Mitiglinide calcium hydrate, S-21403, KAD-1229, Glufast, -Drug Synthesis Database

【结构式】

【药物名称】Mitiglinide calcium hydrate, S-21403, KAD-1229, Glufast

【化学名称】(-)-2(S)-Benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt dihydrate

【CA登记号】207844-01-7, 145525-41-3 (anhydrous), 145525-40-2 (anhydrous monoK salt), 145375-43-5 (anhydrous, free acid)

【分子式】C₃₈H₅₂CaN₂O₈

【分子量】704.92674

【开发单位】Kissei (Originator), Servier (Licensee), Takeda (Codevelopment)

【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Secretagogues

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

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

【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

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

【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

合成路线3

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

【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4

The reaction of 2(S)-benzylsuccinic acid 1-benzyl monoester (XXIII) with cis-perhydroisoindole (V) by means of isobutyl chloroformate and NMM in THF gives the succinamic ester (XXIV), which is hydrogenated with H2 over Pd/C in ethanol, yielding the already described succinamic acid (XIII). Finally, this compound is converted into its calcium salt.

参考文献中间体

【1】 Castaner, R.M.; Sorbera, L.A.; Leeson, P.A.; Castaner, J.; Mitiglinide Calcium Hydrate. Drugs Fut 2000, 25, 10, 1034.
【2】 Sato, F.; Tsubaki, A.; Hokari, H.; Tanaka, N.; Saito, M.; Akahane, K.; Kobayashi, M. (Kissei Pharmaceutical Co., Ltd.); Succinic acid cpds.. EP 0507534; JP 1992330055; JP 1992356459; JP 1993230019; US 5202335 .

中间体序号	中间体编号	品名	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
(XXIII)	41073	(3S)-3-benzyl-4-(benzyloxy)-4-oxobutyric acid	C₁₈H₁₈O₄	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

合成路线5

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

【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

Drug NewChemical Entity Original Patent(1)