WO2009010988A1

WO2009010988A1 - An improved, industrially viable process for the preparation of high purity paliperidone

Info

Publication number: WO2009010988A1
Application number: PCT/IN2008/000446
Authority: WO
Inventors: Janaki Rama Rao Ravi; Muddasani Pulla Reddy; Bhujanga Rao Adibhatla Kali Satya; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2007-07-19
Filing date: 2008-07-14
Publication date: 2009-01-22

Abstract

The present invention relates to an improved and industrially viable process for the preparation of high purity ≥ 99.8% chemical of paliperidone of formula-I (3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetra-hydro-9-hydroxy-2- methyl-4H-pyrido[l,2-a]pyrimidin-4-one), involving the novel intermediate, 3-(2- hydroxyethyl)-2-methyl-9-(phenylmethoxy)-4H-Pyrido[l,2-a]pyrimidin-4-one of formula-II. All intermediates encountered in the synthetic pathway of present invention are isolated by simple crystallization techniques in high pure. Paliperidone is useful as anti-psychotic agent in the treatment of psychotic disorders and is marketed under the brand name INVEGA.

Description

AN IMPROVED, INDUSTRIALLY VIABLE PROCESS FOR THE PREPARATION OF HIGH PURITY PALIPERIDONE

FIELD OF INVENTION:

The present invention relates to an improved and industrially viable process for the preparation of high purity paliperidone of formula I₅ involving the novel intermediate, 3-(2-hydroxyethyl)-2-methyl-9-(phenylmethoxy)-4H-Pyrido[l,2-a]pyrimidin-4-one of formula-II. Paliperidone, 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l- piperidinyl]ethyl]-6,7,8,9-tetra-hydro-9-hydroxy-2-methyl-4H-pyrido[l,2- a]pyrimidin-4-one is useful as anti-psychotic agent in the treatment of psychotic disorders.

I

BACKGROUND OF INVENTION:

Paliperidone (I) is reported for the first time by Janssen Pharmaceutica N.V. in the US patent 5158952 (1992). The corresponding European patent is EP 0368388.

The aforesaid US patent describes a process for the preparation of paliperidone of formula-I. Accordingly, 3-(ρhenylmethoxy)-2-pyridinamine of formula-Ill is reacted with 3-acetyl-4,5-dihydro-2-(3H)-furanone of formula-IV in the presence of phosphoryl chloride in toluene medium at 90°C to yield 3-(2-chloroethyl)-2-methyl- 9-(phenylmethoxy)-4H-pyrido[l,2-a] pyrimidin-4-one of formula-V (Scheme-I). Compound of formula-V is hydrogenated at room temperature in the presence of 10% palladium-on-charcoal catalyst to get 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy- 2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one of formula- VI. Compound of formula- VI is reacted with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole monohydrochloride of formula- VII in the presence of diisopropylamine base to get paliperidone of formula- I.

I

Scheme-I

Following are the principal drawbacks of the above mentioned process, i) Requirement of column chromatography technique using halogenated solvents for the isolation of compound of formula V and final product. Column chromatography technique is not suitable for plant scale operations and usage of halogenated solvents is environment unfriendly, ii) Overall yield is low (10%). iii) Quality of paliperidone is not mentioned in the above process.

Upon repetition of the process in our laboratory we observed a lot of gummy material formed in the first step. Color and quality of paliperidone was found to be not suitable for pharmaceutical usage.

Extensive study of the above process in our laboratory led us to the following observations.

(1) Reaction between compounds of formula-Ill and IV in step-I showed formation of lot of impurities on TLC. During isolation of compound of formula- V, lot of ammonia was required. After the neutralization, a tar type insoluble product was observed. Removal of this impurity required column chromatography.

(2) Catalytic hydrogenation of compound of formula-V under pressure also showed generation of lot of impurities on TLC. The pure compound of formula-VI could not be isolated even after employing column chromatography technique. Koen De Smet also mentioned the formation of impurities in the hydrogenation of compound of formula-VI (Org. Proc. Res. Dev., 2005, 9, 344). Some of the impurities listed in this journal are given below.

(3) Quality of paliperidone is not meeting the pharmacoepial requirements. This is mainly due to the usage of impure compound of formula-VI in the paliperidone formation step.

