WO2012134445A1 - Procédé amélioré pour la préparation de palipéridone - Google Patents

Procédé amélioré pour la préparation de palipéridone Download PDF

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Publication number
WO2012134445A1
WO2012134445A1 PCT/US2011/030302 US2011030302W WO2012134445A1 WO 2012134445 A1 WO2012134445 A1 WO 2012134445A1 US 2011030302 W US2011030302 W US 2011030302W WO 2012134445 A1 WO2012134445 A1 WO 2012134445A1
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Prior art keywords
paliperidone
solvent
buffer
acid
acetone
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English (en)
Inventor
Amit Anant Chavan
Manjunath Narayan Bhanu
Ashutosh Vijay Joshi
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Actavis Laboratories UT Inc
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Actavis Laboratories UT Inc
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Priority to PCT/US2011/030302 priority Critical patent/WO2012134445A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a process for preparation of 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, also known as paliperidone or 9-hydroxy risperidone and intermediates useful in the process.
  • the present invention further relates to a process for the preparation of pure and highly pure paliperidone and a process for the preparation of pure and highly pure paliperidone that is free or substantially free of 3-[2-[4-(6-fluoro-l,2-benzisoxazole-3-yl)-l-piperdinyl]ethyl]- 6,7,8,9-2-methyl-4H-pyrido[l,2-a]pyrimidin-4,9-dione (hereinafter "the 9-oxo impurity").
  • the present invention allows the preparation of pure and highly pure paliperidone without the need of tedious purification steps such as multiple solvent extractions or chromatographic purification such as column chromatography.
  • Paliperidone is an atypical antipsychotic drug developed by Janssen Pharmaceuticals.
  • paliperidone is a primary active metabolite of the antipsychotic drug risperidone.
  • Paliperidone is approved by the FDA for treatment of schizophrenia. It is also effective in the treatment of bipolar mania.
  • U.S. Patent No. 5,688,799 discloses preparation of a precursor of paliperidone, namely, 3-(2-hydroxyethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, by using 2-amino-3- pyridinol, 2-acetyl butyrolactone and p-toluene sulfonic acid.
  • U.S. Publication No. 2007/0260061 Al discloses preparation of a starting material of paliperidone, namely, crystalline 3 -(2-hydroxyethyl)-9-hydroxy-2 -methyl -4H-pyrido[ 1,2- a]pyrimidin-4-one, substantially free of 2-acetylbutyrolactone.
  • U.S. Publication No. 2009/0247553 Al discloses preparation of pure paliperidone or pharmaceutically acceptable salts thereof substantially free of the 9-oxo impurity wherein crude paliperidone or a pharmaceutically acceptable salt of crude paliperidone is dissolved or suspended in a first organic solvent. Solid paliperidone is recovered from the first organic solvent and dissolved in a second organic solvent. The dissolved paliperidone and second organic solvent are then combined with a reducing agent, and the pure paliperidone is isolated from the reaction mass.
  • WO 2008/024415 A2 discloses preparation of intermediates useful in preparing paliperidone such as 3-benzyloxy-2-amino-pyridine ("BOP A”), 3-(2-hydroxyethyl)-6, 7,8,9- tetrahydro-9-benzyloxy-2-methyl-4H-pyrrido[ 1 ,2-a]-pyrimidine-4-one ("HMBP”), 3-(2- chloroethyl)-2-methyl-9-benzyloxy-4H-pyrrido[ 1 ,2-a]-pyrimidine-4-one (“CMBP”), 3-(2- chloroethyl)-2-methyl-9-hydroxy-4H-pyrrido[ 1 ,2-a]-pyrimidine-4-one (“CMHP”), 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidine-4-one (“CMHTP”).
  • BOP A 3-benzyloxy-2-amino-
  • WO 2008/021342 A2 discloses preparation of amorphous and crystalline forms of
  • WO 2008/021345 A2 discloses preparation of paliperidone from CMHTP in a variety of solvents under different reaction conditions.
  • WO 2008/021346 A2 discloses a purification process to obtain paliperidone free of impurities.
  • WO 2008/087557 A2 discloses preparation of intermediates of paliperidone such as 9- hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrrido[ 1 ,2-a]-pyrimidine-4-one and 3-(2-chloroethyl)- 6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2-a]-pyrimidine-4-one.
