Title of Invention	PROCESS FOR THE RESOLUTION OF HOMOCYSTEINE-γ-THIOLACTONE
Abstract	The present invention relates to a process for the preparation of enantiomerically pure homocysteine-γ-thiolactone comprising optical res- olution of racemic homocysteine-γ-thiolactone (I) with a chiral organic acid wherein one isomer is recovered as diastereomeric salt with the organic acid and the other isomer remaining in the mother liquor is submitted to racemisa- tion with a catalytic amount of an aromatic aldehyde and submitted again to optical resolution with the same chiral organic acid.

Title of Invention

PROCESS FOR THE RESOLUTION OF HOMOCYSTEINE-γ-THIOLACTONE

Abstract

The present invention relates to a process for the preparation of enantiomerically pure homocysteine-γ-thiolactone comprising optical res- olution of racemic homocysteine-γ-thiolactone (I) with a chiral organic acid wherein one isomer is recovered as diastereomeric salt with the organic acid and the other isomer remaining in the mother liquor is submitted to racemisa- tion with a catalytic amount of an aromatic aldehyde and submitted again to optical resolution with the same chiral organic acid.

Full Text	PROCESS FOR THE RESOLUTION OF HOMOCYSTEINE-?- THIOLACTONE FIELD OF THE INVENTION The present invention relates to the preparation of enantiomerically pure 2-amino-4-mercaptobutyric acid 1,4-thiolactone. DESCRIPTION 2-Amino-4-mercaptobutyric acid 1,4-thiolactone, commonly referred to as homocysteine-?-thiolactone (hereinafter indicated as HCT) I: contains a chiral carbon atom, denoted with a , and thus exists in the form of two distinct enantiomers, the R- and the S-enantiomer. The racemate is commercially available and is usually sold in the form of its hydrochloride salt. A first known method for the preparation of enantiomerically pure HCT comprises the demethylation of enantiomerically pure methionine, to obtain enantiomerically pure homocysteine and then closing the lactone ring, thus obtaining enantiomerically pure HCT. This method is costly and difficult to carry out on an industrial scale. Another method for the preparation of enantiomerically pure HCT is disclosed in JP 2001-199980 and JP 2000-351776, wherein racemic HCT is reacted with an enantiomerically pure acid to form two diastereomeric amides; the diastereoisomers are then separated and the amide is hydrolysed to obtain the desired enantiomer of HCT. Also this method presents many drawbacks, because the separation is performed in three steps and the cleavage of an amide is a difficult reaction. Moreover, it uses costly reagents and yields are low. There is therefore the need for an improved process for the resolution of HCT enantiomers. DESCRIPTION OF THE INVENTION It has now been found that enantiomerically pure homocysteine-?- thiolactone can be prepared through optical resolution of racemic homocysteine-?-thiolactone with a chiral organic acid wherein one isomer is recovered as a diastereomeric salt with the organic acid and the other isomer remaining in the mother liquor is submitted to racemisation with a catalytic amount of an aromatic aldehyde and submitted again to optical resolution with the same chiral organic acid. In greater detail, the invention comprises two main embodiments: a first one (referred to as method 1 in the examples), wherein the diastereomeric salt remaining in the mother liquor is first isolated and then racemised with a catalytic amount of an aromatic aldehyde so as to provide racemic homocysteine-?-thiolactone which is submitted again to optical resolution and a second, more advantageous one (referred to as method 2 in the examples), wherein optical resolution is carried out in the presence of a catalytic amount of an aromatic aldehyde, so that one out of the two diastereomeric salts precipitates and the other one remaining in the mother liquor racemises. In the following, the expression "mother liquor" denotes the solution wherefrom the less soluble diastereoisomer precipitates. In greater detail, the first embodiment comprises the following steps: a) preparing a solution of racemic HCT in a suitable solvent; b) adding the solution with an enantiomerically pure chiral organic acid; c) optionally heating the solution and then cooling it until complete precipitation of the less soluble diastereomeric salt; d) separating the precipitated diastereomeric salt from the solution and liberating enantiomerically pure HCT e) adding the solution from step d) with HCl until complete precipitation of