1. Process for the preparation of (R)-(-)-2-hydroxy-2-(2-chlorophenyl)acetic acid of formula (I), (Formula Removed) characterized in that, the racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid is resolved by a compound of the generalformula (II) (Formula Removed) wherein a) R1 means a hydroxy-methyl group, R2 means a phenyl group and R3 means a hydroxyl- group; or b) R1 means a hydroxy-methyl group, R2 means a 4-nitrophenyl group and R3 means a hydroxyl group; or c) R1 means a carboxyl-group, R2 means a 3-amino-propyl group and R3 means a hydrogen atom using in case a) water-ethylacetate mixtures as solvent or using in case b) water- isopropylacetate-methanol mixtures as solvent, or using in case c) methanol as solvent for salt formation, the optical purity of the crude compound of the formula (I) obtained by resolution is increased by selective recrystallisation, the selective crystallisation is carried out in toluene, and compound of high optical purity of the formula (I) obtained by selective recrystallisation is separated from the solvent at a temperature between+40° and+100 °C.

2. Process as claimed in claim 1, wherein the salt of the racemic 2- hydroxy-2-(2-chlorophenyl)acetic acid and a compound of the general formula (II) - where the meaning of R1, R2 or R3 is as given above - is formed and the salt separated due to its different solubility from the pair of diastereomeric salts is obtained from the reaction mixture and the compound of the formula (I) is obtained from the salt or from the mother lye of the resolution.

3. Process as claimed in claim 1, wherein, the (S)-(+)-2-hydroxy-2-(2-chlorophenyl)acetic acid obtained by resolution is racemised and then it is returned to the resolution process.

4. Process as claimed in claim 3, wherein, the racemisation is carried out with a base preferably with sodium hydroxide, or potassium-hydroxyde.

5. Process as claimed in claim 3, wherein, the racemisation is carried out in water in the presence of a small quantity of aprotic solvent, for example in the presence of dimethyl sulfoxyde, sulfolane, dimethyl formamide, hexamethyl phosphoric acid triamide or N- methyl-pyrrolidone.

RESOLUTION PROCESS FOR (R)-(-)-2-HYDROXY-2-(2-CHLOROPHENYL)ACETIC ACID
The object of the present invention is a new resolution process of the racemic
2-hydroxy-2-(2-chloropheuyl)-acetic acid which makes possible the preparation of (R)-(-)-
2-hydroxy-2-(2-chlorophenyl)acetic acid of the formula (I).
The optically active compound of the formula (I) is one of the starting materials of the
known optically active trombocyta antiaggregant compound clopidogrel (Plavix®) (WO-
99/18110).
The racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid may be obtained by different
processes /Chem. Ber. 37 S. 3173 (1904), J. Am. Chem. Soc. 55 p 2593 (1933), Chem.
Ber. 92 S 1739 (1959)/. Several processes are known for the preparation of the optically
active compound of the formula (I) from the literature (Chirality 7 (8) p 652-76 (1995),
Bull. Soc. Chim. Fr. (1973) 12, Pt 2, 3330) but they have drawbacks from the industrial
point of view because they either use expensive resolution agents (alkaloids) or they
applied microbiological processes requiring large volumes and their productivity is low.
(EP-A-610048, EP-A-44964S, EP-A-527553). It was aimed to find a more advantageous
chemical process than the known ones which give a technically simpler and cheaper
process for the preparation of the compound of the formula (I).
Unexpectedly we found that the compounds of the general formula (II) form a poorly
soluble salt with only one enantiomer or racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid
and thus one of the enantiomers may be selectively removed from the reaction mixture of
the resolution process.
According to the invention the compound of the formula (I) is yielded from its solid
diastereomeric salt formed with a compound of the general formula (II) or it is yielded
from the mother liquor of the resolution process and optionally its optical purity is
increased by selective recrystallization.
The process according to the invention may be carried out preferably in an organic solvent
for example hi methanol or a mixture- of water and an organic solvent for example in a
water - ethylacetate or a water - methanol or an isopropyl acetate -methanol - water
mixture.
As a compound of the general formula (II) the (lS,2S)-(+)-l-phenyl-2-amino-1.3-propane-
diol, (lR.2r)-treo-(-)-l-(4-nitrophenyl)-2-amino-l,3-propane-diol or the L-(+)-lyzine are
applicable-the most preferably,./Aldrich Cat..No,. L-(+)-lizin:1697l-4 (2000-1);(11S,2S)-

