BACKGROUND OF THE INVENTION

Field of the Invention

[0001] This invention broadly relates to a method for synthesizing (S)-α-ethyl-

2-oxo- 1 -pyrrolidineamide (levetiracetam).

Description of Related Art

[0002] Levetiracetam (sold under the tradename Keppra®), possess antiepileptic activity and finds use in connection with the treatment of partial onset seizures in adults with epilepsy.

[0003] The racemic composition, α- ethyl-2-oxo-l -pyrrolidineamide was first described in G.B. 1,309,692 and in addition to epilepsy was thought to be useful for the treatment of motion sickness, hyperkinesias and hypertonia.

[0004] The optically pure levorotatory isomer is described in U.S. 4,696,943 as being useful for the treatment and prevention of hypoxia and ischemic type aggressions of the central nervous system, such as the treatment of (1) the consequences of cerebral vascular accidents and of cranial traumas, (2) the consequences of the ageing process, or (3) circulatory insufficiencies of the central nervous system resulting from cerebral-ischemic or hypoxic accidents occurring for example during birth. This patent also suggests that the compound may be used in the treatment of hypoxic-type diseases of other organs or tissues, such as the heart and the kidneys.

[0005] U.S. 4,696,943 suggests that the optically pure isomer (S)-alpha-ethyl-

2-oxo-l -pyrrolidineacetamide cannot be obtained directly from the racemic form by separating the two enantiomers and generally describes two methods for its preparation.

[0006] In one approach, an (S)-2-amino-butanamide of the general formula:

X-CH ₂ CH ₂ -Y-NHCH(C ₂ H ₅ )CONH ₂

is cyclized in an inert solvent, such as toluene or dichloromethane, in the presence of a basic catalyst, such as 2-hydroxypyridine when the compound is an ester (X is ZOOC — and Y is a methylene) or tetrabutylammonium bromide when the compound is a halide (X is HaICH ₂ - and Y is a carbonyl).

[0007] In the other approach, (S)-α-ethyl-2-oxo-l-pyrrolidineacetic acid

(hereinafter also referred to as levo acid) is reacted successively with (1) an alkyl haloformate of the formula HaICOOZ in which Hal represents a halogen atom and Z an alkyl radical having 1 to 4 carbon atoms and with (2) ammonia. According to U.S. 4,696,943 the alkyl haloformate is preferably ethyl chloroformate and the reaction is generally carried out in dichloromethane at a very low temperature between -10 and - 6O ⁰ C.

[0008] Since levetiracetam constitutes an important therapeutic agent, additional and improved ways of preparing it are of value to the pharmaceutical arts.

SUMMARY OF THE INVENTION

[0009] The present invention is directed to an improved method of producing

(S)-α-ethyl-2-oxo-l-pyrrolidineacetamide (also known as levetiracetam) from (S)-α- ethyl-2-oxo-l-pyrrolidineacetic acid (levo acid).

[0010] In particular, the present invention relates to a method in which (S)-α- ethyl-2-oxo-l-pyrrolidineacetic acid (levo acid) is contacted with di-tert-butyl dicarbonate, ammonium bicarbonate and pyridine in acetonitrile to yield levetiracetam.

[0011] In yet another aspect, the present invention pertains to a method for purifying a crude acetonitrile solution of levetiracetam in which the solution first is concentrated and mixed with ethyl acetate to cause formation of crude levetiracetam

solids. The slurry then is cooled; the levetiracetam solids are filtered, washed with cold ethyl acetate and then dried. The crude levetiracetam solids are dissolved in a hot aqueous acetone solution and then recrystallized, washed with cold acetone and dried to produce the pure levetiracetam product.

DETAILED DESCRIPTION OF THE INVENTION

[0012] According to the method of the present invention, levo acid is contacted with di-tert-butyl dicarbonate, ammonium bicarbonate and pyridine in an inert solvent, e.g., acetonitrile to yield levetiracetam. Acetone can also be used but it tends to reduce the rate of reaction. The reaction is preferably conducted at atmospheric pressure under an inert atmosphere, e.g., nitrogen, at a mild temperature in the range of 10-20 ⁰ C.

