合成路线1

The condensation of 2,4-dichloro-5-fluorobenzoyl chloride (I) with diethyl malonate (II) by means of magnesium ethoxide in ether gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate (III), which is partially hydrolyzed and decarboxylated with p-toluenesulfonic acid water yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate (IV). The condensation of (IV) with triethyl orthoformate (V) in refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate (VI), which is treated with cyclopropylamine (VII) in ethanol to give ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-cyclopropylaminoacrylate (VIII). The cyclization of (VIII) with NaH in refluxing dioxane yields 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IX), which is finally condensed with piperazine (X) in hot DMSO.

合成路线2

The reaction of methyl-2-oxoglutarate (I) with triethyl orthoformate (A) by means of H2SO4 in refluxing methanol gives methyl 2,2-diethoxyglutarate (II), which is hydrolyzed partially with NaOH in water yielding methyl 2,2-diethoxy-4-carboxybutanoate (III). The reduction of (III) with NaBH4 and BF3 ethearate affords methyl 5-hydroxy-2-oxopentanoate (IV). The controlled oxidation of (IV) with pyridinium chlorochromate and sodium acetate in methylene chloride gives methyl 2,5-dioxopentanoate (V), which is condensed with N-ethyltryptamine (VI) by means of acetic acid in refluxing benzene yielding the tricyclic ketoester (VII). Finally, this compound cyclizes again spontaneously.

合成路线3

This compound can be obtained by two related ways: 1) The condensation of 2-aminooctanoic acid (I) with acetic anhydride in pyridine at 100 C gives 3-acetamidononan-2-one (III), which is hydrolyzed with refluxing aqueous concentrated HCl yielding 3-aminononan-2-one hydrochloride (IV). The reduction of (IV) with NaBH4 in methanol affords 3-amino-2-nonanol (V), which is condensed with 4,6-dichloro-5-aminopyrimidine (VI) by means of tributylamine in refluxing pentanol giving 5-amino-6-(2-hydroxy-3-nonylamino)-4-chloropyrimidine (VII). The cyclization of (VII) with ethyl orthoformate (A) by means of ethanesulfonic acid in refluxing CHCl3 affords 9-(2-hydroxy-3-nonyl)-6-chloropurine (VIII), which is finally hydrolyzed with refluxing aqueous 0.5 N NaOH. 2) The chloropurine (VIII) is treated with methanolic NH3 at 80-100 C in a pressure vessel to give 9-(2-hydroxy-3-nonyl)adenine (IX), which is then treated with NaNO2 in acetic acid aqueous HCl.

合成路线4

This compound can be obtained by two related ways: 1) By cyclization of aminomalonamide (I) with ethyl orthoformate (II) at 150 C catalyzed with acetic acid. 2) By cyclization of (I) with ethyl formimidate (III) at 150 C catalyzed with acetic acid.

合成路线5

The alkylation of ethyl benzoylacetate (A) with beta-ethoxyethyl bromide (B) using potassium carbonate in dimethyl formamide at 80 C gives the beta-3-keto ester (I). Condensation of (I) with guanidine hydrochloride (C) using sodium methoxide in tert-butanol at 80 C gives the pyrimidine (II). Protection of the amino group is achieved by tormylation at room temperature with the mixed anhydride (III) from formic and acetic acids. Chlorination with an excess of phosphorus oxychloride at 100 C gives a mixture of (V) and (VIII). The mixture of chloropyrimidines (V, VIII) is stirred at room temperature with excess hydrazi-ne hydrate to give the aminohydrazinopyrimidine (VI). This is heated with ethyl orthoformate in triglyme at 135 C to give the bicyclic compound (VII). This triglyme solution is then heated to 20 C to effect a Dimroth type rearrangement to give SC-33643.

合成路线6

By cyclization of (2-hydroxy-4-isopropoxyphenyl)benzyl ketone (I) with triethyl orthoformate (II) by means of morpholine in hot DMF.

