Process and intermediates for the preparation of 4'-trifluoromethyl-biphenyl-2-carboxylic acid (1,2,3,4-tetrahydro-isoquinolin-6-yl)-amide

A compound of the formula

• A--CHR.sup.1 R.sup.2
• wherein
• A is a group of the formula ##STR29## and R.sup.1 is selected from H and OR.sup.3 wherein R.sup.3 is hydrogen or (C.sub.1 -C.sub.6)alkyl,
• R.sup.2 is selected from OR.sup.3, --CH.sub.2 --NH.sub.2.(R.sup.5 H).sub.n, wherein n is 0 or 1 and R.sup.5 H is an acid selected from mineral acids selected from hydrochloric, sulfuric, nitric and phosphoric acid;
• organic acids selected from sulfonic acids which are selected from benzenesulfonic(besylic), p-toluenesulfonic (PTSA tosylic), methanesulfonic (MSA, mesylic) and trifluoromethanesulfonic (triflic) acid;
• and carboxylic acids which are selected from formic, acetic, propionic, benzoic, citric, tartaric, maleic, fumaric, succinic and malic acid, or --CH.sub.2 --NO.sub.2 ;
• or
• R.sup.1 and R.sup.2 together form an .dbd.O or .dbd.CH--NO.sub.2 group;
• with the proviso when R.sup.2 is OR.sup.3, R.sup.1 is OR.sup.3 and that when R.sup.1 and R.sup.2 are each an OR.sup.3 group then both R.sup.3 s are (C.sub.1 -C.sub.6)alkyl groups and are the same;
• and when R.sup.2 is --CH.sub.2 --NH.sub.2, (R.sup.5 H).sub.n, R.sup.1 is H;
• and when R.sup.2 is CH.sub.2 NO.sub.2, R.sup.1 is OR.sup.3 wherein R.sup.3 is hydrogen.

A process for preparing the compound of the formula ##STR30## which comprises the steps of a) treating the compound of the formula ##STR31## with a compound of the formula R.sup.3 OH, wherein R.sup.3 is (C.sub.1 -C.sub.6)alkyl, or a compound of the formula ##STR32## wherein n, R.sup.6 and R.sup.7 are each selected form H and (C.sub.1 -C.sub.2)alkyl or R.sup.6 and R.sup.7 together with the carbons to which they are attached form a (C.sub.3 -C.sub.6)cycloalkyl or (C.sub.6 -C.sub.10) aryl ring, in the presence of an acid, to form the compound of the formula ##STR33## wherein each R.sup.3 is, independently, selected from (C.sub.1 -C.sub.6)alkyl or both R.sup.3 s together form a the group of the formula ##STR34## wherein n, R.sup.6 and R.sup.7 are as described above;

• b) treating the compound of the formula X with a reducing agent to form the compound of the formula ##STR35## c) treating the compound of the formula IX with the the compound of the formula ##STR36## wherein X is a leaving group for the acylation of amines, to form the compound of the formula ##STR37## wherein R.sup.3 is as described above;
• d) treating the compound of the formula VII with an aqueous acid to form the compound of the formula ##STR38## e) treating the compound of the formula VI with nitromethane in the presence of a base, to form the the compound of the formula ##STR39## f) treating the compound of the formula V with a dehydrating agent, which is (C.sub.1 -C.sub.6)alkyl or (C.sub.6 -C.sub.10)aryl sulfonyl or carbonyl halide or anhydride, in the presence of a base to form the compound of the formula ##STR40## g) treating the compound of the formula IV in an inert medium, containing a first acid, with a reducing agent selected from aluminum hydride, borane, borohydride, and hydrogen in the presence of a hydrogenation catalyst to form the compound of the formula ##STR41## wherein m is 1 and R.sup.5 H is selected from mineral acids which are selected from hydrochloric, sulfuric, nitric and phosphoric acid;
• organic acids selected from sulfonic acids which are selected from benzenesulfonic (besylic), p-toluenesulfonic (PTSA, tosylic), methanesulfonic (MSA, mesylic) and trifluoromethanesulfonic (triflic) acid;
• and carboxylic acids which are selected from formic, acetic, proprionic, benzoic, citric, tartaric, maleic, fumaric, succinic and malic acid;
• and optionally neutralizing the R.sup.5 H to form the the compound of the formula III wherein m is 0;
• and
• h) treating the compound of the formula III, with a source of formaldehyde in the presence of a second acid.