合成路线1

The Friedel-Crafts condensation of 1,3-difluorobenzene (I) with 1-acetylpiperidine-4-carbonyl chloride (II) by means of AlCl3 in dichloromethane gives 1-acetyl-4-(2,4-difluorobenzoyl)piperidine (III), which is hydrotyzed with refluxing 6N HCl to yield 4-(2,4-difluorobenzoyl)piperidine (IV). The reaction of (IV) with hydroxylamine in refluxing ethanol affords the corresponding oxime (V), which is cyclized by means of KOH in boiling water giving 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI). Finally, this compound is condensed with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (VII) by means of K2CO3 and Kl in a variety of solvents.

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

Reaction of 6-aminobenzothiazole (I) with phosgene in refluxing tolene affords isocyanate (II). Alkylation of 6-fluoro-3-(4-piperidinyl)-1,2-bensisoxazole hydrochloride (III) with 3-bromopropanol (IV) in the presence of potassium carbonate in acetone gave alcohol (V). Finally, condensation of this alcohol (V) with isocyanate (II) in DMF at 100 C yielded the title carbamate.

合成路线4

Condensation of phenyl isocyanate (I) with diethanolamine (II) produced 1,1-bis(2-hydroxyethyl)-3-phenylurea (III), which was converted into the bis(chloroethyl) derivative (IV) upon treatment with SOCl2. Cyclization of this compound at 140 C furnished imidazolinone (V). Finally, condensation of (V) with benzisoxazolylpiperidine (VI) in the presence of K2CO3 and KI in refluxing methyl isobuyl ketone yielded the title compound.

合成路线5

The reduction of 3,5-dimethoxybenzoic acid (I) first with Li in liquid NH3 and methanol, and then with LiAlH4 in THF gives 3,5-dimethoxy-1,4-dihydrobenzyl alcohol (II), which is cyclized with phenylhydrazine (III) in refluxing 4% sulfuric acid yielding 2-(hydroxymethyl)-1,2,3,4-tetrahydrocarbazol-4-one (IV). The reaction of (IV) with tosyl chloride in pyridine affords the corresponding tosylate (V), which is finally condensed with 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (VI) in N-methyl-2-pyrrolidone.

合成路线6

The condensation of 3,5-dimethoxybenzoic acid (I) with 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (II) by means of DCC and HOBT in DMF gives the piperidide (III), which is reduced with LiAlH4 in THF to yield 1-(3,5-dimethoxybenzyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (IV). The reduction of (IV) with Li in liquid ammonia affords the 1,4-dihydro derivative (V), which is finally cyclized with phenylhydrazine (VI) in refluxing aqueous sulfuric acid to provide the target tetrahydrocarbazolone.

合成路线7

2',4'-Dihydroxyacetophenone (I) was selectively alkylated at position 4' with 1-bromo-3-chloropropane (II) in the presence of K2CO3 in refluxing acetone to yield the 4'-(3-chloropropyl)ether (III). Further condensation of (III) with Vilsmeier reagent, followed by aqueous work up, provided the 3-formylchromenone (IV), which was subsequently reduced with sodium borohydride in CHCl3-EtOH at 0 C to give the (hydroxymethyl)chromenone (V). Finally, alkylation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (VI) with chloride (V) in the presence of K2CO3 and KI in refluxing acetonitrile yielded the title compound, which was isolated as the hydrochloride salt from methanol.

合成路线8

This compound has been obtained by several related ways: 1.- The Sam and Thompson cyclization of 3-(2-thienyl)acrylic acid (I) gives the thienocyclopentanone (II), which is condensed with oxoacetic acid (III) yielding 2-(4-oxo-5,6-dihydro-4H-cyclopenteno[b]furan-5-ylidene)acetic acid (IV). The reduction of (IV) with Zn and acetic acid affords the corresponding saturated compound (V), which is condensed with 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (VI) by means of DCC and HOBt in dichloromethane to give the corresponding piperidide (VII). The protection of the ketonic group of (VII) with ethylene glycol and TsOH yields the ethylene ketal (VIII), which is reduced at the piperidide group with LiAlH4 in ethyl ether yielding the final intermediate (IX). Finally, this compound is treated with HCl to eliminate the ethylene ketal protecting group. 2.- The condensation of the thienocyclopentanone (II) with ethyl bromoacetate (X) by means of LDA gives the acetate (XI), which is hydrolyzed with KOH in ethanol affording the previously reported saturated acetic acid derivative (V). 3.- The condensation of acetate (XI) with piperidine (VI) by means of Me3Al gives also the previously reported piperidide (VII).

合成路线9

Acidic hydrolysis of the enol ether groups of 1,4-dihydro-3,5-dimethoxybenzyl alcohol (I) gave diketone (II). Subsequent condensation of (II) with chloroacetaldehyde in the presence of NaHCO3, followed by dehydration of the intermediate (III) upon acidic treatment, yielded the tetrahydrobenzofuranone (IV). Tosylate (V) was then prepared by reaction of alcohol (IV) with p-toluenesulfonyl chloride in cold pyridine. Finally, nucleophilic displacement of the tosylate group with benzisoxazolylpiperidine (VI) in N-methylpyrrolidone provided the title amine.

合成路线10

Heck reaction of aryl bromide (IX) with vinyl tributyltin (X) in the presence of palladium catalyst gave the vinyl tetrahydronaphthalene (XI), which was converted to the primary alcohol (XII) by means of hydroboration with borane in THF followed by oxidative treatment with H2O2 and NaOH. Reaction of alcohol (XII) with p-toluenesulfonyl chloride and Et3N produced the corresponding tosylate (XIII) (1). This was then condensed with 6-fluoro-3-(4-piperidinyl)benzisoxazole (XIV), yielding adduct (XV). Finally, basic hydrolysis of the ester group of (XIV) provided the title carboxylic acid.

合成路线11