Intermediates useful for the preparation of antihistaminic piperidine derivatives

  • US 6,555,689 B2
  • Filed: 12/01/2000
  • Issued: 04/29/2003
  • Est. Priority Date: 06/25/1993
  • Status: Expired due to Fees
First Claim
Patent Images

1. A process for preparing a compound of the formula embedded imagewhereinW 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 cumene compound of the formula embedded imagewherein A is as defined above with a ω

    -halo compound of the formula embedded imagewherein 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 a ω

    -halo cumylketone compound;

    (b) reacting the ω

    -halo cumylketone compound with a suitable halogenating agent to give a ω

    -halo-halocumylketone compound;

    (c) reacting the ω

    -halo-halocumylketone compound compound with a suitable cyanating agent to give a ω

    -halo-cyanocumylketone compound;

    (d) reacting the ω

    -halo-cyanocumylketone compound with an appropriate straight or branched C1-C6 alcohol in the presence of a suitable anhydrous acid to give a ω



    -halo-α



    -keto-α



    -dimethylphenylacetic acid imidate compound;

    (e) reacting the ω



    -halo-α



    -keto-α



    -dimethylphenylacetic acid imidate compound with water to give a ω



    -halo-α



    -keto-α



    -dimethylphenylacetic acid ester compound;

    (f) reacting the ω



    -halo-α



    -keto-α



    -dimethylphenylacetic acid ester compound with a piperidine compound of the formula embedded image

    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



    -dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is —

    C(═

    O)—

    ;

    (g) optionally hydrolyzing the ω



    -piperidine- α



    -keto-α



    -dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is —

    C(═

    O)—

    to produce a ω

    -piperidine- α



    -hydroxy-α



    -dimethylphenyl derivative of formula (I) wherein R3 is COOH and W is —

    C(═

    O)—

    ;

    (h) optionally reacting the ω



    -piperidine-α



    -keto-α



    -dimethylphenyl derivative of formula (I) wherein R3 is COOalkyl and W is —

    C(═

    O)—

    or the ω



    -piperidine-α



    -keto-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



    -dimethylphenyl derivative of formula (I) wherein R3 is —

    COOH and W is —

    CH(OH)—

    or the ω



    -piperidine-α



    -hydroxy-α



    -dimethylphenyl derivative of formula (I) wherein R3 is —

    COOalkyl and W is —

    CH(OH)—

    ; and

    (i) optionally reacting the ω



    -piperidine-α



    -hydroxy-α



    -dimethylphenyl derivative of formula (I) wherein R3 is —

    COOH and W is —

    CH(OH)—

    or the appropriate ω



    -piperidine-α



    -keto-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



    -dimethylphenyl derivative of formula (I) wherein R3 is —

    COOalkyl and W is —

    CH(OH)—

    or a ω



    -piperidine-α



    -keto-α



    -dimethylphenyl derivative wherein R3 is —

    COOalkyl and W is —

    C(═

    O)—

    ; and

    (j) optionally reacting the ω



    -piperidine-α



    -keto-α



    -dimethylphenyl derivative of formula (I) wherein R3 is —

    COOH and W is —

    C(═

    O)—

    , the ω



    -piperidine-α



    -keto-α



    -dimethylphenyl derivative of formula (I) wherein R3 is —

    COOalkyl and W is —

    C(═

    O)—

    , the ω



    -piperidine-α



    -hydroxy-α



    -dimethylphenyl derivative of formula (I) wherein R3 is —

    COOH and W is —

    CH(OH)—

    or the ω



    -piperidine-α



    -hydroxy-α



    -dimethylphenyl derivative 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-i are optionally protected or unprotected.

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