Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-07
2002-03-19
Aulakh, Charanjit S. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06359139
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to methods for more efficient production of d-threo piperidyl acetamide stereoisomers through racemization of l-threo-piperidyl acetamides by reacting the l-threo piperidyl acetamides with an alkanoic acid.
BACKGROUND OF THE INVENTION
Substituted piperidines have found use in the treatment of many nervous system disorders. For example, methylphenidate has been used to treat Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD) and cognitive decline in Acquired Immunodeficiency Syndrome (AIDS) and AIDS Related Complex (ARC) patients. (See, e.g., Greenhill,
Child
&
Adol. Psych. Clin. N.A
., 1995, 4, 123, and Brown,
Intl. J Psychl. Med
., 1995, 25, 21).
Many currently available synthetic routes to methylphenidate and other substituted piperidines involve preparation of racemic mixtures. (See, e.g., U.S. Pat. No. 2,507,631, to Harttnanm, et al., and U.S. Pat. No. 2,957,880, to Rometsch, et al.). There are, however, a number of disadvantages associated with racemic mixtures of such drugs. Current administration of racemic methylphenidate often results in notable side effects such as anorexia, weight loss, insomnia, dizziness and dysphoria. Additionally, racemic methylphenidate produces a euphoric effect when administered intravenously or through inhalation, and thus carries a high potential for substance abuse in patients.
U.S. Pat. Nos. 2,507,631 and 2,957,880 disclose synthetic procedures wherein methylphenidate, alternatively known as methyl &agr;-piperid-2-ylphenylacetate, is prepared through a multi-step process in which 2-chloropyridine and phenylacetonitrile initially are coupled to form &agr;-pyrid-2-ylphenylacetonitrile. The resulting &agr;-pyrid-2-ylphenylacetonitrile then is hydrated in the presence of acid to yield &agr;-pyrid-2-ylphenylacetamide which, in turn, is either: (a) catalytically hydrogenated to yield &agr;-piperid-2-ylphenylacetamide and then converted to methyl &agr;-piperid-2-ylphenylacetate, or (b) converted to methyl &agr;-pyrid-2-ylphenylacetate which, in turn, is hydrogenated to yield methyl &agr;-piperid-2-ylphenylacetate.
In the first embodiment of U.S. Pat. No. 2,507,631 and in the process described in U.S. Pat. No.2,957,880, &agr;-piperid-2-ylphenylacetamide is first separated into the threo and erythro diastereomeric racemates. This is accomplished through evaporation of the solvent utilized in the hydrogenation (i.e., acetic acid), addition of sodium hydroxide to precipitate the &agr;-piperid-2-ylphenylacetamide free base, recrystallization of this amide from ethyl acetate, and preferential crystallization of the erythro form by passing gaseous hydrogen chloride through an ethanolic solution of the amide.
The isolated erythro racemate then is resolved through formation of the l-tartrate salt, repeated recrystallizations of this salt from 96% ethanol are performed until a constant rotation is obtained, and the l-erythro form of a piperid-2-ylphenylacetamide is precipitated with sodium hydroxide. The l-erythro form of &agr;-piperid-2-ylphenylacetamide thus obtained is said to be subjected to epimerization to yield the desired d-threo diastereomer of &agr;-piperid-2-ylphenylacetamnide through treatment with 6 M potassium hydroxide. According to the disclosed procedure, the &agr;-piperid-2-ylphenylacetamide thus obtained is converted to d-threo methyl &agr;-piperid-2-ylphenylacetate through hydrolysis and esterification.
Some in the art have raised doubts as to whether the procedures disclosed in U.S. Pat. Nos. 2,507,631 and 2,957,880 do, in fact, produce the desired d-threo isomer. Indeed, J. R. Soares, “Stereochemical Studies On Potential Central Nervous System Active Agents and Studies On The Chemistry Of Some 3-Benzoylpiperidines,” 1971, Columbia University Ph.D. dissertation, p. 115, discloses that “all attempts to epimerize the resolved erythro-amides to the corresponding threo-amides by the procedure outlined in [U.S. Pat. No. 2,957,880] failed completely.”
In any event, the synthetic procedure described in U.S. Pat. Nos. 2,507,631 and ,957,880 is wasteful in that it involves discarding the threo &agr;-piperid-2-ylphenylacetamide acemate which is isolated following the recrystallization step and which typically represents approximately 25% of the acetamide product obtained via hydrogenation.
Consequently, there remains a need in the art for alternative synthetic procedures for the preparation of methylphenidate and other substituted piperidines. In particular, there is a need for synthetic procedures that do not require separating and discarding threo stereoisomers from the hydrogenation reaction product.
OBJECTS OF THE INVENTION
It is an object to provide methods of producing piperidyl acetamides that proceed more efficiently than the methods disclosed by the prior art.
SUMMARY OF THE INVENTION
These and other objects are satisfied by the present invention, which provides methods for preparing piperidyl acetamides. According to the methods of the present invention, both d-threo and l-threo piperidyl acetamide stereoisomers are utilized in the production of the substituted piperidines, resulting in more efficient and economical production.
In some embodiments, the methods of the invention comprise reacting l-threo piperidyl acetamide stereoisomers having formula IIa
(R
1
=aryl having about 6 to about 28 carbon atoms) with an alkanoic acid, such as acetic acid or propionic acid, for a time and under conditions effective to form a mixture of piperidyl acetamide stereoisomers having the following formulas:
In other embodiments, methods of the present invention comprise the steps of:
providing a mixture of d-threo and l-threo and d-erythro and l-erythro piperidyl acetamides having the following formulas:
wherein R
1
is aryl having about 6 to about 28 carbon atoms;
contacting said piperidyl acetamides with an organic base, thereby converting said erythro piperidyl acetamides to threo acetamides;
reacting said threo acetamides with an acid resolving agent in a first organic solvent, thereby precipitating d-threo piperidyl acetamide salts preferentially with respect to l-threo piperidyl acetamide salts;
isolating said l-threo piperidyl acetamide salts from said first organic solvent;
contacting said l-threo piperidyl acetamide salts with a reagent capable of forming the free base l-threo-piperdyl acetamide from said salts;
contacting said l-threo-piperidyl acetamide with an alkanoic acid in a second organic solvent for a time and under conditions effective to provide a mixture of piperidyl acetamide stereoisomers having the formulas:
REFERENCES:
patent: 2507631 (1950-05-01), Hartmann et al.
patent: 2957880 (1960-10-01), Rometsch
patent: 5965734 (1999-10-01), Ramaswamy et al.
Greenhill, L.L., “Attention-deficit hyperactivity disorder,”Child and Adolescent Psychiatric Clinics of North America, Pediatric Psychopharmacology I, Riddle, M.A. (Ed.), 1995, 4(1), 123-168.
Soares, J.R., “Sterochemical studies on potential central nervous system active agents and studies on the chemistry of some 3-bonzoylpiperidines,”UMI Dissertation Services, 1971, 1-180.
Ge Chuansheng
Khetani Vikram
Konnecke William
Aulakh Charanjit S.
Celgene Corporation
Woodcock & Washburn LLP
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