CLIAMS:1. An improved process for the preparation of pure Paliperidone, the process comprising the following steps:

a) preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H- pyrido[1,2-a]pyrimidin-4-one (CMHTP) by hydrogenation of 9-benzyloxy-3-(2- chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (CMBP) in two steps via production and isolation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2- a]pyrimidin-4-one hydrochloride (CMHP.HCl) by selective debenzylation of CMBP, followed by hydrogenation of thus obtained CMHP.HCl;

b) preparation of crude Paliperidone by N-alkylation of 6-fluoro-3-(piperidin-4-yl)-1,2-benzisoxazole hydrochloride (FBIP.HCl) with 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (CMHTP) in the presence of a base, wherein the paliperidone crystals obtained are recrystallized from an acetonitrile/water solvent mixture in a volume ratio of (4:1);

c) preparation of pure Paliperidone by purification of crude Paliperidone via formation of Paliperidone oxalate.

2. The process of claim 1 which further comprises the preparation of Paliperidone palmitate by reaction of Paliperidone with palmitic acid.

3. The process of claim 2 wherein the preparation is carried out in the presence of benzoyl chloride and an acylation catalyst such as N,N-dimethylaminopyridine(DMAP).

4. The process according to claim 2 wherein the preparation of Paliperidone palmitate is carried out in toluene at 80-90°C.

5. The process according to claim 1, wherein the preparation of CMHTP at step a) is performed in a two-steps hydrogenation process comprising:

i) debenzylation of 9-benzyloxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (CMBP) at ambient temperature in a C1-5 alcohol solvent under a hydrogen pressure of 2-4 kg/cm2 in the presence of a Pd/C catalyst at a temperature of 25 to 35°C to yield CMHP;followed by salt formation and isolation of CMHP.HCl; and

ii) hydrogenation of CMHP.HCl obtained at a temperature of 40 to 45°C in methanol under a hydrogen pressure of 6-8 kg/cm2 in the presence of aryl halides and using a Pd/C as catalyst; and after isolation, purification of CMHTP by recrystallizationfrom isopropyl acetate.

6. The process of claim 5 wherein the C1-5 alcohol solvent is selected from methanol, ethanol and isopropanol, preferably methanol.

7. The process of claim 5 wherein the aryl halide is selected from fluorotoluene, chlorotoluene, iodotoluene, bromotoluene or mixture thereof, preferably 4-chlorotoluene.

8. The process of claim 5, wherein the formation and the isolation of CMHP.HCl comprises:
i1) addition of dichloromethane to the hydrogenation reaction mixture of step i) followed by filtration and evaporation of the solvent from the filtrate;
i2) addition of dichloromethane to the residue of step i1) followed by addition of isopropyl alcohol hydrochloride (IPA.HCl) and isolation of precipitated CMHP.HCl.

9. The process of claim 8 wherein the addition of IPA.HCl is performed at a temperature of 35 to 40°C.

10. The process of claim 8, wherein isolated CMHP.HCl can be further purified by washings with isopropanol.

11. The process of claim 5, wherein isolation of CMHTP comprises:
(ii1) filtration of the hydrogenation reaction mixture of step ii) and evaporation of the solvent from the filtrate;
(ii2) addition of water to the residue of step ii1) and stirring at a temperature of 70 to 85°C;
(ii3) cooling to a temperature of 25 to 35°C and addition of toluene;

(ii4) separation of the phases, treatment of the aqueous phase with aqueous potassium acetate at a temperature of 15 to 25°C;
(ii5) further cooling to a temperature of 0 to 10°C and isolation of precipitated CMHTP by filtration.

12. The process of claim 5 wherein purification of CMHTP comprises:
(ii6) purification of CMHTP obtained from step ii5) by treatment of CMHTP with activated carbon in isopropyl acetate at a temperature of 50 to 55°C, filtration of the solution and crystallization of CMHTP by first cooling the filtrate to a temperature of 25 to 35°C followed by furthercooling of the filtrate to a temperature of 0 to 5°C and isolation of pure CMHTP.

13. The process according to claim 5, wherein the content of unreacted CMBP in CMHP.HCl is less than or equal to 0.01% as determined by HPLC.

14. The process according to claim 5, wherein the content of CMHTP in CMHP.HCl is less than or equal to 0.1% as determined by HPLC.

