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PROCESS FOR THE PREPARATION OF (3aR,4S,7R,7aS)-HEXAHYDRO-1H-4,7-METHANOISOINDOLE-1,3(2H)-DIONE, AN INTERMEDIATE OF ((1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-BENZISOTHIAZOL-3-YL)-PIPERAZIN-1-YLMETHYL]-CYCLOHEXYLMETHYL]-BICYCLO[2.2.1]HEPTANE-2,3-DICARBOXIMIDE HYDROCHLORIDE)

IP.com Disclosure Number: IPCOM000204532D
Publication Date: 2011-Mar-02
Document File: 2 page(s) / 19K

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 PROCESS FOR THE PREPARATION OF (3aR,4S,7R,7aS)-HEXAHYDRO- 1H-4,7-METHANOISOINDOLE-1,3(2H)-DIONE, AN INTERMEDIATE OF ((1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-BENZISOTHIAZOL-3-YL)-PIPERAZIN- 1-YLMETHYL]-CYCLOHEXYLMETHYL]-BICYCLO[2.2.1]HEPTANE-2,3-

DICARBOXIMIDE HYDROCHLORIDE)

((1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-piperazin-1-ylmethyl]- cyclohexylmethyl]-bicyclo[2.2.1]heptane-2,3-dicarboximide hydrochloride), referred to as "LUR" of the following formula:

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,

is a potent antagonist of dopamine D2, serotonin 2A, and serotonin 7 receptors with a high affinity for serotonin 1A receptor.

    Described hereinafter, is a process for the preparation of (3aR,4S,7R,7aS)- hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione ("EXO NRB"), an intermediate of LUR.

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    (3aR,4S,7R,7aS)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)- dione ("ENDO- NRBE") can be prepared by reacting maleimide and cyclopentadiene.

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    ENDO- NRBE can then be used for the preparation of an isomerization mixture of ENDO- NRBE and (3aR,4R,7S,7aS)-3a,4,7,7a-tetrahydro-1H-4,7- methanoisoindole-1,3(2H)-dione ("EXO-NRBE"). The isomerization process comprises heating ENDO- NRBE using high boiling fluid.

    The obtained isomerization mixture can then be used for the preparation of EXO- NRBE. The process for the preparation of EXO- NRBE comprises recrystallization the obtained isomeri...