.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Claims for Patent: 8,497,393

« Back to Dashboard

Claims for Patent: 8,497,393

Title:Process to prepare treprostinil, the active ingredient in Remodulin.RTM.
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)
Application Number:13/548,446
Patent Claims: 1. A product comprising a compound of formula I ##STR00019## 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, ##STR00020## 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 (h) with a base B to form a salt of formula I.sub.s. ##STR00021## (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.sub.2).sub.wCN, Br(CH.sub.2).sub.wCN, or I(CH.sub.2).sub.wCN.

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.sub.2SO.sub.4.

7. The product of 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.

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 ##STR00022## 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, ##STR00023## (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.sub.s, and ##STR00024## (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.sub.2CN.

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).
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

How are People Using DrugPatentWatch?

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc