Claims
- 1. A process for the preparation of (-)-3,4-trans-compounds of the following formula I ##STR15## wherein R.sup.1, R.sup.4 and R.sup.5 are individually hydrogen, hydroxy, halogen, trifluoromethyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or --O--(CH.sub.2).sub.n --NR.sup.6 R.sup.7 wherein n is an integer in the range of 1 to 6 and R.sup.6 and R.sup.7 independently are C.sub.1-6 alkyl or R.sup.6 and R.sup.7 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) which heterocyclic group is optionally substituted with C.sub.1-6 alkyl; and R.sup.2 and R.sup.3 are individually hydrogen or C.sub.1-6 alkyl; or a salt thereof, which comprises treating a cis-racemate of a compound of formula II ##STR16## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above or a salt thereof with a chiral acid in an inert organic solvent, crystallizing the chiral acid salt of the (-)-3,4-cis enantiomer, hydrolyzing the optically active acid salt and rearranging the resulting (-)-3,4-cis enantiomer to the corresponding (-)-3,4-trans enantiomer of above formula I by treatment with a strong base in an aprotic solvent and optionally forming a salt thereof.
- 2. A process according to claim 1, wherein R.sup.1 is hydroxy or C.sub.1-6 alkoxy, R.sup.2 and R.sup.3 are the same and are C.sub.1-6 alkyl, R.sup.4 is hydrogen and R.sup.5 is --O--(CH.sub.2).sub.n --NR.sup.6 R.sup.7 wherein n is 2 and R.sup.6 and R.sup.7 together with the N atom is a saturated or unsaturated 5- or 6- membered heterocyclic group containing one or two heteroatom(s) and optionally substituted with C.sub.1-6 alkyl.
- 3. A process according to claim 1 wherein R.sup.1 is in the 7-position and R.sup.5 is in the 4-position.
- 4. A process according to claim 1 wherein R.sup.1 is methoxy.
- 5. A process according to claim 1 wherein R.sup.1 is hydroxy.
- 6. A process according to claim 1 wherein R.sup.2 is methyl.
- 7. A process according to claim 1 wherein R.sup.3 is methyl.
- 8. A process according to claim 1 wherein R.sup.4 is hydrogen.
- 9. A process according to claim 1 wherein R.sup.5 is pyrrolidinoethoxy.
- 10. A process according to claim 1, wherein (-)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-�2-(pyrrolidin-1-yl)ethoxy!phenyl}chromane or a salt thereof is prepared from 3,4-cis-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-�2-(pyrrolidin-1-yl)ethoxy!phenyl}chromane or a salt thereof.
- 11. A process according to claim 10 wherein (-)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-�2-(pyrrolidin-1-yl)ethoxy!phenyl}chromane is isolated as the hydrogen fumarate salt.
- 12. A process according to claim 1, wherein the reaction with the chiral acid is carried out in an C.sub.1-6 alkanol or mixtures thereof with water, tetrahydrofuran, acetone or acetonitril.
- 13. A process according to claim 1 wherein the chiral acid is (-)-di-p-toluoyltartaric acid.
- 14. A process according to claim 13, wherein the reaction with the (-)-di-p-toluoyltartaric acid is carried out in an C.sub.1-6 alkanol.
- 15. A process according to claim 14, wherein the reaction with the (-)-di-p-toluoyltartaric acid is carried out in methanol.
- 16. A process according to claim 1 wherein the rearrangement of the (-)-3,4-cis enantiomer to the (-)-3,4-trans enantiomer is carried out with potassium hydroxide in dimethylsulfoxide and toluene.
- 17. A process according to claim 1 wherein the rearrangement of the (-)-3,4-cis enantiomer to the (-)-3,4-trans enantiomer is carried out with potassium t-butoxide in N-methylpyrrolidine and toluene.
- 18. A process according to claim 1 wherein the cis-racemate of formula II is obtained by hydrogenation of the corresponding 3-chromene.
- 19. A process according to claim 18 wherein the 3-chromene is obtained by oxidation of the corresponding (+)-3,4-cis-chromane.
- 20. A process according to claim 19 wherein the oxidation is carried out with chloranil and sulphur in xylene in the presence of acetic acid.
- 21. A process according to claim 19 wherein the oxidation is carried out with chloranil in ethylenglycol on the hydrochloride of the cis-chromane.
Priority Claims (2)
Number |
Date |
Country |
Kind |
1194/96 |
Oct 1996 |
DKX |
|
1108/97 |
Sep 1997 |
DKX |
|
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. 119 of United States provisional application Ser. No. 60/031,247 filed on Nov. 12, 1996 and Danish application serial nos. 1194/96 filed Oct. 28, 1996 and 1108/97 filed on Sep. 26, 1997, the contents of which are fully incorporated herein by reference.
US Referenced Citations (2)
Number |
Name |
Date |
Kind |
3340276 |
Carney et al. |
Sep 1967 |
|
4447622 |
Salman et al. |
May 1984 |
|
Non-Patent Literature Citations (3)
Entry |
Saeed et al., Chemical Abstracts, 102:40068, 1985. |
Salman et al., J. Med. Chem., 26, pp. 592-595, (1983). |
Ray et al., J. Med. Chem., vol. 19, No. 2, pp. 276-279, (1976). |