- CARBONYL ASYMMETRIC ALKYLATION
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This invention relates to processes and intermediates for the stereoselective alkylation of carbonyl groups. The invention in particular allows the stereoselective preparation of the antidepressant drug escitalopram. It has been found that boric or boronic acid derivatives are useful bridging elements for the attachment of a chiral group to a compound containing a carbonyl group to be alkylated. The said borates and boronates are thus useful in a process for the asymmetric alkylation of a carbonyl group in a compound containing a carbonyl group and an anchor group capable of reacting with a boric or boronic acid derivative. The asymmetric alkylation can be carried out by admixing the compound containing a carbonyl group to be alkylated and the anchor group capable of reacting with a boric or boronic acid derivative with a boric or boronic acid derivative, adding a chiral alcohol, and adding an organometallic compound. After the alkylation reaction, the borate and boronate can be easily removed by hydrolysis.
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Page/Page column 21
(2010/11/28)
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- ONE POT SYNTHESIS OF CITALOPRAM FROM 5-CYANOPHTHALIDE
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A process for one pot synthesis of citalopram is disclosed. The process comprises subjecting 5-cyano phthalide to Grignard reduction followed cyclization and followed by C-alkylation reaction to obtain citalopram without isolation and purification of any intermediates. In another embodiment, 5-cyano phthalide is subjected to sequential Grignard reactions followed by cyclization to obtain citalopram without isolation and purification of any intermediate stages.
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Page/Page column 8-9
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF A CYANO-ISOBENZOFURAN
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A process for the preparation of citalopram and the pharmaceutically acceptable salts therof is disclosed by reacting 5-cyanophthalide with a 4-fluorophenyl magnesium halide, reducing the 3-hydroxymethyl-4-(4-fluoro-benzoyl)benzonitrile with an agent reducing ketones to alcohols, submitting the thus-obtained 3-hydroxymethyl-4- [(4-fluorophenyl)hydroxymethyl) benzonitrile to a cyclization reaction to give 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile without 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile and treating 1,1-bis(4 fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile with a 3-(dimetylamino)propyl halide in the presence of a base.
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Page 18-19; 20-21; 13; 7
(2008/06/13)
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- IMPROVED PROCESS FOR THE PREPARATION OF 5-SUBSTITUTED-1-(4--FLUOROPHENYL)-1,3-DIHYDROISOBENZOFURANS
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The present invention provides a process for the preparation of a 5-substituted-l-(4-fluorophenyl)-1,3-dihydro-isobenzofuran of Formula (2), an intermediate for the manufacture of citalopram, which process comprises: (a) carrying out a Grignard reaction on a corresponding 5-substituted phthalide of Formula (3) in a co-solvent system, comprising adding (i) prepared 4-fluorophenyl magnesium halide in an ether solvent to (ii) the 5-substituted phthalide in a suitable organic co-solvent to the ether solvent, to form a corresponding 4-substituted-2-hydroxymethyl-4'-fluorobenzophenone of Formula (4); (b) carrying out a ketone reduction of the 4-substituted-2-hydroxymethyl-4'-fluorobenzophenone of Formula (4) following the Grignard reaction, to form a corresponding 4-substituted-2-hydroxymethylphenyl- 1-(4-fluorophenyl) methanol of Formula (5); and (c) carrying out a cyclisation reaction on the 4-substituted-2 hydroxymethylphenyl- 1-(4-fluorophenyl) methanol of Formula (5) following the reduction reaction, to form said intermediate of Formula (2); wherein R represents Br or CN.
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- Method for the preparation of citalopram
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A method for the preparation of citalopram is described comprising reduction of the oxo group of a compound of formula (IV), wherein R1is CN, C1-6alkyloxycarbonyl or C1-6alkylaminocarbonyl, ring closure of the resulting hydroxy compound thereby obtaining the corresponding 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran, then if R1is cyano using it directly in the next step and if R1is C1-6alkyloxycarbonyl or C1-6alkylaminocarbonyl, conversion of the compound to the corresponding compound wherein R1is a cyano; and alkylation of the resulting 5-cyano compound with 3-dimethyl-aminopropylhalogenide in basic conditions thereby obtaining citalopram.
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