  • WO 2009/060297 discloses preparation of paliperidone which includes the steps of reacting paliperidone free base with an acid in the presence of an organic solvent, isolating the paliperidone acid addition salt and converting the paliperidone salt to paliperidone free base.
  • the identified acids are hydrochloric, hydrobromic, hydroiodic, ortho phosphoric acid, fumaric acid, and oxalic acid.
  • EP 368388 Bl also discloses preparation of paliperidone (formula I) by condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (hereinafter referred to as "formula II" or "II")
  • EP 368388 Bl further discloses that the compound of formula II is condensed with the compound of formula III in the presence of an amine and methanol to obtain crude paliperidone (I).
  • the crude paliperidone is purified by subjecting the crude paliperidone to two column chromatographic separations using a mixture of methanol and chloroform saturated with ammonia.
  • the paliperidone obtained from the column chromatographic separations is further crystallized by using 2-propanone and finally recrystallized from 2-propanol.
  • the object of the present invention is to provide a simple and efficient process for the preparation of paliperidone.
  • Another object of the present invention is to provide a simple and efficient process for purifying paliperidone that avoids the use of column chromatography and/or eliminates the necessity of column chromatography for separation and/or purification.
  • a further object of the present invention is to provide a simple and efficient process for preparation of intermediates useful in the preparation of paliperidone.
  • An additional object of the present invention is to provide a process for preparation of 3- (2-Chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[ 1 ,2-a]pyrimidin-4-one (formula VI) which can be used in the preparation of paliperidone.
  • the present invention relates to a process for preparation of 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, also referred to as paliperidone, 9-hydroxy risperidone or formula I.
  • the process comprises reacting the compound of formula II with the compound of formula III in inert solvents.
  • the reaction is conducted in the presence of a base or a buffer and at a suitable temperature that avoids and/or eliminates the use of column chromatography.
  • the present invention also relates to processes for the preparation of pure and highly pure paliperidone by means of simple purification techniques.
  • "highly pure paliperidone” refers to paliperidone that is at least 99.5% paliperidone, preferably at least
  • the amount of 9-oxo impurity should be less than 0.5%>, preferably less than 0.3% and most preferably less than 0.1% as determined by HPLC.
  • One embodiment of the invention comprises the preparation of the compound of formula II by hydrogenation of the compound of formulas IV or VI in the presence of a hydrogenation catalyst and hydrogen in an acidic medium.
  • a further aspect of this embodiment produces the compound of formula II with less than 25% of the compound of formula V, preferably less than 20% of the compound of formula V and most preferably less than 15% of the compound of formula V as determined by HPLC.
  • Another embodiment of the invention comprises the preparation of 3-(2-Chloroethyl)-2- methyl-9-hydroxy-4H-pyrido[l,2-a]pyrimidin-4-one (formula VI) by reacting 3-benzyloxy-2- amino pyridine with 2-acetyl butyrolactone and phosphorus oxychloride in the presence of a solvent.
  • This aspect of the invention may also include quenching of the reaction with water or a mixture of water and an organic solvent, adjusting the pH of the reaction and isolation of 3-(2- Chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[l,2-a]pyrimidin-4-one (formula VI).
  • a further aspect of this embodiment may include the step of extracting the compound of formula VI from the quenched reaction mass by use of a suitable extraction solvent such as methylene chloride prior to isolating the compound of formula VI.
  • a suitable extraction solvent such as methylene chloride
  • the compound for formula VI may be isolated without an extraction solvent by adding a suitable base to the quenched reaction mass. Once the compound of formula VI is isolated, it may be crystallized using an appropriate solvent system.
  • a further embodiment of the present invention is a process for the preparation of pure paliperidone that comprises reacting the compound of formula II with the compound of formula III in inert solvents and in the presence of a base or a buffer at a suitable temperature to obtain crude paliperidone.
  • Crude paliperidone refers to paliperidone than is less than 99.3% pure as determined by HPLC.
  • the crude paliperidone is purified into pure or highly pure paliperidone by a process that does not require the use of column chromatography and preferably by direct filtration.