(+)-1 -fenil-2-amino-1 ;3-propan-diol: 18654-6(2000-1): (1R, 2R)-treo-(-)-l-(4-nitrofenil)-
2-amino-l,3-propan-diol: A 7070-4 (2000-1)/.
The compounds of the general formula (II) are generally' used in an equimolar ratio
counted to the racemic acid.
The resolution process is carried out preferably between 10°C and 30°C. The optical purity
of the crude compound of the formula (I) thus obtained is 84-98%. The compound of the
formula (I) in almost 100% optical purity may be received by a recrystallization of the
crude compound of the formula (I) at 40-100°C using toluene or isopropyl-acetate as
solvent. The solvent is used between 1.5-10 volumetric units preferably 6-S volumetric
units counted on a mass unit of the compound to be recrystallized.
Another object of the present invention are salts of the compound of the formula (I) formed
with compounds of the general formula (II).
Efficiency of this invented process is increased by the decomposition of the
diastereometric .salt formed from (S)-(+)-2-hydroxy-2-(2-chlorophenyI)acetic acid and
from a compound of the general formula (I), the (S)-(+)-isomer is racemized and it is
resolved again according to the present invention.
The racemisation process is a further object of the present invention.
Thus the starting racemic compound can be transformed into the desired enantiomer almost
in full extent.
The racemisation can be carried out in the presence of a base, preferably aqueous sodium-
hydroxyde or potassium-hydroxyde may be used. The use of a small amount of aprotic
solvent in the aqueous medium accelarate the racemisation process. Preferred aprotic
solvents are dimethysulfoxide, sulfolane, dirnethylformamide, hexaniethylphosphotriamide
or the N-methyl-pyrroIidone. The racemisation is made preferably at the boiling point of
the reaction mixture in the presence of 0.1 - 0.5 volumetric units of aprotic solvent.
Further details of the present invention are shown in the following examples without
limiting our claims to their content.
Example 1
Resolution of racemic 2-hydroxy-2-(2-chlorophenyl)-acetic acid by (1S.2S)-(+)-1-phenvl-
2-amino-1.3-propane diol
(The compound of the general formula (II) - wherein R1 is a hydroxy-methyl group, R~ is a
phenyl group, RJ is a hydroxy group)

Racernic 2-hydrox}'-2-(2-cliIoroph.enyl)acetic acid (20.0 g 107 mmol) was dissolved in 60 cm3 of ethylacetate saturated with water and (lS.2S)-(+)-l-phenyl-2-amino-1.3-propane-diol (18.0 g 107.5 mmol) was added thereto and then the mixture was seed by a salt formed from (S)-(+)-2-hydroxy-2-(2-chlorophenyl)acetate and (lS,2S)-(+)-l-phenyl 2-amino-l,3-propane-diol at room temperature.
The mixture was stirred for 3 hours at room temperature, the precipitated substance was filtered off and it was washed with ethyl-acetate and it was dried: 30.7 g of white crystalline substance were received. This substance was dissolved in a mixture of 50 cm of water and 15 cm3 of 37% hydrochloric acid and it was extracted with methyl-tert.buryl-ether. The extract was dried on sodium-sulfate and the solvent was evaporated: 15,3 g of enantiomeric mixture rich in (S)-(+)-2-hydroxy-2-(2-clilorophenyl)acetic acid were obtained ([α]D20 = +38° (c = 4, methyl alcohol/, optical purity is 24%) which can be racemized according to Example 4 and recycled into the process.
The mother liquor obtained from the resolution was concentrated, dissolved in the mixture of 15 cm3 of water and 4.0 cm3 of 37% hydrochloric acid and it was extracted with methyl-tert.-butyl-ether. The combined extracts were dried on sodium sulfate and concentrated: 4.3
g of (R)-(-)-2-hydroxy-2-(2-chlorophenyl)acetic acid were obtained ([Α]D20 = -132.2° (c - 4, methyl-alcohol) with optical purity of 84.2%. This product was recrystallized from toluene, it was filtered at 60°C, washed with toluene. After drying 3.62 g (19.4 mmol 18.1%)'of R-(-)-2-hydroxy-2-(2-chlorophenyl)acetic acid were obtained ([α]D20 = -157°
(c = 4, methyl-alcohol).
Example 2
Resolution of racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid by (1R,2R)-(-)-treo-l-(4-
nitrophenyl)-2-ammo-1.3-propane-dial) (compound of the general formula (IT) wherein R1
is a hvdroxyrnethvl group. R2 is a p-nitrophenyl group. RJ is a hydroxy group)
Racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid (20.0 g 107 mmol) was dissolved in a
mixture of 120 g of isopropyl acetate. 16 cm3 of methanol and 2 cm3 of water.
22.8 g (107 mmol) of (lR.2R)-(-)-treo-l-(4-nitrophemd)-2-amino-1.3-propane-dioI were
added thereto during mild heating to help the dissolution. At room temperature the mixture
was seeded with salt of (lR?2R)-(-)-treo-l-(4-nitrophenyl)-2-amino-1.3-propane-diol
formed with R-(-)-2-hydroxy-2-(2-chlorophenyl)acetic acid. The reaction mixture was
stirred for 3 hours at room-temperature- and the precipitated substance was filtered .off....

