Prostaglandin synthesis

1. A process for synthesising Latanoprost comprising the steps of:

a) preparing a compound of formula (3):

 said preparing comprising converting a compound of formula (1):

 to a cuprate reagent and performing a 1,4 addition reaction between the cuprate reagent and a compound of formula (2):

b) selectively reducing the compound of formula (3) to provide a compound of formula (4):

c) dihydroxylating the compound of formula (4) to provide a compound of formula (7):

d) reducing the compound of formula (7) to provide a compound of formula (10):

e) performing a diol cleavage reaction on the compound of formula (10) to provide a compound formula (13):

f) performing a Wittig reaction on the compound of formula (13) to provide a compound of formula (16):

g) esterifying the compound of formula (16) to provide a compound of formula (19):

h) deprotecting the compound of formula (19) to provide Latanoprost.

2. A process for synthesising Latanoprost comprising the steps of:

a) preparing a compound of formula (3):

 said preparing comprising converting a compound of formula (1):

 to a cuprate reagent and performing a 1,4 addition reaction between the cuprate reagent and a compound of formula (2):

b) selectively reducing the compound of formula (3) to provide a compound of formula (4):

c) protecting the compound of formula (4) to provide a compound of formula (5):

d) dihydroxylating the compound of formula (5) to provide a compound of formula (8):

e) reducing the compound of formula (8) to provide a compound of formula (11):

f) performing a diol cleavage reaction on the compound of formula (11) to provide a compound of formula (14):

g) performing a Wittig reaction on the compound of formula (14) to provide a compound of formula (17):

h) esterifying the compound of formula (17) to provide a compound of formula (20):

i) deprotecting the compound of formula (20) to provide Latanoprost.

3. A process for synthesising Latanoprost comprising the steps of:

a) preparing a compound of formula (3):

 said preparing comprising converting a compound of formula (1):

 to a cuprate reagent and performing a 1,4 addition reaction between the cuprate reagent and a compound of formula (2):

b) selectively reducing the compound of formula (3) to provide a compound of formula (4):

c) deprotecting the compound of formula (4) to provide a compound of formula (6):

d) dihydroxylating the compound of formula (6) to provide a compound of formula (9):

e) reducing the compound of formula (9) to provide a compound of formula (12):

f) performing a diol cleavage reaction on the compound of formula (12) to provide a compound of formula (15):

g) performing a Wittig reaction on the compound of formula (15) to provide a compound of formula (18):

h) esterifying the compound of formula (18) to provide Latanoprost.

4. A process for the preparation of a prostaglandin compound having the formula (I):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; B is selected from OR″ and NHR″ wherein R″ is C 1 –C 6 alkyl groups; and

represents a double bond or a single bond;

the process comprising a step of preparing a compound of formula (VIII):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; P is a hydroxyl protecting group; and

represents a double bond or a single bond; said step comprising converting a compound of formula (IX):

wherein A, P and

are as defined above and X is a leaving group, to a cuprate reagent and performing a 1,4 addition reaction between the cuprate reagent and a compound of formula (X):

wherein P is as defined above.

5. A process for the preparation of a prostaglandin compound having the formula (I):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; B is selected from OR″ and NHR″ wherein R″ is C 1 –C 6 alkyl groups; and

represents a double bond or a single bond;

the process comprising a step of preparing a compound of formula (VIIa):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; P is a hydroxyl protecting group and

represents a double bond or a single bond;

said step comprising selectively reducing a compound of formula (VIII):

wherein A, P and

are as defined above.

6. A process for the preparation of a prostaglandin compound having the formula (I):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; B is selected from OR″ and NHR″ wherein R″ is C 1 –C 6 alkyl groups; and

represents a double bond or a single bond;

the process comprising a step of preparing a compound of formula (VIIb):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; P is a hydroxyl protecting group and

represents a double bond or a single bond;

said step comprising protecting a compound of formula (VIIa):

wherein A, P and

are as defined above, with a hydroxyl protecting group.