HCT hydrochloride enriched in the enantiomer which remained in solution; f) recovering the precipitate and treating it with a carboxylic acid, preferably acetic acid, in the presence of an aromatic aldehyde so as to precipitate racemic HCT hydrochloride salt; g) isolating racemic HCT hydrochloride salt; h) dissolving the salt in the same organic solvent as step a) and adding a base so as to liberate racemic HCT; i) repeating steps b)-d) and optionally e) - h) one or more times. The solvent used for the preparation of the solution of racemic HCT of step a) is a solvent or a mixture of solvents selected from water, alcohols, such as methanol, ethanol, propanol, isopropanol, or another suitable organic solvent, for example acetone or tetrahydrofuran. Enantiomerically pure chiral organic acids suitable for carrying out step b) are, for example, dibenzoyltartaric acid, ditoluoyltartaric acid, mandelic acid, tartaric acid, camphorsulfonic acid, ascorbic acid, malic acid, pyrogluthammic acid, aspartic acid, chinic acid, the most preferred being ditoluoyltartaric acid and mandelic acid. When heating of the solution is necessary in order to precipitate the less soluble diastereomeric salt, the temperature varies according to the solvent and can be increased up to the reflux temperature. Enantiomerically pure HCT recovered from step d) is preferably converted into the hydrochloride salt by dissolution in acetone and addition of hydrogen chloride, until complete precipitation of HCT hydrochloride. The starting solution of HCT can be prepared by dissolving commercially available racemic HCT hydrochloride in one or more of the above-mentioned solvents and adding an organic or inorganic base, such as triethylamine or hydroxides of alkaline metals. The same base is also used for step h). As indicated above, preferred resolving agents are ditoluoyltartaric acid and mandelic acid, since they allow to obtain yields ranging from 70 to 80 percent based on the theoretical amount of the desired enantiomer. When using ditoluoyltartaric acid, the process is carried out by dissolving HCT hydrochloride in methanol and adding ditoluoyltartaric acid at room temperature. The resulting solution is added with a stoichiometric amount of triethylamine, so that triethylamine hydrochloride and the most soluble diastereomeric salt remain in the solution, while the less soluble diastereomeric salt precipitates. The precipitate is collected by filtration and further purified by treatment in acetone at room temperature. After filtration, HCT dibenzoyltartrate is suspended again in acetone and hydrochloric acid is added until complete precipitation of enantiomerically pure HCT hydrochloride. When using instead mandelic acid as the resolving agent, HCT hydrochloride is suspended in acetone and a stoichiometric amount of triethylamine is added. Triethylamine hydrochloride is filtered off and mandelic acid is added to the filtrate (which contains HCT as free base), until complete precipitation of the less soluble diastereomeric salt. The precipitate is collected by filtration, then suspended again in acetone and acidified with hydrochloric acid until precipitation of enantiomerically pure HCT hydrochloride. The aromatic aldehyde used in step f) is preferably selected from salicylaldehyde, m-hydroxy-benzaldehyde, p-hydroxy-benzaldehyde, o-anisaldehyde, m- anisaldehyde, p- anisaldehyde, salicylaldehyde being preferred; heating is required in order to accomplish racemisation. After 1-12 hours, depending on the temperature, the solution is cooled until complete precipitation of racemic HCT hydrochloride, which is collected by filtration and washed with acetone, then submitted again to the resolution process. This first embodiment can be represented as in the following Scheme 1: in which B denotes a base and AH denotes a chiral acid (resolving agent). The second embodiment of the invention comprises the following steps: a) preparing a solution of racemic HCT in a suitable solvent; b) adding the solution with an enantiomerically pure chiral organic acid and a catalytic amount of an aromatic aldehyde; c) heating the solution and then cooling it until precipitation of the less soluble diastereomeric salt of HCT with the chiral organic acid is complete; d) separating the precipitated diastereomeric salt from the solution and liberating enantiomerically pure 2-amino-4-mercaptobenzobutyric acid e) optionally adding HC1 to the solution from step d) and recovering racemic HCT hydrochloride to be submitted