合成路线:The protection of ethanolamine (I) with trityl chloride (II) in isopropanol gives N-tritylethanolamine (III),which is condensed with ethyl 4-chloroacetoacetate (IV) by means of NaH in THF to yield ethyl 4-[2-(tritylamino)ethoxy]acetoacetate (V).The cyclization of (V) with 2-chlorobenzaldehyde (VI) and methyl 3-aminocrotonate (VII) in refluxing methanol affords the protected dihydropyridine (VIII),which,without isolation,is finally detritylated by a treatment with aqueous benzenesulfonic acid.
参考文献标题:3-Ethyl 5-methyl (+)2-[2-(N-tritylamino)ethoxymethyl]-4-(2-chloro-phenyl)-1,4-dihydro-6-methyl-6-methyl-3,5-pyridinedicarboxylate
文献作者:Furlan,B.; Copar,A.; Jeriha,A.(LEK Pharmaceutical and Chemical Co.)
参考来源:EP 0599220; US 5389654
合成路线:Preparation of a key intermediate in the synthesis of amlodipine:The reaction of ethyl 4-(2-phthalimidoethoxy)acetoacetate (I) with ammonium acetate in refluxing toluene gives the corresponding 3-aminocrotonic acid (II),which is then cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (III) in refluxing ethanol.
参考文献标题:Intermediate for the synthesis of amlodipine,preparation process and corresponding utilization
文献作者:Campon Pardo,J.; Coppi,L.; Gasanz Guillen,Y.(Laboratorios del Dr.Esteve,SA)
参考来源:WO 0024714
合成路线:The reaction of 4-[2-(acetylamino)ethyl]phenol (I) with ethyl bromoacetate (II) by means of K2CO3 in refluxing butanone gives 4-[2-(acetylamino)ethyl]phenoxyacetic acid ethyl ester (III),which is hydrolyzed with refluxing aqueous HCl to 4-(2-aminoethyl)phenoxyacetic acid (IV).Finally,this compound is acylated with benzenesulfonyl chloride (V) by means of K2CO3 in hot water.
合成路线:The reduction of 2,2-diethoxyacetic acid ethyl ester (I) with NaBH4 in dimethoxyethane gives 2,2-diethoxyethanol (II),which is condensed with ethyl 4-chloroacetoacetate (III) by means of NaH in hot THF to yield ethyl 4-(2,2-diethoxyethoxy)acetoacetate (IV).The condensation of (IV) with 2-chlorobenzaldehyde (V) by means of piperidine in refluxing toluene affords the acrylic ester (VI),which is cyclized with methyl 3-aminocrotonate (VII) in refluxing toluene to provide the dihydropyridine (VIII).The reaction of (VIII) with hydroxylamine in refluxing methanol/water gives the hydroxyimino derivative (IX),which is finally reduced to the target compound by means of H2 over Pd/C in acetic acid or with NaBH4 and NiCl2 in methanol.Alternatively,intermediate dihydropyridine (VIII) can be obtained as follows: The reaction of acetoacetate (IV) with ammonium acetate in refluxing ethanol gives ethyl 3-amino-4-(2,2-diethoxyethoxy)crotonate (X),which is cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (XI) in refluxing toluene to yield the target intermediate the dihydropyridine (VIII).
参考文献标题:Process for the preparation of 1,4-dihydropyridines and cpds.used in this process
文献作者:Karup,G.L.; Preikschat,H.F.(GEA A/S Farmaceutisk Fabrik)
参考来源:WO 9925688
合成路线:The reaction of 4,5-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane (I) with ethyl 4-chloroacetoacetate (II) gives the bis adduct (III),which is cyclized with 2-chlorobenzaldehyde (IV) and methyl 3-aminocrotonate (V) in refluxing ethanol to yield the dimeric dihydropyridine (VI).The cleavage of the dioxolane ring of (VI) by means of Ts-OH in methanol affords the vicinal diol (VII),which is cleaved by means of NaIO4 in methanol to provide the acetaldehyde derivative (VIII).The reaction of (VIII) with hydroxylamine and TEA in methanol affords the corresponding oxime (IX),which is finally reduced to the target compound with Pd(OH)2/carbon and ammonium formate in refluxing methanol.Alternatively,the reductive amination of acetaldehyde (VIII) with ammonium acetate and sodium cyanoborohydride in methanol yields also the target compound.