  • An alternative embodiment of the present invention is a process for the purification of the crude paliperidone by reacting the crude paliperidone with an acid to prepare an acid addition salt of paliperidone, isolating the acid addition salt of paliperidone, preferably in a solid form, dissolving or suspending the acid addition salt of paliperidone in a suitable solvent, adding a base to the dissolved or suspended reaction mass of the acid addition salt of paliperidone and isolating pure or highly pure paliperidone from the pH adjusted reaction mass.
  • the pure or highly pure paliperidone may be isolated by direct filtration and without the need for column
  • a still further embodiment of the invention further comprises preparing the compound of formula II by hydrogenation of the compound of formula IV or VI in the presence of a hydrogenation catalyst and hydrogen in an acidic medium to produce the compound of formula II with less than 25% of the compound of formula V, preferably less than 20% of the compound of formula V and most preferably less than 15% of the compound of formula V as determined by HPLC.
  • the compound of formula VI when used in this embodiment is prepared by reacting 3- benzyloxy-2-amino pyridine with 2-acetyl butyrolactone and phosphorus oxychloride in the presence of a solvent.
  • Figure 1 is a representative XRD pattern of the paliperidone prepared in accordance with one embodiment of the present invention.
  • the present invention relates to a process for preparation of 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, also referred to as paliperidone, 9-hydroxy risperidone or formula I comprising:
  • step (i) isolating the compound of formula I from the reaction mass of step (i).
  • Suitable solvents for the reaction described in step (i) include alcohols, ketones, esters, ethers, hydrocarbons and mixtures thereof.
  • the solvent is an alcohol or mixture of alcohols, preferably Ci to C 4 alcohols such as methanol or IPA.
  • the solvent for the reaction in step (i) is a ketone or mixture of ketones, preferably a C 3 to Cs ketone, and most preferably acetone.
  • a base may be an organic base, an inorganic base or a mixture thereof.
  • organic bases that may be used are tertiary amines such as triethylamine or N-(l-methylethyl)-2-propanamine.
  • inorganic bases that may be used are alkali metal or alkaline earth metal carbonates, bicarbonates or hydroxides such as sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide.
  • the solvent for the reaction described in step (i) is a mixture of solvents selected from the group consisting of alcohols, ketones, esters, ethers and hydrocarbons.
  • the mixture of solvents is a mixture of ketones and alcohols, most preferably a mixture of ketones and Ci to C 4 alcohols, such as an acetone/methanol mixture.
  • the ratio of ketone to alcohol is preferably about 1 :9 to about 1 : 1, more preferably about 1 :4 to about 1 :2 and most preferably about 3:7.
  • the reaction temperature is typically between 25- 64°C.
  • the preferred reaction temperature is about 60°C to about 63°C.
  • the reaction is preferably conducted at reflux temperature.
  • a ketone such as acetone is used as the solvent in step (i)
  • the reaction is preferably carried out at reflux temperature.
  • the process may further employ the step of removing the solvent prior to isolating the compound of formula I.
  • the solvent can be removed by any means known in the art such as vacuum or distillation.
  • Isolating the compound of formula I in step (ii) when a base is employed may be performed with a solvent selected from water, alcohols, ketones and mixtures thereof.
  • a preferred solvent is alcohols such as methanol, water or a mixture of a Ci to C 4 alcohol and water, such as a methanol/water mixture.
  • the ratio of alcohol to water used for the isolation is preferably between about 5:95 to about 50:50, most preferably between about 5:95 to about 65:35.
  • isolating the compound of formula I in step (ii) when a base is employed may be performed with a solvent selected from water, alcohols, ketones and mixtures thereof.
  • a preferred solvent is a ketone such as acetone, water or a mixture of a ketone and water, such as an acetone/water mixture.
  • the ratio of ketone to water used for the isolation is preferably between about 5:95 to about 50:50, most preferably between about 5:95 to about 65:35.
  • a buffer may be selected from any known buffer, preferably an inorganic buffer and most preferably an inorganic phosphate buffer such as potassium hydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate or mixtures thereof.
  • the amount of the buffer present in the reaction mass may range from about 1 mole to about 5 moles of buffer for each mole of the compound of formula II present in the reaction, preferably about 1.5 moles to about 4 moles of buffer for each mole of the compound of formula II present and most preferably about 2 moles to about 3 moles of buffer for each mole of the compound of formula II present in the reaction.
