Process for the preparation of prostaglandin derivatives
The invention provides a novel process for the preparation of prostaglandins and analogues thereof, and new crystalline intermediates in the process.
1. A process for the preparation of alkyl 5Z-prostenoates of formula [1]
wherein R is 3-CF 3 C 6 H 4 O—, 3-ClC 6 H 4 O—, PhO—, Bn—, Bu—, Me(CH 2 ) 5 —; A is —CH 2 CH 2 — or —CH═CH—; X is X 1 , O or (α-OH, H); X 1 is (α-OR 3 , H), —OCH 2 CH 2 O—; (F, F); R 1 is C 1 –C 10 alkyl group; R 3 is selected from the group consisting of trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl group; α is down;
such process comprising:
(a) contacting Corey aldehyde of formula [7]
wherein R 2 is arylcarbonyl group, with a β-ketophosphonate of formula [8]
RCH 2 COCH 2 PO(OR 4 ) 2 8
wherein R 4 is C 1 –C 4 alkyl, Ph or Bn and where R is as defined above, in the presence of an aqueous alkali;
(b) converting the compound of formula [6]
prepared at the step (a), to compound of formula [5]
wherein X 1 is (α-OR 4 , H), —OCH 2 CH 2 O—, (F, F); A, R, R 2 and R 4 are as defined above;
(c) reducing the compound [5] with diisobutylaluminum hydride at a temperature range from −30 to 0° C. to give the compound [4]
wherein A, R and X 1 are as defined above;
(d) reacting compound [4] with a metal salt of 5-(triphenylphosphoranylidene)pentanoic acid, to obtain the 5Z-prostenoic acid of formula [3]
wherein A, R and X are as defined above;
(e) converting 5Z-prostenoic acid [3] to cesium 5Z-prostenoate of formula [2]
wherein A, R and X are as defined above; and
(f) esterifying the cesium 5Z-prostenoate [2] with compound R 1 Y
wherein Y is a leaving group and R 1 is as defined above; to give the desired [1].
2. A process for the preparation of alkyl 5Z-prostenoate of formula [1]
wherein R is 3-CF 3 C 6 H 4 O—, 3-ClC 6 H 4 O—, PhO—, Bn—, Bu—, Me(CH 2 ) 5 —; A is —CH 2 CH 2 — or —CH═CH—; X is X 1 , O or (α-OH, H); X 1 is (α-OR 3 , H), —OCH 2 CH 2 O— or (F, F); R 1 is C 1 –C 10 alkyl group; R 3 is selected from the group consisting of trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl group; α is down;
such process comprising esterifying the cesium 5Z-prostenoate [2]
wherein A, R and X are as defined above, with compound R 1 Y
wherein Y is a leaving group and R 1 is as defined above;
to give the desired alkyl 5Z-prostenoate [1].
3. A process for the preparation of lactol of formula [4]
R is 3-CF 3 C 6 H 4 O—, 3-ClC 6 H 4 O—, PhO—, Bn—, Bu—, Me(CH 2 ) 5 —; A is —CH 2 CH 2 — or —CH═CH—;
X 1 is (α-OR 3 , H), —OCH 2 CH 2 O— or (F, F); R 3 is selected from the group consisting of trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl group; α is down;
such process comprising reducing the compound [5]
wherein X 1 , A, R and R 2 are as defined above;
with diisobutylaluminum hydride at a temperature range from −30 to 0° C. to give the compound [4].
4. A process for the preparation of compound of formula [6]
wherein R is 3-CF 3 C 6 H 4 O—, 3-ClC 6 H 4 O—, PhO—, Bn—, Bu—, Me(CH 2 ) 5 —; R 2 is arylcarbonyl group;
such process comprising contacting Corey aldehyde of formula [7]
wherein R 2 is as defined above, with a β-ketophosphonate of formula [8]
RCH 2 COCH 2 PO(OR 4 ) 2 8
wherein R 4 is C 1 –C 4 alkyl, Ph or Bn and where R is as defined above, in the presence of an aqueous alkali.
