合成路线1

The condensation of piperidine-4-carboxylic acid (VI) with ethyl chloroformate (VII) by means of Na2CO3 in toluene/water gives 1-(ethoxycarbonyl)piperidine-4-carboxylic acid (VIII), which is treated with SOCl2 to yield the corresponding acyl chloride (IX). The Friedel-Crafts condensation of (IX) with refluxing 1,3-difluorobenzene (X) by means of AlCl3 gives 4-(2,4-difluorobenzoyl)piperidine-1-carboxylic acid ethyl ester (XI), which is treated with concentrated HCl at 100 C to yield 4-(2,4-difluorobenzoyl)piperidine (XII). The condensation of piperidine (XII) with the 2-chloroethyl intermediate (V) by means of KI and NaHCO3 in refluxing acetonitrile affords the adduct (XIII), which is treated with hydroxylamine hydrochloride and KOH in refluxing pyridine/ethanol to provide the corresponding oxime (XIV). Finally, this compound is cyclized by means of KOH in refluxing water or with NaH in refluxing THF to afford in both cases the target 1,2-benzisoxazole.

合成路线2

The reaction of piperidine-4-carboxylic acid (I) with formic acid and acetic anhydride gives 1-formylpiperidine-4-carboxylic acid (II), which is treated with SOCl2 and acetic anhydride to yield the corresponding acyl chloride (III). The Friedel-Crafts condensation of (III) with refluxing 1,3-difluorobenzene (IV) by means of AlCl3 affords 4-(2,4-difluorobenzoyl)-1-formylpiperidine (V), which is treated with hydroxylamine in refluxing ethanol to give the corresponding oxime (VI). The cyclization of (VI) by means of NaH in hot THF/DMF yields 6-fluoro-3-(1-formylpiperidin-4-yl)-1,2-benzisoxazole (VII), which is treated with HCl in refluxing ethanol to afford 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazole (VIII). Finally, this compound is condensed with 4-(3-chloropropoxy)-3-methoxyacetophenone (IX) by means of K2CO3 in hot DMF. The intermediate 4-(3-chloropropoxy)-3-methoxyacetophenone (IX) can be obtained by condensation of 4-hydroxy-3-methoxyacetophenone (IX) with 3-chcloropropyl bromide (X) by means of NaH or K2CO3 in DMF.

合成路线3

2) Racemic MDL-100907 (VII) can also be obtained by reaction of piperidine-4-carboxylic acid (X) with di-tert-butyl dicarbonate (XI) by means of NaOH in tert-butanol/ water, giving piperidine-1,4-dicarboxylic acid 1-mono-tert-butyl ester (XII), which is treated with N,O-dimethylhydroxylamine (XIII) and carbonyldiimidazole (CDI) in dichloromethane to afford the methoxy(methyl)amide (XIV). The condensation of (XIV) with veratrole (VI) by means of BuLi in THF gives 4-(2,3-dimethoxybenzoyl)-piperidine-1-carboxylic acid tert-butyl ester (XV), which is decarboxylated by means of trifluoroacetic acid, yielding ketone (XVI). The condensation of (XVI) with 2-(4-fluorophenyl)ethyl bromide (II) by means of K2CO3 in DMF affords 1-(2,3-dimethoxyphenyl)-1-[1-[2-(4-fluorophenyl)-ethyl]piperidin-4-yl]methanone (XVII). Finally, this compound is reduced with NaBH4 in methanol

合成路线4

The monosulfonation of orcinol (I) with 2-chlorobenzenesulfonyl chloride (II) in ethyl ether/aqueous NaHCO3 gives the monosulfonate (III), which is condensed with 4-(methanesulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (IV) by means of NaH in DMF to yield the aryl ether (V). The deprotection of (V) with 4N HCl in dioxane affords the piperidine (VI), which is finally treated with amidinosulfonic acid (VII) and TEA in DMF. The 4-(methanesulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (IV) has been obtained as follows: The reaction of piperidine-4-carboxylic acid (VIII) with Boc2O and NaHCO3 in dioxane/water gives the protected piperidine (IX), which is reduced at the carboxyl group by means of BH3/THF yielding the carbinol (X). Finally, this compound is mesylated with MsCl and TEA in dichloromethane to afford the target intermediate.

