合成路线1

Two new related ways for the synthesis of lercanidipine have been reported: 1) The condensation of diketene (I) with the aminoalcohol (II) gives the corresponding acetoacetate ester (III), which is allowed to react with 3-nitrobenzaldehyde (IV) by means of HCl in chloroform yielding the expected benzylidene derivative (V). Finally, this compound is cyclized with methyl 3-aminocrotonate (VI) in refluxing isopropanol. 2) By esterification of 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (VIII) with alcohol (II) by means of SOCl2 in DMF/dichloromethane.

合成路线2

The reaction of diketene (I) with 2-ethylhexylamine (II) gives N-(2-ethylhexyl)acetoacetamide (III), which is reduced to the target compound with H2 over Raney-Ni in methanol.

合成路线3

The methylation of 2-amino-5-chlorobenzophenone (I) with dimethyl-sulfate affords the 5-chloro-2-methylaminobenzophenone (II), which is conden-sed with bromoacetyl bromide (A) to yieId 2-(2-bromo-N-methylacetamido)-5-chlorobenzophenone (III). The amonolysis of (III) with ammonia in methanol gives 2-(2-amino-N-methylacetamido)-5-chlorobenzophenone (IV), which is finally condensed with diketene (B) in refluxing acetone. This product can also be obtained by condensation of 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (V) with acetyl chloride (C) and triethylamine in ether or with diketene (B) in acetone.

合成路线4

Reaction of 6-chlorohexanol (I) with 3-phenyl-5-pyrazolone (II) in the presence of K2CO3 in DMF gives 6-(5-phenyl-3-pyrazolyloxy)hexyl alcohol (III), which affords the crystalline acetoacetate derivative (IV) by esterification of (III) with diketene in the presence of triethylamine. Reaction of (IV) and ammonium carbonate in refluxing methanol gives 3-aminocrotonic acid 6-(5-phenyl-3-pyrazolyloxy)hexyl ester (V). This compound is finally cyclized with methyl 3-nitrobenzylidene acetoacetate (VI) in ethanol.

合成路线5

Leflunomide can be obtained by several related ways: 1) The reaction of diketene (I) with 4-(trifluoromethyl)-aniline (II) in hot acetonitrile gives N-[4-(trifluoro-methyl) phenyl]acetoacetamide (III) , which by reaction with triethyl orthoformate (IV) in refluxing acetic anhydride yields the corresponding ethoxymethylene derivative (V). Finally, this compound is cyclized with hydroxylamine in refluxing ethanol/water. 2) The reaction of ethyl acetoacetate (VI) with triethyl orthoformate (IV) as before gives the corresponding ethoxymethylene derivative (VII), which by cyclization with hydroxylamine as before affords 5-methylisoxazole-4-carboxylic acid ethyl ester (VIII). The hydrolysis of (VIII) under acidic conditions yields the free acid (IX), which is converted into the acid chloride (X) by standard methods. Finally, this compound is condensed with 4-(trifluoro-methyl)aniline (II) by means of triethylamine in acetonitrile. 3) The formation of leflunomide from acid (IX) or its derivatives such as ethyl (VIII) or other esters can also be performed through other standard procedures of amide formation. 4) The N-[4-(trifluoromethyl)phenyl]acetoacetamide (III) can also be obtained by reaction of 4-(trifluoro-methyl) aniline (II) with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (XI) in refluxing xylene.

合成路线6

This compound can be prepared in two related ways: 1) The condensation of diketene (I) with 2,2-(ethylenedioxy)propanol (II) by means of NaH in refluxing benzene gives 2,2-(ethylenedioxy)propyl acetylacetate (III), which is condensed with 2-nitrobenzaldehyde (IV) by means of piperidine and acetic acid in benzene, yielding 2,2-(ethylenedioxy)propyl 2-(2-nitrobenzylidene)acetoacetate (V). The cyclization of (V) with methyl 3-aminocrotonate (VI) in refluxing ethanol affords the protected dihydropyridine (VII), which is finally hydrolyzed with acetic acid in hot water. 2) The reaction of the acetoacetate (III), obtained as before, with ammonia in methanol gives the 3-aminocrotonate (VIII), which is cyclized with methyl 2-(2-nitrobenzylidene)acetoacetate (IX) in refluxing ethanol to afford the dihydropyridine (VII), already obtained.