In the above mentioned journal, a process for the preparation of compound of formula VI (as HCl salt) is disclosed starting from the HCl salt of compound of formula-XI

(Scheme-II). A process for the preparation of starting compound of formula XI is not given in this publication. Compound of formula-XI is subjected to hydrogenation in the presence of 10% palladium-on-carbon at 50⁰C and 150mbar pressure. Progress of the reaction was followed by near IR spectroscopy. Yield of required product is 69% with 99.4% purity. Composition of remaining 31% was not disclosed in this publication.

Scheme-II

During the study of this process in our laboratory we observed that maintaining constantly 150mbar pressure at 5O⁰C and following the progress of the reaction by near IR is difficult and not feasible

A process for the preparation of 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H- pyrido[l,2-a] pyrimidin-4-one of formula-XII is disclosed in WO2006/027370. The process comprises the reaction between 2-amino-3-hydroxypyridine of formula-XIII and 3-acetyl-4,5-dihydro-2-(3H) furanone of formula-IV in toluene medium in the presence of an acid catalyst to get the compound of formula-XII in 67% yield (Scheme-Ill). It is mentioned in this patent that the intermediate compound of formula XII is converted to 2-chloroethyl derivative by reaction with thionyl chloride in DMF. No further details like reaction conditions, yield and quality of product are disclosed.

XiIi iv XN

Scheme-Ill

In a recently published PCT publication WO 2008/021342 A2, authors disclosed the crystalline forms of paliperidone of formula-I. According to this application paliperidone was prepared by coupling a compound of formula-VI with compound of formula- VII in solvents like N, N-dimethylformamide, acetonitrile, and isopropyl alcohol in the presence of sodium carbonate. The crude paliperidone was crystallized from acetonitrile to get more than 90% purity. Recrystallization of this material from various solvents produced various polymorphic forms of paliperidone. However, purity of the paliperidone is not disclosed in this patent application.

During the study of above process in our laboratory we observed that the purity of paliperidone produced is not exceeding 98%. Therefore, purity of paliperidone obtained from the above processes is not suitable for pharmaceutical applications.

In another recent PCT publication WO 2008/021346, a process for the purification of paliperidone containing two identified impurities, namely, 3-[2-[4-(6- fluorobenzo[d]isoxazol-3-yl-oxypiperidin-l-yl]ethyl]-7-hydroxy-4-methyl-l,5- diazabicyclo[4.4.0]deca-3,5-dien-2-one of formula-XTV and 2-[4-(6-fluoro-l,2- benzisoxazol-3-yl)piperidin-l-carboxylic acid]-7-hydroxy-2-methyl-6,7,8,9- tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one-3-yl-ethyl ester of formula-XV was disclosed.

As used therein the term "PLP-NO" refers to compound of formula-XIV and the term "PLP-car" refer to compound of formula-XV.

The process described for purification of paliperidone involves conventional techniques such as recrystallization, precipitation by adding anti-solvent and slurrying in an organic solvent at different temperatures, etc.

According to data given in this patent, it was observed that all purification techniques reduced the impurity level of compound of formula-XIV (PLP-NO) in paliperidone from 0.67% to 0.35% and from 0.41% to 0.20% only. Repetition of purification process was required to reduce impurity level further. It is also observed that the same thing in the purification of paliperidone containing impurity of formula-XV (PLP- car). Yield of the product was not mentioned in these purification processes.

Upon repetition of the process given in above-mentioned patent in our laboratory we observed that the level of above identified impurities could not be brought down to below 0.1%. Recovery of paliperidone was also 40-70% only. Therefore, the purification processes described in PCT publication WO 2008/021346 are not suitable for preparation of pharmaceutically acceptable grade paliperidone of formula I.

Impurities in paliperidone or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dose form containing the API. The International Conference on Harmonization of Technical Requirements for Registration for Human Use ("ICH") Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials. Hence there is a need to develop an improved and commercially viable process for preparing pharmaceutically acceptable grade paliperidone. SUMMARY OF INVENTION:

Keeping in view of the difficulties in commercialization of the above mentioned processes for the preparation of pure paliperidone, we aimed to develop a simple and economical process for commercial production of paliperidone, by introducing a novel intermediate of formula-II.

We observed that a promising approach for a process for the preparation of pharmaceutically acceptable grade paliperidone would be:

a) To avoid the formation of tar like polymeric materials in stage-I, which decreases yield and quality of final product. b) To avoid the column chromatography technique used for the purification of compound of formulae-V and I. c) Improve the process parameters such as avoiding high temperature and sub- atmospheric pressure used in hydrogenation stage.

Accordingly, the main objective of the present invention is to provide an improved process for the preparation of paliperidone, which is commercially applicable.

