2-[(Z)-benzylidene]succinic acid -Drug Synthesis Database

【结构式】

【分子编号】41057

【品名】2-[(Z)-benzylidene]succinic acid

【CA登记号】

【分子式】C₁₁H₁₀O₄

【分子量】206.198

【元素组成】C 64.07% H 4.89% O 31.04%

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：(III)

The condensation of dimethyl succinate (I) with benzaldehyde (II) by means of NaOMe in refluxing methanol followed by hydrolysis with NaOH in methanol/water gives 2-benzylidenesuccinic acid (III). Compound (III) is treated with refluxing Ac2O, yielding the corresponding anhydride (IV), which by reaction with cis-perhydroisoindole (V) in toluene affords the monoamide (VI). This amide is reduced with H2 over a chiral Rhodium catalyst and treated with (R)-1-phenylethylamine (VII) to provide the chiral salt (VIII) as a single diastereomer isolated by crystallization. Finally, this salt is treated first with aqueous NH4OH and then with aqueous 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】 Lecouve, J.-P.; Souvie, J.-C.; Fugier, C. (ADIR et Cie.); Method for preparing a substd. perhydroisoindole. FR 2765578; US 6133454; WO 9901430 .

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)	41056	dimethyl succinate	106-65-0	C₆H₁₀O₄	详情	详情
(II)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(III)	41057	2-[(Z)-benzylidene]succinic acid		C₁₁H₁₀O₄	详情	详情
(IV)	41058	3-[(Z)-benzylidene]-2,5(4H)-furandione		C₁₁H₈O₃	详情	详情
(V)	41059	(3aR,7aS)octahydro-1H-isoindole		C₈H₁₅N	详情	详情
(VI)	41060	(Z)-2-[2-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-oxoethyl]-3-phenyl-2-propenoic acid		C₁₉H₂₃NO₃	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
(VIII)	41061	(1R)-1-phenyl-1-ethanaminium (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate		C₂₇H₃₆N₂O₃	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 condensation of diethyl succinate (IX) with benzaldehyde (II) gives 2-benzylidenesuccinic acid (III), which is treated with refluxing Ac2O to yield the corresponding anhydride (IV). Reaction of (IV) with cis-perhydroisoindole (V) in toluene affords the monoamide (VI), which is reduced with H2 over Pd/C in ethanol to provide the racemic benzylsuccinamic acid (X). Esterification of (X) with (S)-N-benzylmandelamide (XI) by means of DCC and DMAP in dichloromethane gives a mixture of diastereomeric esters, which were separated by column chromatography on silica gel to provide the desired diastereomer (XII). The hydrolysis of (XII) with NaOH in methanol yields the chiral acid (XIII), which is finally treated first with NaOH and then with CaCl2 in water. The preceding optical resolution of racemic acid (X) can also be performed with (R)-1-phenylethylamine (VII) or (R)-1-(1-naphthyl)ethylamine (XIV) by fractional crystallization of the corresponding diastereomeric salts and treatment with 2N HCl.

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.; et al.; Preparation of optically active succinic acid derivatives. I. Optical resolution of 2-benzyl-3-(cis-hexahydroisoindolin-2-ylcarbonyl)propionic acid. Chem Pharm Bull 1997, 45, 9, 1518.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(III)	41057	2-[(Z)-benzylidene]succinic acid		C₁₁H₁₀O₄	详情	详情
(IV)	41058	3-[(Z)-benzylidene]-2,5(4H)-furandione		C₁₁H₈O₃	详情	详情
(V)	41059	(3aR,7aS)octahydro-1H-isoindole		C₈H₁₅N	详情	详情
(VI)	41060	(Z)-2-[2-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-oxoethyl]-3-phenyl-2-propenoic acid		C₁₉H₂₃NO₃	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
(IX)	12313	diethyl succinate	123-25-1	C₈H₁₄O₄	详情	详情
(X)	41062	4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutyric acid		C₁₉H₂₅NO₃	详情	详情
(XI)	41063	(2S)-N-benzyl-2-hydroxy-2-phenylethanamide		C₁₅H₁₅NO₂	详情	详情
(XII)	41065	(1S)-2-(benzylamino)-2-oxo-1-phenylethyl (2S)-4-[(3aR,7aS)octahydro-2H-isoindol-2-yl]-2-benzyl-4-oxobutanoate		C₃₄H₃₈N₂O₄	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

Extended Information