合成路线7

Synthesis of intermediate (I): 1c) The bromination of diketene (XIII) followed by reaction with diphenylmethanol gives diphenylmethyl 4-bromoacetoacetate (XIV), which by cyclization with thiourea by means of K2CO3 yields diphenylmethyl 2-(2-aminothiazol-4-yl)acetate (XV). The reaction of (XV) with benzyloxycarbonyl chloride and pyridine affords the protected compound (XVI), which is formylated with diphenyl methyl formiate (XVII) and NaH to afford diphenyl methyl 2-(2-benzyloxycarbonylamino)thiazol-4-yl-3-hydroxyacrylate (XVIII) The Wittig condensation of (XVIII) with benzyl triphenylphosphoranylidene acetate (XIX) gives diphenylmethyl 2-[2-(benzyloxycarbonylamino)thiazol-4-yl]-4-(benzyloxycarbonyl)-2-butenoate (XX), which is selectively hydrolyzed with trifluoroacetic acid and anisole lo acid.

合成路线8

Cerebrocrast is prepared in Hantzsch-type reaction from 2-(propoxy)ethyl acetoacetate (III), 2-(difluoromethoxy)benzaldehyde and ammonia, or from 2-(propoxy)ethyl beta-aminocrotonate (IV) and 2-(difluoromethoxy)benzaldehyde. The necessary raw material, 2-(propoxy)ethyl acetoacetate (III), is prepared from 2-(propoxy)ethanole (II) by acetoacetylation with diketene (I).

合成路线9

A new synthesis for TC-81 has been described: By condensation of 2-(2-fluoro-5-nitrobenzylidene)acetoacetic acid methyl ester (I) with 3-aminocrotonic acid 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl ester (II) by means of triethylamine in refluxing isopropanol. The starting products (I) and (II) are prepared as follows: The condensation of 2-fluoro-5-nitrobenzaldehyde (III) with methylacetoacetate (IV) by means of HCl in toluene gives the benzylidene derivative (I). The condensation of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (V) with diketene (VI) in hot benzene gives the acetoacetic ester (VII), which is treated with gaseous ammonia in ethanol, yielding crotonate (III).

合成路线10

1) The reaction of N-methyl-N-benzylamine (I) with isobutyraldehyde (II) and formaldehyde (III) in refluxing isopropanol, followed by hydrogenation with NaBH4 gives 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (IV), which is condensed with diketene (V) in refluxing benzene to yield 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate (VI). Finally, this compound is submitted to cyclization with 2-fluoro-5-nitrobenzeldehyde (VII) (prepared by oxidation of 2-fluoro-5-nitrotoluene (VIII) with CrO3 in acetic ahydride-H2SO4) and methyl 3-aminocrotonate (IX) in refluxing isopropanol.

合成路线11

By cyclocondensation of 3-nitrobenzaldehyde (I) with methyl 3-aminocrotonate (II) and 1-benzyl-3-(acetoacetoxy)pyrrolidine (III) in refluxing isopropanol. The pyrrolidine (III) is obtained as follows: The condensation of 2-hydroxysuccinic acid (IV) with benzylamine (VI), which is reduced with LiAlH4 in dry THF yielding N-benzyl-3-hydroxypyrrolidine (VIII). Finally, this compound is condensed with diketene (VII) by means of sodium acetate at 80 C.

合成路线12

The reaction of diketene (I) with 2-bromoethanol (II) by means of dimethylaminopyridine (DMAP) in dichloromethane gives acetoacetic acid 2-bromoethyl ester (III), which is condensed with 3-nitrobenzaldehyde (IV) by means of piperidine acetate in isopropanol yielding the corresponding 3-nitrobenzylidene derivative (V). The cyclization of (V) with methyl 3-aminocrotonate (VI) by heating at 80 C affords 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-bromoethyl) 5-methyl diester (VII), which is condensed with chloromethyl ethyl ether (VIII) by means of NaH in THF to afford the corresponding 1-ethoxymethyl derivative (IX). The reaction of diester (IX) with NaCN and tetrabutylammonium cyanide or sodium p-toluenesulfonate and benzyltriethylammonium chloride (BTEACl) in DMF gives 1-(ethoxymethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (X). The optical resolution of (X) through the cinchonidine salt yields, after crystallization, the cinchonidine salt of the (R)-enantiomer (XI), which is treated with HCl to eliminate the cinchonidine, and esterified with 1,3-dibromopropane and K2CO3 in acetone to afford (R)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(3-bromopropyl) 5-methyl diester (XII). Finally, this compound is condensed with 4,4-diphenylpiperidine (XIII) by means of K2CO3 in DMF at 100 C.

