FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"A PROCESS FOR THE PREPARATION OF PALIPERIDONE
INTERMEDIATES"
Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
The following specification describes the nature of the invention:

FIELD OF THE INVENTION
1. Technical Field
The present invention relates to a process for the preparation of paliperidone intermediates. The invention also relates to a process for preparation of paliperidone. Back ground of the invention;
2. Description of the Related Art
Paliperidone is a psychotropic agent belonging to the chemical class of benzisoxazoles. It is marketed under the name INVEGA™ for the treatment of psychosis. Paliperidone is chemically known as (±)-3-[2-[4-(6-fluoro-l, 2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6, 7, 8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l, 2-a]pyrimidin-4-one and has the structural formula I:

Formula I
The present invention particularly relates to a process for the preparation of paliperidone intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one represented by structural formula II

0
Formula II
US 5,158,952 describes a group of benzisoxazoles derivatives including paliperidone, which acts as psychotropic agents.
US'952 also describes the process for the synthesis of intermediates of paliperidone including 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9- hydroxy-2-methyl-
4H-pyrrido[l,2-a]-pyrimidin-4-one of formula II comprising debenzylation and double bond reduction of the intermediate compound 3-(2-chloroethyl)-2-methyl-9-


benzyloxy-4H-pyrido[l,2-a]pyrimidine-4-one using hydrogen and 10% palladium on carbon in the presence of methanol. International application publication WO2008024415A2 describes the processes for the synthesis of intermediates of paliperidone, 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9- hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one of formula II comprising debenzylation of 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[l ,2-a]pyrimidine-4-one using hydrogen and palladium on carbon in the presence of methanol and 32% HC1 to give 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[l,2-a]pyrimidine-4-one which is further reacted to afford the desired compound.
Aforementioned processes results in the formation of impurities and side products.
Accordingly, there remains a need to provide a process for the preparation of impurity free intermediates to produce the final product paliperidone with high yield and purity.
The process of the present invention provides a process which is simple, ecofriendly, inexpensive, reproducible, robust and well suited on commercial scale.
SUMMARY OF THE INVENTION
In one aspect the present invention provides a process for the preparation of intermediate compound of formula II which is useful in the synthesis of paliperidone which the process comprises:
converting the compound of Formula III

o
(III)
where R= hydroxyl protecting group
to the compound 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-
pyrrido[l,2-a]-pyrimidin-4-one of formula II


CI
,N. XH3

OH

(II)
by subjecting the compound of formula III to hydrogenation in aqueous acid.
In another aspect, the present invention provides a process for the preparation of 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-l - piperidyl]ethyl]-7-hydroxy-4-methyl-l ,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one (Paliperidone) Formula I:

comprising condensation of compound 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one of formula II:
OH



N^ ^CH3
CI

(ID
with compound 6-fluoro-3-piperidino-l,2-benzisoxazole of formula V or a salt thereof:



in an organic solvent in the presence of a base at a temperature of about 25°C to about 100 °C, followed by isolation of the resulting compound of formula I, wherein the compound of formula II is prepared by the above process.
The process of present invention is simple, ecofriendly, inexpensive, reproducible and well suited on an industrial scale to produce the desired compound of formula I with high purity and yield.
DETAILED DISCRETION OF THE INVENTION
In one embodiment of the present invention, there is provided a process for the preparation of intermediate compound of formula II which is useful in the synthesis of Paliperidone of Formula I. which the process comprises:
a) converting the compound of Formula III

(III) where R= hydroxyl protecting group
(II)
to the compound 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one of formula II


by subjecting the compound of formula III to hydrogenation in aqueous acid.
The hydrogenation agents that can be used in the reaction step (a) include but are not limited to metal catalysts such as platinum, palladium, nickel, rhodium or ruthenium of various percentages and grades supported on solid support such as calcium carbonate, alumina, barium sulfate, silica or activated carbon or by the hydrogenation catalysts referred in Introduction to Organic Chemistry, Ch 15, pp. 376-403, (1976) and Heterogeneous Catalysis for the Synthetic Chemist By Robert L. Augustine
[For more on reduction of a double bond, see Advanced Organic Chemistry 2.sup. Ed. Vol 1,779-834.]
The hydrogenation is carried out in the presence of hydrogen or hydrogen transfer reagents selected from the group consisting of formic acid, salts of formic acid, phosphonic acid, hydrazine, monosodium dihydrogen orthophosphate, cyclohexene or mixtures thereof.
The acids that can be used in the reaction step (a) include but are not limited to mineral acids selected from hydrochloric acid, phosphoric acid, trifluoracetic acid, trifluoromethane sulfonic acid, methane sulfonic acid, nitric acid, sulfuric acid or the mixture of the above acids.
The temperatures for conducting the reaction step (a) can range from about 35 °C to about 100 °C or reflux temperatures of the solvents used.
The time period for conducting the reaction step (a) can range from about 1 to about 10 hours or until the required product purity and yield is achieved, time periods from about 1 to 20 hours frequently being sufficient.
The protecting groups for the hydroxyl function in the compound of structural Formula [III] there may be mentioned, without implying any limitation, the groups alkyl such as methyl, ethyl, isopropyl, tertiary butyl, and the like; tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, trialkyl silyl or any suitable hydroxy protecting group disclosed in the book 'Greene's Protective Groups in Organic Syntheses, 4th edition, by P. G. M. Wuts and T. W. Greene, A John Wiley & Sons, Inc., Publication, 2007.


