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【结 构 式】 
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【分子编号】16198 【品名】3-Methoxy-3-oxopropionic acid; Malonic acid monomethyl ester 【CA登记号】16695-14-0 |
【 分 子 式 】C4H6O4 【 分 子 量 】118.08924 【元素组成】C 40.68% H 5.12% O 54.19% |
合成路线1
该中间体在本合成路线中的序号：(XXXVI)(S)-2-(Allyloxycarbonylamino)-3-[4-methoxy-3,5-bis(tert-butyldimethylsilyloxy)phenyl]propionic acid methyl ester (scheme 13922101a, cp. (IX)). The silylation of 3,5-dihydroxy-4-methoxybenzoic acid methyl ester (XXXII) with TBDMS-Cl, TEA and DMAP in dichloromethane gives the silylated compound (XXXIII), which is reduced with DIBAL in dichloromethane yielding the corresponding benzyl alcohol (XXXIV). The oxidation of (XXXIV) with pyridinium dichromate (PDC) in dichloromethane affords the benzaldehyde (XXXV), which is condensed with malonic acid monomethyl ester (XXXVI) by means of piperidine/AcOH in toluene providing the corresponding benzylidene derivative (XXXVII). The reaction of (XXXVII) with (PhO)2PO-N3 and benzyl alcohol in hot toluene affords the benzyloxycarbonylamino derivative (XXXVIII), which is enantioselectively reduced with H2 over a chiral Rh catalyst in methanol providing and (S)-2-(benzyloxycarbonylamino)-3-[4-methoxy-3,5-bis(tert-butyldimethylsilyloxy)phenyl]propionic acid methyl ester (XXXIX). Elimination of the benzyl protecting group of (XXXIX) with H2 over Pd/C in ethyl acetate gives the free aminoester (XL), which is finally reprotected with allyl chloroformate (XLI) and pyridine to furnish the desired intermediate (IX).
| 【1】 Gin, D.Y.; Corey, E.J.; Kania, R.S.; Enantioselective total synthesis of Ecteinascidin 743. J Am Chem Soc 1996, 118, 38, 9202-03. |
| 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) | 36457 | methyl (2S)-2-[[(allyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate | C27H47NO7Si2 | 详情 | 详情 | |
| (XXXII) | 38107 | methyl 3,5-dihydroxy-4-methoxybenzoate | C9H10O5 | 详情 | 详情 | |
| (XXXIII) | 38108 | methyl 3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzoate | C21H38O5Si2 | 详情 | 详情 | |
| (XXXIV) | 38109 | (3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)methanol | C20H38O4Si2 | 详情 | 详情 | |
| (XXXV) | 38110 | 3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde | C20H36O4Si2 | 详情 | 详情 | |
| (XXXVI) | 16198 | 3-Methoxy-3-oxopropionic acid; Malonic acid monomethyl ester | 16695-14-0 | C4H6O4 | 详情 | 详情 |
| (XXXVII) | 38111 | (E)-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)-2-(methoxycarbonyl)-2-propenoic acid | C24H40O7Si2 | 详情 | 详情 | |
| (XXXVIII) | 38112 | methyl (Z)-2-[[(benzyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)-2-propenoate | C31H47NO7Si2 | 详情 | 详情 | |
| (XXXIX) | 38113 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate | C31H49NO7Si2 | 详情 | 详情 | |
| (XL) | 38114 | methyl (2S)-2-amino-3-(3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)propanoate | C23H43NO5Si2 | 详情 | 详情 | |
| (XLI) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 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 hydrolysis of N-(tert-butoxycarbonyl)-4(R)-(tert-butyldimethylsilyloxy)-L-proline methyl ester (I) with NaOH gives the corresponding protected amino acid (II), which is condensed with malonic acid monomethyl ester (II) by means of carbonyldiimidazole (CDI) in THF to afford the L-prolylacetate (IV). The reduction of (IV) with NaBH4 in refluxing THF-methanol gives (2S,4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-2-(1,3-dihydroxypropyl)pyrrolidine (V), which is acylated with tosyl chloride to the primary monotosylate (VI). The chromatographic separation of (VI) over SiO2 yields the [2S(1'R),4R]-enantiomer (VII), which by treatment first with methylamine followed by 4,6-dimethyl-2-(4-nitrobenzyloxycarbonylthio)pyrimidine (PNZ-Pym) affords the N-protected methylamino derivative (VIII). The mesylation of (VIII) with methanesulfonyl chloride followed by reaction with potassium thioacetate gives (2S,4S)-4-acetylthio-2-[1(R)-hydroxy-3-(4-nitrobenzyloxycarbonylamino) propyl]-1-(4-nitrobenzyl)pyrrolidine (IX), which is treated with NaOH in methanol-water to afford the corresponding thiol (X). The condensation of (X) with (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[1(R)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester (XI) by means of diisopropylethylamine in acetonitrile yields the protected compound (XII), which is finally hydrolyzed and deprotected by hydrogenation with H2 over Pd/C and treatment with HCl.
