Process to prepare treprostinil, the active ingredient in Remodulin®

1. A product comprising a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein said product is prepared by a process comprising

(a) alkylating a compound of structure II with an alkylating agent to produce a compound of formula III,

wherein

w=1, 2, or 3;

Y 1 is trans-CH═CH—, cis-CH═CH—, —CH 2 (CH 2 ) m —, or —C≡C—; m is 1, 2, or 3;

R 7 is

(1) —C p H 2p —CH 3 , wherein p is an integer from 1 to 5, inclusive,

(2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C 1 -C 3 ) alkyl, or (C 1 -C 3 )alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R 7 is phenoxy or substituted phenoxy, only when R 3 and R 4 are hydrogen or methyl, being the same or different,

(3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C 1 -C 3 )alkyl, or (C 1 -C 3 )alkoxy, with the proviso that not more than two substituents are other than alkyl,

(4) cis-CH═CH—CH 2 —CH 3 ,

(5) —(CH 2 ) 2 —CH(OH)—CH 3 , or

(6) —(CH 2 ) 3 —CH═C(CH 3 ) 2 ;

—C(L 1 )—R 7 taken together is

(1) (C 4 -C 7 )cycloalkyl optionally substituted by 1 to 3 (C 1 -C 5 )alkyl;

(2) 2-(2-furyl)ethyl,

(3) 2-(3-thienyl)ethoxy, or

(4) 3-thienyloxymethyl;

M 1 is α-OH:β-R 5 or α-R 5 β-OH or α-OR 1 :β-R 5 or α-R 5 :β-OR 2 , wherein R 5 is hydrogen or methyl, R 2 is an alcohol protecting group, and

L 1 is α-R 3 :β-R 4 , α-R 4 :β-R 3 , or a mixture of α-R 3 :β-R 4 and α-R 4 :β-R 3 , wherein R 3 and R 4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R 3 and R 4 is fluoro only when the other is hydrogen or fluoro,

(b) hydrolyzing the product of formula III of step (a) with a base,

(c) contacting the product of step (h) with a base B to form a salt of formula I s .

(d) optionally reacting the salt formed in step (c) with an acid to form the compound of formula I.

2. The product of claim 1 , wherein the purity of compound of formula I in said product is at least 99.5%.

3. The product of claim 1 , wherein the alkylating agent is Cl(CH 2 ) w CN, Br(CH 2 ) w CN, or I(CH 2 ) w CN.

4. The product of claim 1 , wherein the base in step (b) is KOH or NaOH.

5. The product of claim 1 , wherein the base B in step (c) is selected from the group consisting of ammonia, N-methylglucamine, procaine, tromethanine, magnesium, L-lysine, L-arginine, triethanolamine, and diethanolamine.

6. The product of claim 1 , wherein the acid in step (d) is HCl or H 2 SO 4 .

7. The product of claim 1 , wherein Y 1 is —CH 2 CH 2 —; M 1 is α-OH:β-H or α-H:β-OH; —C(L 1 )-R 7 taken together is —(CH 2 ) 4 CH 3 ; and w is 1.

8. The product of claim 1 , wherein the process does not include purifying the compound of formula (III) produced in step (a).

9. A product comprising a compound having formula IV

or a pharmaceutically acceptable salt thereof, wherein the product is prepared by the process comprising

(a) alkylating a compound of formula V with an alkylating agent to produce a compound of formula VI,

(b) hydrolyzing the product of formula VI of step (a) with a base,

(c) contacting the product of step (h) with a base B to form a salt of formula IV s , and

(d) optionally reacting the salt formed in step (c) with an acid to form the compound of formula IV.

10. The product of claim 9 , wherein the purity of product of step (d) is at least 99.5%.

11. The product of claim 9 , wherein the alkylating agent is ClCH 2 CN.

12. The product of claim 9 , wherein the base in step (b) is KOH.

13. The product of claim 9 , wherein the base B in step (c) is selected from a group consisting of ammonia, N-methylglucamine, procaine, tromethanine, magnesium, L-lysine, L-arginine, triethanolamine, and diethanolamine.

14. The product of claim 9 , wherein the base B is diethanolamine.

15. The product of claim 9 , wherein the acid in step (d) is HCl.

16. The product of claim 9 , wherein the process does not include purifying the compound of formula (VI) produced in step (a).

17. The product of claim 16 , wherein the base B in step (c) is selected from a group consisting of ammonia, N-methylglucamine, procaine, tromethanine, magnesium, L-lysinc, L-arginine, tricthanolamine, and diethanolamine.

18. The product of claim 17 , wherein the base B is diethanolamine.

19. The product of claim 1 , wherein the base in step (b) is KOH or NaOH and wherein the base 13 in step (c) is selected from the group consisting of ammonia. N-methyl glucamine, procaine, tromethanine, magnesium, L-lysine, L-arginine, triethanolamine, and diethanolamine.

20. The product of claim 9 , wherein the base in step (b) is KOH or NaOH and wherein the base B in step (c) is selected from the group consisting of ammonia, N-methylglucamine, procaine, tromethanine, magnesium, L-lysine, L-arginine, triethanolamine, and diethanolamine.

21. The product of claim 1 , wherein step (d) is performed.

22. The product of claim 21 , wherein the product comprises a pharmaceutically acceptable salt formed from the product of step (d).