(2S)-2-benzylbutanedioic acid -Drug Synthesis Database

【结构式】

【分子编号】41068

【品名】(2S)-2-benzylbutanedioic acid

【CA登记号】

【分子式】C₁₁H₁₂O₄

【分子量】208.21388

【元素组成】C 63.45% H 5.81% O 30.74%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XVII)

The optical resolution of racemic 2-benzylsuccinic acid (XV) using the chiral amines (R)-1-phenylethylamine (VII), (R)-1-(1-naphthyl)ethylamine (XIV) or (S)-1-phenyl-2-(4-tolyl)ethylamine (XVI) is carried out by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl, providing the desired enantiomer 2(S)-benzylsuccinic acid (XVII). Reaction of (XVII) with SOCl2 gives the corresponding acyl chloride (XVIII), which is treated with 4-nitrophenol (XIX) and TEA in dichloromethane to yield the activated diester (XX). The regioselective reaction of (XX) with cis-perhydroisoindole (V) in dichloromethane affords the monoamide (XXI), which by reaction with HCl and methanol provides the corresponding methyl ester (XXII). This ester is hydrolyzed with NaOH to the previously described chiral succinamic acid (XIII), which is finally converted into its calcium salt.

参考文献中间体

合成目标

【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034.
【2】 Mukaiyama, Y.; Hokari, H.; Kamijo, T.; Yanagi, T.; Yamaguchi, T.; Yamamoto, I.; Preparation of optically active succinic acid derivatives. II. Efficient and practical synthesis of KAD-1229. Chem Pharm Bull 1998, 46, 2, 337-340.
【3】 Yamaguchi, T.; et al.; Synthesis of KAD-1229, a succinic acid derivative with optical activity. 118th Annu Meet Pharmaceut Soc Jpn (March 31 1998, Kyoto) 1998, Abst 31(XP)9-9.
【4】 Yamaguchi, T.; Kamijo, T.; Yanagi, T. (Kissei Pharmaceutical Co., Ltd.); Process for producing optically active benzylsuccinic acid and intermediate therefor. WO 9832727 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	41059	(3aR,7aS)octahydro-1H-isoindole		C₈H₁₅N	详情	详情
(VII)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(XIII)	41064	(2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid		C₁₉H₂₅NO₃	详情	详情
(XIV)	17443	(1R)-1-(1-naphthyl)ethylamine; (1R)-1-(1-naphthyl)-1-ethanamine	3886-70-2	C₁₂H₁₃N	详情	详情
(XV)	41066	2-benzylsuccinic acid		C₁₁H₁₂O₄	详情	详情
(XVI)	41067	(1S)-2-(4-methylphenyl)-1-phenylethylamine; (1S)-2-(4-methylphenyl)-1-phenyl-1-ethanamine	30339-30-1	C₁₅H₁₇N	详情	详情
(XVII)	41068	(2S)-2-benzylbutanedioic acid		C₁₁H₁₂O₄	详情	详情
(XVIII)	41069	(2S)-2-benzylbutanedioyl dichloride		C₁₁H₁₀Cl₂O₂	详情	详情
(XIX)	11236	4-Nitrophenol; p-Nitrophenol	100-02-7	C₆H₅NO₃	详情	详情
(XX)	41070	bis(4-nitrophenyl) (2S)-2-benzylbutanedioate		C₂₃H₁₈N₂O₈	详情	详情
(XXI)	41071	4-nitrophenyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate		C₂₅H₂₈N₂O₅	详情	详情
(XXII)	41072	methyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate		C₂₀H₂₇NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

The condensation of 2(S)-benzylsuccinic acid (XVII) with cis-perhydroisoindole (V) by means of imidazole, SOCl2 and TEA in ethyl acetate gives the succinamic acid (XIII), which is esterified with benzyl bromide (XXV) and K2CO3 in ethyl acetate or with benzyl alcohol (XXVI) and DCC in the same solvent, yielding the succinamic ester (XXIV). Finally, this compound is treated with NaOH or with H2 over Pd/C and reacted with CaCl2, yielding high purity mitiglinide calcium. The one-pot sequential reaction of imidazole with SOCl2, 2(S)-benzylsuccinic acid (XVII) and cis-perhydroisoindole (V), followed by hydrolysis with HCl, gives succinamic acid (XIII), which is finally treated with 2N NaOH and CaCl2.

参考文献中间体

合成目标

【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034.
【2】 Yamaguchi, T.; Yanagi, T.; Yamamoto, I.; Mukaiyama, Y.; Kamijo, T.; Hokari, H.; Preparation of optically active succinic acid derivatives. III. Regioselective condensation reactions of optically active 2-substituted succinic acids with diimidazolide. Yakugaku Zasshi 1998, 118, 6, 248-255.
【3】 Yamaguchi, T.; et al.; Synthesis of KAD-1229, a succinic acid derivative with optical activity (1). 118th Annu Meet Pharmaceut Soc Jpn (March 31 1998, Kyoto) 1998, Abst 01(XD)13-1.
【4】 Yanagi, T.; Kamijo, T.; Yamaguchi, T. (Kissei Pharmaceutical Co., Ltd.); Process for producing benzylsuccinic acid derivs.. EP 0967204; WO 9832736 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	41059	(3aR,7aS)octahydro-1H-isoindole		C₈H₁₅N	详情	详情
(XIII)	41064	(2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid		C₁₉H₂₅NO₃	详情	详情
(XVII)	41068	(2S)-2-benzylbutanedioic acid		C₁₁H₁₂O₄	详情	详情
(XXIV)	41074	benzyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate		C₂₆H₃₁NO₃	详情	详情
(XXV)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(XXVI)	18710	Benzyl alcohol; Phenylmethanol	100-51-6	C₇H₈O	详情	详情

Extended Information