合成路线: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).
参考文献标题:(S)(+)-2-(Ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl] aminocarbonylmethyl]benzoic acid
文献作者:Grell,W.; Greischel,A.; Zahn,G.; Mark,M.; Knorr,H.; Rupprecht,E.; M黮ler,U.(Dr.Karl Thomae GmbH)
参考来源:EP 0589874; JP 1994508816; WO 9300337
合成路线: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.
合成路线:The addition of glycine ethyl ester (I) to 2-propenenitrile (II) by means of KOH in water gives N-(2-cyanoethyl)glycine ethyl ester (III),which is cyclized by means of di-tert-butyl dicarbonate yielding the protected pyrrolidinone (IV).The reduction of (IV) with NaBH4 in ethanol affords the pyrrolidinol (V),which is further reduced with LiAlH4 in THF and protected with di-tert-butyl dicarbonate to give the fully N-protected compound (VI).The oxidation of (VI) with pyridine/SO3 complex yields the pyrrolidinone (VII),which is treated with O-methylhydroxylamine (VIII) to afford the correponding oxime (IX).The deprotection of (IX) with acetyl chloride in cool methanol gives 4-(aminomethyl)pyrrolidin-3-one O-methyloxime (X),which is finally condensed with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (XI) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile.
参考文献标题:Novel quinoline carboxylic acid derivs.having 7-(4-amino-methyl-3-oxime)pyrrolidine substituents and processes for their preparation
文献作者:Kwak,J.H.; Jeong,Y.N.; Oh,J.I.(LG Chem Ltd.)
参考来源:CA 2151890; EP 0688772; JP 1996041050; US 5633262; US 5698570; US 5776944
合成路线: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).
参考文献标题:Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid,a key acid synthon of repaglinide
文献作者:Kumar,N.; Biswas,S.; Salman,M.; Babu,S.J.; Ray,P.C.(Ranbaxy Laboratories Ltd.)
参考来源:WO 0135900
合成路线: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.
参考文献标题:Process for the preparation of repaglinide
文献作者:Kumar,N.; Salman,M.; Ray,P.C.; Babu,J.S.(Ranbaxy Laboratories Ltd.)
参考来源:WO 0327072
合成路线: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.
合成路线: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).
参考文献标题:Repaglinide
文献作者:Graul,A.; Castar,J.
参考来源:Drugs Fut 1996,21(7),694
合成路线: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.
合成路线: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).
参考文献标题:Repaglinide and related hypoglycemic benzoic acid derivatives
文献作者:Grell,W.; Hurnaus,R.; Griss,G.; Sauter,R.; Rupprecht,E.; Mark,M.; Luger,P.; Nar,H.; Wittneben,H.; Muller,P.
参考来源:J Med Chem 1998,41(26),5219
产品链接: CAS No. 135062-02-1›› 产品链接: CAS No.135969-54-9››