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1. WO1999003821 - PROCEDE

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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CLAIMS

1. A process for preparing Tilidine comprising: - mixing a substantially pure cis Tilidine base with either (a) water and an inorganic acid at pH values between 2 and 6, or (b) with a solvent and a base at pH values between 8 and 14; and

heating the reaction mixture thus formed to yield isomerised cis/trans Tilidine base with an enhanced content of the trans isomer.

2. A process as claimed in claim 1 comprising mixing a substantially pure cis Tilidine base with water and an inorganic acid at pH values between 2 and 6, and heating the reaction mixture thus formed to yield isomerised cis/trans

Tilidine base with an enhanced content of the trans isomer.

3. A process as claimed in claim 2, wherein the pH is from 3 to 6.

4. A process as claimed in any preceding claim wherein the acid is phosphoric acid.

5. A process as claimed in any of claims 1 to 4 wherein the acid is added in from 0.5 to 2.0 molar equivalents of the Tilidine base.

6. A process as claimed in claim 5 wherein the acid is added in from 0.9 to 1.1 molar equivalents of the Tilidine base.

7. A process as claimed in claim 5 or 6 wherein the acid is added in approximately equimolar equivalent to Tilidine base.

8. A process as claimed in any preceding claim wherein the reaction mixture is heated to a temperature of from 90°C to 100°C and kept at this temperature for a period of from 15 to 30 hours.

9. A process for preparing Tilidine comprising mixing cis/trans Tilidine base with water and phosphoric acid, and heating the reaction mixture thus formed to yield isomerised cis/trans Tilidine base with an enhanced content of the trans isomer.

10. A process as claimed in any preceding claim, wherein isomerised Tilidine base has a content of greater than 10% of the trans isomer.

11. A process as claimed in claim 10 wherein isomerised Tilidine base has a content of greater than 60% of the trans isomer.

12. A process as claimed in any preceding claim, wherein the acid comprises a mixture of phosphoric acid and salts thereof.

13. A process as claimed in any preceding claim, wherein after heating, the reaction mixture is cooled and the cis/trans Tilidine base is extracted by liquid-liquid extraction.

14. A process as claimed in claim 13, wherein a solvent such as petroleum ether is added to the solution, the pH is adjusted with a base to 12 - 14, the aqueous layer is separated and the organic layer is evaporated to give the isomerised cis/trans Tilidine base.

15. A process for preparing Tilidine as defined in claim 2 substantially as hereinbefore described with reference to the examples.

16. Tilidine whenever prepared by a process as claimed in any preceding claim.

17. A process for preparing Tilidine as claimed in claim 1 comprising mixing a substantially pure cis Tilidine base with a solvent and a base at pH values between 8 and 14, and heating the reaction mixture thus formed to yield isomerised cis/trans Tilidine base with an enhanced content of the trans isomer.

18. A process as claimed in claim 17, wherein the pH is from 9 to 10.

19. A process as claimed in claim 17 or 18, wherein the solvent is dusopropylethylamine .

20. A process as claimed in claim 19, wherein the reaction mixture is heated to a temperature of from 130°C to 140°C.

21. A process as claimed in claim 17 or 18, wherein the solvent is dimethylformamide.

22. A process as claimed in claim 21, wherein the reaction mixture is heated to a temperature of from 140°C to 150°C.

23. A process as claimed in any of claims 17 to 22, wherein the isomerised Tilidine base has a content of greater than 10% of the trans isomer.

24. A process as claimed in any of claims 17 to 23, wherein isomerised Tilidine base has a content of greater than 15% of the trans isomer.

25. A process as claimed in any of claims 17 to 24, wherein the solvent is added in a ratio of approximately 1:1 wt:wt equivalent of the Tilidine base.

26. A process for preparing Tilidine as defined in claim 17 substantially as hereinbefore described with reference to the Examples.

27. Tilidine whenever prepared by a process as claimed in any of claims 17 to 26.