to a further resolution cycle. The starting solution can be prepared in the same way and with the same solvents as the first embodiment and steps c) - d) are also carried out as described above. This second embodiment has the remarkable advantage that the most soluble diastereomeric salt continuously racemise in the solution, while the less soluble one precipitates subtracting from the racemisation reaction, which is an equilibrium. Thus, at any point of the process only the racemate is present in the solution. The process continues until an equilibrium is reached between the solubility of the precipitated salt (regulated by its Ksp) and the kinetics of the racemisation reaction (regulated by its kinetic constant). Enantiomerically pure HCT is preferably isolated in the form of the hydrochloride salt by suspension in acetone and treatment with HC1. This embodiment allows to obtain yields of enantiomerically pure HCT hydrochloride higher than the theoretical amount, usually not lower than 140%, calculated on the amount of the desired enantiomer in the racemate. This is possible because the undesired enantiomer is converted in situ into the desired one. After acidification and filtration, racemic HCT hydrochloride can be recovered from the mother liquor and can be submitted to a further resolution cycle, thus increasing yields further. This second preferred embodiment can be represented as in the following scheme 2, wherein the aromatic aldehyde is salicylaldehyde: The invention will be now illustrated in greater detail by means of the following examples. EXAMPLES Example 1 - Resolution (method 1) R,S-HCT hydrochloride (154 g) and acetone (2500 mL) are charged into a reactor, added with triethylamine (139 mL) and stirred for an hour. Triethylamine hydrochloride is filtered off and the light yellow filtrate is charged again into the reactor with L-(+)-mandelic acid (114 g). A solid soon begins to precipitate; the suspension is cooled to 10°C for one hour and then filtered. S-HCT mandelate (118 g dry weight) is obtained, while the mother liquors are saved for the racemisation process. S-HCT mandelate is charged into the reactor with acetone (1500 mL) and hydrochloric acid 37% (44 mL) is added to the stirred suspension. Stirring is maintained for one hour at 15°C and the solid is filtered and washed with acetone. S-HCT hydrochloride is obtained (60.5 g dry weight, 78.5% yield), with an [a]D =+21.9°. Example 2 - Resolution (method 1) R,S-HCT hydrochloride (154 g), methanol (3000 mL) and (-)-ditoluoyl-L- tartaric acid (145 g) are charged into a reactor and the mixture is stirred until complete dissolution, then triethylamine (139 mL) is added dropwise at 20°C. Stirring is maintained at the same temperature for one hour, then the precipitated solid is filtered and washed with methanol; the mother liquors are saved for the racemisation process. The precipitate is instead charged again into the reactor with acetone (1500 mL) and stirred for one hour at room temperature, then filtered, obtaining L-HCT ditoluoyltartrate (120 g dry weight). S-HCT ditoluoyltartrate is suspended again in acetone (1500 mL) and 37% hydrochloric acid (40 mL) is added to the stirred suspension. Stirring is maintained for one hour at 15°C and the resulting product is filtered and washed with acetone, obtaining 55.5 g of L-HCT hydrochloride (dry weight, 72% yield), with an [a]D = +22.1°. Example 3 - Racemisation (method 1) The mother liquors from Example 1 are acidified to pH 1 with 37% hydrochloric acid and then concentrated to dryness under vacuum. The residue is dissolved in acetic acid (150 mL), added with salicylaldehyde (2 mL) and the solution is heated to 50°C for 5 hours, then cooled to 5°C for 2 hours. The resulting solid is filtered and washed thoroughly with acetone, obtaining racemic R,S-HCT hydrochloride (65.5 g dry weight). Example 4 - Resolution (method 2) R,S-HCT hydrochloride (250 g) is suspended in acetone (1250 mL) into a reactor and added with triethylamine (226.5 mL) under stirring. Stirring is continued for at least one hour, then triethylamine hydrochloride is filtered off and the light yellow filtrate is charged again into the reactor with L-(+)-mandelic acid (250 g) and salicylaldehyde (25 g). The solution turns persistent yellow, indicating imine formation, then a solid begins to precipitate. The suspension is stirred at room temperature for 5 hours, then the solid is collected by filtration and washed with acetone; the mother liquors are saved for the