Processes and intermediates for the preparations of isomer free prostaglandins

1. A process for preparing a compound of Formula I-2 substantially free of the 5,6-trans isomer:

wherein

 is

  is a single or double bond; R 2 is a single bond or a C 1-4 -alkylene or —CH 2 O—; and R 3 is a C 1-7 -alkyl or an aryl or an aralkyl, each of which is unsubstituted or substituted by a C 1-4 -alkyl, a halogen or a trihalomethyl; R 4 is C 1-7 -alkyl,

comprising the steps of:

(1) macrolactonization of a compound of Formula IV-1 containing 0˜5% 5,6-trans isomer

wherein

 is

 or a protecting group for the carbonyl group; P 1 and P 2 are protecting groups for hydroxyl groups; , R 2 and R 3 are as defined above, to form a compound of Formula III:

wherein

  , P 1 , R 2 and R 3 are as defined above for Formula IV-1;

(2) removing P 1 or/and P 2 ; and

(3) opening the macrolactone ring by transesterification.

2. A process according to claim 1 , wherein said transesterification comprises hydrolysis of the macrolactone to form a compound containing a hydroxyl group and a carboxylic acid

and then esterification of the carboxylic acid.

3. A process according to claim 1 , wherein said transesterification comprises reacting the macrolactone with a nucleophile selected from the group consisting of a C 1-7 alkanol, a C 1-7 alkoxide, a C 1-7 alkoxide salt, or a mixture thereof to form a compound containing a hydroxyl group and an ester group.

4. A process according to claim 3 , wherein the nucleophile is 2-propanol, sodium 2-propoxide, or a mixture thereof.

5. A process according to claim 1 , further comprising purification of the compound of Formula I-2 by silylating all the hydroxyl groups in the compound of Formula I-2 with a silylating agent to form a compound of Formula I-2″,

wherein

 is

 R a , R b and R c are each independently a C 1-8 alkyl, phenyl, benzyl, a substituted phenyl, or a substituted benzyl; , R 2 and R 3 are as defined claim 1 ; removing the impurities; and then desilylating the resultant compound to form a compound of Formula I-2 having an improved purity.

6. A process according to claim 5 , wherein the silylating agent is selected from chlorotrimethylsilane, chlorotriethylsilane, chlorodimethyl(octyl)silane, and tert-butylchlorodimethylsilane.

7. A process according to claim 1 , wherein the compound of Formula I-2 is selected from the group consisting of Latanoprost, Travoprost, Tafluprost, Isopropyl Cloprostenol, and Isopropyl Unoprostone.

8. A process according to claim 1 , for preparing Travoprost:

comprising the steps of:

(1) macrolactonization of a compound of Formula IV-1a containing 0˜5% 5,6-trans isomer

wherein P 1 and P 2 are protecting groups for hydroxyl groups to form a compound of Formula IIIa

wherein P 1 and P 2 are as defined above;

(2) deprotecting the compound of Formula IIIa by removing P 1 and P 2 to form the compound of Formula IIa

and

(3) opening the macrolactone ring in the compound of Formula IIa by transesterification to form Travoprost.

9. A process according to claim 8 , wherein said transesterification comprises hydrolysis of the compound of Formula IIa to form Travoprost acid and then esterification of the Travoprost acid to form Travoprost.

10. A process according to claim 1 , for preparing Latanoprost:

comprising the steps of:

(1) macrolactonization of a compound of Formula IV-1b containing 0˜5% 5,6-trans isomer

wherein P 1 and P 2 are protecting groups for hydroxyl groups to form a compound of Formula IIIb

wherein P 1 and P 2 are as defined above;

(2) deprotecting the compound of Formula IIIb by removing P 1 and P 2 to form a compound of Formula IIb

and

(3) opening the macrolactone ring in the compound of Formula IIb by transesterification to form Latanoprost.

11. A process according to claim 10 , wherein said transesterification comprises hydrolysis of the compound of Formula IIb to form Latanoprost acid and then esterification of the Latanoprost acid to form Latanoprost.

12. A process according to claim 1 , for preparing Tafluprost:

comprising the steps of:

(1) macrolactonization of a compound of Formula IV-1c containing 0˜5% 5,6-trans isomer

wherein P 1 is a protecting group for the hydroxyl group to form a compound of Formula IIIc

wherein P 1 is as defined above;

(2) deprotecting the compound of Formula IIIc by removing P 1 to form a compound of Formula IIc

and

(3) opening the macrolactone ring of the compound of Formula IIc by transesterification to form Tafluprost.

13. A process according to claim 12 , wherein said transesterification comprises hydrolysis of the compound of Formula IIc to form Tafluprost acid and then esterification of the Tafluprost acid to form Tafluprost.

14. A process according to claim 12 , further comprising acylating the compound of Formula IIc to form a compound of Formula IIc′

wherein R 8 is C 1-7 -alkyl, unsubstituted phenyl or substituted phenyl, crystallizing the compound of Formula IIc′, and removing the acyl group by transesterification.

15. A process according to claim 14 , wherein said transesterification comprises opening the macrolactone ring and removing the acyl group by hydrolysis of compound of Formula IIc′ to form Tafluprost acid and then esterification of Tafluprost acid to form Tafluprost.

16. A process according to claim 1 , for preparing Isopropyl unoprostone:

comprising the steps of:

(1) macrolactonization of a compound of Formula IV-1d containing 0˜5% 5,6-trans isomer

wherein

 is

 or a protecting group for carbonyl group; P 1 and P 2 are protecting groups for the hydroxyl groups to form a compound of Formula IIId

wherein

 and P 1 are as defined above;

(2) removing the P 1 of the compound of Formula IIId wherein

 is

 or a protecting group of the carbonyl group to form a compound of Formula IId

and

(3) opening the macrolactone ring of the compound of Formula IId by transesterification to form a compound of Formula I-2d′:

wherein

 is a protecting group of the carbonyl group.

17. A process according to claim 16 , wherein said transesterification comprises hydrolysis of the compound of Formula IId to form keto-function protected Unoprostone or Unoprostone, and then esterification of the keto-function protected Unoprostone or Unoprostone to form keto-function protected Isopropyl Unoprostone or Isopropyl Unoprostone.

18. A process according to claim 16 , further comprising removing the protecting groups for carbonyl groups in the compound of Formula IIId, IId, or I-2d′ to form the corresponding compounds of Formula IIId, IId, or I-2d′ wherein

is

19. A process according to claim 16 , further comprising removing the protecting groups P 2 in the compound of Formula IIId wherein

is

and then oxidizing the resulting hydroxyl group to form the corresponding compound of Formula IIId wherein

is