Repaglinide, NN-623, AG-EE-623 ZW, AG-EE-388(racemate), GlucoNorm, Actulin, Prandin, NovoNorm, -Drug Synthesis Database

【结构式】

【药物名称】Repaglinide, NN-623, AG-EE-623 ZW, AG-EE-388(racemate), GlucoNorm, Actulin, Prandin, NovoNorm

【化学名称】(+)-2-Ethoxy-4-[N-[3-methyl-1(S)-[2-(1-piperidinyl)phenyl]butyl]carbamoylmethyl]benzoic acid

【CA登记号】135062-02-1, 135969-54-9 (racemate)

【分子式】C₂₇H₃₆N₂O₄

【分子量】452.59897

【开发单位】Boehringer Ingelheim (Originator), Menarini (Marketer), Novo Nordisk (Licensee), Fournier (Comarketer), Takeda (Comarketer)

【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6

合成路线1

1) The condensation of 3-methyl-1-[2-(1-piperidinyl)phenyl)butylamine (I) with 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid (II) by means of triphenylphosphine, triethylamine and CCl4 gives the corresponding amide-ester (III), which is then hydrolyzed with NaOH in ethanol/water to the racemic repaglinide. 2) The condensation of amine (I) with 2-[4-(ethoxycarbonyl)-3-hydroxyphenyl]acetic acid (IV) by means of triphenylphosphine as before yields the corresponding amide-ester (V), which is then submitted to ethoxylation with NaH and ethyl bromide in DMF to afford the racemic amide-ester (III), already obtained.

参考文献中间体

【1】 Graul, A.; Castaner, J.; Repaglinide. Drugs Fut 1996, 21, 7, 694.
【2】 Grell, W. (Dr. Karl Thomae GmbH); New solid forms of 2-ethoxy-4-[N-[1-(2-piperidino-phenyl)-3-methyl-1-butyl] aminocarbonylmethyl]benzoic acid, medicines containing them and process for their preparation. AU 8659139; DE 3522604; EP 0207331; ES 8802145; JP 1987000474 .
【3】 Kwak, J.H.; Jeong, Y.N.; Oh, J.I. (LG Chem Ltd.); Novel quinoline carboxylic acid derivs. having 7-(4-amino-methyl-3-oxime)pyrrolidine substituents and processes for their preparation. CA 2151890; EP 0688772; JP 1996041050; US 5633262; US 5698570; US 5776944 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	15300	3-methyl-1-(2-piperidinophenyl)-1-butanamine; 3-methyl-1-(2-piperidinophenyl)butylamine	C₁₆H₂₆N₂	详情	详情
(II)	15301	2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid	C₁₃H₁₆O₅	详情	详情
(III)	15302	ethyl 2-ethoxy-4-(2-[[3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate	C₂₉H₄₀N₂O₄	详情	详情
(IV)	15303	2-[4-(ethoxycarbonyl)-3-hydroxyphenyl]acetic acid	C₁₁H₁₂O₅	详情	详情
(V)	15304	ethyl 2-hydroxy-4-(2-[[3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate	C₂₇H₃₆N₂O₄	详情	详情