合成路线7

The reaction of 2,3-O-isopropylidene-D-ribofuranose (I) with cyanoformidic acid hydrazone (II) and formic acid gives N1-(2,3-O-isopropyliene-D-ribofuranosyl)formamidrazone (III), which is cyclized with triethyl orthoformate (IV) by means of bis(p-nitrophenyl)phosphate (PNPP) yielding 1-(2,3-O-isopropylidene-D-ribofuranosyl)-1,2,4-triazole-3-carbonitrile (V). The amonolysis of the nitrile group of (V) with NH4OH in refluxing ethanol affords the corresponding carboxamide as a mixture of the alpha and beta isomers that are separated by column chromatography. The desired beta isomer (VI) is finally deprotected with 80% aqueous trifluoroacetic acid. The reaction of 1,2,4-triazole-3-carboxylic acid methyl ester (VII) with aqueous NH4OH gives the corresponding amide (VIII), which is condensed with D-ribofuranose-1-phosphate (IX) by digestion with the enzyme Nucleoside Phosphorylase (purified calf spleen).

合成路线8

The reaction of 4,6-dichloropyrimidin-5-amine (I) with 5-aminopentanol (I) gives 4-chloro-6-(5-hydroxypentylamino)pyrimidin-5 amine (III), which is cyclized with triethyl orthoformate (IV) yielding 6-chloro-9-(5-hydroxypentyl)purine (V). The hydrolysis of (V) with formic acid affords 9-(5-hydroxypentyl) hypoxanthine (VI), which is treated with phosgene (VII) to give 9-[5-(chlorocarbonyloxy)pentyl]hypoxanthine (VIII). Finally, this compound is condensed with arginine (IX).

合成路线9

1) The condensation of 2,4-dichloro-5-fluoro-benzoyl chloride (I) with diethyl malonate (II) by means of magnesium ethoxide gives diethyl 2,4-dichloro-5-fluorobenzoylmalonate (III), which is partially decarboxylated with p-toluenesulfonic acid yielding ethyl 2,4-dichloro-5-fluorobenzoylacetate (IV). The condensation of (IV) with triethyl orthoformate (V) by means of refluxing acetic anhydride affords ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-ethoxyacrylate (VI), which is treated with cyclopropylamine (VII) in ethanol giving ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-(cyclopropylamino)acrylate (VII). The cyclization of (VII) by means of NaH in refluxing dioxane yields 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX), which is finally condensed with N-ethylpiperazine (X) by heating at 140 C in DMSO.

合成路线10

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11

The reaction of beta-ionon (X) with triethyl orthoformate (A) by means of H2SO4 in dioxane gives beta-ionon enolether (XI), which by reaction with NBS in CCl4 and hydrolysis with acetic acid is converted into 4-acetoxyonon (XII). The Grignard reaction of (XII) with vinylmagnesium bromide (B) in THF and hydrolysis with KOH in methanol gives 5-(3-hydroxy-2,6,6-trimethylcyclohex-1-en-1-yl)-3-methylpenta-1,4-dien-3-ol (XIII), which is oxidized with MnO2 in methylene chloride yielding 5-(3-oxo-2,6,6-trimethylcyclohex-1-en-1-yl)-3-methylpenta-1,4-dien-3-ol (XIV). Finally, this compound by reaction with triphenylphosphonium bromide (C) in DMF is converted into the phosphonium salt (VIII), which is finally condensed in a Wittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial (IX) by means of sodium methoxide in dichloromethane.