washed and dried, 13.6 g of crystalline substance were obtained, which is the salt of the
above diol and the (R)-(-)-2-hydroxy-2-(2-chlorophenyl)acetic acid. •
This salt was dissolved in 20 cmj of water and the solution was acidified by 5.7 cmj of
concentrated hydrochloric acid and it was extracted with methyl-tert.-butylether, the
extracts were combined, dried, concentrated and 5.84 g (31.3 rnmoi) of crude (R)-(-)-2-
hydroxy-(2-chlorophenyl)acetic acid were obtained ([α]D20 = -151° (c = 4, methyl alcohol),
its optical purity is 96%.
This crude acid was recrystallized from 41 cm3 of toluene at 60°C and the product was
dried. The weight of (R)-(-)-2-hydroxy-2-(2-chlorophenyl)acetic acid is 5.6 g (30.0 rnmol).
Yield is 28%. ([α]D2° = -157° (c - 4, methyl alcohol).
The mother liquor of the resolution was concentrated, dissolved in 40 cm3 of water,
acidified with 12.3 cm3 of 37% hydrochloric acid and it was extracted with niethyl-tert-
butylether and the obtained substance rich in (S)-(+)-2-hydroxy-2-(2-chloropehyI)acetic
acid which is an enantiomeric mixture is 13.8 g (73.95 rnmol) ([α]D20 = +61° (c = 4,
methyl alcohol), optical purity is 39%. This substance is racemisable and its recyclation
into the process is possible.
Example 3
Resolution of racemic 2-hydi-oxv-2-(2-chlorophenyI')acetic acid with L-(+)-lyzine ('compound of the Reneral formula (II) - wherein R1 is a carboxyl group. R2 is a 3-amino-propyl group and R3 is a hydrogen atom)
15.64 g (107 mmol) of L-(+)-lyzine were dissolved in 60 cm3 of methanol and in an another 60 cm3 of memanol 20 g (107 mmol) of racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid were dissolved. These two solutions were combined and heated till the total dissolution to 40-45°C. The mixture was seeded with L-(+)-lyzine salt of (R)-(-)-2-hydroxy-2-(2-chlorophenyl)acetic acid at 40°C. The mixture was stirred at 40°C for two hours and at 30°C for two hours, then it was filtered and the precipitated substance was washed with methanol and dried thus 9.44 g of (R)-(-)-2-hydroxy-2-(2-chlorophenyl)acetic acid-(L)-(+)-lyzine salt were obtained. This obtained dry salt was dissolved in 10 cm3 of water and it was acidified with 5.4 cm3 of 37% hydrochloric acid and extracted with methyl-tert.-butyl-ether. The extract was dried on sodium sulfate and concentrated: 5.3 g of R-(-)-2-hydroxy-2-(2-chlorophenyl)acetic acid were obtained, ([α]D20 = -153.8° (c - 4, methyl alcohol )-, optical purity is 98.%) which was recrystallized witii-toluene,-(42 cm3) and it was filtered off at 60°C and covered with toluene.