合成路线2

3) The reaction of 3-methyl-1-[2-(1-piperidinyl)phenyl]butan-1-imine (VI) with acetic acid, triphenylphosphine and CCl4 (or with acetic anhydride and NaHCO3) gives N-[3-methyl-2-(1-piperidinyl)phenyl]-1(Z)-butenyl]acetamide (VII), with some of the (E)-isomer. The stereoselective reduction of the (Z)-isomer (VII) with the chiral complex Ru(OAc)2[(S)-2,2'-bis(diphenylphosphino-1,1'-binaphthyl] (S-BINAP), triethylamine and titanium tetraisopropoxide in methanol/methylene chloride yields N-[3-methyl-1(S)-[2-(1-piperidinyl)phenyl]butyl]acetamide (VIII). The hydrolysis of the chiral amide (VIII) with refluxing concentrated HCl affords the chiral amine (S-I), which is then condensed with the phenylacetic acid (II) by means of triphenylphosphine as before (or with dicyclohexylcarbodiimide) to give the chiral amide-ester (S-III). Finally, this ester is hydrolyzed to repaglinide with NaOH in hot ethanol. 4) The reductocondensation of 3-methyl-1-[2-(1-piperidyl)-1-butanone (IX) with 1(S)-phenylethylamine (S-X) yields the (S)-chiral ketimine (XI), which is reduced with TiCl4 in toluene yielding the (S,S)-chiral secondary amine (S,S-XII). Finally, the 1(S)-phenylethyl group of (S,S-XII) is eliminated by hydrogenolysis with H2 over Pd/C in diluted aqueous HCl to afford the (S)-chiral amine (S-I), already obtained. 5) The condensation of 1(R)-phenylethylamine (R-X) with 2-(1-piperidinyl)benzaldehyde (XIII) gives the corresponding chiral (R)-aldimine (XIV), which is converted into the (S,R)-chiral secondary amine (S,R-XII) by a Grignard reaction with isobutyl bromide in THF. Finally, the 1(R)-phenylethyl group of (S,R-XII) is eliminated by hydrogenolysis as before to afford the previously obtained (S)-chiral amine (S-I).

参考文献中间体

【1】 Graul, A.; Castaner, J.; Repaglinide. Drugs Fut 1996, 21, 7, 694.
【2】 Grell, W.; Greischel, A.; Zahn, G.; Mark, M.; Knorr, H.; Rupprecht, E.; Muller, U. (Dr. Karl Thomae GmbH); (S)(+)-2-(Ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl] aminocarbonylmethyl]benzoic acid. EP 0589874; JP 1994508816; WO 9300337 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	22876	bromo(isobutyl)magnesium	926-62-5	C₄H₉BrMg	详情	详情
(R-X)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(S,S-XII)	15312	(1S)-3-methyl-N-[(1S)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine; N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1S)-1-phenylethyl]amine		C₂₄H₃₄N₂	详情	详情
(S;R-XII)	15313	N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1R)-1-phenylethyl]amine; (1S)-3-methyl-N-[(1R)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine		C₂₄H₃₄N₂	详情	详情
(S-I)	15315	(1S)-3-methyl-1-(2-piperidinophenyl)butylamine; (1S)-3-methyl-1-(2-piperidinophenyl)-1-butanamine		C₁₆H₂₆N₂	详情	详情
(S-III)	15316	ethyl 2-ethoxy-4-(2-[[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate		C₂₉H₄₀N₂O₄	详情	详情
(S-X)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(II)	15302	ethyl 2-ethoxy-4-(2-[[3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate		C₂₉H₄₀N₂O₄	详情	详情
(VI)	15305	3-methyl-1-(2-piperidinophenyl)-1-butanimine		C₁₆H₂₄N₂	详情	详情
(VII)	15306	N-[(Z)-3-methyl-1-(2-piperidinophenyl)-1-butenyl]acetamide		C₁₈H₂₆N₂O	详情	详情
(VIII)	15307	N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]acetamide		C₁₈H₂₈N₂O	详情	详情
(IX)	15308	3-methyl-1-(2-piperidinophenyl)-1-butanone		C₁₆H₂₃NO	详情	详情
(XI)	15311	N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-N-[(1S)-1-phenylethyl]amine; (1S)-N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-1-phenyl-1-ethanamine		C₂₄H₃₂N₂	详情	详情
(XIII)	15314	2-piperidinobenzaldehyde		C₁₂H₁₅NO	详情	详情
(XIV)	63965	(1R)-1-phenyl-N-{(E)-[2-(1-piperidinyl)phenyl]methylidene}-1-ethanamine; N-[(1R)-1-phenylethyl]-N-{(E)-[2-(1-piperidinyl)phenyl]methylidene}amine		C₂₀H₂₄N₂	详情	详情