recovery of racemic HCT. The wet solid is suspended again in acetone (2500 mL) and added under stirring with 37% hydrochloric acid (109 mL). Stirring is maintained for one hour at 5°C and the solid is filtered and washed with acetone, obtaining 175 g of S-HCT hydrochloride (dry weight, 140% yield based on the desired enantiomer), with an [a]D = +22.5°. Example 5 - Recovery of starting material (Method 2) The mother liquors from Example 4 are acidified to pH 1 with hydrochloric acid and cooled to 5°C for 4 hours. The solid is collected by filtration and dried under vacuum, yielding 25 g of racemic R,S-HCT hydrochloride. CLAIMS 1. A process for the preparation of enantiomerically pure homocysteine-?- thiolactone comprising optical resolution of racemic homocysteine-?- thiolactone (HCT) with a chiral organic acid wherein one isomer is recovered as diastereomeric salt with the organic acid and the other isomer remaining in the mother liquor is submitted to racemisation with a catalytic amount of an aromatic aldehyde and submitted again to optical resolution with the same chiral organic acid. 2. A process a according to claim 1 wherein the diastereomeric salt remaining in the mother liquor is first isolated and then racemised with a catalytic amount of the aromatic aldehyde so as to provide racemic homocysteine-?-thiolactone which is submitted again to optical resolution. 3. A process according to claim 2 which comprises the following steps: a) preparing a solution of racemic HCT in a suitable solvent; b) adding the solution with an enantiomerically pure chiral organic acid; c) optionally heating the solution and then cooling it until complete precipitation of the less soluble diastereomeric salt; d) separating the precipitated diastereomeric salt from the solution and liberating enantiomerically pure HCT e) adding the solution from step d) with HC1 until complete precipitation HCT hydrochloride salt enriched in the enantiomer which remained in the solution; f) recovering the precipitate and treating it with acetic acid in the presence of an aromatic aldehyde so as to precipitate racemic HCT hydrochloride salt; g) isolating racemic HCT hydrochloride salt; h) dissolving the salt in the same organic solvent as step a) and adding a base so as to liberate racemic HCT; i) repeating steps b)-d) and optionally e) - h) one or more times. 4. A process according to claim 1 wherein optical resolution is carried out in the presence of a catalytic amount of an aromatic aldehyde, so that one out of the two diastereomeric salts precipitates and the other one remaining in the solution racemises. 5. A process according to claim 4 which comprises the following steps: a) preparing a solution of racemic HCT in a suitable solvent; b) adding the solution with an enantiomerically pure chiral organic acid and a catalytic amount of an aromatic aldehyde; c) heating the solution and then cooling it until complete precipitation of the less soluble diastereomeric salt of HCT with the chiral organic acid; d) separating the precipitated diastereomeric salt from the solution and liberating enantiomerically pure 2-amino-4-mercaptobenzobutyric acid e) optionally adding HCl to the solution from step d) and recovering racemic HCT. 6. A process according to any one of claims 1 to 5 wherein the enantiomerically pure organic acid is selected from dibenzoyltartaric acid, ditoluoyltartaric acid, mandelic acid, tartaric acid, camphorsulfonic acid, ascorbic acid, malic acid, pyrogluthammic acid, aspartic acid, chinic acid, the most preferred being ditoluoyltartaric acid and mandelic acid. 7. A process according to claim 6 wherein the enantiomerically pure organic acid is ditoluoyltartaric acid or mandelic acid. 8. A process according to any one of claims 1 to 7 wherein the aromatic aldehyde is selected from salicylaldehyde, m-hydroxy-benzaldehyde, p- hydroxy-benzaldehyde, o-anisaldehyde, m- anisaldehyde, p- anisaldehyde. 9. A process according to claim 8 wherein the aromatic aldehyde is salicylaldehyde. The present invention relates to a process for the preparation of enantiomerically pure homocysteine-γ-thiolactone comprising optical res- olution of racemic homocysteine-γ-thiolactone (I) with a chiral organic acid wherein one isomer is recovered as diastereomeric salt with the organic acid and the other isomer remaining in the mother liquor is submitted to racemisa- tion with a catalytic amount of an aromatic aldehyde and submitted again to optical resolution with the same chiral organic acid.