合成路线13

Iganidipine can be obtained by two similar ways: 1) The condensation of 1-(tert-butoxycarbonyl)piperazine (I) with isobutyraldehyde (II) and formaldehyde in acetic acid gives 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-2,2-dimethylpropionaldehyde (III), which is reduced with NaBH4 in isopropanol to the corresponding alcohol (IV). The condensation of (IV) with diketene (V) by mens of dimethylaminopyridine (DMAP) in dichloromethane affords the acetoacetic ester (VI), which is cyclized with 3-nitrobenzaldehyde (VII) and methyl 3-aminocrotonate (VIII) in refluxing isopropanol to give the protected dihydropyridine (IX). The elimination of the tert-butoxycarbonyl group of (IX) with HCl in ethanol yields dihydropyridine (X), which is finally alkylated with allyl chloride (XI) and triethylamine in hot THF. 2) The condensation of 3-(4-allylpiperazin-1-yl)-2,2-dimethylpropanol (XII) with diketene (V) in dichloromethane gives the corresponding acetoacetic ester (XIII), which is treated with dry NH3 in methanol to yield the 3-aminocrotonic ester (XIV). Finally, this compound is cyclized with 2-(3-nitrobenzylidene)acetoacetic acid methyl ester (XV) in hot isopropanol.

合成路线14

The starting products are prepared as follows: The reaction of pyridine-3-carboxylic acid methyl ester (I) with ethanolamine (II) gives the 2-hydroxyethylamide (III), which by reaction with diketene in THF yields the corresponding acetoacetic ester (V). The reaction of (V) with ammonia in THF affords the expected 3-aminocrotonate ester (VI).

合成路线15

Reaction of 2-(4-aminophenyl)ethanol (I) with bis(2-chloroethyl)amine hydrochloride (II) in butanol gives 2-[4-(1-piperazinyl)phenyl]ethanol (III), which is alkylated with diphenylbromomethane (IV) and potassium carbonate in dimethyl formamide to afford 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethanol (V). Treatment of (V) with diketene (VI) in the presence of 4-dimethylaminopyridine in tetrahydrofuran yields 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl acetoacetate (VII), which is finally condensed with 3-nitrobenzaldehyde (VIII) and methyl 3-aminocrotonate (IX) in isopropanol (1-5). This last condensation can be performed in two steps by reaction of compound (VII) with compound (VIII) in the presence of piperidine and acetic acid in benzene to give 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl 2-(3-nitrobenzylidene)acetoacetate (X), which is finally treated with (IX) in isopropanol. An alternative procedure involves condensation of 3-nitrobenzaldehyde (VIII), diketene (VI), methyl 3-aminocrotonate (IX) and 3-hydroxypropionitrile (XI) in isopropanol to give 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 2-cyanoethyl ethyl diester (XII), which is hydrolyzed with sodium hydroxide to 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (XIII). Compound (XIII) is finally esterified with compound (V) in a mixture of dimethylformamide and chloroform.

合成路线16

2) The condensation of 7-(formamido)-3-(hydroxymethyl)-3-cephem-4-carboxylic acid diphenylmethyl ester (XV) with trichloromethyl chloroformate and dimethylamine in THF gives the corresponding dimethylcarbamoyloxy derivative (XVI), which is hydrolyzed with trifluoroacetic acid and anisole to the corresponding acid (as Na salt) (XVII). The esterification of (XVII) with 1-(isopropoxycarbonyloxy)ethyl iodide (XIV) in DMF as before affords the corresponding ester (XVIII), which is deformylated with HCl in methanol/THF to the 7-amino derivative (XIX). The acylation of (XIX) with 4-bromo-3-oxobutyryl bromide (XX) (obtained from diketene (XXI) with Br2) by means of bis(trimethylsilyl)acetamide in dichloromethane affords the 7-(4-bromo-3-oxobutyramido)-derivative (XXII), which is treated with NaNO2 and acetic acid to obtain the hydroxyimino compound (XXIII). Finally, this compound is cyclized with thiourea in dimethylacetamide. 3) The 7-amino cephem derivative (XIX) can also be acylated with 4-chloro-3-oxobutyryl chloride (XXV) (obtained from diketene (XXI) with Cl2) to yield the 7-(4-chloro-3-oxobutyramido)-derivative (XXVI), which is treated with amyl nitrite and acetyl chloride to afford the hydroxyimino compound (XXVII). Finally, this compound is cyclized with thiourea as before.