合成路线:The reaction of 2,2-dimethyl-1,3-dioxolane-4-methanol (X) with ethyl 4-chloroacetoacetate (II) gives the adduct (XI),which is cyclized with 2-chlorobenzaldehyde (IV) and methyl 3-aminocrotonate (V) in refluxing ethanol to yield the dihydropyridine (XII).The cleavage of the dioxolane ring of (XII) by means of Ts-OH in methanol affords the vicinal diol (XIII),which is cleaved by means of NaIO4 in methanol to provide the already reported acetaldehyde derivative (VIII).
参考文献标题:1,4-Dihydropyridines,N-substd.bicyclic 4-hydropyridines,and bicyclic N-substd.4,5-dihydropyridines
文献作者:Karimian,K.; Leung-Toung,R.C.S.H.; Tam,T.F.(Apotex Inc.)
参考来源:US 5723618
合成路线:The reduction of 2,2-diethoxyacetic acid ethyl ester (I) with NaBH4 in dimethoxyethane gives 2,2-diethoxyethanol (II),which is condensed with ethyl 4-chloroacetoacetate (III) by means of NaH in hot THF to yield ethyl 4-(2,2-diethoxyethoxy)acetoacetate (IV).The condensation of (IV) with 2-chlorobenzaldehyde (V) by means of piperidine in refluxing toluene affords the acrylic ester (VI),which is cyclized with methyl 3-aminocrotonate (VII) in refluxing toluene to provide the dihydropyridine (VIII).The reaction of (VIII) with hydroxylamine in refluxing methanol/water gives the hydroxyimino derivative (IX),which is finally reduced to the target compound by means of H2 over Pd/C in acetic acid or with NaBH4 and NiCl2 in methanol.Alternatively,intermediate dihydropyridine (VIII) can be obtained as follows: The reaction of acetoacetate (IV) with ammonium acetate in refluxing ethanol gives ethyl 3-amino-4-(2,2-diethoxyethoxy)crotonate (X),which is cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (XI) in refluxing toluene to yield the target intermediate the dihydropyridine (VIII).
参考文献标题:Process for the preparation of acetal derivs.of 1,4-dihydropyridines
文献作者:Pedersen,S.B.; Preikschat,H.F.; Karup,G.L.(GEA A/S Farmaceutisk Fabrik)
参考来源:WO 9925689
合成路线:The reaction of ethyl 4-bromoacetoacetate (I) with 2-chloroethanol (II) by means of NaH in THF gives ethyl 4-(2-chloroethoxy)acetoacetate (III),which is treated with NaI in refluxing acetone to yield the corresponding 2-iodoethoxy derivative (IV).The condensation of (IV) with 2-chlorobenzaldehyde (V) by means of piperidine acetate in isopropanol affords ethyl 2-(2-chlorobenzylidene)-4-(2-iodoethoxy)acetoacetate (VI),which is cyclized with methyl 3-aminocrotonate (VII) in refluxing isopropanol to provide the dihydropyridine (VIII).The reaction of (VIII) with hexamethylenetetramine (IX) in hot acetonitrile gives the aminium salt (X),which is finally treated with benzenesulfonic acid in refluxing butanol (methanol)/water.Alternatively,the intermediate dihydropyridine (VIII) can be obtained as follows: The condensation of ethyl 4-(2-chloroethoxy)acetoacetate (III) with the aldehyde (V) by means of piperidine acetate in isopropanol gives ethyl 2-(2-chlorobenzylidene)-4-(2-chloroethoxy)acetoacetate (XI),which is cyclized with methyl 3-aminocrotonate (VII) in refluxing isopropanol to yield the corresponding dihydropyridine (XII).Finally,this compound is treated with NaI in refluxing isopropanol to afford the target intermediate dihydropyridine (VIII).
参考文献标题:A process and intermediate cpds.for the preparation of amlodipine benzene sulphonate
文献作者:N閙eth,N.; Vereczkey,G.D.; Krasznai,G.; Kov醤yi,G.; N閙et,G.; Blask,G.; T鰉pe,P.; Nagy,K.; Bozsing,D.; Simig,G.(Egis Pharmaceuticals Ltd.)
参考来源:EP 0902016
产品链接: CAS No. 88150-42-9››