[0013] The levo acid ((S)-α-ethyl-2-oxo-l-pyrrolidineacetic acid) used in this reaction, can be obtained from the racemic α-ethyl-2-oxo-l-pyrrolidineacetic acid by chemical resolution in accordance with known methods, for example, by forming a salt of this acid with an optically active base and isolating the salt formed with the isomer, (S)-α-2-oxo-l-pyrrolidineacetic acid, by successive crystallizations in an appropriate solvent (for example benzene).

[0014] Optically active bases which can be used for this resolution include alkaloids such as brucine, quinine, strychnine, quinidine and cinchonidine and amines such as α-methylbenzylamine and dehydroabietylamine. (for example, please see S. H. WILEN et al., Tetrahedron, 33, (1977), pp. 2725-2736, which is incorporated herein by reference). It is known that an acceptable resolution is obtained by using α- methyl-benzylamine and dehydroabietylamine.

[0015] The racemic α-ethyl-2-oxo-l-pyrrolidineacetic acid used as the starting material for the resolution can be obtained by saponifying a corresponding alkyl ester, the synthesis of which has been described previously in the earlier mentioned G.B. Pat. 1,309,692 (also incorporated herein by reference).

[0016] Other ways of obtaining the levo acid also can be used and the present invention is not to be limited to any particular way for its preparation.

[0017] In the initial step of the present invention, the levo acid is slurried in an inert solvent, preferably acetonitrile under an inert atmosphere, e.g., nitrogen, at a mild temperature of about 10-15 ⁰ C to establish a concentration of about 10 to 20 g/ml. Then, the levo acid is treated with about a 5 to 20% molar excess of di-tert- butyl dicarbonate (DiBOC). The level of excess DiBOC is an economic consideration but does not affect the yield of quality of the product. As understood by those skilled in the art, water needs to be excluded from the equipment and reagents as DiBOC is very moisture sensitive.

[0018] Ammonium bicarbonate in about a 10 to 40% molar excess also is added with mixing to the levo acid slurry. After the addition of the ammonium bicarbonate is complete, pyridine in an amount of about 50 mole % of the ammonium bicarbonate is added and mixing is continued. The addition of the ammonium bicarbonate must precede the addition of the pyridine. Otherwise, uncontrolled gas generation will occur.

[0019] In order to maximize the formation of levetiracetam, it is important that the reaction temperature not exceed about 20 ⁰ C; higher temperatures contribute to racemization and formation of the undesired (R)-isomer.

[0020] As the reaction progresses, carbon dioxide gas is generated and the slurry is gradually transformed into a true solution. As understood by skilled workers, the extent of the conversion of the levo acid to levetiracetam can be monitored using HPLC.

[0021] Once the reaction is completed, the solution is heated to a temperature of about 25-30 ⁰ C and then the reaction mixture is filtered to remove un-dissolved solids. The solids can be washed with acetonitrile and the wash liquid collected and mixed with the filtrate from the initial filtration. The washed solids are discarded.

[0022] Relative to the process describe in U.S. 4,696,943, the process of the present invention provides for the conversion of levo acid to levetiracetam at a very mild temperature (about 10-20 ⁰ C) instead of the very low temperatures required by the prior art (-60 to -10 ⁰ C). The process of the present invention also avoids the use of hazardous reagents, such as ammonia, instead replacing ammonia with an easy to handle ammonium salt.

[0023] The combined filtrate and wash is then subjected to a vacuum distillation, with mild heating. It may be necessary to heat the solution to a temperature of about 25-40 ⁰ C during the distillation. With the vacuum distillation, the solution is concentrated, preferably to less than about 20% of its original volume. The distillate is discarded. As the solution becomes more concentrated, solids will begin to precipitate from the solution. Once one obtains about an 80% reduction in volume, ethyl acetate (EA) is added to the slurry.