5.2 g (27.86 mmol) of (K)-(-)-2-hydrox3'-2-(2-chloropiienyI)acetic acid were received, after drying. Yield: 26% [α]D20 = -157° (c = 4, methyl alcohol).
The mother liquor of the resolution was concentrated, dissolved in 40 crn3 of water, acidified with 13.2 cm3 of 37% hydrochloric acid and it was extracted with methyl-tert.-buryl ether. After evaporation 13.9 g (74.54 mmol) of enantiomeric mixture rich in (S)-(+)-2-hydroxy-2-(2-chlorophenyl)-acetic acid were obtained. ([α]D20 = +57° (c = 4, methyl alcohol) which was racemisable and recyclable into the process.
Example 4
Racemisation
13.5 g of enantiomeric mixture rich in (S)-(+-)-2-hydroxy-2-(2-chlorophenyl)-acetic acid
obtained in Example 3 were dissolved in 24 cm3 of water and it was alkalized with 11.56 g
(289 mmol) of sodium hydroxyde, 2.4 cm3 of dimethyl-sulfoxide were added and the
mixture was stirred for 5 hours at 100°C.
The received reaction mixture was diluted with 20 cm3 of water and acidified with 24.3
cm3 of 37% hydrochloric acid (289 mmol) and it was extracted with methyl-tert.-butyl
ether.
Extract was dried, clarified with 1.5 g of activated charcoal, filtered, concentrated and
recrystallized from 17.4 cm3 of toluene at 5°C, after filtering it was washed with toluene.
The substance obtained after drying was 12.8 g (68.6 mmol) of 2-hydroxy-2-(2-
chlorophenyl)acetic acid ([α]D20 = 0.0° (c = 4, methyl alcohol).
Figure 1 shows the compound of formula (I) and Figure 2 shows the compounds of the
general formula (II).

We claim:
1. Process for the preparation of (R)-(-)-2-hydroxy-2-(2-chlorophenyl)acetic acid of formula (I),
(Formula Removed)
characterized in that, the racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid is resolved by a compound of the generalformula (II)
(Formula Removed)
wherein
a) R1 means a hydroxy-methyl group, R2 means a phenyl group and R3 means a hydroxyl-
group; or
b) R1 means a hydroxy-methyl group, R2 means a 4-nitrophenyl group and R3 means a
hydroxyl group; or
c) R1 means a carboxyl-group, R2 means a 3-amino-propyl group and R3 means a hydrogen
atom using in case a) water-ethylacetate mixtures as solvent or using in case b) water-
isopropylacetate-methanol mixtures as solvent, or using in case c) methanol as solvent
for salt formation,
the optical purity of the crude compound of the formula (I) obtained by resolution is increased by selective recrystallisation,
the selective crystallisation is carried out in toluene, and
compound of high optical purity of the formula (I) obtained by selective recrystallisation is separated from the solvent at a temperature between+40° and+100 °C.
2. Process as claimed in claim 1, wherein the salt of the racemic 2- hydroxy-2-(2-chlorophenyl)acetic acid and a compound of the general formula (II) - where the meaning of R1, R2 or R3 is as given above - is formed and the salt separated due to its different solubility from the pair of diastereomeric salts is obtained from the reaction mixture and the compound of the formula (I) is obtained from the salt or from the mother lye of the resolution.
3. Process as claimed in claim 1, wherein, the (S)-(+)-2-hydroxy-2-(2-chlorophenyl)acetic
acid obtained by resolution is racemised and then it is returned to the resolution process.
4. Process as claimed in claim 3, wherein, the racemisation is carried out with a base
preferably with sodium hydroxide, or potassium-hydroxyde.
5. Process as claimed in claim 3, wherein, the racemisation is carried out in water in the
presence of a small quantity of aprotic solvent, for example in the presence of dimethyl
sulfoxyde, sulfolane, dimethyl formamide, hexamethyl phosphoric acid triamide or N-
methyl-pyrrolidone.