15. The process according to claim 5, wherein the content of CMHP.HCl in CMHTP is less than 0.05% as determined by HPLC.

16. The process according to claim 5, wherein the content of deschloro impurity (impurity C) is less than 0.5%, preferably less than 0.3% as determined by HPLC.

17. The process of claim 1, wherein the preparation of crude Paliperidone at step b) comprises:

i) condensation of CMHTP obtained from step a) with 6-fluoro-3-(piperidinyl)-1,2-benzisoxazole hydrochloride in methanol in the presence of a base, preferably N,N-diisopropylamine (DIPA) at 60 to 70°C;
ii) coolingthe reaction mixture of step i) to a temperature of -5 to 5°C and isolating Paliperidone crystals;
iii) optionally, washing the wet crystals successively with methanol and water; and
iv) recrystallization of crystals obtained from step ii) or iii) from an acetonitrile/water solvent mixture in a volume ratio of (4:1); and

v) optionally, further washing the crystals obtained from step iv) with an acetonitrile/water solvent mixture.

18. The process of claim 17, wherein the content of keto impurity (impurity B) in crude Paliperidone is less than 0.50% as determined by HPLC.

19. The process of claim 17, wherein the content of CMHTP in crude Paliperidone is less than 0.1% as determined by HPLC.

20. The process of claim 17, wherein the content of Paliperidone N-oxide, unreduced Paliperidone and Risperidone in crude Paliperidone is respectively less than or equal to 0.01%, less than 0.1% and less than or equal to 0.02% as determined by HPLC.

21. The process for the preparation of pure Paliperidone of claim 1, wherein step d) comprises:
i) reaction of Paliperidone obtained at step c) with a methanolic solution of oxalic acid dihydrate in dichloromethane at a temperature of 30 to 45°C;
ii) isolation of Paliperidone oxalate obtained in step i);
iii) treatment of Paliperidone oxalate obtained in step ii) witha reducing agent selected from sodium dithionite, sodium dithionate, sodium metabisulfite and potassium metabisulfite followed by filtration;
iv) treatment of the filtrate obtained from step iii) with a liquid ammonia solution;
v) isolation of pure Paliperidone; and
vi) optionally, further washings of pure Paliperidone obtained at step v) successively with water and ethanol.

22. The process of claim 21 wherein step ii) is carried out by cooling the reaction mixture of step i) to a temperature of 0 to 5°C, stirring for 50 to 60 minutes and isolating Paliperidone oxalate by filtration.

23. The process of claim 21 wherein in step iii), the preferred reducing agent is sodium dithionite.

24. The process of claim 21 wherein the treatment in step iii) is preferably carried out in an isopropyl alcohol/water solvent mixture, most preferably in a volume ratio of (1:1.5) to (1:2) at a temperature of 25 to 35°C for 15 to 30 minutes.

25. The process of claim 21 wherein the treatment in step iv) is preferably carried out at a temperature of 25 to 35°C under stirring for 55 to 65 minutes.

26. The process of claim 21 wherein the isolation of pure Paliperidone at step v) is carried out by cooling the reaction mixture of step v) to a temperature of 0 to 5°C, stirring at said temperature for 30 to 45 minutes and isolating pure Paliperidone.

27. The process of claim 21, wherein pure Paliperidone obtained contains less than 0.1%, preferably less than 0.05% of any single impurity.

28. The process of claim 21, wherein the content of deschloro impurity in pure Paliperidone is less than 0.01% as determined by HPLC.

29. The process of claim 21, wherein the content of keto impurity in pure Paliperidone is less than 0.05% as determined by HPLC.
,TagSPECI:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of highly pure Paliperidone and more particularly to an economically viable and industrially advantageous process for the preparation of Paliperidone and intermediates thereof.

BACKGROUND OF THE INVENTION

Paliperidone, chemically designated as 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 Ishown below, molecular formula C23H27FN4O3 and molecular weight of 426.49 g/mol is a 5-HT antagonist of the benzisoxazole derivatives class.

formula-I

Paliperidone is the major active metabolite of the antipsychotic Risperidone; Risperidone being metabolized in the liver mainly through hydroxylationvia the cytochrome (CYP) P450 2D6 pathwayinto 9-hydroxy Risperidone or Paliperidone. Paliperidone has a pharmacological profile and potency comparable with that of the parent drug Risperidone but with a longer elimination half-time Paliperidone differs from Risperidone and most other antipsychotics by its relatively low extent of enzymatic metabolism.

