PREPARATION DE (7S,TRANS)-2-(2-PYRIMIDINYL)-7-(HYDROXYMETHYL)OCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZINE

PREPARATION OF (7S,TRANS)-2-(2-PYRIMIDINYL)-7-(HYDROXYMETHYL)OCTAHYDRO-2H-PYRIDO[1,2-A]PYRAZINE

Abrégé français

Procédé de séparation des énantiomères d'un mélange racémique de trans-2-(2-pyrimidinyl)-7-(hydroxyméthyl)octahydro-2H-pyridol[1,2-a]pyrazine, qui consiste à effectuer la réaction du mélange racémique avec de l'acide tartarique D-(-) ou L-(+) et à séparer les sels diastéréomères de tartrate obtenus.

Abrégé anglais

A process for separating the enantiomers of a racemic mixture of trans-2-(2-
pyrimidinyl)-7-(hydroxymethyl)octahydro-2H-pyrido[1,2-a]pyrazine comprising
reacting the racemic mixture with D-(-) or L-(+) tartaric acid and separating
the resulting diastereomeric tartrate salts.

Revendications

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CLAIMS
1. A process for separating a racemic mixture of an enantiomer of the
formula
<IMG>
and an enantiomer of the formula
<IMG>
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.
2. The process of claim 1 wherein the temperature in steps (b) and (c) is
from about 50 to about 60 °C.
3. The process of claim 1 wherein the temperature in steps (b) and (c) is
from about 50 to about 55 °C.

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4. The process of claim 1 wherein the D-(-) or L-(+)tartaric acid added in
step (c) is about 0.75 equivalents of the D-(-) or L-(+)tartaric acid.
5. The process of claim 1 further including after said separating step
converting at least one of said tartrate salts to the free base thereof.
6. The process of claim 1 wherein said racemic mixture is reacted with
D-(-)tartaric acid.
7. The process of claim 6, wherein said separating step includes isolating
an insoluble tartrate salt from a soluble tartrate salt.
8. The process of claim 7, wherein said insoluble tartrate salt is a salt of
the enantiomer of formula I.
9. The process of claim 1, wherein said racemic mixture is reacted with
L-(+)tartaric acid.
10. The process of claim 8 wherein said separating step includes isolating
an insoluble tartrate salt from an soluble tartrate salt.
11. The process of claim 11 wherein said insoluble tartrate salt is a salt of
the enantiomer of formula II.
12. The process of claim 1 wherein said reacting step includes reacting the
racemic mixture with D-(-) tartaric acid to form a precipitate in a solution said
precipitate being the tartrate salt of the enantiomer of formula I;
said separating step includes separating the precipitate from the solution; and
further including converting the tartrate salt of the diastereomer of formula I to
the free base thereof.
13. The process of claim 1 wherein said reacting step includes reacting the
racemic mixture with L-(+)tartaric acid to form a precipitate in a solution the solution
including the tartrate salt includes separating the precipitate from the solution and
evaporating away the solution to leave the salt of the enantiomer of formula I: and
further including converting the tartrate salt of the enantiomer of formula I to the
free base thereof.

Description

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PREPARATION OF (7S.TRANS)-2-(2-PYRIMIDINYL)-7-
(HYDROXYMETHYL)OCTAHYDRO-2H-PYRIDO~1 ,2-AlPYRAZlNE
Backqround 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]pyrazine which is used to
prepare pyrazine compounds, both of which are disclosed in European Patent
App 1. c ~tion 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 pr~se"~ 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-py, ir".di. Iyl)-
7-(hydroxymethyl) octahydro-2H-pyrido[1 ,2-alpyrazine which is a racemic mixture of an
enantiomer of the formula
H0
1' 1
~",1
N~J
and an enantiomer of the formula
H~-_""",4
N
by diaster~omeric salt fo",.dtion such that the optical purity of the separated
diastereomer is at least about 98.5%, cG",p,ising:
(a) combining the racemic mixture with methanol to form a solution;
.. . . . . . . ... . .......