合成路线12

The reduction of 2,3,4-trichloro-5-fluoronitrobenzene (I) with Fe - HCl in hot water gives 2,3,4-trichloro-5-fluoroaniline (II), which by diazotation with NaNO2 - HCl and reaction with sodium tetrafluoroborate and cuprous cyanide is converted to 2,3,4-trichloro-5-fluorobenzonitrile (III). The reaction of (III) with KF in DMSO at 140 C affords 3-chloro-2,4,5-trifluorobenzonitrile (IV), which by hydrolysis with 30% HBr in refluxing acetic acid gives 3-chloro-2,4,5-trifluorobenzamide (V). The hydrolysis of (V) with 18N H2SO4 at 135 C yields the corresponding benzoic acid (VI), which is treated with refluxing SOCl2 to afford the acyl chloride (VII). The condensation of (VII) with diethyl malonate (VIII) by means of Mg - ethanol in hot toluene gives diethyl 3-chloro-2,4,5-trifluorobenzoylmalonate (IX), which is partially decarboxylated with p-toluenesulfonic acid in refluxing water to give ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (X). The condensation of (X) with triethyl orthoformate (XI) in refluxing acetic anhydride yields ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate (XII), which is treated with cyclopropylamine (XIII) in ethanol to afford ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)acrylate (XIV). The cyclization of (XIV) by means of NaF in DMF at 150 C gives ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (XV), which is hydrolyzed with H2SO4 in refluxing water - acetic acid to the corresponding carboxylic acid (XVI). The condensation of (XVI) with 3-(tert-butoxycarbonylamino)pyrrolidine (XVII) by means of 1,8-diazabicyclo [5.4.0]undecane (DBU) in refluxing acetonitrile yields 7-[3-(tert-butoxycarbonylamino)-1-pyrrolidinyl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XVIII), which is finally deprotected by a treatment with concentrated HCl in methanol.

合成路线13

The reaction of cycloheptylamine (I) with triethyl orthoformate (II) and diethyl phosphite (III) at 150 gives cycloheptylaminomethylenediphosphonic acid tetraethyl ester (IV), which is then hydrolyzed with refluxing concentrated hydrochloric acid.

合成路线14

This compound has been obtained by several related ways: 1) The reaction of ethyl butyrylacetate (I) with triethyl orthoformate and Ac2O gives acrylate (II), which by reaction with o-toluidine (III) yields the aminoacrylate (IV). The cyclization of (IV) by heating at 255 C in diphenyl ether affords the quinolone (V), which is treated with refluxing POCl3 to give 1-(4-chloro-8-methoxyquinolin-3-yl)-1-butanone (VI). The demethylation of (VI) with AlCl3 or BBr3 yields the 8-hydroxyquinoline (VII), which is condensed with o-toluidine (VIII) in refluxing dioxane affording 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX). Finally, this compound is condensed with 2-bromomethanol (X) by means of potassium tert-butoxide or with ethylene carbonate (XI) by means of K2CO3. 2) The condensation of chloroquinoline (VI) with o-toluidine (VIII) in refluxing dioxane gives 1-[8-methoxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (XII), which is demethylated with AlCl3 or BBr3 as before yielding the previously reported 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX).

合成路线15

Reaction of 2,3,5,6-tetrafluoropyridine (I) with benzylamine (II) in refluxing acetonitrile gives 2-(benzyl-amino)-3,5,6-trifluoropyridine (III), which is debenzylated with H2 over Pd/C in methanol to yield 3,5,6-trifluoropyridine-2-amine (IV). Reaction of amine (IV) with 4-methoxybenzylamine (V) in N-methylpyrrolidone at 140 C affords 3,5-difluoro-6-(4-methoxybenzylamino)pyridine-2-amine (VI), which is cyclized with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) ­ obtained by condensation of 2-(3-chloro-2,4,5-trifluorobenzoyl)acetic acid ethyl ester (VIII) with triethyl orthoformate (IX) by means of acetic anhydride ­ in hot DMF in the presence of K2CO3 to provide the N-protected aminoquinolone derivative (X). Reaction of quinolone (X) with HCl in refluxing acetic acid gives 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI), which is finally condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in refluxing acetonitrile.