  • Suitable initiators may include inorganic salts of a halide and an alkali metal or alkali earth metal such as sodium or potassium iodide.
  • the amount of the initiator present in the reaction mass may range from about 0.01 mole to about 0.5 moles of initiator for each mole of the compound of formula II present in the reaction, preferably about 0.05 moles to about 0.25 moles of initiator for each mole of the compound of formula II present and most preferably about 0.075 moles to about 0.2 moles of initiator for each mole of the compound of formula II present in the reaction.
  • the solvent for the reaction described in step (i) is a mixture of solvents selected from the group consisting of alcohols, ketones, esters, ethers and hydrocarbons.
  • the solvent is a C 3 to Cs ketone or mixture thereof and most preferably the solvent is acetone.
  • Water may also be present in the reaction of step (i). If water is employed with a buffer in step (i) the ratio of water to solvent should be about 10:90 to about 0.5:99.5, preferably about 5:95 to about 0.75:99.25 and most preferably about 3:97 to about 1 :99.
  • water may optionally be present in a ratio of water: acetone of about 5:95 to about 0.5:99.5, preferably about 2:98 to about 0.75:99.25 and most preferably about 1 :99.
  • the reaction temperature for step (i) is preferably between 25-75°C, and if a ketone such as acetone is used as the solvent in step (i), the reaction is preferably conducted at reflux temperature.
  • step (i) When a buffer is employed in step (i), the reaction should be allowed to proceed to completion which generally means the amount of compound of formula II in the reaction mass is not more than 10% as determined by HPLC.
  • step (i) employing a buffer the reaction mass is cooled to about 0° to about 35°C, preferably about 20° to about 30°C, and the crude paliperidone is isolated from the reaction mass by known techniques such as filtration and may be washed with a suitable solvent such as water, a C 3 to Cs ketone or mixture thereof.
  • the crude paliperidone may also be dried by conventional methods.
  • step (ii) when isolated in step (ii), does not exhibit sufficient purity, it may be further processed according to the present invention to increase the purity level.
  • the crude paliperidone obtained from step (ii) above, or any other method, may be purified without the use of column chromatography by a purification process comprising:
  • organic solvent selected from the group consisting of esters, chlorinated solvents, hydrocarbons and mixtures thereof and creating an aqueous layer and an organic layer;
  • step (b) separating the aqueous layer and organic layer of step (b);
  • the acid employed in step (a) may be an organic acid, a mineral acid or mixtures thereof.
  • the acid is an organic acid such as acetic acid.
  • the amount of acid employed should impart a pH to the reaction mixture of about 3 to about 5, preferably about 3.5 to about 4.5.
  • the organic solvent employed in step (b) can be selected from the group consisting of esters, chlorinated solvents, hydrocarbons and mixtures.
  • a preferred solvent is a chlorinated solvent such as methylene chloride.
  • the pH of the aqueous layer in step (d) may be adjusted with an organic base, an inorganic base or mixtures thereof. Examples of possible bases are described above. Some of the preferred bases that may be used include liquid ammonium or ammonium hydroxide.
  • the pH of the aqueous layer in step (d) should be adjusted to a pH of about 8 to about 10, and preferably a pH of about 8.5 to about 9.5.
  • the isolation of the paliperidone in step (h) is preferably performed with solvents selected from ketones, alcohols, water and mixtures thereof, more preferably water, Ci to C 4 alcohols such as methanol, acetone, isopropyl alcohol and mixtures thereof.
  • the crude paliperidone obtained from step (ii) above or any other method may alternatively be purified without the use of column chromatography by a purification process comprising:
  • step (C) dissolving or suspending the solid acid addition salt of paliperidone in a suitable solvent; D) adjusting the pH of the reaction mass of step (C) with a base to form the free base form of the compound of formula I;
  • the acid employed in step (A) may be an organic acid, a mineral acid or mixtures thereof.
  • the acid is an organic acid, preferably a mono-carboxylic acid such as acetic acid.
  • the amount of acid employed in step (A) should be at least present in equal molar amounts to the amount of crude paliperidone present in step (A).
  • the amount of acid should be about 1 mole to about 3 moles for every mole of crude paliperidone and most preferably about 1 mole to about 2 moles of acid for every mole of crude paliperidone employed in step (A).