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(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
5 form the tartrate salts of each of the enar,tio",ers; and
(d) separating each of the resulting diastereomeric tartrate salts from the
solution.
Detailed Desc,iutio,) of the Invention
In the process of the present invention trans-2-(2-pyrimidinyl)-7-
10 (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 precirlt~tçs. When the L-(+) tartaric salt is formed the 7S enantiomer remains in
15 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
precipit~tes. 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-
20 py,i", ~iuyl)-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 ~lisclosed in Enantiomers~ Racemates
25 and Resolutions J Jacques, et al., John Wlley & 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 fro~
about 50 to about 55 ~C. ~rom about 0.5 to about 1.0 equivalents, preferably ab~0.75 equivalents, of D-(-) or L-(~)tartaric acid is added to the pyrazine and methar
30 solution, while maintaining the temperature, to form the tartrate salts of each of t~,c
enantiomers. Upon a cooling of the reaction mixture to ambient temperature (fromabout 20 to about 30~C), one of the diastereomeric tartrate salts prec~p'~tes, as

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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 betv:~en about 10 to about 14 prefer-d~ly pH 12, using an inorganic
base, and the base is extld.;t~d from the aqueous layer using an inert non-polarsolvent, such as isopropyl ether, diethyl ether, 1,1,1-trichloroethane, or methylene
chlonde, preferably the latter, or is collected by filtration.
For use in alleviating the sy",plo",s of anxiety in a human subject, the pyrazine
compoundsdisclosedinEuropeanpatentArFli~tiGnpublicationNumbero38o217(A1)
are administered in an anti~nxiety amount of about 2 to about 200 mg/day, in single or
divided daily doses. In particular cases, dosages outside that range are presc~ibed at
the discretion of the attending physician. The preFel,ed route of administration is
generally oral, but parenler~l 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 pharm2ceutic~1 compositions including a pharmaceutically
acceptable vehicle or diluent. Such are generally formulated in a conventional manner
utilizing solid or liquid vehicles or diluents as apprup,idte to the mode of desired
administration: for oral ad"l;"iO~,dtion, in the form of tablets, hard or soft gelatin
capsules, suspensions, granules, powders and the like; and, for parenteral
adminiatralion, in the fomm of in,sct~hle 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-Pvrimidinyl)-7-(hvdroxYmethvl)octahYdr~2H-Dvrido~1.2-ahYrazine
A. To a heated (60~C) solution of 50.0 9 (0.201 mol) of trans-2-(2-Py,i",idi,lyl)-7-
(hydroxymethyl)octahydro-2H-pyridol1,2-alpyrazine in 750 ml of ".etl,anol was added
30 9 (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 filteredt washed two times with 50ml
of methanol and vacuum dried to provide 39.5 9 (49.4%, 98.7% of theory) of the
desired diaslereo",elic salt. m.p. 201-203~C [O~D = J,4.2~(c = 0.186, MeOH).
The above mentioned salt (38.2 9) was slurried in refluxing methanol (395 ml)
for 8 hours, cooled to 25~C and filtered. The solids were washed with 50 ml of
_ ,, .

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methanol and vacuum dried to yield 34.4 9 (90%) of salt. m.p. 202-204~C. la~D =
44.2~(c = 0.186, MeOH).
B. The above tartrate salt (36.0 9, 0.103 mol) was di..solv0d in 190 ml of
water, adjusted to pH 12 with 2M NaOH and extracted twice with 300 ml of methylene
5 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. [a]D= -42.8~ C=1.075, methanol. 13C NMR (300 MHz, CDCI3): ~ 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-l2-Dvrimidinvl~-7-(hYdroxYmethYl)octahvdro-2H-~yrido~1~2
alpyrazine
A. 5.5 g (0.022 mol) of trans-2-(2-pyrimidinyl)-7-(hydroxymethyl)octahy-
dro-2H-pyrido~1,2-alpyrazine and 3.33 9 (0.022 mol) of L-(+)tartaric acid were then
added to 88 ml of methanol ~oll~vJ~d 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 bsse, the tartrate salt (3.0 9, 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 evapoldled 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-DvrimidinYI)-7-(hvdroxvmethvl)octahYdro-2H-Dyridol~1.2-a1~Yrazin
trans-2-(2-Pyrimidinyl)-7-(hydroxymethyl)octahydro-2H-pyrido[1 ,2-alpyrazine
(10.0 9, 0.04û 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 9, 0.030 mol) wasadded. 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 hltered and washed with 30 ml
of methanol, then dried in a vacuum oven at 3540~C ovemight. The desired salt (7.73

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9, 48%) was obtained as a free-flowing off-white solid. m.p. 195.5-196.0~C. [OjD =
-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,
5 the resulting slurry was flltered under vacuum and washed with 30 ml of water. It was
dried in a vacuum oven overnight at 3540~C to provide 5.219 (83.6%) of the desired
free base. [a]0 = -50.2~(c = 0.103, MeOH);