Its racemic mixture is marketed under the trade name INVEGA® and is used for the treatment of schizophrenia.

3-Piperidinyl-1,2-benzisoxazoles, including Paliperidone, and methods for their preparation were first disclosed in EP Patent No. 0368388. EP ‘388 also described processes for the preparation of useful intermediates.

One of the disclosed processes for the preparation of Paliperidone involves the hydrogenation of 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[1,2-a]pyrimidine-4-one at normal pressure and at room temperature with 2.0 parts of 10% palladium-on-charcoal catalyst in 120 parts of methanol to form 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or its HCl salt as an oily residue; said residue is then taken up in 2-propanol and 2,2’-oxybispropane to form a precipitated compound which is then condensed with 6-fluoro-3(4-piperidinyl)-1,2-benzisoxazole monohydrochloride in presence of a base in an appropriate solvent or alternatively by applying art-known conditions of phase transfer catalysis reactions. The oily residue obtained at the end of the reaction is taken up in chloroform and purified twice by column chromatography first using a mixture of chloroform and methanol and then a mixture of trichloromethane and methanol saturated with ammonia as eluents. The residue obtained after evaporation is crystallized from 2-propanone further washed and recrystallized.

The major drawbacks of the above process are: (i) the use of chloroform which is known to irritatethe respiratory tract and cause central nervous system effects such as headaches, drowsiness, dizziness; it may also cause liver & blood disorders and is suspected human carcinogen; (ii) the use of tedious column chromatography purifications which are generally undesirable for large-scale operations; (iii) the catalytic hydrogenation reactionwhich is incomplete, lengthy and with by-products formation; and finally, (iv) despite repeated purification steps, Paliperidone obtained by the process of EP ‘388 patent does not have satisfactory purity for pharmaceutical use, necessary conditions for commercialization.

The ICH guidelines recommend levels of impurities within specific limits i.e. any single impurity below 0.1% and the total amount of impurities below 0.5%.

The major known potential impurities in Paliperidone API are Paliperidone N-oxide (impurity A), keto Paliperidone (impurity B), and at an earlier stage of the preparation process: deschloro impurity (impurity C) which chemical structures are shown below.

impurity A impurity B
impurity C

In view of the above, intensive efforts were made to overcome these drawbacks.

PCT publication No.WO 2008/021346 discloses various methods for the purification of Paliperidone: (i) by crystallization in a solvent (various solvents screened), (ii) by crystallization by solvent/anti-solvent method; (iii) by filtration through activated carbon to avoid tedious column chromatographic purification.

Paliperidone is nearly insoluble in most organic solvents, which makes its purification difficult and requires the use of large volumes of solvents which in addition of being costly might also be dangerous.

PCT publication No.WO 2008/024415 discloses a process for the preparation of key intermediates for the preparation of Paliperidone. The method involves the use of 32% HCl in the presence of methanol, corrosive conditions and yield to Paliperidone containing not less than 5% of deschloro-impurity.

PCT publication No. WO 2009/060297 discloses a process for the preparation of pure Paliperidone via formation of its acid addition salts; said acid addition salts are further converted into Paliperidone free base by reaction with a base.

PCT publication No. WO 2010/004578 discloses a process wherein obtained Paliperidone is further treated with suitable reducing agent, sodium borohydride, to reduce the formed keto impurity into Paliperidone.

PCT publication No. WO 2011/006638 discloses a process for the preparation of Paliperidone by condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[1,2-a]-pyrimidin-4-one or salt thereof with 6-fluoro-3-(piperidin-4-yl)-1,2-benzisoxazole or salt thereof in an organic solvent in the presence of water and wherein the pH of the reaction medium is between 6 and 14. Purification by crystallization of Paliperidone is achieved by filtration of hot2-propanol solution of Paliperidone with active charcoal of neutral pH.

None of the methods taught by the prior art were sufficiently good either in their attempt to obtain Paliperidone of high purity or in their attempt to provide a viable, economic & eco-friendly process for the preparation of Paliperidone.

Thus, there is still a need for an improved process suitable for industrial production of Paliperidone and its intermediates with high purity and greater yield.