5. A process for the preparation of compound
[X 1 =(α-OR 3 , H)]
wherein R is 3-CF 3 C 6 H 4 O—, 3-ClC 6 H 4 O—, PhO—, Bn—, Bu—, Me(CH 2 ) 5 —; A is —CH═CH— or —CH 2 CH 2 —; R 2 is arylcarbonyl group; R 3 is selected from the group consisting of trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-yl group;
such process comprising:
stereoselective reduction of the carbonyl group of the compound [6]
wherein R and R 2 are as defined above,
to yield a mixture of compounds of formulae [5-1] and [9-1]
wherein R and R 2 are as defined above, and where [5-1] is the predominant isomer, which are subsequently converted into a mixture of compounds of formulae [5] [A=—CH═CH—; X 1 =(α-OR 3 , H)]
[A=—CH═CH—; X 1 =(α-OR 3 , H)]
and [9-2]
followed by isolation of the compound [5] [A=—CH═CH—; X 1 =(α-OR 3 , H)] from the mixture and, if desired, hydrogenation of the compound [5] [A=—CH═CH—; X 1 =(α-OR 3 , H)] in the presence of catalyst to give compound of formula [5] [A=—CH 2 CH 2 —; X 1 =(α-OR 3 , H)]
[A=—CH 2 CH 2 —; X 1 =(α-OR 3 , H)]
wherein R, R 2 and R 3 are as defined above.
6. A process according to claim 4 which process comprising the steps of converting compound [9-2] into compound [9-1], oxidizing the hydroxyl group of the compound [9-1] to yield the compound [6] and recycling the compound [6] to the beginning of the process.
7. A process according to any one of claims 1 and 2 wherein R 1 is methyl or isopropyl.
8. A process according to any one of claims 1 and 2 wherein Y is bromide or iodide.
9. A process according to any one of claims 1 – 5 wherein R 2 is benzoyl, p-toluoyl, p-chlorobenzoyl, p-bromobenzoyl or p-phenylbenzoyl (PPB).
10. A process according to any one of claims 1 , 2 , 4 and 5 wherein R 3 is tetrahydro-2H-pyran-2-yl or t-butyldimethylsilyl group.
11. A process according to claim 5 wherein said stereoselective reduction of the carbonyl group of the compound [6] is carried out by (−)-B-chlorodiisopinocampheylborane.
12. A process according to claim 5 , which further comprises purifying the compound of formula 5 [X=(α-OR 3 , H)] by re-crystallization.
13. A process for the preparation of compound of formula [5] [A=—CH 2 CH 2 —; X=(α-OR 3 , H)]
[A=—CH 2 CH 2 —; X=(α-OR 3 , H)]
wherein R is 3-CF 3 C 6 H 4 O—, 3-ClC 6 H 4 O—, PhO—, Bn—, Bu—, Me(CH 2 ) 5 —; R 2 is arylcarbonyl group; R 3 is selected from the group consisting of trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-yl group;
which process comprising catalytic hydrogenation of compound of formula [5] [A=—CH═CH—; X=(α-OR 3 , H)]
[A=—CH═CH—; X=(α-OR 3 , H)]
14. A process according to claim 13 wherein said catalyst comprises palladium, platinum or nickel.
15. A process according to claim 13 wherein said catalyst is palladium on carbon.
16. (3aR,4R,5R,6aS)-4-[3S-(t-Butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one of the formula
17. Crystalline MTBE solvate of (3aR,4R,5R,6aS)-4-[3S-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one.
18. Crystalline (3aR,4R,5R,6aS)-4-[3R-(t-butyldimethylsiloxy)-4-[3-(trifluoromethyl)phenoxy]-1E-butenyl]-5-(4-phenylbenzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one of the formula
19. Crystalline (3aR,4R,5R,6aS)-4-[3R-(t-butyldimethylsiloxy)-4-[3-(trifluoromethyl)phenoxy]-1E-butenyl]-5-hydroxy-hexahydro-2H-cyclopenta[b]furan-2-ol of the formula
20. (3aR,4R,5R,6aS)-4-[3S-(t-Butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-hydroxy-hexahydro-2H-cyclopenta[b]furan-2-ol of the formula
21. Crystalline (3aR,4R,5R,6aS)-4-[3S-(t-butyldimethylsiloxy)-5-phenyl-1E-pentenyl]-5-hydroxy-hexahydro-2H-cyclopenta[b]furan-2-ol.
22. Crystalline (3aR,4R,5R,6aS)-4-[3R-(t-butyldimethylsiloxy)-5-phenylpentyl]-5-hydroxy-hexahydro-2H-cyclopenta[b]furan-2-ol.