(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 -Drug Synthesis Database

【结构式】

【分子编号】15312

【品名】(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

【CA登记号】

【分子式】C₂₄H₃₄N₂

【分子量】350.54744

【元素组成】C 82.23% H 9.78% N 7.99%

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：(S,S-XII)

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

合成目标

【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2

该中间体在本合成路线中的序号：(VI)

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

合成目标

【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

Extended Information