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Details for Patent: 8,242,305

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Details for Patent: 8,242,305

Title:Process to prepare treprostinil, the active ingredient in remodulin
Abstract: This present invention relates to an improved process to prepare prostacyclin derivatives. One embodiment provides for an improved process to convert benzindene triol to treprostinil via salts of treprostinil and to purify treprostinil.
Inventor(s): Batra; Hitesh (Herndon, VA), Tuladhar; Sudersan M. (Silver Spring, MD), Penmasta; Raju (Herndon, VA), Walsh; David A. (Palmyra, VA)
Assignee: United Therapeutics Corporation (Silver Spring, MD)
Filing Date:Dec 15, 2008
Application Number:12/334,731
Claims:1. A process for the preparation of a compound of formula I ##STR00022## comprising (a) alkylating a compound of structure II with an alkylating agent to produce a compound of formula III, ##STR00023## wherein w=1, 2, or 3; Y.sub.1 is trans-CH.dbd.CH--, cis-CH.dbd.CH--, --CH.sub.2(CH.sub.2).sub.m--, or --C.ident.C--; m is 1, 2, or 3; R.sub.7 is (1) --C.sub.pH.sub.2p--CH.sub.3, wherein p is an integer from 1 to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1-C.sub.3) alkyl, or (C.sub.1-C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.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.sub.1-C.sub.3)alkyl, or (C.sub.1-C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH.dbd.CH--CH.sub.2--CH.sub.3, (5) --(CH.sub.2).sub.2--CH(OH)--CH.sub.3, or (6) --(CH.sub.2).sub.3--CH.dbd.C(CH.sub.3).sub.2; --C(L.sub.1)-R.sub.7 taken together is (1) (C.sub.4-C.sub.7)cycloalkyl optionally substituted by 1 to 3 (C.sub.1-C.sub.5)alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; M.sub.1 is .alpha.-OH:.beta.-R.sub.5 or .alpha.-R.sub.5:.beta.-OH or .alpha.-OR.sub.1:.beta.-R.sub.5 or .alpha.-R.sub.5:.beta.-OR.sub.2, wherein R.sub.5 is hydrogen or methyl, R.sub.2 is an alcohol protecting group, and L.sub.1 is .alpha.-R.sub.3:.beta.-R.sub.4, .alpha.-R.sub.4:.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3:.beta.-R.sub.4 and .alpha.-R.sub.4:.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.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 (b) with a base B to form a salt of formula I.sub.s, ##STR00024## (d) reacting the salt formed in step (c) with an acid to form the compound of formula I.

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

3. The process according to claim 2, wherein the product of step (d) has the purity of compound of formula I of at least 90.0%.

4. The process according to claim 1, further comprising a step of isolating the salt of formula I.sub.s.

5. The process according to claim 1, wherein the alkylating agent is Cl(CH.sub.2).sub.wCN, Br(CH.sub.2).sub.wCN, or I(CH.sub.2).sub.wCN.

6. The process according to claim 1, wherein the base in step (b) is KOH or NaOH.

7. The process according to 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.

8. The process according to claim 1, wherein the acid in step (d) is HCl or H.sub.2SO.sub.4.

9. The process according to claim 1, wherein Y.sub.1 is --CH.sub.2CH.sub.2--; M.sub.1 is .alpha.-OH:.beta.-H or .alpha.-H:.beta.-OH; --C(L.sub.1)-R.sub.7 taken together is --(CH.sub.2).sub.4CH.sub.3; and w is 1.

10. The process according to claim 1, wherein the compound of formula I is a compound of formula IV, ##STR00025##

11. A process for the preparation of a compound having formula IV ##STR00026## comprising (a) alkylating a compound of formula V with an alkylating agent to produce a compound of formula VI, ##STR00027## (b) hydrolyzing the product of formula VI of step (a) with a base, (c) contacting the product of step (b) with a base B to form a salt of formula IV.sub.s, and ##STR00028## (d) reacting the salt formed in step (c) with an acid to form the compound of formula IV.

12. The process of claim 11, which does not include purifying the compound of formula (VI) produced in step (a).

13. The process according to claim 12, wherein the product of step (d) has the purity of the compound of formula IV of at least 90.0%.

14. The process according to claim 11, further comprising a step of isolating the salt of formula IV.sub.s.

15. The process according to claim 11, wherein the alkylating agent is ClCH.sub.2CN.

16. The process according to claim 11, wherein the base in step (b) is KOH.

17. The process according to claim 11, 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.

18. The process according to claim 17, wherein the base B is diethanolamine.

19. The process according to claim 11, wherein the acid in step (d) is HCl.

20. The process of claim 2, wherein the product of step (d) has the purity of compound of formula I of at least 95%.

21. The process of claim 12, wherein the product of step (d) has the purity of compound of formula I of at least 95%.

22. The process of claim 12, 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.

23. The process of claim 22, wherein the base B is diethanolamine.

24. A process for the preparation of a compound having formula IV, or pharmaceutically acceptable salt thereof ##STR00029## comprising (a) alkylating a compound of formula V with an alkylating agent to produce a compound of formula VI, ##STR00030## (b) hydrolyzing the product of formula VI of step (a) with a base, and (c) contacting the product of step (b) with a base B to form a salt of formula IV.sub.s ##STR00031## wherein the process does not comprise purifying the compound of formula (VI) produced in step (a).

25. The process according to claim 24, 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 and wherein the compound produced is a compound of the formula IV.sub.s, ##STR00032## wherein the base B is selected from a group consisting of ammonia, N-methylglucamine, procaine, tromethanine, magnesium, L-lysine, L-arginine, triethanolamine, and diethanolamine.

26. The process according to claim 25, wherein the base B is diethanolamine and wherein the compound produced is a compound of the following formula: ##STR00033##

27. The process according to claim 1, 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.

28. The process according to claim 11, 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.
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