合成路线3

A new synthesis of repaglinide has been described: The reaction of 2-(1-piperidinyl)benzonitrile (I) with isobutylmagnesium bromide (II) in THF followed by hydrolysis with aqueous NH4Cl/NH3 gives 3-methyl-1-[2-(1-piperidinyl)phenyl]butanone (III), which is condensed with 1(S)-phenylethylamine (IV) by means of TiCl4/triethylamine in toluene yielding the imine (V). The hydrogenation of (V) with H2 over Raney Nickel in ethanol affords the chiral secondary amine (IV), which is further hydrogenated with H2 over Pd/C in ethanol/aqueous HCl giving 3-methyl-2(S)-[2-(1-piperidinyl)phenyl]butylamine (VII). The condensation of (VII) with 4-(carboxymethyl)-2-ethoxybenzoic acid ethyl ester (VIII) by means of SOCl2 or carbonyldiimidazole (CDI) or triphenylphosphine/CCl4/triethylamine gives the ethyl ester of repaglinide (IX), which is finally hydrolyzed with NaOH as usual.

参考文献中间体

【1】 Grell, W.; Hurnaus, R.; Griss, G.; Sauter, R.; Rupprecht, E.; Mark, M.; Luger, P.; Nar, H.; Wittneben, H.; Muller, P.; Repaglinide and related hypoglycemic benzoic acid derivatives. J Med Chem 1998, 41, 26, 5219.

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)	25112	2-(1-piperidinyl)benzonitrile	72752-52-4	C₁₂H₁₄N₂	详情	详情
(II)	22876	bromo(isobutyl)magnesium	926-62-5	C₄H₉BrMg	详情	详情
(III)	15308	3-methyl-1-(2-piperidinophenyl)-1-butanone		C₁₆H₂₃NO	详情	详情
(IV)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(V)	15311	N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-N-[(1S)-1-phenylethyl]amine; (1S)-N-[(E)-3-methyl-1-(2-piperidinophenyl)butylidene]-1-phenyl-1-ethanamine		C₂₄H₃₂N₂	详情	详情
(VI)	15312	(1S)-3-methyl-N-[(1S)-1-phenylethyl]-1-(2-piperidinophenyl)-1-butanamine; N-[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]-N-[(1S)-1-phenylethyl]amine		C₂₄H₃₄N₂	详情	详情
(VII)	15315	(1S)-3-methyl-1-(2-piperidinophenyl)butylamine; (1S)-3-methyl-1-(2-piperidinophenyl)-1-butanamine		C₁₆H₂₆N₂	详情	详情
(VIII)	15301	2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid		C₁₃H₁₆O₅	详情	详情
(IX)	15316	ethyl 2-ethoxy-4-(2-[[(1S)-3-methyl-1-(2-piperidinophenyl)butyl]amino]-2-oxoethyl)benzoate		C₂₉H₄₀N₂O₄	详情	详情

合成路线4

The reaction of 2-hydroxy-4-methylbenzoic acid (I) with ethyl bromide (II) and K2CO3 in acetone at 150 C gives 2-ethoxy-4-methylbenzoic acid ethyl ester (III), which is brominated with Br2 and AIBN in CCl4 to yield the bromomethyl derivative (IV). The reaction of (IV) with NaCN and benzyl-tributylammonium chloride affords the cyanomethyl compound (V), which is hydrolyzed with HCl (g) in refluxing ethanol to provide 2-ethoxy-4-(ethoxycarbonylmethyl)benzoic acid ethyl ester (VI). Finally, this compound is selectively hydrolyzed with 2N NaOH in ethanol to furnish the target intermediate, the 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid (VII).