[0024] After mixing the slurry with EA, a further vacuum distillation is conducted to concentrate the mixture again and remove as much solvent as possible. The distillate is again discarded. Once the mixture has been concentrated, for example to less than 20% of its original volume, the vacuum is released and the mixture is cooled, as necessary, to a temperature of less than about 30 ⁰ C.

[0025] An additional amount of ethyl acetate is added to the slurry and the mixture is heated to a temperature of about 70-80 ⁰ C to dissolve solids. Once the solids have dissolved, the solution is cooled to a temperature of about 30-45 ⁰ C and held at that temperature for 30 minutes to an hour. Over the next 30 minutes to an hour the mixture then is cooled further to a temperature of about 0-10 ⁰ C and then is again held at that temperature for an additional 30 minutes to an hour.

[0026] The slurry which results from the controlled cooling is filtered and the recovered solids are washed with cold ethyl acetate. The filtrate and wash liquids are both discarded. The recovered solids are dried under a vacuum (<20 in. Hg) for a time period of 8 to 12 hours and at a temperature of about 60-70 ⁰ C. These solids constitute a crude levetiracetam product.

[0027] To purify the recovered levetiracetam solids, the solids are mixed with sufficient water and acetone to produce a mixture containing about 18% solids by weight per liquid volume. The aqueous acetone solution preferably contains about 1% water (by volume). The initial slurry so-formed then is heated to a temperature of about 50-55 ⁰ C to dissolve the solids.

[0028] For best results both the amount of water in the acetone and the quantity of aqueous acetone used to prepare the initial solution are important. As the level of water in the acetone increases the ultimate yield of levetiracetam recovered suffers. At too low a level of water, the level of residual impurities in the product is not acceptable. An aqueous concentration of between 0.5 and 2.0 % by volume is preferred. Preferably, the aqueous acetone is used in an amount (volume) about 5 to 7 times the weight of the product. Lower amounts adversely impacts the purity of the product, while higher amounts are economically disadvantageous.

[0029] The aqueous acetone solution is passed though a filter provided with a filter aid, such as a diatomaceous earth (Celatom®) to remove any undissolved solids. The filter cake is washed with another portion of the 1% water/acetone solution and the wash liquid is combined with the original filtrate. The filter cake is discarded.

[0030] The combined filtrate and wash liquid is stirred for about 30 minutes at a temperature of about 35-45 ⁰ C and then over the next 30 minutes to an hour the solution is cooled to a temperature of about 0 to 10 ⁰ C. The mixture is held at a temperature of 0 to 10 ⁰ C for an additional 30 minutes to an hour and then filtered to recover the pure levetiracetam product solids. The solids are washed with acetone, which has been cooled to a temperature of about 0 to 10 ⁰ C, and then the solids are dried on the filter with vacuum and nitrogen. The solids are further dried at a temperature of 60 to 70 ⁰ C under a vacuum (<20 in. Hg) for 8 to 12 hours to yield the final purified levetiracetam product.

[00031] It will be understood that while the invention has been described in conjunction with specific embodiments thereof, the foregoing description and the following illustrative examples are intended to illustrate, but not limit the scope of the invention. Other aspects, advantages and modifications will be apparent to those

skilled in the art to which the invention pertains, and these aspects and modifications are within the scope of the invention, which is limited only by the appended claims.

EXAMPLE 1

Preparation of Crude Levetiracetam

[0032] 75 parts by weight (pbw) of (S)-α-ethyl-2-oxo-l-pyrrolidineacetic acid

(levo acid) is charged to a dry flask equipped with means for establishing a nitrogen atmosphere, with a mechanical stirrer and with a cooling bath. About 373 pbw of acetonitrile is added and the mixture is stirred at a temperature of 10 - 15 ⁰ C under a nitrogen atmosphere. A suspension is formed. About 105 pbw of DiBOC is added to the suspension and is stirred at a temperature of 10 - 15 ⁰ C. Thereafter, 42 pbw of ammonium bicarbonate is added to the mixture with further stirring at a temperature of 10 - 15 ⁰ C. Finally, about 21 pbw of pyridine is added to the mixture and the resulting mixture is stirred at a temperature of 10 - 20 ⁰ C. As the reaction progresses, CO ₂ gas is generated and the suspension gradually becomes a solution. The reaction temperature should be controlled such that it does not exceed 20 ⁰ C. Higher temperatures lead to undesired racemization.