Full Text

PROCESS FOR THE RESOLUTION OF HOMOCYSTEINE-?-
THIOLACTONE
FIELD OF THE INVENTION
The present invention relates to the preparation of enantiomerically
pure 2-amino-4-mercaptobutyric acid 1,4-thiolactone.
DESCRIPTION
2-Amino-4-mercaptobutyric acid 1,4-thiolactone, commonly referred to
as homocysteine-?-thiolactone (hereinafter indicated as HCT) I:

contains a chiral carbon atom, denoted with a *, and thus exists in the
form of two distinct enantiomers, the R- and the S-enantiomer. The racemate
is commercially available and is usually sold in the form of its hydrochloride
salt.
A first known method for the preparation of enantiomerically pure HCT
comprises the demethylation of enantiomerically pure methionine, to obtain
enantiomerically pure homocysteine and then closing the lactone ring, thus
obtaining enantiomerically pure HCT. This method is costly and difficult to
carry out on an industrial scale.
Another method for the preparation of enantiomerically pure HCT is
disclosed in JP 2001-199980 and JP 2000-351776, wherein racemic HCT is
reacted with an enantiomerically pure acid to form two diastereomeric amides;
the diastereoisomers are then separated and the amide is hydrolysed to obtain
the desired enantiomer of HCT. Also this method presents many drawbacks,
because the separation is performed in three steps and the cleavage of an
amide is a difficult reaction. Moreover, it uses costly reagents and yields are
low.
There is therefore the need for an improved process for the resolution of
HCT enantiomers.
DESCRIPTION OF THE INVENTION
It has now been found that enantiomerically pure homocysteine-?-
thiolactone can be prepared through optical resolution of racemic
homocysteine-?-thiolactone

with a chiral organic acid wherein one isomer is recovered as a
diastereomeric salt with the organic acid and the other isomer remaining in the
mother liquor is submitted to racemisation with a catalytic amount of an
aromatic aldehyde and submitted again to optical resolution with the same
chiral organic acid.
In greater detail, the invention comprises two main embodiments: a first
one (referred to as method 1 in the examples), wherein the diastereomeric salt
remaining in the mother liquor is first isolated and then racemised with a
catalytic amount of an aromatic aldehyde so as to provide racemic
homocysteine-?-thiolactone which is submitted again to optical resolution and
a second, more advantageous one (referred to as method 2 in the examples),
wherein optical resolution is carried out in the presence of a catalytic amount
of an aromatic aldehyde, so that one out of the two diastereomeric salts
precipitates and the other one remaining in the mother liquor racemises. In the
following, the expression "mother liquor" denotes the solution wherefrom the
less soluble diastereoisomer precipitates.
In greater detail, the first embodiment comprises the following steps:
a) preparing a solution of racemic HCT in a suitable solvent;
b) adding the solution with an enantiomerically pure chiral organic
acid;
c) optionally heating the solution and then cooling it until complete
precipitation of the less soluble diastereomeric salt;
d) separating the precipitated diastereomeric salt from the solution
and liberating enantiomerically pure HCT