  • the solvent employed in step (A) can be selected from the group consisting of alcohols, ketones, ethers, hydrocarbons or mixtures thereof.
  • the solvent employed in step (A) is a Ci to C 4 alcohol, a mixture of Ci to C 4 alcohols, a C 3 to Cs ketone, a mixture of C 3 to Cs ketones, a C 2 to Cs ether, a mixture of C 2 to Cs ethers, a C 3 to C 6 amide, a mixture of C 3 to C 6 amides, a C 2 to C 6 alkyl acetates, a mixture of C 2 to C 6 alkyl acetates, a C 6 to C 12 aromatic hydrocarbon, a mixture of C 6 to C 12 aromatic hydrocarbons, acetonitrile, propylene glycol, dimethyl sulphoxide and mixtures thereof.
  • the solvent for step (A) is a C 3 to Cs ketone or mixture thereof, and most preferably the solvent is acetone.
  • the reaction temperature of step (A) is preferably about 25°C to about 110°C. If the solvent for step (A) is acetone, ethyl acetate or tetrahydrofuran, the reaction temperature is preferably conducted at reflux temperature. If an aromatic solvent such as toluene is used in step (A), the reaction temperature is preferably about 60° to about 90°C, most preferably about 70°C to about 80°C.
  • the reaction mass may be cooled to about 0°C to about 20°C, preferably about 0°C to about 15°C, prior to isolating the solid acid addition salt of paliperidone.
  • the solvents suitable for dissolving or suspending the solid acid addition salt of the paliperidone in step (C) include alcohols, ketones, ethers, hydrocarbons, chlorinated
  • the solvent is water, a Ci to C 4 alcohol, a mixture of Ci to C 4 alcohols, a C 3 to Cs ketone, a mixture of C 3 to Cs ketones, a C 2 to Cs ether, a mixture of C 2 to Cs ethers, a C 3 to C 6 amide, a mixture of C 3 to C 6 amides, a C 2 to C 6 alkyl acetates, a mixture of C 2 to C 6 alkyl acetates, a C 6 to C 12 aromatic hydrocarbon, a mixture of C 6 to C 12 aromatic hydrocarbons, acetonitrile, propylene glycol, dimethyl sulphoxide and mixtures thereof.
  • a preferred solvent for step (C) is water and a C 3 to Cs ketone such as acetone.
  • the pH of the reaction mass of step (D) may be adjusted with an organic base, an inorganic base or mixtures thereof. Examples of possible bases are described above. Some of the preferred bases are nitrogen containing bases such as liquid ammonium, ammonium hydroxide, triethylamine, N-(l-methylethyl)-2-propanamine or mixtures thereof.
  • the pH of the aqueous layer should be adjusted to a pH of about 8 to about 10, and preferably a pH of about 9.0 to about 10.0.
  • the amount of base employed should at least be present in at least equal molar amounts to the amount of acid addition salt paliperidone present in step (D).
  • the amount of acid should be about 1.1 moles to about 3 moles for every mole of crude paliperidone and most preferably about 1.2 mole to about 2 moles of acid for every mole of crude paliperidone employed in step (D).
  • the isolation of the paliperidone in step (E) is preferably performed by filtration, and the filtrate may be washed and dried using conventional techniques.
  • the final paliperidone should be pure with the amount of 9-oxo impurity being less than 0.5%, preferably less than 0.3% and most preferably less than 0.1% as determined by HPLC.
  • the final paliperidone should also be "highly pure paliperidone" meaning the paliperidone is at least 99.5% paliperidone, preferably at least 99.75%) paliperidone and most preferably at least 99.8%> paliperidone as determined by HPLC.
  • the paliperidone obtained in accordance with embodiments of the present invention was subjected to recrystallization and precipitation in a variety of solvents and mixtures of solvents.
  • the x-ray diffraction data revealed a nearly identical pattern regardless of the solvent or solvent system utilized.
  • samples of paliperidone obtained from Examples 13 and 14 below, as well as samples prepared by recrystallization/leaching of paliperidone in a variety of solvents such as acetone, isopropyl alcohol, ethyl acetate, DMF, methanol, acetonitrile, toluene, methanol/isopropyl ether, methanol/water, DMF/water and toluene/hexane exhibited nearly identical XRD patterns to the representative pattern shown in Figure 1.