合成路线16

Reaction of 2-hydroxy-4-methoxypyridine-3-carbonitrile (X) with 85% phosphoric acid at 180 C gives 2,4-dihydroxypyridine (XI), which is nitrated with HNO3 in hot acetic acid to yield 2,4-dihydroxy-3-nitropyridine (XII). The reaction of (XII) with POCl3 in hot toluene affords 4-chloro-3-nitropyridin-2(1H)-one (XIII), which is condensed with the previously described amine (II) by means of DIEA in isopropanol to afford the aminopyridinol (XIV). Chlorination of (XIV) with POCl3 in toluene gives the previously described 4-amino-2-chloro-3-nitropyridine derivative (III), which is condensed with the described cyclopentanecarboxamide (IV) by means of K2CO3 in toluene, yielding the already known 2,4-diamino-3-nitropyridine (V). The reduction of (V) with ammonium formate over Pt/C or with Zn and ammonium acetate affords the described 2,3,4-triaminopyridine (VI), which is treated with HCl in THF in order to eliminate the acetonide group, providing the deprotected triaminopyridine derivative (XV). Finally, this compound is cyclized with formamidine (VII), triethyl orthoformate (XVI) or dimethylformamide dimethylacetal (XVII) in a suitable solvent.

合成路线17

1. The reaction of benzocycloheptanone (I) with dimethyl carbonate (II) and NaOMe gives the beta ketoester (III), which is reduced with NaBH4 in methanol to yield the hydroxyester (IV). The dehydration of (IV) by means of Ms-Cl and DBU, followed by hydrolysis with NaOH, affords the unsaturated carboxylic acid (V), which by reaction with oxalyl chloride is converted into the acyl chloride (VI). The condensation of (V) with aniline (VII) by means of TEA in DMF provides the amide (VIII), which by reaction with trimethyl phosphate (IX) gives the adduct (X), which rearranges to the ammonium phosphate (XI). Finally, this compound is converted into the target ammonium chloride by treatment with HCl. 2. Alternatively, benzocycloheptanone (I) is condensed with triethyl orthoformate (XII) by means of BF3 /Et2O giving the aldehyde diethyl acetal (XIII), which by reduction with NaBH4 and dehydration with 6N HCl yields the unsaturated aldehyde (XIV). Finally, this compound is oxidized with NaClO2 and H2O2 in toluene/phosphate buffer to afford the already reported unsaturated carboxylic acid (V).

合成路线18

Pyridine (III) was prepared by condensation of malononitrile (I) with triethyl orthoformate (II) in refluxing pyridine, followed by treatment with concentrated HCl. Dechlorination of (III) was effected by hydrogenolysis in the presence of Pd on BaCO3. The dechlorinated pyridine dinitrile (IV) was cyclized with guanidine (V), yielding the pyridopyrimidine (VI). Reduction of the nitrile function of (VI) to aldehyde (VII) was carried out using formic acid and Raney-Ni. This was further reduced to alcohol (VIII) with NaBH4. Bromination of the alcohol (VIII) by means of HBr resulted in bromide (IX). Nucleophilic displacement of the bromide group of (IX) with the sodium salt of 1-naphthalenethiol (X) afforded the target sulfide.

合成路线19

The reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with morpholine-4-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.

合成路线20

The reductocondensation of 3-bromo-4-fluorobenzaldehyde (I) with morpholine (II) by means of NaBH(OAc)3 in dichloroethane gives 4-(3-bromo-4-fluorobenzyl)morpholine (III), which is condensed with N-methoxy-N-methylacetamide (IV) by means of BuLi in THF to yield 1-[2-fluoro-5-(4-morpholinylmethyl)phenyl]ethanone (V). The reaction of (V) with an excess diethyl carbonate (VI) by means of NaH affords the 3-oxopropanoate derivative (VII), which is treated with triethyl orthoformate (VIII) and Ac2O at 150 C to provide the ethoxymethylene compound (IX). The reaction of (IX) with piperazine-1-amine (X) in ethanol gives the aminomethylene derivative (XI), which is cyclized by means of NaH in hot THF to yield the quinolone-3-carboxylate (XII). Finally, this compound is condensed with 4-chlorobenzylamine (XIII) by heating at 190 C to afford the target quinolone-3-carboxamide.

合成路线21

合成路线22