e) adding the solution from step d) with HCl until complete
precipitation of HCT hydrochloride enriched in the enantiomer which remained in
solution;
f) recovering the precipitate and treating it with a carboxylic acid,
preferably acetic acid, in the presence of an aromatic aldehyde so as to precipitate
racemic HCT hydrochloride salt;
g) isolating racemic HCT hydrochloride salt;
h) dissolving the salt in the same organic solvent as step a) and adding a
base so as to liberate racemic HCT;
i) repeating steps b)-d) and optionally e) - h) one or more times.
The solvent used for the preparation of the solution of racemic HCT of
step a) is a solvent or a mixture of solvents selected from water, alcohols, such
as methanol, ethanol, propanol, isopropanol, or another suitable organic
solvent, for example acetone or tetrahydrofuran. Enantiomerically pure chiral
organic acids suitable for carrying out step b) are, for example,
dibenzoyltartaric acid, ditoluoyltartaric acid, mandelic acid, tartaric acid,
camphorsulfonic acid, ascorbic acid, malic acid, pyrogluthammic acid,
aspartic acid, chinic acid, the most preferred being ditoluoyltartaric acid and
mandelic acid. When heating of the solution is necessary in order to
precipitate the less soluble diastereomeric salt, the temperature varies
according to the solvent and can be increased up to the reflux temperature.
Enantiomerically pure HCT recovered from step d) is preferably converted
into the hydrochloride salt by dissolution in acetone and addition of hydrogen
chloride, until complete precipitation of HCT hydrochloride.
The starting solution of HCT can be prepared by dissolving
commercially available racemic HCT hydrochloride in one or more of the
above-mentioned solvents and adding an organic or inorganic base, such as
triethylamine or hydroxides of alkaline metals. The same base is also used for
step h).
As indicated above, preferred resolving agents are ditoluoyltartaric acid
and mandelic acid, since they allow to obtain yields ranging from 70 to 80
percent based on the theoretical amount of the desired enantiomer.
When using ditoluoyltartaric acid, the process is carried out by
dissolving HCT hydrochloride in methanol and adding ditoluoyltartaric acid at
room temperature. The resulting solution is added with a stoichiometric
amount of triethylamine, so that triethylamine hydrochloride and the most
soluble diastereomeric salt remain in the solution, while the less soluble
diastereomeric salt precipitates. The precipitate is collected by filtration and
further purified by treatment in acetone at room temperature. After filtration,
HCT dibenzoyltartrate is suspended again in acetone and hydrochloric acid is
added until complete precipitation of enantiomerically pure HCT
hydrochloride.
When using instead mandelic acid as the resolving agent, HCT
hydrochloride is suspended in acetone and a stoichiometric amount of
triethylamine is added. Triethylamine hydrochloride is filtered off and
mandelic acid is added to the filtrate (which contains HCT as free base), until
complete precipitation of the less soluble diastereomeric salt. The precipitate
is collected by filtration, then suspended again in acetone and acidified with
hydrochloric acid until precipitation of enantiomerically pure HCT
hydrochloride.
The aromatic aldehyde used in step f) is preferably selected from
salicylaldehyde, m-hydroxy-benzaldehyde, p-hydroxy-benzaldehyde,
o-anisaldehyde, m- anisaldehyde, p- anisaldehyde, salicylaldehyde being
preferred; heating is required in order to accomplish racemisation. After 1-12
hours, depending on the temperature, the solution is cooled until complete
precipitation of racemic HCT hydrochloride, which is collected by filtration
and washed with acetone, then submitted again to the resolution process.
This first embodiment can be represented as in the following Scheme 1:

in which B denotes a base and *AH denotes a chiral acid (resolving
agent).
The second embodiment of the invention comprises the following steps:
a) preparing a solution of racemic HCT in a suitable solvent;
b) adding the solution with an enantiomerically pure chiral organic
acid and a catalytic amount of an aromatic aldehyde;
c) heating the solution and then cooling it until precipitation of the
less soluble diastereomeric salt of HCT with the chiral organic acid is
complete;
d) separating the precipitated diastereomeric salt from the solution
and liberating enantiomerically pure 2-amino-4-mercaptobenzobutyric acid

e) optionally adding HC1 to the solution from step d) and recovering
racemic HCT hydrochloride to be submitted to a further resolution cycle.
The starting solution can be prepared in the same way and with the
same solvents as the first embodiment and steps c) - d) are also carried out as
described above.
This second embodiment has the remarkable advantage that the most
soluble diastereomeric salt continuously racemise in the solution, while the
less soluble one precipitates subtracting from the racemisation reaction, which
is an equilibrium. Thus, at any point of the process only the racemate is
present in the solution. The process continues until an equilibrium is reached
between the solubility of the precipitated salt (regulated by its Ksp) and the
kinetics of the racemisation reaction (regulated by its kinetic constant).
Enantiomerically pure HCT is preferably isolated in the form of the
hydrochloride salt by suspension in acetone and treatment with HC1.
This embodiment allows to obtain yields of enantiomerically pure HCT
hydrochloride higher than the theoretical amount, usually not lower than
140%, calculated on the amount of the desired enantiomer in the racemate.
This is possible because the undesired enantiomer is converted in situ into the
desired one.
After acidification and filtration, racemic HCT hydrochloride can be
recovered from the mother liquor and can be submitted to a further resolution
cycle, thus increasing yields further.
This second preferred embodiment can be represented as in the
following scheme 2, wherein the aromatic aldehyde is salicylaldehyde:

