(ΗYDROXYMETHYL)OCTAHYDRO-2H-PYRIDOf1.2-AlPYRAZINE

Background of the Invention

The present invention relates to a process for the preparation of (7S,trans)-2-(2- pyrimidinyl)-7-(hydroxymethyl)octahydro-2H-pyrido[1,2-a]pyra zine which is used to prepare pyrazine compounds, both of which are disclosed in European Patent

Application Publication Number 0380217 (A1 ), the pyrazine compounds being anxiolytic agents. The process involves resolution of trans-2-(2-pyrimidinyl)-7-

(hydroxymethyl)octahydro-2H-pyrido[1,2-a]pyrazine using D-(-) or L-(+)tartaric acid.

The present invention also relates to the tartrate salts that are formed as intermediates in the foregoing process.

Summary of the Invention The present invention relates to a process for separating trans-2-(2-pyrimidinyl)- 7-(hydroxymethyl) octahydro-2H-pyrido[1 ,2-a]pyrazine which is a racemic mixture of an enantiomer of the formula

and an enantiomer of the formula

by diastereomeric salt formation such that the optical purity of the separated diastereomer is at least about 98.5%, comprising:

(a) combining the racemic mixture with methanol to form a solution;

(b) adjusting the temperature of the solution to a temperature of from about 50 to about 70 °C;

(c) adding from about 0.5 to about 1.0 equivalents of D-(-) or L-(+)tartaric acid to the solution while maintaining the temperature of from about 50 to about 70 °C to form the tartrate salts of each of the enantiomers; and

(d) separating each of the resulting diastereomeric tartrate salts from the solution.

Detailed Description of the Invention In the process of the present invention trans-2-(2-pyrimidinyl)-7- (hydroxymethyl)octahydro-2H-pyrido[1 ,2-a]pyrazine is resolved using either L-(+) or D-(-)-tartaric acid. The pyrazine is reacted with the tartaric acid in an inert polar solvent. Suitable solvents include methanol, isopropanol, ethyl acetate and tetrahydrofuran. Methanol is the preferred solvent. One of the diastereomeric tartrate salts precipitates. When the L-(+) tartaric salt is formed the 7S enantiomer remains in solution and the salt of the 7R enantiomer precipitates. When the D-(-) tartaric salt is formed, the 7R enantiomer remains in solution and the salt of the 7S enantiomer precipitates. If the salt of the desired enantiomer remains in solution, it is recovered by evaporating the liquid.

In the preferred embodiment, in the process of the present invention trans-2-(2- pyrimidinyl)-7-(hydroxymethyl)octahydro-2H-pyrido[1 ,2-a]pyrazine is resolved using either L-(+) or D-(-)-tartaric acid, producing a salt with an optical purity of at least 98.5%, in order to result in an enantiomer with an optical purity of at least 99.7% and to commercially produce the final product. The optical purity can be evaluated using methods known in the art, such as the method disclosed in Enantiomers. Racemates and Resolutions J Jacques, et al., John Wiley & Sons, New York 1981. The pyrazine is combined with methanol and the temperature is adjusted to a temperature of from about 50 to about 70 °C, preferably from about 50 to about 60 °C, most preferably fron about 50 to about 55 °C. From about 0.5 to about 1.0 equivalents, preferably abc 0.75 equivalents, of D-(-) or L-(+)tartaric acid is added to the pyrazine and metha ^r solution, while maintaining the temperature, to form the tartrate salts of each of the enantiomers. Upon a cooling of the reaction mixture to ambient temperature (from about 20 to about 30°C), one of the diastereomeric tartrate salts precipitates, as

described in the previous paragraph. As previously stated, if the desired diastereomeric salt remains in solution, it is recovered by evaporating the liquid.

In order to convert the salt to the free base, the salt is dissolved in water and the pH is raised to between about 10 to about 14 preferably pH 12, using an inorganic base, and the base is extracted from the aqueous layer using an inert non-polar solvent, such as isopropyl ether, diethyl ether, 1 ,1 ,1-trichloroethane, or methylene chloride, preferably the latter, or is collected by filtration.

For use in alleviating the symptoms of anxiety in a human subject, the pyrazine compounds disclosed in European Patent Application Publication Number 0380217 (A1) are administered in an antianxiety amount of about 2 to about 200 mg/day, in single or divided daily doses. In particular cases, dosages outside that range are prescribed at the discretion of the attending physician. The preferred route of administration is generally oral, but parenteral administration (e.g., intramuscular, intravenous, intradermal) will be preferred in special cases, e.g. where oral absorption is impaired as by disease, or the patient is unable to swallow. These compounds are generally administered in the form of pharmaceutical compositions including a pharmaceutically acceptable vehicle or diluent. Such are generally formulated in a conventional manner utilizing solid or liquid vehicles or diluents as appropriate to the mode of desired administration: for oral administration, in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders and the like; and, for parenteral administration, in the form of injectable solutions or suspensions, and the like.