Another objective of the present invention is to provide an improved process for the preparation of paliperidone avoiding the column chromatography purification technique for isolating intermediate compound of formula-V and paliperidone of formula-I thereby making the process further simpler and economical.

Still another objective of the present invention is to provide an improved process for the preparation of paliperidone avoiding the sub-atmospheric pressure reaction condition during hydrogenation stage and yet another objective of the present invention is to provide an improved process for the preparation of paliperidone, wherein the over all yield is consistent during scale-up operations.

Still another objective of the present invention is to provide an improved process for the preparation of pharmaceutically acceptable paliperidone of the formula-I which is directly obtained from the reaction mass by simple crystallization techniques. DESCRIPTION OF INVENTION:

Accordingly, the present invention provides an improved process for the preparation of paliperidone of formula-I as given in Scheme-IV.

Scheme-IV

The process comprises of: (i) Reaction of 3-(phenylmethoxy)-2-pyridinamine of formula-iπ

with 3-acetyl-4,5-dihydro-2-(3H)-fiiranone of formula-IV

in the presence of catalytic amount of acid catalyst, in hydrocarbon solvent at elevated temperature to yield the novel compound, 3-(2-hydroxyethyl)-2- methyl-9-(phenylmethoxy)-4H-pyrido[ 1 ,2-a]pyrimidin-4-one of formula-II

(«) Chlorination of compound of formula-II with a chlorinating agent at elevated temperature in the presence or absence of a solvent to get the solid chloro compound of formula- V after triturating with a suitable solvent.

(iii) Debenzylation of compound of formula- V by treating with an acid at elevated temperature to get the acid addition salt of debenzylated compound of formula-XI

Xl (iv) Hydrogenation of compound of formula XI using a metal catalyst in the presence of a solvent under hydrogen bubbling conditions (atmospheric pressure) to get the hydrogenated compound of formula-VI

(V) Reaction of compound of formula-VI with the amino compound of formula- VII

VII in the presence of a base in a polar solvent medium at elevated temperature to get crude paliperidone of formula-I.

(vi) Purification of crude paliperidone by recrystallization from a suitable solvent OR

(vii) Optionally purification by a suitable chemical method. The acid catalyst used in step (i) can be selected from a group consisting of mineral acids such as sulphuric acid, nitric acid, hydrochloric acid, phosphoric acid and an organic acid such as p-toluenesulphonic acid, methanesulphonic acid and the like, preferably sulphuric acid and p-toluene sulphonic acid more preferably sulphuric acid. The hydrocarbon solvent used in step (i) is selected from toluene, xylene, mesitylene, chlorobenzene, fluorobenzene, cyclohexane, preferably toluene, cyclohexane more preferably cyclohexane. Preferred temperature of the reaction mass in step (i) is 75°C -150°C, preferably 80-120⁰C more preferably 80-90⁰C. The product formed in the reaction is simply isolated by crystallization from solvents such as toluene and ethyl acetate. The melting point of compound of formula-II is 132 to 138°C and the purity is found to be >99% by HPLC.

The chlorinating reagent used in step (ii) is selected from thionyl chloride, POCb PCl₃, or PCI₅, preferably POCI₃. The solvent used in step (ii) is selected from hydrocarbon solvents like, cyclohexane, heptane, toluene, xylene, preferably toluene or cyclohexane. The temperature of the reaction is reflux or below reflux temperature of the solvent employed in the reaction. The reaction is carried out preferably in the presence of excess reagent as a solvent. The excess reagent is removed from the reaction mass by distillation and reused for the same purpose. The product is isolated by simple crystallization from alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; preferably alcohol, more preferably isopropanol. Purity of isolated product was found to be more than 99% by HPLC. The benzylating agent, used for debenzylation of compound of formula-V in step (iii) is selected from aq. mineral acids like aq. HBr, aq. HCl, sulphuric acid; Lewis acids like aluminum chloride, boron trifluoride, boron trichloride, ferric chloride etc. preferable aq. mineral acids more preferably aq. HCl. Amount of aq. HBr used in step (iii) is preferably 5 to 10 molar equivalents. Yield of the required product is 85-95% and the purity by HPLC is >99%. Product is isolated directly from the reaction mass by simple filtration.

The metal catalyst used in step (iv) is selected from 1-20% palladium-on-carbon, preferably, 10%. The hydrogenation is performed by bubbling hydrogen gas into the reaction mass. Avoiding sub-atmospheric pressure and elevated temperature in the reaction helped in controlling the formation of impurities. Yield and quality of compound of formula- VI is improved. It is found that the hydrogenation can be done on both hydrochloride and hydrobromide salt without affecting the yield and quality of required product, it is found to be hydrochloride salt seems to be better.