The invention will be now illustrated in greater detail by means of the
following examples.
EXAMPLES
Example 1 - Resolution (method 1)
R,S-HCT hydrochloride (154 g) and acetone (2500 mL) are charged
into a reactor, added with triethylamine (139 mL) and stirred for an hour.
Triethylamine hydrochloride is filtered off and the light yellow filtrate is
charged again into the reactor with L-(+)-mandelic acid (114 g). A solid soon
begins to precipitate; the suspension is cooled to 10°C for one hour and then
filtered. S-HCT mandelate (118 g dry weight) is obtained, while the mother
liquors are saved for the racemisation process.
S-HCT mandelate is charged into the reactor with acetone (1500 mL)
and hydrochloric acid 37% (44 mL) is added to the stirred suspension. Stirring
is maintained for one hour at 15°C and the solid is filtered and washed with
acetone. S-HCT hydrochloride is obtained (60.5 g dry weight, 78.5% yield),
with an [a]D =+21.9°.
Example 2 - Resolution (method 1)
R,S-HCT hydrochloride (154 g), methanol (3000 mL) and (-)-ditoluoyl-L-
tartaric acid (145 g) are charged into a reactor and the mixture is stirred until
complete dissolution, then triethylamine (139 mL) is added dropwise at 20°C.
Stirring is maintained at the same temperature for one hour, then the precipitated
solid is filtered and washed with methanol; the mother liquors are saved for the
racemisation process. The precipitate is instead charged again into the reactor
with acetone (1500 mL) and stirred for one hour at room temperature, then
filtered, obtaining L-HCT ditoluoyltartrate (120 g dry weight).
S-HCT ditoluoyltartrate is suspended again in acetone (1500 mL) and
37% hydrochloric acid (40 mL) is added to the stirred suspension. Stirring is
maintained for one hour at 15°C and the resulting product is filtered and
washed with acetone, obtaining 55.5 g of L-HCT hydrochloride (dry weight,
72% yield), with an [a]D = +22.1°.
Example 3 - Racemisation (method 1)
The mother liquors from Example 1 are acidified to pH 1 with 37%
hydrochloric acid and then concentrated to dryness under vacuum. The residue
is dissolved in acetic acid (150 mL), added with salicylaldehyde (2 mL) and
the solution is heated to 50°C for 5 hours, then cooled to 5°C for 2 hours. The
resulting solid is filtered and washed thoroughly with acetone, obtaining
racemic R,S-HCT hydrochloride (65.5 g dry weight).
Example 4 - Resolution (method 2)
R,S-HCT hydrochloride (250 g) is suspended in acetone (1250 mL) into
a reactor and added with triethylamine (226.5 mL) under stirring. Stirring is
continued for at least one hour, then triethylamine hydrochloride is filtered off
and the light yellow filtrate is charged again into the reactor with
L-(+)-mandelic acid (250 g) and salicylaldehyde (25 g). The solution turns
persistent yellow, indicating imine formation, then a solid begins to
precipitate. The suspension is stirred at room temperature for 5 hours, then the
solid is collected by filtration and washed with acetone; the mother liquors are
saved for the recovery of racemic HCT. The wet solid is suspended again in
acetone (2500 mL) and added under stirring with 37% hydrochloric acid
(109 mL). Stirring is maintained for one hour at 5°C and the solid is filtered
and washed with acetone, obtaining 175 g of S-HCT hydrochloride (dry
weight, 140% yield based on the desired enantiomer), with an [a]D = +22.5°.
Example 5 - Recovery of starting material (Method 2)
The mother liquors from Example 4 are acidified to pH 1 with
hydrochloric acid and cooled to 5°C for 4 hours. The solid is collected by
filtration and dried under vacuum, yielding 25 g of racemic R,S-HCT
hydrochloride.
CLAIMS
1. A process for the preparation of enantiomerically pure homocysteine-?-
thiolactone comprising optical resolution of racemic homocysteine-?-
thiolactone (HCT)