参考文献中间体

【1】 Salman, M.; et al.; An efficient and cost-effective synthesis of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid: A key acid synthon of repaglinide. Org Process Res Dev 2002, 6, 2, 184.
【2】 Grell, W.; Hurnaus, R.; Griss, G.; Sauter, R.; Rupprecht, E.; Mark, M.; Luger, P.; Nar, H.; Wittneben, H.; Muller, P.; Repaglinide and related hypoglycemic benzoic acid derivatives. J Med Chem 1998, 41, 26, 5219.

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)	53446	2-Hydroxy-4-methylbenzoic acid; 2-Hydroxy-p-toluic Acid; 4-Methylsalicylic acid; m-Cresotinic acid	50-85-1	C₈H₈O₃	详情	详情
(II)	19502	Propyl bromide; 1-Bromopropane	106-94-5	C₃H₇Br	详情	详情
(III)	53447	ethyl 2-ethoxy-4-methylbenzoate	88709-17-5	C₁₂H₁₆O₃	详情	详情
(IV)	53448	ethyl 4-(bromomethyl)-2-ethoxybenzoate	n/a	C₁₂H₁₅BrO₃	详情	详情
(V)	53449	ethyl 4-(cyanomethyl)-2-ethoxybenzoate	n/a	C₁₃H₁₅NO₃	详情	详情
(VI)	53450	ethyl 2-ethoxy-4-(2-ethoxy-2-oxoethyl)benzoate	n/a	C₁₅H₂₀O₅	详情	详情
(VII)	15301	2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid		C₁₃H₁₆O₅	详情	详情

合成路线5

The reaction of 2-hydroxy-4-methylbenzoic acid (I) with ethyl bromide (II) and K2CO3 in DMSO gives 2-ethoxy-4-methylbenzoic acid ethyl ester (III), which is carboxylated by reaction with LDA and CO2 in THF/1,3-dimethylperhydropyrimidin-2-one to furnish the target intermediate the 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid (IV).

参考文献中间体

【1】 Salman, M.; et al.; An efficient and cost-effective synthesis of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid: A key acid synthon of repaglinide. Org Process Res Dev 2002, 6, 2, 184.
【2】 Kumar, N.; Biswas, S.; Salman, M.; Babu, S.J.; Ray, P.C. (Ranbaxy Laboratories Ltd.); Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide. WO 0135900 .

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)	53446	2-Hydroxy-4-methylbenzoic acid; 2-Hydroxy-p-toluic Acid; 4-Methylsalicylic acid; m-Cresotinic acid	50-85-1	C₈H₈O₃	详情	详情
(II)	19502	Propyl bromide; 1-Bromopropane	106-94-5	C₃H₇Br	详情	详情
(III)	53447	ethyl 2-ethoxy-4-methylbenzoate	88709-17-5	C₁₂H₁₆O₃	详情	详情
(IV)	15301	2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid		C₁₃H₁₆O₅	详情	详情

合成路线6

The condensation of 2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid (I) with 3-methyl-1(S)-(2-(1-piperidinyl)phenyl)butylamine (II) by activation with pivaloyl chloride and TEA in toluene gives the corresponding amide (III), which is finally hydrolyzed by means of NaOH water/denaturated spirit to afford the target Repaglinide.

参考文献中间体

【1】 Kumar, N.; Salman, M.; Ray, P.C.; Babu, J.S. (Ranbaxy Laboratories Ltd.); Process for the preparation of repaglinide. WO 0327072 .

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)	15301	2-[3-ethoxy-4-(ethoxycarbonyl)phenyl]acetic acid		C₁₃H₁₆O₅	详情	详情
(II)	15315	(1S)-3-methyl-1-(2-piperidinophenyl)butylamine; (1S)-3-methyl-1-(2-piperidinophenyl)-1-butanamine		C₁₆H₂₆N₂	详情	详情
(III)	15361	4-Aminobenzonitrile	873-74-5	C₇H₆N₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)