WO2010089643A1

WO2010089643A1 - An improved process for the preparation of paliperidone

Info

Publication number: WO2010089643A1
Application number: PCT/IB2010/000178
Authority: WO
Inventors: Keval Rameshchandra Sodagar; Vineet Malik; Sudhir Hukamchand Jain; Sanjay Natvarlal Parikh; Arun Omprakash Sharma; Uday Rajaram Bapat; Indravadan Ambalal Modi
Original assignee: Cadila Pharmaceuticals Ltd
Current assignee: Cadila Pharmaceuticals Ltd
Priority date: 2009-02-03
Filing date: 2010-02-01
Publication date: 2010-08-12
Anticipated expiration: 2011-08-03

Abstract

The invention relates to an improved process for the preparation of Palϊperidone in high yield and purity. The purity of Paliperidone is ~99.7 % by HPLC, wherein total impurity is less than about 0.3 % and each individual impurity is less than about 0.1 %. The invention also relates to provide the alcohol-water co-solvent for the purification of Paliperidone.

Description

TITLE : AN IMPROVED PROCESS FOR THE PREPARATION OF PALIPERIDONE

FIELD OF THE INVENTION

The invention relates to an improved process for the preparation of paliperidone in high yield and purity. The purity of paliperidone obtained by the present invention is ~99.7 % by HPLC₁ wherein total impurity is less than about 0.3 % and each individual impurity is less than about 0.1 %.

BACKGROUND OF THE INVENTION Paliperidone, chemically known as 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1- yπ-ethylJ-θ-hydroxy^-methyl-ej^.θ-tetrahydro^H-pyrido-II^-aJ-pyrimidin-Φoπe is a benz- isoxazole derivative having the structural formula 1.

Paliperidone is known as 9-hydroxy risperidone and useful for the treatment of schizophrenia. 9-hydroxy risperidone is a metabolite of risperidon.

US Patent No. 4,804,663 and 5,158,952 describes a variety of 3-piperidinyM ,2- benzisoxazole derivatives and their processes along with their pharmaceutical compositions and methods of use. Paliperidone was first disclosed in US patent No. 5,158,952, and 5,254,556 (herein after designated as US '952 & US '556 patents respectively). US '952 patent describes process for the synthesis of paliperidone by condensation of 6-fluoro-3- piperidin-4-yI-1 ,2-benzisoxazole hydrochloride (formula-2) and 3-(2-chloroethyl)-9-hydroxy-2- methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidin-4-one (formula-3) in presence of organic base. Both the compounds of formula 2 and formula 3 are key intermediates useful in synthesis of Paliperidone. The benzisoxazole hydrochloride intermediate of formula-2 is commonly used for preparation of Risperidone and Paliperidone.

PCT applications WO 2008/140641 and WO2008/021346 provide processes for the purification of paliperidone. WO2008/021346 describes the purification of paliperidone wherein paliperidone is crystallized by combining a solution of paliperidone in a first solvent followed by addition of an anti solvent and discloses the use of C₁^ alcohol as solvent followed by water as anti-solvent wherein water is used in large quantity. The first solvent is selected from group consisting of dichloromethane, dioxane, and C₁ to C₄ alkyl alcohols. The anti-solvent is selected from group consisting of C₃ to C₆ ketones, C₃ to C₆ ethers, aceton^'rtrile, C₃ to C₇ straight and cyclic carbohydrates and water. PCT applications WO 2008/021345 describes a process for preparing paliperidone comprising reacting 3-(2-chloroethyl)-6,7,8.9-tetrahydro-9-hydroxy-2-methyl-4H-pymdo-[1 ,2- a]- pyrimidin-4-one or salt thereof and 6-fluoro-3-piperidino-1,2-benzisoxazole or salt thereof in the presence of an inorganic base. US publication No. 2005/0232995 A1 in fig.-7 illustrates potential degradation pathways for paliperidone under stress conditions- As Paliperidone, is reported to degrade under certain conditions, like pH, aerial exposure, it is preferable to avoid extensive purification at the finished product stage

The prior art processes described above, provide paliperidone which is contaminated with several impurities, which are difficult to remove by purification of paliperidone.

SUMMARY OF THE INVENTION

The object of present invention is to provide simple, reproducible, cost-effective, industrially scalable process for the preparation of paliperidone giving purity over 99.5%. Another object of the invention is to provide an alternative process for the preparation of paliperidone by reacting 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9- tetrahydro-4W-pyrido-[1,2-a]-pyrimidin-4-one or its acid addition salt with 6-fluoro-3- pϊperidin-4-yl-1 ,2-benzisoxazole or its acid addition salt in presence of an organic base.