The base used in step (v) is selected from alkali metal and alkali earth metal carbonates, bicarbonates, hydroxides; organic bases such as secondary and tertiary alkyl amines such as triethyl amine, diisopropyl amine, diisopropyl ethyl amine etc. Preferably alkali metal carbonates more preferably potassium carbonate. The solvent employed in the reaction is selected .from dipolar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, N-methylpyrrolidone, hydrocarbon solvents such as toluene, cyclohexane, xylene, etα preferably dimethyl formamide. The temperature of reaction is 40-150⁰C, preferably 50-75⁰C more preferably 60-65⁰C.

The solvent used for recrystallization of product is selected from aliphatic alcohols from C₁-C₃, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone etc, chlorinated solvents like dichloro methane, chloroform, carbon tetra chloride, ethylene chloride etc, cyclic ethers such tetra hydro fϊiran, esters like ethyl acetate, isopropyl acetate, methyl acetate etc, amides like N,N-dimethylformamide, N₅N- dimethylacetamide, etc., preferably aliphatic alcohols, more preferably methanol. The suitable chemical method employed for purification of paliperidone in step-(v) is carried out by choosing inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid etc, organic acids such as acetic acid, oxalic acid, p-toluene sulphonic acid, methane sulphonic acid etc. preferably inorganic acids, more preferably hydrochloric acid. Purity of paliperidone by HPLC is > 99.8%.

Compared to the prior art process, the present process gives higher (35%) yield and better quality (> 99.8%) of paliperidone.

The present invention is illustrated by the following examples, which is not intended to limit the effective scope of the invention.

Example 1

Preparation of 3-(2-Hydroxyethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[l,2- a]pyrimidin-4-one (Formula-H)

Into a clean and dry 5L, four-necked RB flask, equipped with shaft, condenser, Dean- Strack apparatus, thermo socket, addition funnel and stopper was charged 15O g (0.78 moles) of 3-(phenylmethoxy)-2-pyridinamine and 2500ml of cyclohexane. The reaction mass was kept under stirring and 192 g (1.498 moles) of alpha-acetyl- butyrolactone was added dropwise through addition funnel during 30-40 min period.

Addition funnel was rinsed with 100ml of cyclohexane and charged to the reaction mass. Cone, sulphuric acid (18.36g; 0.1872 moles) was added slowly to the reaction mass by using addition funnel, and the addition funnel was rinsed with 100ml of cyclohexane. Reaction mass was heated to reflux temperature and maintained for 30h.

Solvent was distilled off from the reaction mass under mild vacuum and applied high vaccum at the end of distillation. To the yellow colored semisolid residue 990ml of methylene chloride and 345ml of DM water were added and stirred for lOmin. Layers were separated. The organic layer was dried over sodium sulfate, filtered and distilled of solvent keeping the temperature below 40⁰C to yield ~ 350g of brown colored crystalline mass.

To the above crystalline mass 150ml of toluene was added and the resulting suspension was stirred for Ih at room temperature (25-30°C). The reaction mass was filtered and the wet cake washed with 100ml of chilled (0-5°C) toluene. The wet solid was suction dried for 15min to yield 130 g of title compound. .

The filtrate obtained above was transferred into a 500ml, single-necked RB flask and distilled off at solvent at 70-75⁰C on rotavapor under plant vacuum. The resulting solution containing some toluene was stirred at 25-30⁰C for 30-45 min and filtered to get 15 of title compound as second crop. Combined 1^st and 2^nd crop material was dried in a drier at 70-75⁰C for 4-5h to get 142 g (61.07%) title compound. Melting point: 135 - 139°C. Purity by HPLC is > 99.5%. ¹H-NMR (CDCl₃): 2.56 (s, 3H, - CH₃), 2.97 (t, 2H, -CH₂CH₂OH, J = 7.8Hz), 4.35 (t, 2H₅ -CH₂CH₂OH, J = 7.8 Hz), 5.19 (s, 2H, bezylic CH₂), 6.80 - 7.80 (m, 8H, aromatic H), and 11.0 (s, IH, -OH). Example 2

Preparation of 3-(2-Chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[l,2- a]pyrimidin-4-one (Formula- V) Into a clean and dry 3L, three-necked RB flask equipped with shaft, condenser, CaCl₂ guard tube and thermo socket was charged lOOg (0.322 moles) of 3-(2- Hydroxyethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[l,2-a]pyrimidin-4-one (formula-II) and 250ml (2.682 moles) of phosphorus oxychloride. The reaction mass was stirred to dissolve the solids. The reaction mass was heated to 100-110⁰C and maintained for 2.5h.