OBJECTIVE OR SUMMARY OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of Paliperidone, in an effort to overcome the deficiencies of the prior art processes.

A first object of the present invention is to provide an improved process for the preparation of highly pure Paliperidone in good yield.

Another object of the present invention is to provide an improved method for the preparation of Paliperidone by selecting the appropriate conditions for the preparation of its key intermediates and limiting the formation and content of any contaminants and process related impurities so that the purity and yield of the key intermediates are increased. A more particular effort was made in minimizing the content of deschloro impurity (impurity C) & keto-impurity (impurity B).

Therefore, an additional goal of the present invention is to provide an improved process for the preparation of intermediates useful in the manufacture of Paliperidone or salts or esters thereof.

In accordance with the above objects of the present invention, an improved process for the preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (CMHTP), compound of formula V shown below, is provided.

Formula V

BRIEF DESCRIPTION OF THE DRAWING:

FIG.1 shows an HPLC chromatogram of CMHP.HCl obtained by process of the present invention.

FIG.2 shows anHPLC chromatogram of CMHTP obtained by process of the present invention.

FIG.3 shows an HPLC chromatogram of Paliperidone crude obtained by process of the present invention.

FIG.4 shows an HPLC chromatogram of Paliperidone pure obtained by process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION:

As previously mentioned, the main object of the present invention is to provide an improved process for the preparation of Paliperidone in high purity.
The process of the present invention is depicted in the following scheme:

Stage-I

Stage-II

Stage-III

According to the present invention, said process comprises:

Stage-I: preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (CMHTP) by hydrogenation of 9-benzyloxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (CMBP) in a two-steps process via production and isolation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride (CMHP.HCl) by selective debenzylation of CMBP, followed by hydrogenation of thus obtained CMHP.HCl;

Stage-II: preparation of crude Paliperidone by N-alkylation of 6-fluoro-3-(piperidin-4-yl)-1,2-benzisoxazole hydrochloride with CMHTP of stage-II in the presence of a base;

Stage-III: purification of crude Paliperidone involving the preparation of Paliperidone oxalate which is then converted to pure Paliperidone free base by reacting said oxalate salt with a base.

The term “crude” Paliperidone refers to Paliperidone containing unreacted starting materials, chemical derivatives contained in starting materials, by-products of the reaction, products of side reactions &/or degradation products, commonly known as impurities; by the term impurities, we also wish to include residual solvents.

The term “pure” Paliperidone refers to Paliperidone containing less than 0.1% of each single impurity; preferably, less than about 0.05% and a total amount of impurities below 0.5% as per recommended level of impurities of ICH guidelines, preferably below 0.3%, most preferably below 0.25%.

The purity is measured by HPLC and represented as a % area as shown in the attached HPLC chromatograms.

Optionally, Paliperidone prepared in accordance with the present invention, as described above, may be used for the preparation of Paliperidone palmitate by reaction of said Paliperidone with palmitic acid in presence of benzoyl chloride and an acylation catalyst such as N,N-dimethylaminopyridine (DMAP).

Paliperidone palmitate is the palmitate ester of Paliperidone, chemically known as3-(2-(4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidin-9-yl hexadecanoate and marketed under the trade name INVEGA SUSTENNA (US) and XEPLION (EU).

INVEGA SUSTENNA is a long-acting injectable formulation of Paliperidone palmitoylester indicated for maintenance treatment of schizophrenia when received as a once-monthly injection in adult patients stabilized with Paliperidone.

Pure Paliperidone was obtained by careful control of the purity of key intermediates of its synthesis, namely: CMHTP (Stage-II), Paliperidone crude (Stage-III) and Paliperidone (Stage-IV) which was achieved by improving the processes for the preparation of said key intermediates thanks to fine adjustments of the reactions conditions.

As mentioned previously, the authors of the present invention concentrated their efforts in developing improved processes for the preparation of key intermediates.
The formation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (CMHTP) is a key step in the synthesis of Paliperidone.