7. A process for the preparation of a prostaglandin compound having the formula (I):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; B is selected from OR″ and NHR″ wherein R″ is C 1 –C 6 alkyl groups; and

represents a double bond or a single bond;

the process comprising a step of preparing a compound of formula (VIIc):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 and

represents a double bond or a single bond;

said step comprising deprotecting a compound of formula (VIIa):

wherein A and

are as defined above and P is a protecting group.

8. A process for the preparation of a prostaglandin compound having the formula (I):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; B is selected from OR″ and NHR″ wherein R″ is C 1 –C 6 alkyl groups; and

represents a double bond or a single bond;

the process comprising a step of preparing a compound of formula (VIa), (VIb), (VIc), (Va), (Vb) or (Vc):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and P is a hydroxyl protecting group;

said step comprising dihydroxylating a compound of formula (VIIa), a compound of formula (VIIb) or a compound of formula (VIIc):

wherein A and P are as defined above and

is a double or single bond.

9. A process for the preparation of a prostaglandin compound having the formula (I):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; B is selected from OR″ and NHR″ wherein R″ is C 1 –C 6 alkyl groups; and

represents a double bond or a single bond;

the process comprising a step of preparing a compound of formula (Va), (Vb) or (Vc):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and P is a hydroxyl protecting group;

said step comprising reducing a double bond of a compound of formula (VIa), a compound of formula (VIb) or a compound of formula (VIc):

wherein A and P are as defined above.

10. A process for the preparation of a prostaglandin compound having the formula (I):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; B is selected from OR″ and NHR″ wherein R″ is C 1 –C 6 alkyl groups; and

represents a double bond or a single bond;

the process comprising a step of preparing a compound of formula (IVa), (IVb) or (lVc):

wherein A is selected from the group consisting of C 1 –C 6 alkyl groups; C 7 –C 16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; and (CH 2 ) n OR′ wherein n is an integer from 1 to 3 and R′ represents a C 6 –C 10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C 1 –C 6 alkyl groups, halo and CF 3 ; P is a hydroxyl protecting group and

represents a double bond or a single bond;

said step comprising performing a diol cleavage reaction on a compound of formula (VIa), (Va), (VIb,), (Vb), (VIc) or (Vc):

wherein A and P are as defined above.

11. The process according to claim 4 , wherein P is a tetrahydropyranyl (THP) protecting group.

12. The process according to claim 4 or claim 11 , wherein X is iodine.

13. The process according to claim 4 , wherein A is (CH 2 ) 2 Ph,

represents a double bond, P is THP and X is I.

14. The process according to claim 5 , wherein P is a tetrahydropyranyl (THP) protecting group.

15. The process according to claim 5 , wherein A is (CH 2 ) 2 Ph,

represents a double bond and P is THP.

16. The process according to claim 6 , wherein P is a tetrahydropyranyl (THP) protecting group.

17. The process according to claim 6 , wherein A is (CH 2 ) 2 Ph,

represents a double bond and P is THP.

18. The process according to claim 7 , wherein P is a tetrahydropyranyl (THP) protecting group.

19. The process according to claim 7 or claim 18 , wherein A is (CH 2 ) 2 Ph and

represents a double bond.

20. The process according to claim 8 , wherein P is a tetrahydropyranyl (THP) protecting group.

21. The process according to claim 8 , wherein A is (CH 2 ) 2 Ph, P is THP,

represents a double bond, and compound (VIIa) reacts to give compound (VIa).

22. The process according to claim 8 , wherein A is (CH 2 ) 2 Ph, P is THP,

represents a double bond, and compound (VIIb) reacts to give compound (VIb).

23. The process according to claim 8 , wherein A is (CH 2 ) 2 Ph,

represents a double bond, and compound (VIIc) reacts to give compound (VIc).