Excess phosphorus oxychloride was distilled of from the reaction mass under mild vacuum keeping the bath temperature at 110-120⁰C. The dark pink colored residue was cooled to 35-40⁰C and charged lOOOg of ice. After stirring the reaction mass for lOmin, 250ml of water was added and extracted the product into 1000ml of methylene chloride. Organic layer was separated and washed with 2 x 1000ml of water. The separated organic layer was dried over sodium sulfate and the solvent distilled of using rotavapor. Finally vacuum was applied to get 90 g of crude title compound as pink colored solid.

The above solid was triturated with 475ml of isopropyl alcohol, stirred for Ih at 25- 30⁰C. The slurry was filtered under vacuum and the solid washed with 270ml of chilled (0-5⁰C) isopropyl alcohol. The wet solid was dried at 70-75⁰C for 4-5h in a drier, to afford 76g (71.7%) of required product. Melting point: 136 - 14O⁰C, Purity by HPLC is > 99.5%. ¹H-NMR (CDCl₃): 2.64 (s, 3H, -CH₃), 3.20 (t, 2H, - CH₂CH₂Cl, J = 6.84 Hz), 3.83 (t, 2H, -CH₂ CH₂Cl, J = 6.84 Hz), 5.39 (s, 2H, bezylicCH₂), 6.92 (m, 2H, aromatic-H), 7.30-7.47 (m, 5H aromatic-H), and 8.60 (m, IH aromatic-H).

Example 3 Preparation of 3-(2-ChIoroethyI)-9-hydroxy-2-methyl-4H-pyrido[l,2- a]pyrimidin-4-one mono hydrobromide (FormuIa-XI)

Into a clean and dry 2L, three-necked RB flask equipped with shaft, condenser and thermo socket was charged 20Og (0.608 moles) of compound of formula-V obtained in Example 2, 1000 ml (5.930 moles) of 48% aq. hydrobromic acid and stirred the resulting reaction mass at 50-55°C for 5h. The reaction mass was cooled to 25-3O⁰C, stirred for Ih and filtered under vaccum to get 23O g of title compound as wet solid.

The above solid and 1000ml of acetone were charged into a 2L, RB flask and stirred at 25-3O⁰C for 45min. The reaction mass was filtered and the solid dried in a drier at 70-75⁰C for 6-8 h to get 194.46 g (88.45%) of the required product. Purity by HPLC is > 97%.

Example 4 Preparation of 3-(2-Chloroethyl)-9-hydroxy-2-methyI-4H-pyrido[l,2- a]pyrimidin-4-one mono hydrochloride (formula-XI)

Into a clean 2L, three-necked RB flask equipped with shaft, condenser and thermo socket was charged 20Og (0.608 moles) of compound of formula-V obtained from Example 2, 640ml of cone, hydrochloric acid and stirred to dissolve. The reaction mass was heated to 70-75⁰C and maintained for 2.5h. The reaction mass was cooled to 25-30⁰C, charged 640ml of acetone and further cooled to 5-10⁰C, stirred for Ih. The reaction mass was filtered of under suction and.

The above wet cake was charged into a 2L, RB flask containing 1600ml of acetone. The resultant suspension as stirred at 25-30⁰C for 45min and filtered under vacuum to get 143 g of wet solid. The wet product was dried in a drier at 70-75⁰C for 6-8 h to get 139g (82.82%) of the title product as white crystalline solid. Purity by HPLC is > 99.5%. ¹H-NMR (DMSOd₆): 2.58 (s, 3H, -CH₃), 3.06 (t, 2H, CH₂CH₂Cl , J = 7.14 Hz), 3.80 (t, 2H, CH₂CuCl, J =7.14 Hz), 7.38 (m, IH, aromatic-H), 7.49 (m, IH, aromatic-H), 8.5 (d, IH, aromatic-H J= 6.67), and 11.0-12.2 (br s, IH, -OH, exchangeable with D₂O).

