合成路线1

The reaction of phenol (I) with ethyl 4-chloroacetoacetate (II) by means of KOH in DMSO gives ethyl 4 phenoxyacetoacetate (III), which by treatment with NH3 is converted into ethyl 3-amino-4-phenoxycrotonate (IV). The cyclization of (IV) with propargyl aldehyde (V) in hot toluene affords ethyl 2-(phenoxymethyl)nicotinate (VI), which is cyclized again by means of polyphosphoric acid (PPA) to yield 5,11-dihydro[1]benzoxepino[3,4-b)pyridin-5-one (VII). The reduction of (VII) with NaBH4 in ethanol gives the corresponding alcohol (VIII), which is finally condensed with N,N-diethylethylene diamine (IX) by means of SOCl2 in dichloromethane.

合成路线2

The condensation of ethyl 4-chloroacetoacetate (I) with 2-azidoethanol (II) by means of NaH in THF gives ethyl 4-(2-azidoethoxy)acetoacetate (III), which is submitted to a Hantzsch cyclocondensation with methyl 3-aminocrotonate (IV) and 2-chlorobenzaldehyde (V) in refluxing methanol affording 3-ethyl 5-methyl 2-(2-azidoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate (VI), Finally, this compound is reduced with Zn and 3N HCl in methanol, or with H2 over Pd/CaCO3 in ethanol.

合成路线3

The reaction of ethyl 4-chloroacetoacetate (I) with 2-azidoethanol (II) by means of NaH in THF gives ethyl 4-(2-azidoethoxy)acetoacetate (II), which is cyclized with methyl 2-(2-chlorobenzylidene)acetoacetate (IV) and ammonium acetate in refluxing ethanol to yield the azido-dihydropyridine (V). Finally, the azido group of (V) is reduced with H2 over Pd/C in ethanol to afford the target amlodipine.

合成路线4

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).

合成路线5

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.

合成路线6

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7

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).

合成路线8

The 2-(chloromethyl)quinoline (III) was synthesized by Friedländer reaction of aminobenzophenone (I) with ethyl 4-chloroacetoacetate (II) in the presence of H2SO4 in AcOH at 100 C. Then, displacement of the halogen atom of (III) with the sodium salt of 1,2,4-triazole (IV) in DMF at 80 C afforded the target compound.

合成路线9

Thiol (II) was prepared by reduction of 4-ethylbenzenesulfonyl chloride (I) with LiAlH4. Subsequent alkylation of (II) with ethyl 4-chloroacetoacetate (III) provided sulfide (IV), which was cyclized to the required benzothiophene (V) on heating with polyphosphoric acid in toluene. Basic hydrolysis of the ester group of (V) gave carboxylic acid (IV). After conversion of (VI) to the corresponding acid chloride with SOCl2, treatment with NH4OH yielded amide (VII). This was dehydrated to nitrile (VIII) using trifluoroacetic anhydride and triethylamine. Reduction of the nitrile function of (VIII) by means of LiAlH4 and AlCl3 gave rise to the corresponding primary amine, which was isolated as the hydrochloride salt (IX). Finally, acylation with acetyl chloride furnished the title acetamide.

合成路线10

3,5-Di-tert-butyl-4-hydroxybenzoic acid (I) was converted to amide (III) via activation as the acyl imidazole (II) followed by treatment with aqueous ammonia. Subsequent condensation of (III) with ethyl 4-chloroacetoacetate (IV) produced oxazole (V). Basic hydrolysis of the ethyl ester of (V) yielded carboxylic acid (VI), which was reduced to alcohol (VII) with borane in THF. Treatment of (VII) with methanesulfonyl chloride and triethylamine generated mesylate (VIII). This was coupled with 4-hydroxybenzaldehyde (IX), yielding ether (X). Finally, reductive condensation of (X) with ethyl methylamine in the presence of NaBH3CN furnished the corresponding tertiary amine.