24. The process according to claim 9 , wherein P is a tetrahydropyranyl (THP) protecting group.

25. The process according to claim 9 , wherein A is (CH 2 ) 2 Ph, P is THP and compound (VIa) reacts to give compound (Va).

26. The process according to claim 9 , wherein A is (CH 2 ) 2 Ph, P is THP and compound (VIb) reacts to give compound (Vb).

27. The process according to claim 9 , wherein A is (CH 2 ) 2 Ph and compound (VIc) reacts to give compound (Vc).

28. The process according to claim 10 , wherein P is a tetrahydropyranyl (THP) protecting group.

29. The process according to claim 10 , wherein A is (CH 2 ) 2 Ph, P is THP,

represents a single bond, and compound (Va) reacts to give compound (IVa).

30. The process according to claim 10 , wherein A is (CH 2 ) 2 Ph, P is THP,

represents a single bond, and compound (Vb) reacts to give compound (IVb).

31. The process according to claim 10 , wherein A is (CH 2 ) 2 Ph,

represents a single bond, and compound (Vc) reacts to give compound (IVc).

32. The process according to claim 11 , wherein the compound having the formula (I) is Travoprost.

33. The process according to claim 4 , wherein the compound having the formula (I) is Travoprost.

34. The process according to claim 4 , wherein A is CH 2 CH 2 -Ph,

represents a double bond and P is THP, the process further comprising selectively reducing the compound of formula (VIII) to provide a compound of formula (4):

dihydroxylating the compound of formula (4) to provide a compound of formula (7):

performing a diol cleavage reaction on the compound of formula (7) to provide a compound of formula (23):

performing a Wittig reaction on the compound of formula (23) to provide a compound of formula (26):

amidating the compound of formula (26) to provide a compound of formula (29):

deprotecting the compound of formula (29) to provide Bimatoprost.

35. The process according to claim 4 , wherein A is CH 2 CH 2 -Ph,

represents a double bond and P is THP, the process further comprising selectively reducing the compound of formula (VIII) to provide a compound of formula (4):

protecting the compound of formula (4) to provide a compound of formula (5):

dihydroxylating the compound of formula (5) to provide a compound of formula (8):

performing a diol cleavage reaction on the compound of formula (8) to provide a compound of formula (24):

performing a Wittig reaction on the compound of formula (24) to provide a compound of formula (27):

amidating the compound of formula (27) to provide a compound of formula (30):

deprotecting the compound of formula (30) to provide Bimatoprost.

36. The process according to claim 4 , wherein A is CH 2 CH 2 -Ph,

represents a double bond and P is THP, the process further comprising selectively reducing the compound of formula (VIII) to provide a compound of formula (4):

deprotecting the compound of formula (4) to provide a compound of formula (6):

dihydroxylating the compound of formula (6) to provide a compound of formula (9):

performing a diol cleavage on the compound of formula (9) to provide a compound of formula (25):

performing a Wittig reaction on the compound of formula (25) to provide a compound of formula (28):

amidating the compound of formula (28) to provide Bimatoprost.

37. The process according to claim 14 , wherein the compound having the formula (I) is Travoprost.

38. The process according to claim 5 , wherein the compound having the formula (I) is Travoprost.

39. The process according to claim 16 , wherein the compound having the formula (I) is Travoprost.

40. The process according to claim 6 , wherein the compound having the formula (I) is Travoprost.

41. The process according to claim 18 , wherein the compound having the formula (I) is Travoprost.

42. The process according to claim 7 , wherein the compound having the formula (I) is Travoprost.

43. The process according to claim 20 , wherein the compound having the formula (I) is Travoprost.

44. The process according to claim 8 , wherein the compound having the formula (I) is Travoprost.

45. The process according to claim 24 , wherein the compound having the formula (I) is Travoprost.

46. The process according to claim 9 , wherein the compound having the formula (I) is Travoprost.

47. The process according to claim 28 , wherein the compound having the formula (I) is Travoprost.

48. The process according to claim 10 , wherein the compound having the formula (I) is Travoprost.