Example 5

Preparation of 3-(2-Chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H-pyrido[l,2- a]pyrimidin-4-one ( formula- VI)

Into a clean and dry 3L, four-necked RB flask equipped with shaft, condenser, gas passing tube and thermo socket was charged lOOg (0.363 moles) of (2-chloroethyl)-9- hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one mono hydrochloride (formula- XI) and 2000ml of methanol. The reaction mass was slowly heated to 50-55⁰C using a water bath. After reaching 50-55⁰C, 2Og of 10% palladium-on-charcoal catalyst was charged and hydrogen gas was slowly bubbled into the reaction mass. Progress of the reaction was monitored by TLC and found to be over after 8h.

Reaction mass was filtered of and the filtrate is evaporated at 60-65°C on a rotavapor under vacuum to get yellow colored syrup. The syrup was dissolved in 370ml of water at 80-82⁰C and cooled to 25-35°C. Aqueous potassium acetate (prepared from 71.28 g of potassium acetate and 70ml of water) was added to the reaction mass. The resulting suspension was cooled to 5-10⁰C, stirred for 2h and filtered under suction, washed with 200ml of water to get 92g of wet solid.

The above wet solid was recrystallized from methanol to yield 60.2Og (yield 68.25%) the title compound. Melting point: 102-105⁰C. Purity by HPLC is >97%. ¹H-NMR (CDCl₃): 1.8 (m, IH, aliphatic-H), 1.96 (m, IH, aliphatic-H), 2.16 (m, IH, aliphatic- H)₅ 2.37 (m, 4H, aliphatic-H), 3.0 (m, 2H aliphatic-H,), 3.75 (t, 2H, -CH2-, J= 6.84 Hz), 3.97 (m, 2H₅ aliphatic-H), 4.17 (s, IH₅ -OH₅ D2O exchangeable), and 4.50 (m, IH, aliphatic-H).

Example 6 Preparation of paliperidone 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l- piperidinyI]-ethyl]-6,7,8,9-tetra-hydro-9-hydroxy-2-methyI-4H-pyrido[l,2- a]pyrimidin-4-one (paliperidone, formula-I)

Into a clean 2L, three-necked RB flask equipped with shaft, condenser, and thermo socket was charged 600 ml of DMF, lOOg (0.404 moles) of 3-(2-Chloroethyl)-6,7,8,9- tetrahydro-9-hydroxy-4H-pyrido[l₅2-a]pyrimidin-4-one of formula- VI obtained from Example 5, 67.19g (0.404 moles) of potassium iodide, 111.91g (0.808moles) of potassium, carbonate and 103.68g (0.404 moles) of 6- fluoro-3-(4- piperidinyl)-l,2- benzisoxazole HCl (formula-VII). The reaction mass was heated to 60-65⁰C and maintained for 18h. Reaction mass was cooled to 25-30⁰C, stirred for Ih and filtered under vacuum. The wet cake was washed with 200ml of DMF. The wet cake was leached with 2 x 500ml of water and 1 x 500ml of methanol. The wet material was dried in the oven at 70-75⁰C for Ih to yield 114g of technical grade paliperidone. Above technical grade paliperidone was recrystallized from methanol via charcoal treatment to get 6Og (34.74% yield) of pure paliperidone. Purity by HPLC is > 99.8%.

S Alternatively technical grade paliperidone was purified by the following chemical method.

Above technical grade paliperidone (114g) was dissolved in 6.84L of methanol at 65- 7O⁰C. Charcoal (20 g) was added to the resultant solution and filtered under vacuum using a filter aid. The solvent was distilled of from the filtrate at 60-65⁰C using0 rotavapor under vacuum to get a cream colored solid. Methanol (575 ml) was added to the solid and stirred for 45min at 25-30⁰C. The reaction mass was filtered and dried in an oven at 70-75⁰C to get 90 g of paliperidone.

Into a clean and dry IL, three-necked RB flask equipped with shaft, thermo socket,5 addition funnel and stopper was charged 57.0 ml of cone. HCl and 570 ml of water.

The reaction mass was stirred for 5min and charged the above solid (9Og). The reaction mass was stirred for 5-10min at 25-30⁰C to get yellow colored clear liquid. pH of the reaction mass was adjusted to 6.0 to 6.5 by dropwise addition of dilute

(concentrated aq ammonia solution was diluted with equal volume of water) aq.0 ammonia solution. The reaction mass was stirred for 30min and filtered under vacuum. The wet solid was dried in the oven at 70-75⁰C to get 88g of paliperidone

HCl.

Above solid was transferred taken into a IL RB flask containing 570 ml of methanol.5 The suspension was stirred for 30min at 25-3O⁰C, filtered under vacuum and dried in the oven at 70-75⁰C for Ih to get 85 g pure paliperidone HCl. HPLC purity is > 99.80%.