| 【1】 Nakagawa, S.; Kato, S.; Murase, S.; Okamoto, O.; Mitomo, R.; Yamamoto, K.; Yamada, K.; Fukatsu, H. (Banyu Pharmaceutical Co., Ltd.); Aminoalkylpyrrolidinylthiocarbapenem derivs. EP 0545290; JP 1994087858; US 5550121; WO 9311128 . |
| 【2】 Graul, A.; Rabasseda, X.; Castaner, J.; Prous, J.; BO-2727. Drugs Fut 1994, 19, 8, 731. |
| 【3】 Rabasseda, X.; Prous, J.; Castaner, J.; Biapenem. Drugs Fut 1994, 19, 7, 631. |
| 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) | 16196 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C17H33NO5Si | 详情 | 详情 | |
| (II) | 16197 | (2S,4R)-1-(tert-butoxycarbonyl)-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-2-carboxylic acid | C16H31NO5Si | 详情 | 详情 | |
| (III) | 16198 | 3-Methoxy-3-oxopropionic acid; Malonic acid monomethyl ester | 16695-14-0 | C4H6O4 | 详情 | 详情 |
| (IV) | 16199 | tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-methoxy-3-oxopropanoyl)tetrahydro-1H-pyrrole-1-carboxylate | C19H35NO6Si | 详情 | 详情 | |
| (V) | 16200 | tert-butyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(1,3-dihydroxypropyl)tetrahydro-1H-pyrrole-1-carboxylate | C18H37NO5Si | 详情 | 详情 | |
| (VI) | 16201 | tert-butyl (2S,4R)-2-[3-[(benzylsulfonyl)oxy]-1-hydroxypropyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-1-carboxylate | C25H43NO7SSi | 详情 | 详情 | |
| (VII) | 16202 | tert-butyl (2S,4R)-2-[(1R)-3-[(benzylsulfonyl)oxy]-1-hydroxypropyl]-4-[[tert-butyl(dimethyl)silyl]oxy]tetrahydro-1H-pyrrole-1-carboxylate | C25H43NO7SSi | 详情 | 详情 | |
| (VIII) | 16203 | 4-nitrobenzyl (2S,4R)-4-hydroxy-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate | C24H28N4O10 | 详情 | 详情 | |
| (IX) | 16204 | 4-nitrobenzyl (2S,4S)-4-(acetylsulfanyl)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate | C26H30N4O10S | 详情 | 详情 | |
| (X) | 16205 | 4-nitrobenzyl (2S,4S)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-4-sulfanyl-1-pyrrolidinecarboxylate | C24H28N4O9S | 详情 | 详情 | |
| (XI) | 16206 | (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrobenzyloxy)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl diphenylphosphinate | C29H27N2O8P | 详情 | 详情 | |
| (XII) | 16207 | 4-nitrobenzyl (2S,4S)-4-([(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2-[2-(4-nitrophenyl)acetyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]sulfanyl)-2-[(1R)-1-hydroxy-3-(methyl[[(4-nitrobenzyl)oxy]carbonyl]amino)propyl]-1-pyrrolidinecarboxylate | C41H44N6O14S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)Amine (VII) is coupled to N-Boc-4-piperidineacetic acid (VIII) by means of EDC/HOBt to afford amide (IX). Subsequent acidic cleavage of the N-Boc group of (IX) leads to amine (X) (1,2). Piperidine (X) is finally coupled with malonic acid mono-amide (XI) to furnish the title compound (1,2). In a related method, piperidine (X) is coupled to mono-methyl malonate (XII), yielding the amide ester (XIII). Basic hydrolysis of the methyl ester group of (XIII) then leads to the sodium carboxylate salt (XIV), which is finally reacted with ammonium chloride in the presence of EDC/HOBt to produce the target amide (3).
| 【1】 Njoroge, F.G.; Vibulbhan, B.; Pinto, P.; Strickland, C.L.; Bishop, W.R.; Kirschmeir, P.; Girijavallabhan, V.; Ganguly, A.K.; Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of farnesyl protein transferase. Bioorg Med Chem 2003, 11, 1, 139. |
| 【2】 Doll, R.J.; Njoroge, F.G.; Remiszewski, S.W.; Taveras, A.G.; Lalwani, T.; Alvarez, C. (Schering Corp.); Cpds. useful for inhibition of farnesyl protein transferase. US 6030982 . |
| 【3】 Doll, R.J.; Njoroge, F.G.; Remiszewski, S.W.; Taveras, A.G.; Lalwani, T.; Alvarez, C. (Schering Corp.); Cpds. useful for inhibition of farnesyl protein transferase. WO 9830558 . |
| 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) | 19345 | (11R)-3,10-dibromo-8-chloro-11-(4-piperidinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | C19H19Br2ClN2 | 详情 | 详情 | |
| (VIII) | 19346 | 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid | 157688-46-5 | C12H21NO4 | 详情 | 详情 |
| (IX) | 19347 | tert-butyl 4-(2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl]-2-oxoethyl)-1-piperidinecarboxylate | C31H38Br2ClN3O3 | 详情 | 详情 | |
| (X) | 19348 | 1-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl]-2-(4-piperidinyl)-1-ethanone | C26H30Br2ClN3O | 详情 | 详情 | |
| (XI) | 63973 | 3-oxo-beta-alanine | C3H5NO3 | 详情 | 详情 | |
| (XII) | 16198 | 3-Methoxy-3-oxopropionic acid; Malonic acid monomethyl ester | 16695-14-0 | C4H6O4 | 详情 | 详情 |
| (XIII) | 63971 | methyl 3-[4-(2-{4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl}-2-oxoethyl)-1-piperidinyl]-3-oxopropanoate | C30H34Br2ClN3O4 | 详情 | 详情 | |
| (XIV) | 63972 | sodium 3-[4-(2-{4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl}-2-oxoethyl)-1-piperidinyl]-3-oxopropanoate | C29H31Br2ClN3NaO4 | 详情 | 详情 |