with a chiral organic acid wherein one isomer is recovered as diastereomeric
salt with the organic acid and the other isomer remaining in the mother liquor
is submitted to racemisation with a catalytic amount of an aromatic aldehyde
and submitted again to optical resolution with the same chiral organic acid.
2. A process a according to claim 1 wherein the diastereomeric salt
remaining in the mother liquor is first isolated and then racemised with a
catalytic amount of the aromatic aldehyde so as to provide racemic
homocysteine-?-thiolactone which is submitted again to optical resolution.
3. A process according to claim 2 which comprises the following steps:
a) preparing a solution of racemic HCT in a suitable solvent;
b) adding the solution with an enantiomerically pure chiral organic acid;
c) optionally heating the solution and then cooling it until complete
precipitation of the less soluble diastereomeric salt;
d) separating the precipitated diastereomeric salt from the solution
and liberating enantiomerically pure HCT

e) adding the solution from step d) with HC1 until complete
precipitation HCT hydrochloride salt enriched in the enantiomer which
remained in the solution;
f) recovering the precipitate and treating it with acetic acid in the
presence of an aromatic aldehyde so as to precipitate racemic HCT
hydrochloride salt;
g) isolating racemic HCT hydrochloride salt;
h) dissolving the salt in the same organic solvent as step a) and
adding a base so as to liberate racemic HCT;
i) repeating steps b)-d) and optionally e) - h) one or more times.
4. A process according to claim 1 wherein optical resolution is carried out
in the presence of a catalytic amount of an aromatic aldehyde, so that one out
of the two diastereomeric salts precipitates and the other one remaining in the
solution racemises.
5. A process according to claim 4 which comprises the following steps:
a) preparing a solution of racemic HCT in a suitable solvent;
b) adding the solution with an enantiomerically pure chiral organic
acid and a catalytic amount of an aromatic aldehyde;
c) heating the solution and then cooling it until complete
precipitation of the less soluble diastereomeric salt of HCT with the chiral
organic acid;
d) separating the precipitated diastereomeric salt from the solution
and liberating enantiomerically pure 2-amino-4-mercaptobenzobutyric acid

e) optionally adding HCl to the solution from step d) and recovering
racemic HCT.
6. A process according to any one of claims 1 to 5 wherein the
enantiomerically pure organic acid is selected from dibenzoyltartaric acid,
ditoluoyltartaric acid, mandelic acid, tartaric acid, camphorsulfonic acid,
ascorbic acid, malic acid, pyrogluthammic acid, aspartic acid, chinic acid, the
most preferred being ditoluoyltartaric acid and mandelic acid.
7. A process according to claim 6 wherein the enantiomerically pure
organic acid is ditoluoyltartaric acid or mandelic acid.
8. A process according to any one of claims 1 to 7 wherein the aromatic
aldehyde is selected from salicylaldehyde, m-hydroxy-benzaldehyde, p-
hydroxy-benzaldehyde, o-anisaldehyde, m- anisaldehyde, p- anisaldehyde.
9. A process according to claim 8 wherein the aromatic aldehyde is
salicylaldehyde.

The present invention relates to a process for the preparation
of enantiomerically pure homocysteine-γ-thiolactone comprising optical res-
olution of racemic homocysteine-γ-thiolactone (I) with a chiral organic acid
wherein one isomer is recovered as diastereomeric salt with the organic acid
and the other isomer remaining in the mother liquor is submitted to racemisa-
tion with a catalytic amount of an aromatic aldehyde and submitted again to
optical resolution with the same chiral organic acid.

Documents:

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Patent Number

269319

Indian Patent Application Number

3094/KOLNP/2009

PG Journal Number

42/2015

Publication Date

16-Oct-2015

Grant Date

15-Oct-2015

Date of Filing

01-Sep-2009

Name of Patentee

EDMOND PHARMA S.r.l.

Applicant Address

VIA G.B. GRASSI, 15, I-20157 MILANO ITALY

Inventors:

#	Inventor's Name	Inventor's Address
1	ZACCHE', MATTEO	VIA MADRE TERESA DI CALCUTTA, 8, I-20010, VANZAGO (MI) ITALY
2	NICOLA, MASSIMO	VIALE CANTON NICINO, 22, I-27100, PAVIA ITALY
3	GATTI, PIER, ANDREA	VIA CERTOSA, 1/E, I-27010 SAN GENESIO ED UNITI (PV) ITALY

PCT International Classification Number

C07D 333/36

PCT International Application Number

PCT/EP2008/001346

PCT International Filing date

2008-02-21

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	07004341.9	2007-03-02	EUROPEAN UNION