The present invention is related to a novel process for preparing certain piperidine derivatives which are useful as antihistamines, antiallergy agents and bronchodilators [U.S. Pat. No. 4,254,129, Mar. 3, 1981, U.S. Pat. No. 4,254,130, Mar. 3, 1981 and U.S. Pat. No. 4,285,958, Apr. 25, 1981].
These piperidine derivatives can be described by the following formulas: ##STR1## wherein R.sub.1 represents hydrogen or hydroxy;
R.sub.2 represents hydrogen; or PA1 R.sub.1 and R.sub.2 taken together form a second bond between the carbon atoms bearing R.sub.1 and R.sub.2 ; PA1 n is an integer of from 1 to 5; PA1 R.sub.3 is --CH.sub.2 OH, --COOH or --COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; PA1 each of A is hydrogen or hydroxy; PA1 R.sub.2 represents hydrogen; or PA1 R.sub.1 and R.sub.2 taken together form a second bond between the carbon atoms bearing R.sub.1 and R.sub.2 ; PA1 n is an integer of from 1 to 5; PA1 R.sub.3 is --CH.sub.2 OH, --COOH or --COOalkyl wherein the alkyl moiety has from 1 to 6 carbon atoms and is straight or branched; PA1 each of A is hydrogen or hydroxy; PA1 (a) reacting a benzeneacetic acid compound of the formula ##STR3## wherein A is as defined above and R is hydrogen or C.sub.1 -C.sub.6 alkyl with a suitable reducing agent to give a phenethyl alcohol; PA1 (b) reacting the phenethyl alcohol with a .omega.-halo compound of the formula ##STR4## 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 a .omega.-halo hydroxyethylphenylketone; and PA1 (c) reacting the .omega.-halo hydroxyethylphenylketone with a piperidine compound of the formula ##STR5## wherein R.sub.1 and R.sub.2 are as defined above in the presence of a suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylketone derivative of formula (II) wherein R.sub.3 is --CH.sub.2 OH; PA1 (d) optionally reacting the piperidine hydroxyethylphenylketone derivative of formula (II) wherein R.sub.3 is --CH.sub.2 OH with a suitable oxidizing agent to produce a piperidine carboxyphenylketone derivative of formula (II) wherein R.sub.3 is --COOH; PA1 (e) optionally reacting the piperidine carboxyphenylketone derivative of formula (II) wherein R.sub.3 is --COOH to produce a piperidine carboxyphenylketone ester derivative of formula (II) wherein R.sub.3 is --COOalkyl. PA1 (f) optionally reacting the piperidine carboxyphenylketone derivative of formula (II) wherein R.sub.3 is --COOH or the piperidine carboxyphenylketone ester derivative of formula (II) wherein R.sub.3 is --COOalkyl with a suitable reducing agent to produce a piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH or the piperidine carboxyphenylalcohol ester of formula (I) wherein R.sub.3 is --COOalkyl; PA1 (g) optionally reacting the piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH to produce a piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R.sub.3 is --COOalkyl; and PA1 (h) optionally reacting the piperidine hydroxyethylphenylketone derivative of formula (II) wherein R.sub.3 is --CH.sub.2 OH, the piperidine carboxyphenylketone derivative of formula (II) wherein R.sub.3 is --COOH, the piperidine carboxyphenylketone ester derivative of formula (II) wherein R.sub.3 is --COOalkyl, the piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH or the piperidine carboxyphenylalcohol ester of formula (I) wherein R.sub.3 is --COOalkyl with an appropriate deprotecting reagent, PA1 (a) reacting the .omega.-halo hydroxyethylphenylketone with a suitable reducing agent to produce a .omega.-halo hydroxyethylphenylalcohol; PA1 (b) reacting the .omega.-halo hydroxyethylphenylalcohol with a piperidine compound of the formula ##STR6## wherein R.sub.1 and R.sub.2 are as defined above, in the presence of a suitable non-nucleophilic base to produce a piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH; PA1 (c) optionally reacting the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH with a suitable oxidizing agent to produce a piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH; and PA1 (d) optionally reacting the piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH to produce the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R.sub.3 is --COOalkyl. PA1 (e) optionally reacting the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH, the piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH or the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R.sub.3 is --COOalkyl with an appropriate deprotecting reagent, PA1 (a) reacting the piperidine hydroxyethylphenylketone derivative of formula (II) wherein R.sub.3 is --CH.sub.2 OH with a suitable reducing agent to produce a piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH; PA1 (b) optionally reacting the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH with a suitable oxidizing agent to produce a piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH; and PA1 (c) optionally reacting the piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH to produce the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R.sub.3 is --COOalkyl. PA1 (d) optionally reacting the piperidine hydroxyethylphenylketone derivative of formula (II) wherein R.sub.3 is --CH.sub.2 OH, the piperidine hydroxyethylphenylalcohol derivative of formula (I) wherein R.sub.3 is --CH.sub.2 OH, the piperidine carboxyphenylalcohol derivative of formula (I) wherein R.sub.3 is --COOH or the piperidine carboxyphenylalcohol ester derivative of formula (I) wherein R.sub.3 is --COOalkyl with an appropriate deprotecting reagent, with the proviso that each of the hydroxy groups present in the compounds described in steps a-c are optionally protected or unprotected. PA1 D=hydrogen or a suitable protecting group PA1 R.sub.1 ' and R.sub.2 '=hydrogen, protected hydroxy, hydroxy or taken together to form a second bond between the carbon atoms bearing R.sub.1 ' and R.sub.2 ' PA1 R=C.sub.1 -C.sub.6 alkyl or hydrogen
and pharmaceutically acceptable salts, hydrates and individual optical isomers thereof.
The novel process for preparing the piperidine derivatives of formula (I) and formula (II) of the present invention offers high yields and ease of purification.
USPTO Backgrounds
USPTO Backgrounds