Yet another object of the invention is to provide an improved process for purification of paliperidone having each individual impurity < 0.1 %.

Yet another object of the invention is to provide an improved process for purification of paliperidone having total impurity < 0.3 %.

Yet another object of the invention is to provide alcohol-water mixture as an alternate solvent for purification of paliperidone. Yet another object of the invention is to provide alcohol-water mixture as co-solvent for purification of paliperidone wherein co-solvent ration is ranging from 90:10 to 85:15 respectively.

Yet another object of the invention is to minimize the level of impurities like 3-[2-[4-(6- fluoro-1 , 2-benzisoxazol-3-yl)-1 -oxido-piperidin-1 -yl]-€thyl]-9-hydroxy-2-methyl-6, 7,8, 9- tetrahydro-4H-pyrido-[1 ,2-a]-pyrimidϊn-4-one (N-oxide paliperidone) in desired final product.

BREIF DISCRIPTION OF THE DRAWINGS:

Rg. 1-3 HPLC results of products obtained in example 1-3 respectively. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of paliperidone in high yield and purity over 99% by HPLC comprising reaction of 3-(2- chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1 ,2-a]-pyrimidiπ-4-one or its acid addition salt with 6-fluoro-3-pϊperidin-4-y|-1 ,2-benzisoxazole or its acid addition salt in presence of an organic base. In accordance with the present invention, paliperidone is prepared comprising of following steps: a. reacting 3-(2-chloroethy^])-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]-pyrimidin- 4-oπe or its acid addition salt with 6-fluoro-3-piperidin-4-yl-1 ,2-benzisoxazole or its acid addition salt in organic solvent and involving the use of halogen exchange catalyst in presence of an organic base. Thus obtained solid is washed by an organic solvent to give crude paliperidone. b. purifying crude paliperidone from with mixture of an alcohol and water to give pure paliperidone having HPLC purity about 99.7 % and total impurity < 0.3 % wherein specifically each impurity is < 0.1 %.

The N-alkylation process as described above uses an organic solvent which is preferably selected from Ci_-6 alcohol, more preferably methanol. The process is also carried out in presence of an organic base which is preferably nitrogen containing organic base selected from tertiary amines such as (Ri)(R₂)(R₃)N wherein Ri₁R₂, R₃ is preferably Ci.≤ alkyl; N-C_1-4 alkyl, morpholiπe; N- C₁^ alkyl pyrrolidene; N-C_1-4 alkyl piperidine; N-C₁^ alkyl aniline; preferably selected from trilakylamines such as diisopropyl ethyl amine. The halide of halogen exchange catalysis ion is Br or I, preferably iodide. The halogen exchange catalysis reagent is selected from sodium iodide, potassium iodide, cesium iodide, calcium iodide, ammonium iodide preferably potassium iodide. The reaction is carried at 25⁰C to 150⁰C, preferably at 50⁰C to 125⁰C more preferably at 60°C-65°C. The process involves use of water and / or an organic solvent for the washing of solid material wherein the suitable organic solvent is selected from ethyl acetate, 2-propanol, acetonitrile, alcohol, preferably methanol.

The purification of crude paliperidone is carried out using variety of organic solvent. The acetonitrile, DMF, Ethyl acetate, water, acetone, n-pentanol, hexane and mixtures were used for the purification of crude paliperidone. Alcohol water mixture is preferred for the purification of paliperidone.

The crude paliperidone is purified with alcohol and water mixture wherein alcohol is preferred from C_MO alcohol preferably moderately water soluble alcohols. The more preferable alcohol water mixture is C« alcohol and water mixture. The preferred mode of present invention is performed the purification using pentanol water mixture. The present invention provides a particular ratio of n-pentanol and water mixture wherein alcohol becomes miscible at high temperature and provides homogeneous solvent system wherein water acts as a co-solvent. The crystallization of paliperidone is carried out using the co- solvent system. The n-pentanol-water composition ranges from about 85 to 95 n-pentanol with water in 15 to 5 ratio. The preferable composition is n-pentanol : water is 90 : 10. The purification is optionally repeated upon requirement. The paliperidone obtained by above process is having HPLC purity about ~99.7% or more and chemical purity over 99.9%. The total impurity in end product is < 0.3 % and every impurity is < 0.1%.