Thus, in oneembodiment, the present inventionprovides an improved process for the preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (CMHTP), compound of formula V shown below, starting from 9-benzyloxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (CMBP), compound of formula IIIvia isolation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.HCl (CMHP.HCl), compound of formula IV (Stage I).
Formula V Formula III

Formula IV

Stage-Iof the process of the present invention comprises:
(a) Debenzylation of 9-benzyloxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (CMBP) in a C1-5 alcohol solvent under a hydrogen pressure of 2-4 kg/cm2 and in the presence of a hydrogenation catalyst at a temperature of 25 to 35°C to yield CMHP;
(b) salt formation and isolation of CMHP.HCl at ambient temperature;
(c) hydrogenation of CMHP.HCl obtained from step (b) in the presence of aryl halidesin methanol under a hydrogen pressure of 6-8 kg/cm2 in the presence of a palladium on carbon catalystat temperature of 40 to 45°C;
(d) isolationof CMHTP; and
(e) purification of CMHTP obtained from step (d) by treatment of isolated CMHTP in solution in isopropyl acetate with activated carbon at a temperature of 50 to 55°C, filtration of the solution, followed by cooling the filtrate to a temperature of 25 to 35°C, further cooling to 0 to 5°C and isolation of pure CMHTP.

The C1-5 alcohol solvent used in step-(a) can be selected from methanol, ethanol or isopropanol, preferably methanol.
The preferred hydrogenation catalyst is palladium on charcoal used from about 5 % w/w to about 20 % w/w, preferably 10 % w/w based on charcoal.

Step-(b) is carried out preferably as follows: addition of dichloromethane at a temperature of 25 to 30°C to the reaction mixture of step (a), filtration and evaporation of the solvents; addition of dichloromethane to the residue obtained followed by addition of isopropyl alcohol hydrochloride (IPA.HCl, ~13-18%) at a temperature of 35 to 40°C and stirring at said temperature; isolation of CMHP.HCl is carried out preferably by filtration.

The isolated CMHP.HCl of step (b) can be further purified by washings with isopropanol.
Step (c) hydrogenation step is carried out preferably using 10% Pd/C at a temperature of 40 to 50°C for a period of time of 4 to 8 hours and in presence of aryl halides in a preferred amount of 1.2 v/w equivalent based on CMBP.

The aryl halide used in step-(c) is selected from fluorotoluene, chlorotoluene, iodotoluene, bromotoluene or mixture thereof, and more preferably: 4-chlorotoluene.

The isolation of CMHTP at step-(d) is carried out preferably as follows:
(d1) filtration of the reaction solution of step (c);
(d2) evaporation of the solvent of the filtrate obtained in step-(d1) and stirring the residue obtained in water at a temperature of 70 to 85°C;
(d3) addition of toluene at a temperature of 25 to 35°C to the cooled solution of step-(d2)followed by stirring and separation of the phases;
(d4) treating the aqueous phase obtained from step-(d3) with aqueous potassium acetate at a temperature of 15 to 25°C,
(d5) cooling the solution obtained from step-(d4) to a temperature of 0 to 10°C, and isolating crystals of CMHTP by filtration.

By selecting the appropriate conditions for the preparation of CMHP.HCl and CMHTP, the authors of the present invention managed to minimize the content of deschloro impurity (impurity C) and the content of unreacted starting materials.

CMHP.HCl isolated in step (c) contains less than or equal to 0.01% of unreacted CMBP and less than or equal to 0.10% of CMHTP as determined by HPLC (FIG.1) showing that the first hydrogenation was a selective debenzylation of CMBP.

CMHTP purity was carefully checked regarding presence of deschloro impurity (impurity C), unreacted CMHP.HCl and potentially carried forward unreacted CMBP.

CMHTP obtained by the process of the present invention contains less than 0.05% of CMHP.HCl and less than 0.5% of deschloro impurity, preferably less than 0.3% as determined by HPLC (FIG.2).

With CMHTP of greater purity & yield in hands, the authors of the present invention used said key intermediate for the preparation of Paliperidone.

Stage-II of the process according to the present invention comprises the following steps:

(a) reaction of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[1,2-a]pyrimidin-4-one (CMHTP) obtained in Stage-I with 6-fluoro-3-(piperidinyl)-1,2-benzisoxazole hydrochloride (FBIP.HCl) in methanol in the presence of a base at a temperature of 60 to 70°C;
(b) isolation of Paliperidone crystals;
(c) optionally, washing the wet crystals obtained from step (b) successively with methanol and water; and
(d) recrystallization of the crystals obtained from step (c) from an acetonitrile-watermixture in a (4:1) volume ratio.