Above paliperidone HCl salt (85.0 g) and 2280 ml of water were suspended in a RB0 flask at 25-30⁰C. pH was adjusted to 8.5 to 9.0 by adding aq. potassium carbonate solution (prepared from 57 g of potassium carbonate and 570 ml of water). The resultant cream-colored suspension was stirred for 30 min at 25-30⁰C and filtered under vacuum. The wet cake was washed with 1500ml of water followed by 300ml of methanol. The wet cake was triturated with 450 ml of methanol for 30 min and filtered. Paliperidone was dried in vacuum oven at 65-70°C for 4h to afford 59 g (34.33%) of pure paliperidone. Purity by HPLC is > 99.8%. ¹H-NMR (CDCl₃): 1.75 (m, 2H, aliphatic-H), 1.95 (m, IH, aliphatic-H), 2.15 (m, 5H, aliphatic-H), 2.24 -2.40 (m, 5H, aliphatic-H), 2.56 (t, 2H, -CH₂-, J = 6.84 Hz), 2.76 (t, 2H, -CH₂-, J = 7.82 Hz), 3.09 (m, IH, aliphatic-H), 3.18 (d, 2H, aliphatic-H, J =11.72 Hz), 3.92 (m, 2H, aliphatic-H), 4.15 (s, IH, -OH, D₂O exchangeable), 4.50 (dd, IH, aliphatic-H J = 3.91 Hz), 7.07 (m, IH, aromatic-H), 7.23 (m, IH aromatic-H), 7.70 (dd, IH, aromatic-H, J= 2.93 Hz).

ADVANTAGES OF PRESENT INVENTION:

The present invention is having the following advantages.

1. Present process avoids the column chromatography technique to purify the compound of formula- V as well as final product, paliperidone. 2. Present process avoids the formation of tar like polymeric materials in reaction step.

3. Present process avoids the usage of hydrogen at sub-atmospheric pressure during catalytic hydrogenation process in step (iii).

4. Present process employs simple crystallization techniques to isolate or recrystallize paliperidone.

5. Present process provides a simple, improved, and efficient process suitable for plant scale level by employing simple reaction conditions.

Claims

WE CLAIM:

1. The present invention discloses an improved and industrially viable process for the preparation of high purity (> 99.80% by HPLC) paliperidone of formula-I,

I involving the novel intermediate of formula-II,

which comprises:

(i) Reaction of 3-(phenylmethoxy)-2-pyridinamine of formula-Ill,

with 3-acetyl-4,5-dihydro-2-(3H)-furanone of formula-IV

IV in the presence of an acid catalyst, in a hydrocarbon solvent at elevated temperature to yield the novel compound, 3-(2-hydroxyethyl)-2-methyl-9- (phenylmethoxy)-4H-pyrido[l,2-a]pyrimidin-4-one of formula-II after recrystallization from a solvent

(U) Chlorination of compound of formula-II with a chlorinating agent at elevated temperature in the presence or absence of a solvent to get the solid chloro compound of formula- V after triturating with a suitable solvent.

Xl

HX = HCl₅ HBr₅ H₂SO₄,

(iv) Hydrogenatϊon of compound of formula XI using a metal catalyst in the presence of a solvent under hydrogen bubbling conditions (atmospheric pressure) to get the hydrogenated compound of formula-VI after crystallization from a solvent

(V) Reaction of compound of formula-VI with the amino compound of formula- VII

(vii) Optionally purification by a suitable chemical method.

2. The process according to claim 1, wherein the acid catalyst used in step (i) is selected from a group consisting of mineral acids such as sulphuric acid, nitric acid, hydrochloric acid, phosphoric acid; organic acids such as p-toluenesulphonic acid, methanesulphonic acid and the like, preferably sulphuric acid or p-toluenesulphonic acid, more preferably sulphuric acid.

3. The process according to claims 1 and 2 wherein the hydrocarbon solvent used in step (i) is selected from toluene, xylene, mesitylene, chlorobenzene, fluorobenzene, cyclohexane, preferably toluene or cyclohexane, more preferably cyclohexane.

4. The process according to claims 1-3 wherein the temperature of the reaction mass in step (i) is 75-150°C, preferably 80-120⁰C, more preferably 80-90⁰C.

5. The process according to claims 1-4 wherein the solvent used for crystallization of compound of formula-II in step (i) is selected from hydrocarbons such as cyclohexane, hexane, heptane, benzene, toluene, xylene, etc.; esters such as ethyl acetate, methyl acetate, isopropyl acetate, etc; ketones like acetone, ethyl methyl ketone, methyl isobutyl ketone, etc; preferably aromatic hydrocarbon solvent, more preferably toluene.