合成路线5

The reaction of piperidine-4-carboxylic acid (I) with SOCl2 gives the acyl chloride (II), which is treated with methanol to yield the methyl ester (III). Finally, this compound is condensed with 4-chloro-1-(4-fluorophenyl)-1-butanone (IV) by means of K2CO3 in refluxing acetone.

合成路线6

Protection of isonipecotic acid (I) as the trifluoroacetamide (II), followed by treatment with thionyl chloride, afforded acid chloride (III). Friedel-Crafts reaction of acid chloride (III) with bromobenzene (IV) gave ketone (V), which was further protected as the ethylene ketal (VI). The trifluoroacetamide group of (VI) was then hydrolyzed to amine (VII) using K2CO3 in MeOH. Condensation of amine (VII) with N-Boc-4-piperidone (VIII) in the presence of titanium isopropoxide, and subsequent addition of diethylaluminum cyanide to the intermediate iminium salt, provided amino nitrile (IX). Treatment of (IX) with methylmagnesium bromide afforded the methyl derivative (X). Acid hydrolysis of the ketal and Boc groups of (X), followed by reprotection with Boc2O, furnished ketone (XI). Oxime formation in (XI) with O-ethyl hydroxylamine produced a 1.5:1 mixture of (E)- and (Z)-isomers, which were separated by silica gel chromatography. Previous equilibration of the mixture under acidic conditions favored the desired (Z)-isomer (XII). The Boc protecting group of (XII) was then removed by treatment with trifluoroacetic acid. The resultant piperidine (XIII) was finally coupled with 2,4-dimethylnicotinic acid N-oxide (XIV) using EDC and HOBt to furnish the title compound.

合成路线7

Treatment of 1-bromo-3,3-dimethyl-2-butanone (I) with hexamethylenetetraamine affords the quaternary salt (II), which is then hydrolyzed to amino ketone (III) under acidic conditions (1-3). Alternatively, reaction of butanone (I) with sodium azide in acetone gives the azido derivative (IV), which is reduced with H2 over Pd/C in methanol to yield 1-amino-3,3-dimethyl-2-butanone (III). Acylation of amine (III) with 2-chloroacetyl chloride by means of triethylamine in dichloromethane yields the chloroacetamide (V), which is cyclized in POCl3 at 105 ºC to provide 5-tert-butyl-2-(chloromethyl)oxazole (VI) (1-4). Condensation of chloride (VI) with thiourea gives the S-alkylated thiouronium salt (VII), which is then submitted to alkaline hydrolysis followed by condensation with 2-amino-5-bromothiazole (VIII) under phase-transfer conditions in the presence of tetrabutylammonium sulfate, leading to thioether (IX) (1-3). Acylation of aminothiazole (IX) with 1-Boc-piperidine-4-carboxylic acid (X) —obtained by reaction of piperidine-4-carboxylic acid (XI) with Boc2O and NaOH in dioxane/acetonitrile— by means of EDAC and DMAP in DMF/dichloromethane yields the carboxamide (XII), which is finally deprotected upon treatment with trifluoroacetic acid (1-3) or by means of HCl in hot dioxane/CHCl (4). Scheme 1.

合成路线8

合成路线9

N-Methylation of piperidine-4-carboxylic acid (VIII) by means of HCHO in the presence of H2 over Pd/C in H2O gives 1-methylpiperidine-4-carboxylic acid (IX), which by chlorination with (COCl)2 in the presence of DMF in refluxing CH2Cl2 furnishes 1-methylpiperidine-4-carbonyl chloride hydrochloride (X). Condensation of acid chloride (X) with Me2NH in the presence of Et3N in THF yields N,N,1-trimethylpiperidine-4-carboxamide (XI), which then condenses with 2,6-dibromopyridine (XII) in the presence of BuLi in methyl t-butyl ether (MTBE), affording (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (XIII). Amination of bromo derivative (XIII) with NH3 in the presence of Cu2O in ethylene glycol at 85 °C produces the desired intermediate (V) .