The resultant compound of Formula II is optionally purified by slurry or recrystallization in a solvent or mixture of solvents or aqueous mixtures or by acid base treatment and can be purified by conversion into inorganic or organic acid salts by reacting with the respective acids to form salts and back to the freebase.
In another aspect, the present invention provides a process for the preparation of 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-l - piperidyl]ethyl]-7-hydroxy-4-methyl-l ,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one (Paliperidone) Formula I:

(ID
with compound 6-fluoro-3-piperidino-l,2-benzisoxazole of formula V or a salt thereof
comprising condensation of compound 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one of formula II:



in organic solvent and in the presence of a base at a temperature of about 25°C to about 100 °C, followed by isolation of the resulting compound of formula I, wherein the compound of formula II is prepared by the above process, wherein the resultant compound of formula I has less than about 0.1 area % by HPLC of deschloroimpurity of formula IV

Paliperidone of formula I can also be prepared by the processes known in the art for example US 5,158,952 using the intermediate compound of formula II obtained by the process of present invention.
Paliperidone prepared in accordance with the present invention contains less than about 0.1% of deschloroimpurity of Formula IV or less than about 0.1% of the corresponding impurities as determined by a high performance liquid chromatography ("HPLC") chromatogram obtained from a mixture comprising the desired compound and one or more of the said impurities. The percentage here refers to weight percent obtained from the area-% of the peaks representing the impurities.
The process of the present invention advantageously provides Paliperidone in relatively high purity, e.g., greater than about 95% by HPLC.
The process for the preparation of intermediates of paliperidone of the present invention is simple, eco-friendly and easily scaleable.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.


EXAMPLES
Example-1: Preparation of 3-(2-chloroethyl)-9-hydroxy-6,7,8.9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidine-4-one (Formula II)
3-(2-Chloroethyl)-9-benzyloxy-2-methyl-4H-pyrido[l,2-a]pyrimidine-4-one(15g)was dissolved in water (225 ml) by adjusting the pH to 1-2 using 34% w/w aqueous hydrochloric acid (~ 12 ml). This solution is hydrogenated in an autoclave in the presence of palladium on charcoal (2.8 g) with 3-4 kg /cm of hydrogen pressure at 25-30°C. After the completion of the reaction, the reaction mass was filtered and pH of the filtrate was adjusted to 9-10 using aqueous ammonia solution. The resulted product was extracted with toluene and the extract was filtered through celite and the filtrate was concentrated to yield a 3-(2-chloroethyl)-9-hydroxy-6,7,8.9-tetrahydro-2-methyl-4H-pyrido [l,2-a]pyrimidine-4-one. Purity by HPLC: 96.5% with Deschloro impurity: 2.9%.
Example-2: Preparation of 3-(2-chloroethyl)-9-hydroxy-6,7,8.9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidine-4-one (Formula II)
3-(2-Chloroethyl)-9-benzyloxy-2-methyl-4H-pyrido[ 1,2-a]pyrimidine-4-one(l 5 g) was dissolved in water (225 ml) by adjusting the pH to 1-2 using ortho phosphoric acid (~ 18 ml). This solution is hydrogenated in an autoclave in the presence of palladium on charcoal (2.25 g) with 3-4 kg/ cm2 hydrogen pressure at 25-30°C. After the completion of the reaction, the reaction mass was filtered and pH of the filtrate was adjusted to 9-10 using aqueous ammonia solution. The resulted product was extracted with methylene chloride and the extract was concentrated to yield 3-(2-chloroethyl)-9-hydroxy-6,7,8.9-tetrahydro-2-methyl-4H-pyrido[ 1,2-a]pyrimidine-4-one.
Example-3: Preparation of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-
piperidinyl]ethyl]-9-hydroxy-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one (Formula I)
A mixture of 3-(2-chloroethyl)-9-hydroxy-6,7,8.9-tetrahydro-2-methyl-4H-pyrido[l,2-a]- pyrimidine-4-one (formula II) (l0g) prepared as in Example-1, 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole hydrochloride (formula V)(8.8g) and diisopropylamine