The present invention is illustrated by the following examples, but is not limited to the details thereof.

EXAMPLE 1 (7S.trans)-2-(2-Pyrimidinvπ-7-(hvdroxymethyl)octahvdro-2H-p yridoπ.2-alpyrazine

A. To a heated (60°C) solution of 50.0 g (0.201 mol) of trans-2-(2-Pyrimidinyl)-7- (hydroxymethyl)octahydro-2H-pyrido[1,2-a]pyrazine in 750 ml of methanol was added 30 g (0.201 mol) of D-(-)tartaric acid. The resulting suspension was allowed to cool to 30°C over a period of 5 hours. The solids were filtered, washed two times with 50ml of methanol and vacuum dried to provide 39.5 g (49.4%, 98.7% of theory) of the desired diastereomeric salt. m.p. 201-203°C [σ] _D = -44.2°(c = 0.186, MeOH).

The above mentioned salt (38.2 g) was slurried in refluxing methanol (395 ml) for 8 hours, cooled to 25°C and filtered. The solids were washed with 50 ml of

methanol and vacuum dried to yield 34.4 g (90%) of salt. m.p. 202-204°C. [σ] = -44.2°(c = 0.186, MeOH).

B. The above tartrate salt (36.0 g, 0.103 mol) was dissolved in 190 ml of water, adjusted to pH 12 with 2M NaOH and extracted twice with 300 ml of methylene chloride. The combined organic phases were dried over sodium sulfate, filtered, and evaporated to provide 24.3 g (95%) of the title compound as a light brown solid, pure by NMR. [σ] _D = -42.8° C=1.075, methanol. ¹³ C NMR (300 MHz, CDCI ₃ ): δ 161.2, 157.6, 109.7, 65.5, 60.9, 57.3, 54.8, 48.9, 43.4, 34.8, 26.1 , 25.8.

EXAMPLE 2 (7S. trans)-2-(2-pyrimidinyl.-7-i ^' hvdroxymethvnoctahvdro-2H-pyridon .2- alpyrazine

A. 5.5 g (0.022 mol) of trans-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahy- dro-2H-pyrido[1 ,2-a]pyrazine and 3.33 g (0.022 mol) of L-(+)tartaric acid were then added to 88 ml of methanol followed by stirring at room temperature for 19 hours. After filtration, the mother liquor was evaporated under vacuum to provide 4.33 g (49%, 98% of theory) of the (7S, trans)-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahydro-2H- pyrido[1 ,2-a]pyrazine L-tartrate salt.

B. In order to form the free base, the tartrate salt (3.0 g, 7.54 mmol) is dissolved in 150 ml of water taken to pH 12 with 2M NaOH and extracted twice with 100 ml of methylene chloride. The combined organic phases are then dried over sodium sulfate, filtered, and evaporated to provide the free base as a light brown solid, clean by NMR. To provide an optically pure free base, the free base is then slurried in a mixture of 20 ml of methylene chloride and 20 ml of hexanes of 15 minutes, filtered, washed with hexanes and dried under vacuum to provide the title compound. EXAMPLE 3

_■ 7S. trans)-2-(2-pyrimidinyl)-7-(hvdroxymethyl)octahydro-2H-pyrid olf1.2-alpyrazin trans-2-(2-Pyrimidinyl)-7-(hydroxymethyl)octahydro-2H-pyrido [1 ,2-a]pyrazine (10.0 g, 0.040 mol) was added to 150 ml of methanol at room temperature (20-25°C). The mixture was warmed to 50-55°C and D-(-)-tartaric acid (4.6 g, 0.030 mol) was added. The resulting suspension was stirred at 50-55°C for two hours then cooled to 25-30°C and granulated for one hour. The solids were filtered and washed with 30 ml of methanol, then dried in a vacuum oven at 35-40°C overnight. The desired salt (7.73

g, 48%) was obtained as a free-flowing off-white solid, m.p. 195.5-196.0°C. [σ] _D = -36.3°(c = 0.193, MeOH); The optical purity was 98.7% by chiral HPLC.

B. The tartrate salt (10.0 g) was dissolved in 77 ml of water and stirred for 30 minutes. The pH was adjusted to 11.6 with 50% NaOH. After stirring for 1 hour, the resulting slurry was filtered under vacuum and washed with 30 ml of water. It was dried in a vacuum oven overnight at 35-40°C to provide 5.21 g (83.6%) of the desired free base. [σ] _D = -50.2°(c = 0.103, MeOH);