Asymmetric synthesis of .alpha.-cycloalkylalkyl substituted methanamines
AssigneeBoehringer Ingelheim Pharmaceuticals, Inc.
InventorsGregory Roth, John Landi
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Abstract
This invention relates to process for asymmetrically producing enantiomerically pure .alpha.-cycloalkylalkyl substitututed methanamines from .alpha.-pinene. One key step of the process of this invention utilizes the oxidation product of .alpha.-pinene, hydroxy pinanone, as a chiral auxiliary to direct the stereoselective alkylation of the corresponding ketimine. This invention also relates to key intermediates useful in the processes referred to herein.
Claims21
A process for producing 2-hydroxy-3-pinanone, comprising the steps of reacting .alpha.-pinene with catalytic potassium osmate in solution of pyridine, N-methylmorpholine-N-oxide and aqueous acetone to produce cis-pinanediol;
- and thereafter oxidizing said cis-pinanediol with DMSO activated by pyridine.SO.sub.3 and triethylamine in an appropriate solvent to produce 2-hydroxy-3-pinanone.
A process for producing 2-hydroxy-3-pinanone comprising of the step of oxidizing .alpha.-pinene with potassium permanganate using a phase transfer catalyst in methylene chloride/water solvent.
A process for alkylating a ketimine of 2-hydroxy-3-pinanone comprising the steps of:
- (a) deprotonating a ketimine of 2-hydroxy-3-pinanone using a strong base;
- and
- (b) reacting about 1 equivalent of the deprotonated ketimine with about 1-2 equivalents of an appropriate alkyl halide at a temperature of between about -20.degree. C. and about 5.degree. C.
A process for producing an (S)-.alpha.-cycloalkylalkyl-2-pyridinemethanamine comprising the step of hydrolyzing the corresponding (S)-(.alpha.-cycloalkylalkyl-2-hydroxy-3-(pyridinemethyl) ketimine with hydroxylethylethylamine chloride.
A process for producing (S)-.alpha.-cyclohexylmethyl-2-pyridinemethanamine from (S)-(-)-.alpha.-pinene comprising the steps of:
- (a) oxidizing (S)-.alpha.-pinene with potassium permanganate using a phase transfer catalyst in an appropriate solvent to form (1R, 2R, 5R)-(+)-2-hydroxy-3-pinanone;
- (b) reacting (1R, 2R, 5R)-(+)-2-hydroxy-3-pinanone with 2- (aminomethyl) pyridine and a Lewis acid catalyst in toluene or methyl t-butyl ether to form (1R, 2R, 5R)-(+)-2-hydroxy-3-(pyridinemethyl) ketimine;
- (c) deprotonating (1R, 2R, 5R)-(+)-2-hydroxy-3-(pyridinemethyl) ketimine using a strong base;
- (d) reacting about 1 equivalent of the deprotonated ketimine with about 1-2 equivalents of cyclohexylmethyl halide at a temperature of between about -20.degree. C. and about 5.degree. C. to form (S)-.alpha.-cyclohexylmethyl-2-hydroxy-3-(pyridinemethyl) ketimine;
- and
- (e) hydrolyzing (S)-.alpha.-cyclohexylmethyl-2-hydroxy-3-(pyridinemethyl) ketimine.
A compound having the structure of formula (I):
- ##STR7## wherein:
- R.sub.1 is -(CH.sub.2).sub.n -cycloalkyl, said cycloalkyl being unsubstituted or substituted with C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, hydroxy, amino or halo;
- R.sub.2 is selected from the group consisting of an unsubstituted or substituted naphthyl ring wherein the ring substituents are selected from the group consisting of halo, hydroxy, amino, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 alkoxy;
- 3-methyl- 1,2,4-oxadiazol-5-yl;
- 2- or 3-thienyl;
- 2-, 3-, or 4-pyridyl, unsubstituted or substituted with halo, hydroxy, amino, C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 alkoxy;
- 2-imidazole, unsubstituted or substituted on the nitrogen with methyl;
- 2-thiazole, unsubstituted or substituted at the 4-position with methyl;
- --C(O)R.sub.3 ;
- --CH.sub.2 O (C.sub.1 -C.sub.4 alkyl);
- CH.sub.2 S(C.sub.1 -C.sub.3 alkyl);
- --CH.sub.2 SO.sub.2 (C.sub.1 -C.sub.3 alkyl);
- --CH.sub.2 NH.sub.2 ;
- --CH.sub.2 NHSO.sub.2 (C.sub.1 -C.sub.3 alkyl)2;
- and --CH.sub.2 OC(O)NH(C.sub.1 -C.sub.3 alkyl);
- R.sub.3 is selected from the group consisting of C.sub.1 -C.sub.3 alkyl, phenyl and 1-methylimidazol-2-yl;
- and
- n is an integer from 0-4.
Dependencies are inferred from the claim text.