6. The process according to claims 1-5 wherein the chlorinating reagent used in step (ii) is selected from thionyl chloride, POCl₃, PCl₃, or PCl₅, preferably POCl₃.

7. The process according to claims 1-6 wherein the solvent used in step (ii) is selected from hydrocarbon solvents like, cyclohexane, heptane, toluene, xylene, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, or chlorinating agent itself employed in the reaction, preferably toluene or cyclohexane, more preferably, phosphorus oxychloride.

8. The process according to claims 1-7, wherein the temperature of the reaction mass in step (ii) is preferably 80-120°C, more preferably 90-110°C.

9. The process according to claims 1-8, wherein the solvent used in step (ii) for crystallization of product is selected from alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; preferably alcohol, more preferably isopropanol.

10. The process according to claims 1-9, wherein the acid used in step (iii) is selected from aq. mineral acids like aq. HBr, aq. HCl, sulphuric acid; Lewis acids like aluminum chloride, boron trifluoride, boron trichloride, ferric chloride, etc., preferably aq. mineral acids, more preferably, aq. HCl.

11. The process according to clams 1-10 wherein the temperature of the reaction in step (iii) ranges from 30- 11O⁰C, preferably 50-110°C, more preferably, 70-80⁰C.

12. The process according to claims 1-11, wherein the metal catalyst used for catalytic hydrogenation in step (iv) is selected from 1-20% palladium-on-carbon, preferably, 10% palladium-on-carbon.

13. The process according to claims 1-12, wherein the solvent used for hydrogenation process in step (iv) is selected from polar protic solvents such as C₁-C₄ aliphatic alcohols, aliphatic carboxylic acids such as acetic acid, propionic acid, butyric acid, pentanoic acid, dipolar aprotic solvents such as N, N-dimethylformamide, N, N- dimethylacetamide, etc., preferably aliphatic alcohols, more preferably methanol.

14. The process according to claims 1-13, wherein the solvent used for recrystallization in step (iv) is selected from C₁-C₄ aliphatic alcohols, esters such as ethyl acetate, methyl acetate, isopropyl acetate, etc; ketones like acetone, ethyl methyl ketone, methyl isobutyl ketone, etc; preferably aliphatic alcohols from C₁-C₄, more preferably methanol.

15. The process according to claims 1-14, wherein the base used in step (v) is selected from alkali metal and alkaline earth metal carbonates, bicarbonates, hydroxides; organic bases such as secondary and tertiary alkyl amines such as triethylamine, diisopropylamine, diisopropyl ethyl amine, etc., preferably alkali metal carbonates, more preferably potassium carbonate.

16. The process according to claims 1-15, wherein the solvent employed in step (v) is selected from dipolar aprotic solvents such as N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, hydrocarbon solvents such as toluene, cyclohexane, xylene, etc. preferably N,N-dimethylformamide.

17. The process according to claims 1-16, wherein the temperature of reaction in step (v) is 40-150⁰C, preferably 50-75⁰C, more preferably 60-65⁰C.

18. The process according to claims 1-17, wherein the solvent used for recrystallization of crude paliperidone in step (vi) is selected from aliphatic alcohols such as methanol, ethanol, propanol, isopropyl alcohol, butanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.; chlorinated solvents like dichloromethane, chloroform, carbon tetrachloride, ethylene chloride, etc.; cyclic ethers such as tetrahydrofuran; esters like ethyl acetate, isopropyl acetate, methyl acetate, etc.; amides like N,N-dimethylformamide, N,N-dimethylacetamide, etc., preferably aliphatic alcohols, more preferably methanol.

19. The process according to claims 1-18, wherein the chemical method used for purification of paliperidone in step (vii) comprises: dissolution of technical grade paliperidone in aqueous mineral acid such as hydrochloric acid, adjustment of pH to 3.5-6.5, preferably 4.5-6.5, more preferably 6.0-6.5 using an organic base such as ammonia or an inorganic base such as sodium bicarbonate, isolation of pure paliperidone acid addition salt by filtration, suspension of the salt in water, adjustment of pH of suspension to 8.5-9.0 with an inorganic base such as potassium carbonate or an organic base such as ammonia, filtration of resultant solid and drying after washing with an alcoholic solvent.

20. The compound of formula-II having a melting point of 135 to 139°C and a purity by HPLC of >99%.