Antihistaminic piperidine derivatives and intermediates for the preparation thereof

1. A process for preparing a compound of the formula:

wherein

R 1 is C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched: comprising the steps of:

a) reacting a benzene acetic acid ester of the formula:

wherein

R 1 is C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched; with a 4-halo-substituted butyrylhalide under Friedel-Crafts conditions to provide a mixture of para and meta substituted ω-halo-α-keto-benzeneacetic acid ester of the formula:

wherein

R 1 is as previously defined herein and X is Cl, Br, or I;

(b) hydrolyzing the mixture of para and meta substituted (ω-halo-α-keto substituted benzene acetic acid ester to provide a mixture of para and meta substituted (cyclopropylcarbonyl)benzene acetic acid ester of the formula:

(c) selectively crystallizing and isolating the substantially pure 4-(cyclopropylcarbonyl)benzene acetic acid.

2. A process according to claim 1 wherein X is Cl.

3. A process according to claim 1 comprising steps a), b) and c) of claim 1 and further comprising:

(d) esterifying the substantially pure 4-(cyclopropylcarbonyl)benzene acetic acid to provide a corresponding 4-(cyclopropylcarbonyl)benzeneacetic acid ester of the formula:

wherein

R 1 is C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched;

(e) alkylating the 4-(cyclopropylcarbonyl)benzeneacetic acid ester with a suitable alkylating agent to provide a corresponding alkylated (4-(cyclopropylcarbonyl)phenyl]benzeneacetic acid ester:

wherein

R 1 is as previously defined herein and R 2 and R 3 are each independently C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched;

(f) ring-opening the alkylated [4-(cyclopropylcarbonyl)phenyl]benzene acetic acid ester to provide a corresponding [4-(4-halo-1-oxo-butyl)phenyl]benzene acetic acid ester of the formula:

wherein

R 1 , R 2 and R 3 are as previously defined herein and X is Cl, Br or I;

(g) reacting the alkylated [4-(4-halo-1-oxo-butyl)phenyl]benzeneacetic acid ester with a compound of the formula:

to produce a [4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]benzeneacetic acid ester of the formula:

wherein

R 1 , R 2 and R 3 are as previously defined herein; or

stereoisomers or pharmaceutically acceptable acid addition salt thereof;

h) reacting the [4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]benzeneacetic acid ester with a suitable reducing agent to produce a 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]benzeneacetic acid ester of the formula:

wherein

R 1 , R 2 and R 3 are as previously defined herein; or

stereoisomers or pharmaceutically acceptable acid addition salt thereof;

i) optionally hydrolyzing the 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]benzeneacetic acid ester to produce a compound of the formula:

wherein

R 2 and R 3 are as previously defined herein; or

stereoisomers or pharmaceutically acceptable acid addition salt thereof;

with the proviso that each of the keto groups present in the compounds described in steps d-g are optionally protected or unprotected.

4. A process according to claim 3 wherein R 2 and R 3 of the compound provided in step i) is methyl.

5. A process according to claim 1 comprising steps a), b) and c) of claim 1 and further comprising

(d) esterifying the substantially pure 4-(cyclopropylcarbonyl)benzene acetic acid to provide a corresponding 4-(cyclopropylcarbonyl)benzeneacetic acid ester of the formula:

wherein

R 1 is C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched;

(e) acylating the (cyclopropylcarbonyl)benzeneacetic acid ester to provide a [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester of the formula:

wherein

R 2 is H; and

R 1 and R 3 are each independently C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched;

(f) optionally alkylating the [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester to provide a [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester of the formula:

wherein

R 2 is C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched and R 1 and R 3 are each independently C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched;

(g) reacting the [4-(cyclopropylcarbonyl)phenyl]propanedioic acid diester wherein

R 2 is H or C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched; and

R 1 and R 3 are each independently C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched;

with a suitable hydrogen halide to produce a [4-(4-halo-1-oxo-butyl)phenyl]propanedioic acid diester of formula:

wherein

R 2 is H or C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched;

