oxido(dioxo)-lambda~6~-sulfanyl]sulfanyl}-3-oxo-1-propene | C3H3NaO4S2 | 详情 | 详情 | |
| (IV) | 63458 | isothiazole | C3H3NS | 详情 | 详情 | |
| (V) | 63459 | 5-isothiazolecarbaldehyde | C4H3NOS | 详情 | 详情 | |
| (VI) | 63460 | 5-isothiazolylmethanol | C4H5NOS | 详情 | 详情 | |
| (VII) | 63461 | 5-(bromomethyl)isothiazole | C4H4BrNS | 详情 | 详情 | |
| (VIII) | 63462 | (5-isothiazolylmethyl)(triphenyl)phosphonium bromide | C22H19BrNPS | 详情 | 详情 | |
| (IX) | 49446 | allyl (2S,4R)-2-formyl-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C10H15NO6S | 详情 | 详情 | |
| (X) | 63463 | 2-propenyl 2-[2-(5-isothiazolyl)ethenyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C14H18N2O5S2 | 详情 | 详情 | |
| (XI) | 63464 | 2-propenyl 4-(acetylsulfanyl)-2-[2-(5-isothiazolyl)ethenyl]-1-pyrrolidinecarboxylate | C15H18N2O3S2 | 详情 | 详情 | |
| (XII) | 63465 | 2-propenyl 2-[2-(5-isothiazolyl)ethenyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C13H16N2O2S2 | 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) | 63466 | 2-propenyl 6-(1-hydroxyethyl)-3-({5-[2-(5-isothiazolyl)ethenyl]-1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C26H31N3O6S2 | 详情 | 详情 |