Low-temperature synthesis of methylphenidate hydrochloride

1. A method for the preparation of methylphenidate or a salt thereof, which comprises:

reacting:

(a) ritalinic acid or a salt thereof; and

(b) methanol;

(c) in the presence of an acid catalyst; and

(d) adding, after commencing said reacting, an orthoester of the formula R 2 C(OR 3 ) 3 , wherein

R 2 is hydrogen or alkyl; and

R 3 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, and aralkyl;

in a reaction mixture at a reaction temperature less than 45° C. to obtain a product mixture comprising methylphenidate or a salt thereof.

2. The method of claim 1 , wherein the salt of ritalinic acid is threo ritalinic acid hydrochloride.

3. The method of claim 1 , wherein the salt of methylphenidate is threo methylphenidate hydrochloride.

4. The method of claim 1 , wherein the acid catalyst is an organic acid or an inorganic acid.

5. The method of claim 1 , wherein the acid catalyst is selected from the group consisting of sulfuric acid (H 2 SO 4 ), phosphoric acid (H 3 PO 4 ), hydrogen chloride (HCl), and hydrogen bromide (HBr).

6. The method of claim 1 , wherein the acid catalyst is hydrogen chloride.

7. The method of claim 1 , wherein the reaction temperature is less than 43° C.

8. The method of claim 1 , wherein the ratio of ritalinic acid:methanol is about 1:10 to about 1:100 molar equivalents.

9. The method of claim 2 , wherein the ratio of ritalinic acid hydrochloride:methanol is about 1:9 to about 1:86 molar equivalents.

10. The method of claim 1 , wherein the ratio of ritalinic acid:acid catalyst is about 1:1.1 to about 1:9 molar equivalents.

11. The method of claim 2 , wherein the ratio of ritalinic acid hydrochloride:acid catalyst is about 1:0.1 to about 1:8 molar equivalents.

12. The method of claim 1 , wherein R 3 is methyl.

13. The method of claim 1 , wherein the orthoester is trimethyl orthoformate.

14. The method of claim 1 , wherein the orthoester is trimethyl orthoacetate.

15. The method of claim 1 , wherein said reacting occurs in the presence of a co-solvent.

16. The method of claim 15 , wherein the co-solvent is selected from the group consisting of acetates, ketones, ethers, aromatic solvents, and linear or branched C 4-20 alkanes.

17. The method of claim 15 , wherein the co-solvent is selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, diethyl ether, methyl t-butyl ether, dibutyl ether, cyclopentyl methyl ether, anisole, toluene, xylene, hexanes, heptanes, and mixtures thereof.

18. The method of claim 1 , wherein the orthoester is added after about 95% conversion of the ritalinic acid or salt thereof to the methylphenidate or the salt thereof.

19. The method of claim 1 , wherein the orthoester is added after 98% conversion of the ritalinic acid or salt thereof to the methylphenidate or the salt thereof.

20. The method of claim 1 , wherein the orthoester is added after 99% conversion of the ritalinic acid or salt thereof to the methylphenidate or the salt thereof.

21. The method of claim 1 , wherein the ratio of ritalinic acid:orthoester is from about 1:1.1 to about 1:10 molar equivalents.

22. The method of claim 1 , wherein the ratio of ritalinic acid hydrochloride:orthoester is from about 1:0.1 to about 1:9 molar equivalents.

23. The method of claim 1 , wherein the acid catalyst is HCl and wherein the ratio of HCl:orthoester is from about 1:0.8 to about 1:10 molar equivalents.

24. The method of claim 1 , wherein the acid catalyst is HCl and wherein the ratio of HCl:orthoester is from about 1:0.8 to about 1:2 molar equivalents.

25. The method of claim 1 , further comprising isolating said methylphenidate or salt thereof from the product mixture.

26. The method of claim 25 , wherein said isolating is carried out (i) by cooling the product mixture, (ii) by adding a solvent in which the methylphenidate or methylphenidate salt has reduced solubility to the product mixture, (iii) by removal of at least a portion of the methanol from the product mixture, (iv) by adding a crystallization seed to the product mixture, or (v) by a combination of any of (i) to (iv).

27. The method of claim 26 , wherein said isolating comprises adding a solvent in which the methylphenidate or salt thereof has reduced solubility to the product mixture so as to cause the methylphenidate or salt thereof to precipitate out of solution.

28. The method of claim 27 , wherein the solvent is selected from the group consisting of ethanol, isopropanol, n-propanol, isobutanol, n-butanol, t-amyl alcohol, cyclopentanol, acetates, ketones, ethers, aromatic solvents, and linear or branched C 4-20 alkanes.

29. The method of claim 27 , wherein said solvent is selected from the group consisting of ethanol, isopropanol, n-propanol, isobutanol, n-butanol, t-amyl alcohol, cyclopentanol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, diethyl ether, methyl-t-butyl ether, dibutyl ether, cyclopentyl methyl ether, anisole, toluene, xylene, hexanes, heptanes, and mixtures thereof.

30. The method of claim 27 , which further comprises:

removing at least a portion of the methanol from the product mixture simultaneous with adding said solvent.

31. The method of claim 27 , which further comprises:

removing at least a portion of the methanol from the product mixture prior to adding said solvent.

32. The method of claim 1 , wherein the reaction temperature is from about 35° C. to about 45° C., and the HCl concentration is from about 1.3 M to about 5 M.

33. The method of claim 6 , wherein the hydrogen chloride is generated in situ by the addition of thionyl chloride or acetyl chloride.