Hoechst Aktiengesellschaft

Bernhard Kammermeier

Gerhard Beck

Ulrich Lerch

Wolfgang Holla

Joachim-Heiner Jendralla

Detlef Jacobi

Heiner Jendralla

Berndt Kulitzscher

Jurgen Michalowsky

The present invention relates to a process for the preparation of chiral, nonracemic compounds of the formula I ##STR1## in which R.sup.1 and R.sup.2 have the meanings indicated in claim 1 and which are useful intermediates for the preparation of pharmaceutical active compounds in which, for resolution, a salt is formed from the racemic compound of the formula I and a chiral, nonracemic amino compound. It furthermore relates to compounds of the formula I and esters thereof.

Process for the preparation of chiral, nonracemic

Process for the stereoselective synthesis of 3-substituted

Process for the diastereoselective reductive pinacol coupling of homochiral .alpha.-aminoaldehydes A process for the preparation of optically pure symmetrical compounds of the formula I ##STR1## is described, in which R.sup.1, R.sup.2 and R.sup.3, are explained in the description, with simultaneous control of the four centers of chirality indicated by *.

Process for the diastereoselective reductive pinacol coupling of

Process for the diastereoselective reductive pinacol coupling of homochiral .alpha.-aminoaldehydes A process for the preparation of optically pure symmetrical compounds of the formula I ##STR1## is described in which R.sup.1, R.sup.2 and R.sup.3 are explained in the description, with simultaneous control of the four centers of chirality marked by *.

A process for the preparation of racemic and optically active 1,2.3,4-tetrahydroisoquinoline-3-carboxylic acid is described, in which dihalo-o-xylylenes are cyclized to dicarboxylic acid esters in basic medium using dialkyl N-acylamidomalonates of the formula (CO.sub.2 R.sup.1).sub.2 CHNHCOR.sup.2, in which R.sup.1 is (C.sub.1 -C.sub.4)-alkyl and R.sup.2 is H, (C.sub.1 -C.sub.4)-alkyl or (C.sub.6 -C.sub.12)-aryl, decarboxylated by basic hydrolysis and subsequent acid work-up and then reacted in acid medium to give (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, or dihalo-o-xylylenes are cyclized in basic medium to give the dicarboxylic acid esters and these are reacted directly without isolation in a one-pot process to give (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, if desired the racemic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is reacted with (-)menthol and p-toluenesulfonic acid to give (-)menthyl (D)- or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, then the diastereomers are separated by column chromatography and subjected to basic hydrolysis to give (D)-or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, or (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is esterified by means of benzyl alcohol and p-toluenesulfonic acid, reacted with D(-)mandelic acid to give benzyl (D)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (D)-mandelate and benzyl (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (D)-mandelate or with L(+)mandelic acid to give benzyl (D)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (L)-mandelate and benzyl (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (L)-mandelate and then the compounds obtained are separated into the optical antipodes by fractional crystallization in an inert solvent and the enantiomers (D)- or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are liberated by basic hydrolysis, the chiral auxiliary reagent being recovered.

Process for the preparation of racemic and optically active

A process for the preparation of racemic and optically active 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is described, in which dihalo-o-xylylenes are cyclized to dicarboxylic acid esters in basic medium using dialkyl N-acylamidomalonates of the formula (CO.sub.2 R.sup.1).sub.2 CHNHCOR.sup.2, in which R.sup.1 is (C.sub.1 -C.sub.4)-alkyl and R.sup.2 is H, (C.sub.1 -C.sub.4)-alkyl or (C.sub.6 -C.sub.12)-aryl, decarboxylated by basic hydrolysis and subsequent acid work-up and then reacted in acid medium to give (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, or dihalo-o-xylylenes are cyclized in basic medium to give the dicarboxylic acid esters and these are reacted directly without isolation in a one-pot process to give (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, if desired the racemic 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is reacted with (-)menthol and p-toluenesulfonic acid to give (-)menthyl (D)- or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, then the diastereomers are separated by column chromatography and subjected to basic hydrolysis to give (D)- or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, or (D,L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is esterified by means of benzyl alcohol and p-toluenesulfonic acid, reacted with D(-)mandelic acid to give benzyl (D)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (D)-mandelate and benzyl (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (D)-mandelate or with L(+)mandelic acid to give benzyl (D)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (L)-mandelate and benzyl (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (L)-mandelate and then the compounds obtained are separated into the optical antipodes by fractional crystallization in an inert solvent and the enantiomers (D)- or (L)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are liberated by basic hydrolysis, the chiral auxiliary reagent being recovered.

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Frankfurt am Main, Germany

Bernhard Kammermeier