合成路线11

Imidazopyridazine (III) was prepared by condensation of 3-amino-6-chloropyridazine (I) with ethyl 4-chloroacetoacetate (II) in refluxing ethanol. Alkylation of (III) with iodomethane in the presence of NaH furnished the dimethyl derivative (IV). Alternatively, intermediate (IV) was directly obtained by condensation of 3-amino-6-chloropyridazine (I) with ethyl 4-bromo-2,2-dimethyl-3-oxobutanoate (V) in the presence of disodium phosphate. Reaction of the chloroimidazopyridazine (IV) with 3-[4-(diphenylmethoxy)piperidin-1-yl]propanamine (VI) at 200 C provided adduct (VII). The ethyl ester function of (VII) was finally hydrolyzed to the target carboxylic acid employing NaOH.

合成路线12

Condensation of ethyl 3-(dimethylamino)acrylate (XVIII) with (benzyloxy)acetyl chloride (XIX) by means of pyridine in CH2Cl2 gives ethyl 2-[(benzyloxy)acetyl]-3-(dimethylamino)-2-propenoate (XX), which by cyclocondensation with ethyl oxalyl chloride (XXI) in the presence of LiHMDS in THF at –78 °C followed by heating with NH4OAc and AcOH affords pyridone derivative (XXII). Alkylation of pyridone (XXII) with bromoacetaldehyde dimethyl acetal (XXIII) and Cs2CO3 in DMF yields diethyl 1-(2,2-dimethoxyethyl)-3-(benzyloxy)-1,4-dihydropyridine-2,5-dicarboxylate (XXIV), which can also be obtained by condensation of diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (XXV) with 2,2-dimethoxyethylamine (XXVI) in EtOH. Hydrolysis of acetal (XXIV) with H2SO4 and HCOOH in CH2Cl2 yields aldehyde (XXVII), which upon cyclocondensation with 3(R)-amino-1-butanol (XI) by means of AcOH in refluxing MeOH/toluene provides the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (XXVIII). Hydrolysis of ester (XXVIII) with NaOH in THF/MeOH/H2O gives the corresponding free acid (XXIX), which is finally condensed with 2,4-difluorobenzylamine (XIV) in the presence of HATU and NMM in DMF .
Propenoate (XX) can also be prepared by condensation of ethyl 4-chloroacetoacetate (XXX) with PhCH2OH in the presence of t-AmONa to give benzyl ether (XXXI), which then reacts with N,N-dimethylformamide dimethyl acetal (XXXII) in toluene .

合成路线13

Condensation of ethyl 4-chloro-3-oxobutyrate (XXX) with N,Ndimethylformamide dimethylacetal (XXXII) in EtOAc results in ethyl 2-(chloroacetyl)-3-(dimethylamino)-2-propenoate (LI), which by cyclocondensation with ethyl oxalyl chloride (XXI) by means of LiHMDS in THF affords diethyl 3-chloro-4-oxopyran-2,5-dicarboxylate (LII). Condensation of pyranone (LII) with 2,2-dimethoxyethylamine (XXVI) in EtOH gives pyridone (LIII), which is then hydrolyzed using HCOOH and H2SO4 in CH2Cl2 to yield the corresponding aldehyde (LIV). Cyclization of compound (LIV) with 3(R)-amino-1-butanol (XI) and AcOH in refluxing MeOH/toluene provides the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (LV), which by hydrolysis with KOSiMe3 in DME affords the hydroxy acid (LVI). Finally, acid (LVI) is coupled with 2,4-difluorobenzylamine (XIV) in the presence of HATU and NMM in DMF .

合成路线14

Methyl [6-hydroxy-2,3-dihydro-1-benzofuran-3(S)-yl]acetate (VII) is synthesized as follows:
Cyclization of resorcinol (XI) with ethyl 4-chloroacetoacetate (XII) by means of H2SO4 gives 4-(chloromethyl)-7-hydroxychromen-2-one (XIII), which by treatment with NaOH at reflux affords (6-hydroxybenzofuran-3-yl)acetic acid (XIV). Esterification of carboxylic acid (XIV) with MeOH in the presence of H2SO4 at reflux yields the corresponding methyl ester (XV), which is hydrogenated over Pd/C in MeOH to provide (±)-methyl (6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (XVI) . Finally, the (S)-enantiomer (VII) is isolated by preparative HPLC .
Alternatively, intermediate (XV) can be reduced by H2 in the presence of bis(1,5-cyclooctadiene)rhodium trifluoromethanesulfonate and (S,S)-Et-ferrotane in the presence of NaOMe in MeOH .

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