Process for the preparation of Latanoprost
Disclosed is a process for the preparation of the anti-glaucoma drug Latanoprost, in good yield, in large amounts and with desired purity. Also disclosed are novel intermediates for the above process.
1. A process for the preparation of Latanoprost [1]
which comprises deriving the compound [5]
to give the compound [7]
which is hydrogenated in the presence of catalyst to give the compound of the Formula [9]
which is reduced with diisobutylaluminum hydride at temperature range from −50 to +50° C. followed by hydrolysis of the obtained reaction mixture under basic conditions to give compound [11], which is converted into latanoprost [1]
wherein one of R 1 and R 2 is an aryl carbonyl and the other one is selected from the group consisting of aryl carbonyl, acyl, trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl groups, and R 3 is hydrogen when R 1 is acyl and is equal to R 1 when it is trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted or alkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-yl groups; R 4 is hydrogen when R 2 is acyl and is equal to R 2 when it is trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted or alkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-yl groups.
2. A process according to claim 1 wherein the said reduction of the compound [9] with diisobutylaluminum hydride is provided at temperature range from −20 to +20° C.
3. A process according to claim 1 wherein the said catalyst contains palladium, platinum or nickel.
4. A process according to claim 1 wherein the said catalyst is palladium on carbon.
5. A process according to claim 1 wherein the said hydrogenation of the compound [7] is carried out in the presence of bases and/or salts.
6. The process defined in claim 1 , which comprises isolating the compounds of Formulae [7] and [9] in the course of the synthesis and, if desired, purifying them by re-crystallization.
7. Compound of the formula [7]:
wherein one of R 1 and R 2 is p-phenylbenzoyl group and the other one is selected from the group consisting of aryl carbonyl, acyl, trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl groups.
8. Compound of the formula [9]:
wherein one of R 1 and R 2 is an aryl carbonyl group and the other one is selected from the group consisting of aryl carbonyl, acyl, trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl groups.
9. Compound of the formula [11]:
wherein R 3 and R 4 are selected from the group consisting of hydrogen, trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl groups, and one of the R 3 and R 4 is hydrogen group.
10. (3aR,4R,5R,6aS)-Hexahydro-5-(p-phenylbenzoyloxy)-4-[(3S)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]-1E-pentenyl]-2H-cyclopenta[b]furan-2-one [7a]:
wherein PPB is p-phenylbenzoyl group and THP is tetrahydro-2H-pyran-2-yl group.
11. (3aR,4R,5R,6aS)-Hexahydro-5-(p-phenylbenzoyloxy)-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-one [9a]:
wherein PPB is p-phenylbenzoyl group and THP is tetrahydro-2H-pyran-2-yl group.
12. (3aR,4R,5R,6aS)-Hexahydro-5-hydroxy-4-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-2H-cyclopenta[b]furan-2-ol [11a]:
wherein THP is tetrahydro-2H-pyran-2-yl group.
13. A process according to claim 1 wherein R 1 and R 2 are selected from the group consisting of benzoyl, p-toluoyl, p-phenylbenzoyl and tetrahydro-2H-pyran-2-yl groups, and at least one of the R 1 and R 2 is arylcarbonyl group.
14. A process according to claim 1 , wherein compound [11] is converted into latanoprost [1] by reacting [11] with a metal salt of 5-(triphenylphosphoranylidene)pentanoic acid to form a compound of formula [13]
wherein R 3 and R 4 are as defined above;
and when R 3 and/or R 4 in compound [13] is other than hydrogen, removing the protecting group to yield latanoprost acid [13b]
following esterifycation of compound [13b] with compound [16]:
(CH 3 ) 2 CHX [16]
wherein X is a leaving group, in the presence of a base to obtain latanoprost [1].
15. A process according to claim 14 , wherein said base is cesium carbonate.