(8.8g) was refluxed in methanol (150 ml) at 55-60°C for 12 h. As the reaction proceeds the product starts to crystallizes out in the reaction mass. After completion of the reaction the reaction mixture was cooled to room temperature, the product was filtered and dried. Purity by HPLC: 95.5% with deschloro impurity 0.09%.
COMPARATIVE EXAMPLE-1:
Preparation of 3-(2-chloroethyl)-9-hydroxy-6,7,8.9-tetrahydro-2-methyl-4H-
pyrido[l,2-a]pyrimidine-4-one (Formula II)
A mixture of 3-(2-Chloroethyl)-9-benzyloxy-2-methyl-4H-pyrido[l,2-a]pyrimidine-4-one(5 g) methanol (180) was hydrogenated at normal pressure and at room temperature (180 ml) with (3.03 g) palladium on charcoal catalyst 10% .The reaction was monitored by HPLC. It was observed that even after keeping the reaction for 20hr a substantial quantity (more than 15%) of the debenzyl intermediate i.e. 3-(2-Chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a] pyrimidine-4-one remains unreacted and at the same time unwanted deschloro impurity increases to about 18 %.
COMPARATIVE EXAMPLE-2:
Preparation of 3-(2-chloroethyl)-9-hydroxy-6, 7,8.9-tetrahydro-2-methyl-4H-
pyrido[l,2-a]pyrimidine-4-one (Formula II)
To a mixture of 3-(2-Chloroethyl)-9-benzyloxy-2-methyl-4H-pyrido[l,2-a]pyrimidine-4-one (35 g) and methanol (525 ml) added 34% w/w aqueous hydrochloric acid (8ml) to get a clear solution. This solution is hydrogenated in an autoclave in the presence of palladium on charcoal (17.5 g) with 1.5-2 kg /cm of hydrogen pressure at 25-30°C. The progress of the reaction monitored by HPLC analysis at regular intervals and the results are given below.

Time interval Debenzyl intermediate Product (Formula II) Deschloro impurity
lhr 62% 24.8% 2.1%
2hr 35.9% 42.3% 8.3%
3hr 14.5% 46% 28%
3.5hr 4.6% 48.9% 39%


The present invention particularly provides : A) A process of converting the compound of Formula III
OR
NL .CH3

%^N
(III)
where R= hydroxyl protecting group.
to the compound 3-(2-chloroethyl)- 9-hydroxy-6,7,8,9-tetrahydro-2-methyl-4H-
pyrrido[l,2-a]-pyrimidin-4-one of formula II

comprising subjecting the compound of formula III to hydrogenation in aqueous acid.
B) The process of step A, wherein the reaction is carried out in the presence of
hydrogenation catalyst selected from the group consisting of palladium-carbon,
platinum on carbon, platinum oxide, rhodium on carbon and Raney-
Nickel
C) The process of step A, wherein the acid is mineral acid selected from
hydrochloric acid, phosphoric acid, trifluoracetic, acetic acid, trifluoromethane sulfonic
acid, p-toluenesulfonic acid, methane sulfonic acid, nitric acid, sulfuric acid or the
mixture of the above acids


D) The process of step A, the hydrogenation is carried out in the presence of hydrogen
or hydrogen transfer reagent selected from the group consisting of ammonium
formate, phosphonic acid hydrazinehydrate, monosodium dihydrogen orthophosphate,
cyclohexene, sodium formate.
E) A process for the preparation of 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-l-
piperidyl]ethyl]-7-hydroxy-4-methyl-l,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one of
formula I:

comprising condensation of compound 3-(2-chloroethyl)- 9-hydroxy -6,7,8,9 tetrahydro -2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one of formula II:
OH


(II)
with compound 6-fluoro-3-piperidino-l,2-benzisoxazole of formula V or a salt thereof:


in organic solvent and in the presence of a base at a temperature of about 25°C. to about 100 °C, followed by isolation of the resulting compound of formula I, wherein the compound of formula II is prepared by the process of step A. F). The process of step E, wherein the resultant compound of formula I has less than about 0.1 area % by HPLC of dechloroimpurity of formula IV

(IV)