Methods for preparing D-threo methylphenidate using diazomethane, and compositions thereof
View Patent ↗Novel methods and systems for producing a substantially pure d-threo stereoisomer of methylphenidate or a salt thereof are provided. In particular, methods and systems for producing d-threo-methylphenidate hydrochloride in pure stereoisomeric form from d-threo-ritalinic acid hydrochloride using diazomethane are described. The described methods can be performed on a large scale, and thus provide d-threo methylphenidate or a salt thereof, and particularly the hydrochloride salt of d-threo-methylphenidate, in stereoisomerically pure form and in large quantities from a single batch reaction. Also described are novel compositions of d-threo methylphenidate hydrochloride.
1. A method for preparing substantially pure d-threo-methylphenidate hydrochloride, the method comprising:
(i) obtaining a first solution comprising an aqueous solution of an inorganic base and a water miscible solvent;
(ii) obtaining a second solution comprising an N-methyl-N-nitroso amine of formula (IV):
in a water immiscible organic solvent;
(iii) adding the second solution to the first solution, thereby generating diazomethane; and
(iv) reacting substantially pure d-threo-ritalinic acid hydrochloride with the diazomethane generated in step (iii) for at least about five hours to obtain the substantially pure d-threo-methylphenidate hydrochloride, wherein the reaction is performed at a temperature of about −20° C. to about 10° C.,
wherein R 2 represents a member selected from the group consisting of
R 3 represents a hydrogen atom, an alkyl group having one to four carbon atoms, or a nitro group;
and R 4 represents a hydrogen atom or an alkyl group having one to four carbon atoms; and
wherein a molar ratio of diazomethane to the substantially pure d-threo ritalinic acid hydrochloride is about 4 to 9.
2. The method according to claim 1 , wherein the inorganic base is an alkali metal hydroxide, and the water immiscible organic solvent is an ether.
3. The method according to claim 1 , wherein the reaction of substantially pure d-threo-ritalinic acid hydrochloride with diazomethane is performed in a reaction vessel comprising (a) a generator portion holding the first solution, and (b) a receiver portion holding the substantially pure d-threo-ritalinic acid hydrochloride, the method comprising:
(i) adding the second solution to the generator portion, with the generator portion being maintained at a temperature sufficient to vaporize the organic solvent and the diazomethane that is formed, thereby obtaining a vapor phase;
(ii) condensing the vapor phase in the receiver portion to obtain a reaction solution; and
(iii) recovering the substantially pure d-threo-methylphenidate hydrochloride from the reaction solution.
4. The method according to claim 1 , wherein the N-methyl-N-nitroso amine is selected from the group consisting of N-methyl-N-nitrosurea, N,N′-dimethyl-N-nitrosurea, N-methyl-N′-nitro-N-nitrosurea, N-methyl-N-nitrosoguanidine, N,N′-dimethyl-N-nitrosoguanidine, N-methyl-N′-nitrosoguanidine, N-methyl-N-nitrosocarbamic acid, N-methyl-N-nitrosocarbamate, methyl N-methyl-N-nitrosocarbamate, ethyl N-methyl-N-nitrosocarbamate, and N-methyl-N-nitroso-p-toluenesulfonamide.
5. The method according to claim 1 , wherein an N-methyl species of d-threo-methylphenidate is produced in an amount of about 8% or less based on peak area of a peak corresponding to the N-methyl species as determined by high performance liquid chromatography analysis relative to a total of 100% area based on peak area of peaks corresponding to the substantially pure d-threo-methylphenidate hydrochloride and the N-methyl species.
6. The method according to claim 5 , further comprising separating the N-methyl species from the substantially pure d-threo methylphenidate hydrochloride.
7. The method according to claim 1 , wherein the reaction of the substantially pure d-threo-ritalinic acid hydrochloride with diazomethane produces at least 200 grams of substantially pure d-threo-methylphenidate hydrochloride per batch reaction.