EXAMPLE 2

Isolation of Crude Levetiracetam

[0033] The reaction mixture obtained in accordance with Example 1 is warmed to a temperature of 25 - 30 ⁰ C and is filtered to remove any undissolved solids. The recovered filter cake is washed with about 31 pbw of acetonitrile and the solids are discarded. The wash liquid is combined with the filtrate and transferred to a flask equipped for a vacuum distillation. The solution is concentrated to a volume of less than 20% of its original volume causing solids to form. It may be necessary to heat the contents of the flask to a temperature of 25 to 40 ⁰ C during the distillation to obtain the desired volume reduction. The distillate is discarded and about 54 pbw of ethyl acetate is added to the flask. The contents of the flask are stirred and then vacuum concentration is initiated again. The volume is once again reduced to less than 20% of its original volume, in an attempt to remove all of the solvent. Once the

distillation is completed, the vacuum is released and the residual mixture is cooled to a temperature less 30 ⁰ C. As before, the distillate is discarded. At this point, about 178 pbw of ethyl acetate is added to the flask and the contents of the flask are heated to a temperature of 70 - 80 ⁰ C to dissolve the solids. Once the solids have dissolved the solution is subjected to a controlled cooling. First, the mixture is cooled to a temperature of about 35 - 45 ⁰ C and held for about 30 to 60 minutes. Next, the reaction mixture is cooled further to a temperature of about 0 - 10 ⁰ C over a period of about 30 - 60 minutes and then is held at that temperature for about 30 - 60 minutes. The resulting slurry is filtered and the filtrate is discarded. The solids are washed further with about 107 pbw of cold ethyl acetate (0 - 10 ⁰ C) and the solids are dried at a temperature of about 60 - 70 ⁰ C under a vacuum (<20 in. Hg)) for 8-12 hours. The crude product is expected to contain about 65-68 pbw of crude levetiracetam.

EXAMPLE 3

Preparation of Pure Levetiracetam

[0034] Crude levetiracetam recovered according to Example 2 is transferred to a clean Erlenmeyer flask and 291 pbw of acetone and 3.7 pbw of water are added (1% aqueous acetone solution). The slurry is heated with mixing to a temperature of 50 - 55 ⁰ C to dissolve the solids. The warm solution is filtered through a filter aid, Celatom®, to remove undissolved solids and the filter cake is washed with about 31 pbw of a 1% aqueous acetone solution. The filtrate and the wash liquid are combined and stirred at a temperature of 35 - 45 ⁰ C for about 30 minutes. The solution then is subjected to a controlled cooling. First, the mixture is cooled to a temperature of about 0- 10 C over a period of about 30 - 60 minutes and then the mixture is held at that temperature with mixing for about 30 - 60 minutes. During this time, the pure levetiracetam should precipitate from the solution and the slurry is filtered to collect the pure levetiracetam solids. The filter cake is washed with about 50 pbw of cold (0 - 10 ⁰ C) acetone. The filtrate and wash liquid from both steps are discarded. The levetiracetam wet cake is dried at a temperature of 60 - 70 ⁰ C under a vacuum (<20 in. Hg) for 8 - 12 hours. The pure product is expected to contain about 52-55 pbw of levetiracetam.

[0035] The present invention has been described with reference to specific embodiments. However, this application is intended to cover those changes and substitutions that may be made by those skilled in the art without departing from the spirit and the scope of the invention. Unless otherwise specifically indicated, all percentages are by weight. Also, unless to context shows otherwise, the term "about" is intended to encompass + or - 5% throughout the specification.