The instant invention is further illustrated by following non-limiting example. Example-1 Preparation of Paliperidone

100 gm of 6-fluoro-3-piperidin-4-yl-1 , 2-benzisoxazole hydrochloride, 125.8 gm diiso- propylethyl amine, potassium iodide and methanol were stirred at room temperature. The reaction mixture heated with stirring. 100 gm of 3-(2-chloroethyl)-9-hydroxy-2-methy|-6,7,8,9- tetrahydro-4H-pyrido[1 ,2-a]pyrimidiπ-4-one was added with stirring. The reaction mass was cooled to room temperature and stirred for an hour. The reaction mass was filtered and washed with methanol. The wet cake was stirred with water at 50-55⁰C and washed with water. The product was dried under vacuum to give crude paliperidone (120-125 gm) (HPLC Purity > 97 %; Water content < 1 %)

Example-2 Purification of crude paliperidone:

Take solvent or mix. of solvents as given in table 1 in given volume, and heat up to required temperature. Paliperidone is added with stirring to get clear solution. Add required activated charcoal to the solution and stir, filter the reaction through hyflow bed, wash the with one vol. of same solvent.

Cool the filtrate gradually at 5⁰C and stir for 1 hr at 0- 5⁰C. Filter the reaction mass and wash the product with 1 vol solvent. Dry the product under vacuum at 50⁰C. Table: 1 : Purification of crude ali eridone:

Example-3 Purification of crude palϊperidoπe:

Mixture of 2.160L n-pentanol and 240 ml water was heated to about 75⁰C. 120 gm of crude paliperidone was added with stirring. The reaction mass was cooled to about O⁰C and stirred at 0 to -5⁰C The reaction mass was filtered and washed with n-peπtanol : water mixture. The wet cake was taken out and optionally purification is repeated to give 75-80 gm of purified Paliperidone. (HPLC Purity 99.85%)

Example-4 Purification of crude paliperidone:

Mixture of 2.040L n-peπtanol and 360 ml water was heated to about 75⁰C. 120 gm of crude paliperidone was added with stirring. The reaction mass was cooled to about O⁰C and stirred at 0 to -5⁰C. The reaction mass was filtered and washed with n-pentanol : water mixture. The wet cake was taken out and optionally purification is repeated to give 75-80 gm of purified Paliperidone. (HPLC Purity 99.74%; N-oxide impurity is 0.1%)

Example-5 Purification of crude paliperidone:

Mixture of 2.1L n-pentanol and 300 ml water was heated to about 75⁰C. 120 gm of crude paliperidone was added with stirring. The reaction mass was cooled to about O⁰C and stirred at 0 to -5⁰C. The reaction mass was filtered and washed with n-pentanol : water mixture. The wet cake was taken out and optionally purification is repeated to give 75-80 gm of purified Paliperidone. (HPLC Purity 99.83%)

Claims

We claim,

1. An alternative process for the preparation of paliperidone comprising, a. reacting of 6-fluoro-3-piperidin-4-yM ,

2-benzisoxazole or its acid addition salt with 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8_r9-tetrahydro-4H-pyrido-[1_T2- a]-pyrimidin-4-one or its acid addition salt in presence of an organic base b. stirred the reaction mixture followed by heating. c. cooled to room temperature and stirred, d. the reaction mixture is filtered and washed with organic solvent and e. drying to give title compound 2. The process as claimed in claim 1 wherein an organic base is nitrogen containing organic base.

3. The process as claimed in claim 2 wherein an organic base is diiso-propylethyl amine.

4. The process as claimed in claim 1 step (a) wherein the reaction is carried out in presence of halide of halogen exchange catalysis ion.

5. The process as claimed in claim 1 step (a) wherein the halide of halogen exchange catalysis ion is potassium halide.

6. The process as claimed in claim 1 step (a) wherein the reaction is earned out in presence of an alcohol preferably, methanol.

7. An alternative process for the purification of paliperidone comprising, a. crude paliperidone was added to an alcohol:water co-solvent system, b. the reaction mixture is stirred with heating, c. cooling to about 0 to -5⁰C and stirred, d. washing with alcohol : water mixture, e. wet cake is taken out and optionally further purifying f. drying to give pure Paliperidone.

8. The process as claimed in claim 7 wherein an alcohol:water co-solvent system is of n-pentanol : water.

9. The process as claimed in claim 8 wherein n-pentanol : water co-solvent system is having alcohol and water ratio in the range of 90:10 to 85:15.

10. Pure paliperidone as obtained through process of claim 1 or 7 having HPLC purity over 99.7%, wherein total impurity is less than about 0.3 % and each individual impurity is less than about 0.1 %.