合成路线17

Indolinone intermediate (VII): 1. The reductoalkylation of 4-ethoxyaniline (I) with benzaldehyde and NaBH4 in methanol gives the protected aniline (II), which is condensed with methoxymalonyl chloride (III) by means of TEA in dichloromethane to yield the malonamic derivative (IV). The reaction of (IV) with methanesulfonyl azide (V) and TEA affords the diazo compound (VI), which is finally submitted to a decarboxylative cyclization by means of Nafion H (a perfluorinated ion exchange resin) to provide the target indolinone intermediate (VII). 2. The condensation of the protected aniline (II) with diketene (VIII) by means of TEA in THF gives the 3-oxobutyramide (IX), which is treated with methanesulfonyl azide (V) and TEA to yield the diazo compound (X). The deacylation of (X) with KOH in acetonitrile affords the diazoacetamide (XI), which is finally cyclized to the target indolinone intermediate (VII) by means of Rh(OAc)2 in dichloromethane.

合成路线18

The intermediate 3-(3,4-dichlorophenyl)-3-buten-1-ol silyl ether (XII) was prepared by several procedures: 1) Addition of the organozinc reagent (IX) (generated from 1-bromo-3,4-dichlorobenzene (VIII)) to diketene (X) in the presence of palladium catalyst, followed by esterification with MeOH and H2SO4 furnished 3-arylbutenoate methyl ester (XI), which was reduced to alcohol with LiAlH4 and then silylated with tert-butyldimethylsilyl chloride to give silyl ether (XII). 2) In an alternative procedure, ethyl 3-(3,4-dichlorophenyl)-3-oxopropionate (XIII) was protected with triethyl orthoformate in the presence of p-toluenesulfonic acid and then reduced to alcohol (XIV) with LiAlH4. Ketal deprotection of (XIV) with trifluoroacetic acid provided hydroxy ketone (XV). After silylation of (XV) with tert-butyldimethylsilyl chloride, subsequent Wittig condensation with methylene triphenylphosphorane gave intermediate silyl eher (XII). 3) In a further procedure, the Grignard reagent (XVI) (generated from 1-bromo-3,4-dichlorobenzene (VIII)) was coupled with 3-iodo-3-buten-1-ol silyl ether (XVII) in the presence of palladium catalyst to furnish intermediate ether (XII).

合成路线19

Palladium-catalyzed coupling of 3-bromopyridine (I) with propargyl alcohol (II) produced 3-(3-pyridyl)propargyl alcohol (III). Reaction of alcohol (III) with diketene (IV) in the presence of DMAP gave the acetoacetate ester (V), which was subsequently treated with ammonia in THF to furnish the enamino ester (VI). The title dihydropyridine derivative was then obtained by Hantzsch's synthesis upon condensation between ethyl 4-(2-isopropylimidazo[4,5-c]pyridin-1-yl)benzoylacetate (VII), enamino ester (VI) and 3,3-diphenylpropanal in refluxing EtOH.

合成路线20

合成路线21

Reduction of 2-fluoro-6-(trifluoromethyl)benzonitrile (I) with BH3/THF in refluxing THF gives the benzylamine derivative (II), which by treatment with urea in the presence of HCl in refluxing water yields N-[2-fluoro-6-(trifluoromethyl)benzyl]urea (III). Cyclization of the urea (III) with diketene (IV) by means of NaI and TMSCl in acetonitrile provides the pyrimidine-2,4-dione derivative (V), which is then brominated with Br2 in AcOH to afford the 5-bromopyrimidine-2,4-dione derivative (VI). N-Alkylation of intermediate (VI) with N-Boc-D-phenylglycinol (VII) by means of PPh3 and DBAD in THF gives the 3-[2(R)-amino-2-phenylethyl]pyrimidine-2,4-dione derivative (VIII), which upon Suzuki condensation with 2-fluoro-3-methoxyphenylboronic acid (IX) in the presence of Na2CO3 and Pd(PPh3)4 in H2O/dioxane at 90 °C yields the 5-(2-fluoro-3-methoxyphenyl)pyrimidine-2,4-dione derivative (X). Deprotection of the N-protected benzylamine (X) by means of TFA in CH2Cl2 affords the benzylamine derivative (XI), which is finally N-alkylated with methyl (XIIa) or ethyl (XIIb) 4-bromobutyrate and DIEA or Et3N, respectively, in refluxing acetonitrile and the resulting methyl or ethyl esters, (XIIIa) or (XIIIb), saponified with NaOH or LiOH in THF/H2O or MeOH/H2O at 45-50 °C .