R 1 and R 3 are C 1 -C 6 alkyl and the C 1 -C 6 alkyl moiety is straight or branched;

X is Cl, Br or I or stereoisomers thereof;

(h) reacting the [4-(4-halo-1-oxo-butyl)phenyl]propanedioic acid diester with a compound of formula:

to produce a [4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]propanedioic acid diester compound of formula:

wherein

R 2 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched;

R 1 and R 3 are each independently C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched; or

stereoisomers or pharmaceutically acceptable acid addition salt thereof;

(i) reacting the [4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]propanedioic acid diester compound with a suitable selective reducing agent to give a 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-benzeneacetic acid ester compound of formula:

wherein

R 2 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched;

R 1 is —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; or

stereoisomers or pharmaceutically acceptable acid addition salt thereof; and

(j) optionally hydrolyzing the 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α-(hydroxymethyl)-benzeneacetic acid ester compound to produce a compound of formula:

wherein

R 2 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched;

R 1 is —COOH; or

stereoisomers or pharmaceutically acceptable acid addition salt thereof;

with the proviso that each of the keto groups present in the compounds described in steps d-h are optionally protected or unprotected.

6. A process according to claim 5 wherein R 2 of the compound provided in j) is methyl.

7. A process according to claim 3 wherein R 2 and R 3 of the compound provided in step h) is methyl.

8. In a process for the synthesis of a compound of the formula:

wherein

R 1 is H or C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched;

R 2 is —COOH or —COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; or

stereoisomers or pharmaceutically acceptable acid addition salt thereof, using as an intermediate a carboxylic acid according to the formula:

the improvement wherein said carboxylic acid was prepared according to the process comprising the steps of:

a) reacting a benzene acetic acid ester of the formula:

wherein

R 1 is C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched;

with 4-halo-substituted butyrylhalide under Friedel-Crafts conditions to provide a mixture of para and meta substituted ω-halo-α-keto-benzeneacetic acid ester of the formula:

wherein

R 1 is as previously defined herein and X is Cl, Br, or I;

(b) hydrolyzing the mixture of para and meta substituted ω-halo-α-keto substituted benzene acetic acid ester to provide a mixture of para and meta substituted (cyclopropylcarbonyl)benzene acetic acid ester of the formula:

(c) selectively crystallizing and isolating substantially pure 4-(cyclopropylcarbonyl)benzene acetic acid.

9. A process according to claim 8 wherein the 4-halo-substituted butyrylhalide is 4-chlorobutyrylchloride.

10. A process according to claim 8 wherein X is Cl.

11. In a process for the synthesis of a compound of the formula:

wherein

R 1 is C 1 -C 6 .alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched and R 2 and R 3 are each independently C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched; or

stereoisomers or pharmaceutically acceptable acid addition salt thereof; using as an intermediate a carboxylic acid according to the formula:

the improvement wherein said carboxylic acid was prepared according to the process comprising the steps of:

a) reacting a benzene acetic acid ester of the formula:

wherein R 1 is C 1 -C 6 alkyl wherein the C 1 -C 6 alkyl moiety is straight or branched; with 4-halo-substituted butyrylhalide under Friedel-Crafts conditions to provide a mixture of para and meta substituted ω-halo-α-keto-benzeneacetic acid ester of the formula:

wherein

R 1 is as previously defined herein and X is Cl, Br, or I;

(b) hydrolyzing the mixture of para and meta substituted ω-halo-α-keto substituted benzene acetic acid ester to provide a mixture of para and meta substituted (cyclopropylcarbonyl)benzene acetic acid ester of the formula:

(c) selectively crystallizing and isolating substantially pure 4-(cyclopropylcarbonyl)benzene acetic acid.

12. A process according to claim 11 wherein R 1 is hydrogen and R 2 and R 3 are methyl.

13. A process according to claim 11 wherein the 4-halo-substituted butyrylhalide is 4-chlorobutyrylchloride.

14. A process according to claim 11 wherein X is Cl.