Intermediates useful for the preparation of antihistaminic piperidine derivatives

A process for preparing a compound of the formula

• wherein
• W represents —C(═O)— or —CH(OH)—;
• R1 represents hydrogen or hydroxy;
• R2 represents hydrogen;
• or
• R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
• n is an integer of from 1 to 5;
• m is an integer 0 or 1;
• R3 is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
• each of A is hydrogen or hydroxy;
• and
• pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
• (a) reacting a phenylacetic acid ester compound of the formula
• wherein A is as defined above with a ω-halo compound of the formula
• wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is as defined above, in the presence of a suitable Lewis acid to produce ω-halo-α′-keto-phenylacetic acid ester compound;
• (b) reacting the ω-halo-α′-keto-phenylacetic acid ester compound with a suitable methylating agent in the presence of a suitable base to give a cyclopropylketo-α,α-dimethylphenylacetic acid ester;
• (c) purifying the cyclopropylketo-α,α-dimethylphenylacetic acid ester by distillation and/or recrystallization;
• (d) converting the cyclopropylketo-α,α-dimethylphenylacetic acid ester into a ω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound;
• (e) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound with a piperidine compound of the formula
• wherein R1, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOalkyl and W is —C(═O)—;
• (f) optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOalkyl and W is —C(═O)— to produce a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is —C(═O)—;
• (g) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is —C(═O)— with a suitable reducing agent to produce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOH and W is —CH(OH)—;
• and
• (h) optionally reacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOH and W is —CH(OH)— or the appropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOH and W is —C(═O)— with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOalkyl and W is —CH(OH)— or a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOalkyl and W is —C(═O)—;
• and
• (i) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOH and W is —C(═O)—, the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOalkyl and W is —C(═O)—, the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOH and W is —CH(OH)— or the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R3 is —COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,
• with the proviso that each of the hydroxy groups present in the compounds described in steps a-h are optionally protected or unprotected.

A process for preparing a compound of the formula

• wherein
• W represents —C(═O)— or —CH(OH)—;
• R1 represents hydrogen or hydroxy;
• R2 represents hydrogen;
• or
• R1 and R2 taken together form a second bond between the carbon atoms bearing R1 and R2;
• n is an integer of from 1 to 5;
• m is an integer 0 or 1;
• R3 is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched;
• each of A is hydrogen or hydroxy;
• and
• pharmaceutically acceptable salts and individual optical isomers thereof, with the proviso that where R1 and R2 are taken together to form a second bond between the carbon atoms bearing R1 and R2 or where R1 represented hydroxy, m is an integer 0, comprising the steps of:
• (a) reacting a phenylacetic acid ester compound of the formula
• wherein A is as defined above with a suitable methylating agent to give a α,α-dimethylphenylacetic acid ester;
• (b) reacting the α,α-dimethylphenylacetic acid ester with a ω-halo compound of the formula
• wherein B is halo or hydroxy, Hal represents Cl, Br or I and n is 3, in the presence of a suitable Lewis acid to produce a cyclopropylketo-α-α-dimethylphenylacetic acid ester;
• (c) purifying the cyclopropylketo-α,α-dimethylphenylacetic acid ester by distillation and/or recrystallization;
• (d) converting the cyclopropylketo-α,α-dimethylphenylacetic acid ester into a ω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound;
• (e) reacting the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid ester compound with a piperidine compound of the formula
• wherein R1, R2 and m are as defined above in the presence of a suitable non-nucleophilic base to produce a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOalkyl and W is —C(═O)—;
• (f) optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOalkyl and W is —C(═O)— to produce a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is —C(═O)—;
• (g) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is —C(═O)— with a suitable reducing agent to produce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOH and W is —CH(OH)—;
• and
• (h) optionally reacting the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOH and W is —CH(OH)— or the appropriate ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOH and W is —C(═O)— with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable acid to produce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOalkyl and W is —CH(OH)— or a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOalkyl and W is —C(═O)—;
• and
• (i) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOH and W is —C(═O)—, the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOalkyl and W is —C(═O)—, the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative of formula (I) wherein R3 is —COOH and W is —CH(OH)— or the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl of formula (I) wherein R3 is —COOalkyl and W is —CH(OH)— with an appropriate deprotecting reagent,
• with the proviso that each of the hydroxy groups present in the compounds described in steps a-h are optionally protected or unprotected.

A process for preparing piperidine derivatives of formula

• wherein
• W represents —C(═O)— or —CH(OH)—;
• R3 is —COOH or —COOCH3;
• and
• pharmaceutically acceptable salts and individual optical isomers thereof, comprising the steps of:
• (a) reacting phenylacetic acid methyl ester with a suitable methylating ageant in the presence of a suitable base to give α,α-dimethylphenylacetic acid methyl ester;
• (b) reacting α,α-dimethylphenylacetic acid methyl ester with a ω-halo compound of the formula
• wherein B is halo or hydroxy and Hal represents Cl, Br or I in the presence of a suitable Lewis acid to produce a mixture of meta and para isomers of ω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compounds of the formula
• wherein Hal is defined above;
• (c) separating the para isomer of the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound by crystallization;
• (d) reacting the para isomer of the ω′-halo-α′-keto-α,α-dimethylphenylacetic acid methyl ester compound with a piperidine compound of the formula
• in the presence of a suitable non-nucleophilic base to produce a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula
• wherein
• W represents —C(═O);
• R3 is —COOCH3;
• and
• pharmaceutically acceptable salts and individual optical isomers thereof;
• (e) optionally hydrolyzing the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R3 is COOCH3 and W is —C(═O)— to produce a ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative of formula
• wherein
• W represents —C(═O)—;
• R3 is —COOH;
• and
• pharmaceutically acceptable salts and individual optical isomers thereof;
• (f) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R3 is COOCH3 and W is —C(═O)— or the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R3 is COOH and W is —C(═O)— with a suitable reducing agent to produce a ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R3 is —COOH and W is —CH(OH)— or the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R3 is COOCH3 and W is —CH(OH)—;
• and
• (g) optionally reacting the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R3 is —COOH and W is —C(═O)—, the ω′-piperidine-α′-keto-α,α-dimethylphenyl derivative wherein R3 is —COOCH3 and W is —C(═O)—, the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R3 is —COOH and W is —CH(OH)— or the ω′-piperidine-α′-hydroxy-α,α-dimethylphenyl derivative wherein R3 is —COOCH3 and W is —CH(OH)— with an appropriate deprotecting reagent,
• with the proviso that the hydroxy groups present in the compounds described in steps a-f are optionally protected or unprotected.