The reaction mixture of step-(a) is stirred at mentioned temperature for 20 to 30 hours.
The base is preferably N,N-diisopropylamine (DIPA).

The isolation of Paliperidone in step-(b) is carried out for example by cooling the reaction mixture obtained from step-(a) to a temperature of -5 to 5°C. The crystals obtained are recovered by filtration.

The crystals obtained from step (d) can optionally be further purified by washing the crystals with acetonitrile-water solvent mixture.

The recrystallization from the acetonitrile-water mixture in a (4:1) ratio yielded Paliperidone with reduced content of keto impurity (impurity B) and with reduced content of both unreacted CMHTP and FBIP.HCl.

The content of keto impurity (impurity B) in crude Paliperidone is less than 0.50% and the content of CMHTP in crude Paliperidone is less than 0.1% as determined by HPLC.

Paliperidone obtained at the end of Stage-II, prepared in accordance with the process of the present invention contains also reduced content of unreduced Paliperidone of less than 0.1% as determined by HPLC, Paliperidone N-oxide of less than or equal to 0.01% as determined by HPLC and Risperidone of less than or equal to 0.02% as determined by HPLC (FIG.3).

Paliperidone thus obtained is further purified at Stage-IIIby the process comprising:

(a) reaction of Paliperidone obtained in Stage-II with a methanolic solution of oxalic acid dihydrate in dichloromethane at a temperature of 30 to 45°C;
(b) isolation of Paliperidone oxalate;
(c) treatment of Paliperidone oxalate with a reducing agent selected from sodium dithionite, sodium dithionate, sodium metabisulfite and potassium metabisulfite, followed by filtration;
(d) treatment of the filtrate obtained from step (c) with a liquid ammonia solution until pH 9.5-10.5;
(e) isolation of pure Paliperidone; and
(f) optionally, further washings of pure Paliperidone obtained from step (e) successively with H2O and ethanol.

The isolation in step-(b) is carried out for example by cooling the reaction mixture obtained in step (a) at a temperature of 0 to 5°C and stirring at said temperature for 50 to 60 minutes; the crystals obtained are isolated by filtration.

The treatment in step-(c), preferably using sodium dithionite as a reducing agent, is preferably carried out in an isopropanol/water solvent mixture, most preferably in a (1:2) volume ratio at a temperature of 25 to 35°C for 15 to 30 minutes;

The treatment with liquid ammonia in step-(d) is preferably carried out at a temperature of 25 to 35°C and stirring at the same temperature for 55 to 65 minutes;

The isolation of pure Paliperidone in step-(e) is carried out for example by cooling the reaction mixture of step-(d) to a temperature of 0 to 5°C, stirring at said temperature for 30 to 45 minutes. The obtained Paliperidone may be recovered by conventional techniques known in the art, preferably by filtration.

The purification steps described above are optionally repeated.

The process of the present invention advantageously provides Paliperidone in high purity.

Paliperidone prepared in accordance with the present invention contains any single impurity in less than 0.1 area %, preferably in less than 0.05% as determined by HPLC (FIG.4).

Paliperidone prepared in accordance with the present invention contains less than 0.01% of deschloro impurity as determined by HPLC (FIG.4).

Paliperidone prepared in accordance with the present invention contains less than 0.05% of keto impurity as determined by HPLC (FIG.4).

Finally, Paliperidone palmitate can optionally be prepared by reaction of the pure Paliperidone obtained with palmitic acid in the presence of an acid halide, preferably benzoyl chloride. The reaction may preferably be carried out in the presence of a base, preferably triethylamine and a catalytic amount of a pyridine derivative, preferably N,N-dimethylaminopyridine (DMAP)in an organic solvent, preferably toluene at a temperature of 80 to 90°C for sufficient time to give Paliperidone palmitate.

The present invention is further illustrated by the following examples which are provided to support the disclosure only and do not limit the scope of the invention in any manner.

