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Reaction of the dicarboxylic acid (I) with thionyl chloride in hot toluene gives the di-acid chloride (II). Treatment of (II) with Cl2 in CH2Cl2 gives the sulfenyl chloride (III), which upon reaction with NH4OH affords the benzisothiazole (IV). Chlorination of (IV) in heat POCl3 yields the chlorobenzisothiazole (V). Reaction of (V) and piperazine (VI) in excess molten pipeazine gives the monosubstituted piperazine (VII). Reaction of (VII) with the dibromide (VIII) in refluxing ethanol yields the spiroquaternary (IX). Finally, BMY-13859-1 is obtained by treatment of (IX) with the glutarimide (X) in refluxing xylene followed by treatment with HCl in isopropanol.

合成路线2

This compound can be obtained by two related ways: 1) The reaction of cis-octahydroisobenzofuran-1,3-dione (I) with ammonia in water at 180-90 gives cis-octahydro-1H-isoindole-1,3-dione (II), which is alkylated with 1,4-dibromobutane (III) and K2CO3 in refluxing acetone to yield cis-2-(4-bromobutyl)octahydro-1H-isoindole-1,3-dione (IV). The condensation of (IV) with piperazine (V) in refluxing toluene affords cis-2-(4-piperazinobutyl)octahydro-1H-isoindole-1,3-dione (VI), which is finally condensed with 3-chloro-1,2-benzisothiazole (VII) and K2CO3 in refluxing toluene. 2) The condensation of benzisothiazole (VII) with piperazine (V) by heating at 120 C gives 3-piperazino-1,2-benzisothiazole (VIII), which is then condensed with isoindole (IV) by means of K2CO3 and KI in hot DMF. 3) The 3-chloro-1,2-benzisothiazole (VII) is obtained as follows: The reaction of 2,2'-dithiobenzoic acid (IX) with refluxing SOCl2 gives the corresponding acyl chloride (X), which by treatment with methylamine in THF is converted into the diamide (XI). The reaction of (XI) with PCl5 in refluxing benzene affords 3-chloro-2-methyl-1,2-benzisothiazolium chloride (XII), which is finally heated in refluxing 1,2-dichlorobenzene to give (VII).

合成路线3

Wolff-Kishner reduction of 6-chloroisatin (I) gives 6-chlorooxindole (II), which is treated with chloroacetyl chloride under Friedel-Crafts conditions to yield 5-chloroacetyl-6-chlorooxindole (III). The ketone (III) is reduced using triethylsilane in trifluoroacetic acid to produce 6-chloro-5-(2-chloroethyl)oxindole (IV). 1,2-Benzisothiazolin-3-one (V) is converted to 3-chloro-1,2-benzisothiazole (VI) using phosphorus oxychloride and is then condensed with piperazine to provide 1-(1,2-benzisothiazol-3-yl)piperazine (VII). Finally, intermediate (VII) is alkylated by compound (IV) in the presence of sodium carbonate in water and is converted to the salt with aqueous hydrochloric acid.

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A new synthesis for ziprasidone hydrochloride has been reported: The condensation of 6-chloroindolin-2-one (I) with bromoacetic acid (II) by means of polyphosphoric acid (PPA) gives 5-(bromoacetyl)-6-chloroindolin-2-one (III), which is reduced with triethylsilane and trifluoroacetic acid to the corresponding 2-bromoethyl derivative (IV). Finally, this compound is condensed with 4-(3-benzisothiazolyl)piperazine (V) by means of Na2CO3 in DMF or isobutyl methyl ketone.

合成路线5

The condensation of 1-(1,2-benzoisothiazol-3-yl)piperazine (I) with 6-chloro-5-(2-chloroethyl)-2-indolinone (II) in refluxing water or refluxing methyl isobutyl ketone gives the target indolinone derivative.

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The Friedel Crafts condensation of 6-chloroindolin-2-one (I) with 14C labeled 2-chloroacetyl chloride (II) by means of AlCl3 in CS2 gives 6-chloro-5-(2-chloroacetyl)indolin-2-one (III), which is reduced with trimethylsilane in TFA to yield the labeled chloroethyl derivative (IV). Finally, this compound is condensed with 3-(1-piperazinyl)-1,2-benzoisothiazole (V) by means of Na2CO3 in refluxing water to provide the target radiolabeled compound.

合成路线7

The nitration of 2,5-dichlorotoluene (I) with HNO3 in H2SO4/AcOH gives 2,5-dichloro-4-methylnitrobenzene (II), which is treated with t-butoxybis(dimethylamino)methane (III) in refluxing THF to yield 2,5-dichloro-4-[2-(dimethylamino)vinyl]nitrobenzene (IV). The condensation of (IV) with 1-(1,2-benzoisothiazol-3-yl)piperazine (V) in AcOH affords the disubstituted piperazine (VI), whose double bond is reduced by means of NaBH(OAc)3 in dichloroethane/AcOH to provide the saturated compound (VII). The condensation of (VII) with dimethyl malonate (VIII) by means of KOH in NMP gives the alkylated malonic ester (IX), which is hydrolyzed and monodecarboxylated with refluxing 3N HCl to yield the phenylacetic acid (X). The esterification of (X) with SOCl2 and methanol affords the methyl ester (XI), which is finally cyclized to the target indolone by reduction of its nitro group with sodium hydrosulfite in refluxing THF/ethanol. Alternatively, compound (VII) can be condensed with methyl cyanacetate (XII) by means of KOH in NMP to give the alkylated cyanacetic ester (XIII), which is hydrolyzed with refluxing 3N HCl to afford the already reported phenylacetic acid (X).

合成路线8

Lurasidone hydrochloride can be synthesized as follows. The condensation of 1-(1,2-benzoisothiazol-3-yl)piperazine (I) with (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane (II) in the presence of potassium carbonate and tetrabutylammonium bisulfate in boiling toluene gives the spiropiperazinium salt (III) (1-3), which is further reacted with bicyclo[2.2.1]heptane-2,3-dicarboximide (IV) by means of potassium carbonate in hot xylene or toluene to yield lurasidone (1-4). Lurasidone base is finally converted to the corresponding hydrochloride salt by treatment with HCl in acetone (5). Scheme 1.

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