EXAMPLES

Stage - 1 Preparation of3-(2-Chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidin-4-one (CMHTP):
A solution of 9-benzyloxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (CMBP) (100 g) in methanol (1000 ml) was hydrogenated using 10% palladium on carbon (50% wet) (3 g) as a catalyst under a hydrogen pressure of 2.5-3.0 Kg/cm2. The reaction progression was monitored by HPLC. Upon completion, dichloromethane (500 ml) was added to the reaction mass and the obtained solution was filtered through hyflo bed. After evaporation of the solvents under reduced pressure, fresh dichloromethane (200 ml) was added to the residue followed by addition of isopropanolic HCl (~13-18%) (120 ml) under stirring to precipitate out 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride (CMHP.HCl). After evaporation of dichloromethane under reduced pressure, isopropanol (500 ml) was added to the reaction mass. The reaction solution was stirred for 60 minutesand the solid material was filtered and suck dried to yield CMHP.HCl.
CMHP.HCl was then dissolved in methanol (1000 ml) and 4-chlorotoluene (120 ml) and hydrogenated using 10% palladium on carbon (50% wet) (16 g) as a catalyst under a hydrogen pressure of 6.5-7.5 Kg/cm2 at 40-45°C. The reaction progression was monitored by HPLC.Upon completion, the reaction solution was filtered through hyflo bed and solvent from the filtrate was evaporated under reduced pressureat 50-80°C. Process water (80 ml) was added to the residue and the obtained solution was stirred at 80-85°C for 30-45 minutes; after cooling the solution to room temperature, toluene (80 ml) was added and the solution was further stirred for 50-60 minutes. The layers were separated and aqueous layer was treated with potassium acetate (60 g) followed by cooling to 0-10°C and stirred for 45-60 minutes. The solid material was filtered and heated with isopropyl acetate (1600 ml) at reflux temperature. The reaction mass was then cooled and filtered. The solid material obtained was dried under vacuum at below 70°C to get 40 g of 3-(2-Chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (CMHTP). (HPLC purity >99%)

Stage- 2 Preparation of Paliperidone Crude
A mixture of 3-(2-Chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (CMHTP, 100 g), 6-Fluoro-3-(piperidin-4-yl)1,2-benzisoxazole hydrochloride (FBIP, 106 g), diisopropylamine (DIPA) (98 g) and methanol (500 ml) was heated to 60-70°C and stirred for 24hours. After completion of the reaction, the reaction mixture was cooled to 25-35°C and stirred for 30 minutes followed by further cooling to 0-5°C and further stirring for 60 minutes. The solid material was filtered and crystallized in mixture of acetonitrile (2400 ml) and water (600 ml) to afford 140 g Paliperidone crude. (HPLC purity >98%).
Stage- 3 Preparation of Paliperidone API
Paliperidone crude (100 g) was dissolved in dichloromethane (200 ml) and added a solution of oxalic acid dihydrate (15 g) in methanol (200 ml) at 30-40°C. The reaction mixture was stirred for 1 hour and then cooled to 0-5°C. The reaction mixture was further stirred for 45 minutes at 0-5°C followed by filtration. The solid material was then dissolved in a mixture of isopropanol (900 ml) and water (1500 ml) and treated with sodium dithionite (20 g) and the solution mixturewas stirred for 15-30 minutes. After filtration, the filtrate was treated with liq. ammonia (80 ml) and the reaction mixture was stirred for 1 hour at ambient temperature; the mixture was then cooled to 0-5°C and further stirred for 1-2 hours. The solid obtained was filtered and washed with process water followed by treatment with ethanol (500 ml). The solid material obtained was dried under reduced pressure at 50-80°C to obtain 85 g of Paliperidone API. (HPLC Purity >99.5%; keto impurity: 0.02%).

Stage – 4 Preparation of Paliperidone palmitate:
To a solution of triethylamine (130 ml) in toluene (500 ml) was added palmitic acid (120 g) and the reaction solution was stirred at ambient temperature for 15 minutes. Benzoyl chloride (38 ml) was then added and the reaction was stirred at ambient temperature for 90 minutes. Paliperidone (100 g) and a catalytic amount of N,N-dimethylaminopyridine (DMAP, 14.5 g) were further added and the reaction solution was stirred for 2 hours at 80-85°C. After evaporation of the solvents under reduced pressure, dichloromethane (1400 ml) and water (800 ml) were added to the residue obtained and solution mixed for 15 to 20 minutes. After separation of the phases, the organic phase was evaporated under reduced pressure and the residue recrystallized twice from ethanol to afford 120 g of Paliperidone palmitate. (HPLC purity >99.5%).

While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the scope thereof, as defined in the appended claims.