  • the present invention further relates to processes for the preparation of the compound of formula II comprising:
  • step (i) 2) removing the acidic media from step (i); and 3) isolating the compound of formula II from a solvent selected from a group consisting of ketones, alcohols, water, hydrocarbons and mixtures thereof.
  • the catalyst used in step (1) is preferably Pd/C.
  • Catalyst loading is 10-50% w/w of the wet catalyst, more preferably 10-20%.
  • the hydrogen pressure applied during the reaction is in
  • the reaction is performed at 25- 60°C, more preferably at 30-40°C.
  • the reaction medium used for the hydrogenation is selected from organic acids, aqueous mineral acids or mineral acids absorbed in alcoholic solvents.
  • the preferred acids are organic acids such as acetic acid.
  • the product is isolated in step (2) using a solvent selected from ketones, alcohols, water, hydrocarbons and mixtures thereof. Preferred solvents are a mixture of ketones and hydrocarbons such as acetone/hexane mixtures and/or water.
  • the ratio of ketone to hydrocarbon is preferably about 10:90 to about 90: 10, most preferably about 25:75 to about 50:50.
  • the isolating step may further comprise adjusting the pH of the reaction mass with a base such as those previously described.
  • the preferred base is an inorganic base such as sodium hydroxide.
  • the pH of the reaction mass should be adjusted to about 4.5 to about 7, preferably about 5 to about 6.5, and most preferably about 5.5 to about 6. Isolation in water makes the process attractive industrially in terms of environmental friendliness and ease of operation.
  • reaction mixture (1) reacting 2-amino-3-benzyloxy pyridine with 2-acetyl butyrolactone and POCI 3 in toluene at a suitable temperature to form a reaction mixture;
  • the temperature of the reaction in step (1) is maintained between 50-110°C, more preferably 90-95°C.
  • the base added to the quenched reaction mixture in step (3) may be an organic base, an inorganic base or mixtures of the foregoing.
  • inorganic bases include alkali metal or alkaline earth metal carbonates, bicarbonates or hydroxides such as ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate.
  • organic bases include amines such as ammonium or tertiary amines such as triethylamine.
  • the base should be added to the quenched reaction mixture in an amount that adjusts the pH to about 3.5 to about 7, preferably about 4 to about 5.
  • One embodiment for preparing the compound of formula VI may further comprise the use of an extraction solvent to assist in removing and isolating the compound of formula VI from the reaction mass.
  • the extraction solvent is an organic solvent or a mixture of water and organic solvent.
  • a preferred organic solvent is a chlorinated solvent such as methylene chloride.
  • the extraction solvent may be added during the quenching step or subsequent to the quenching step. If an extraction solvent such as methylene chloride is employed in the process, the extraction solvent should be removed or substantially reduced after the addition of the base and prior to the isolation of the compound of formula VI. Once the extraction solvent has been removed or reduced, the compound of formula VI may be isolated by the addition of an alcohol.
  • Exemplary alcohols for use in step (4) of this embodiment are Ci to C 4 alcohols such as methanol, isopropyl alcohol or mixtures thereof.
  • the compound of formula VI can be isolated from the quenched reaction (step (2)) without the addition of solvents for the extraction.
  • the compound is isolated from the aqueous layer of the quenching step by neutralizing the aqueous layer with a base, preferably an inorganic base such as sodium hydroxide as described above.
  • the compound isolated from the aqueous layer may then be crystallized from a suitable solvent selected from alcohols, ketones, esters, ethers, hydrocarbons and mixtures thereof.
  • Preferred solvents are alcohols, most preferably Ci to C 4 alcohols such as methanol, isopropyl alcohol or mixtures thereof.
  • the pure or highly pure paliperidone prepared in accordance with the present invention may be combined with at least one or more pharmaceutically acceptable excipients to prepare a dosage form for administration to a patient.
  • the dosage form may be a solid, liquid, powder, aerosol, syrup or injectable solution for oral, buccal, parental, ophthalmic, rectal, vaginal or transdermal routes of administration.
  • Pharmaceutically acceptable excipients that may be used to prepare the dosage forms are know in the art and include binders, fillers, diluents, lubricants, glidants, disintegrants, buffering agents, sweetening agents, stabilizers, solubilizers, surfactants and coating agents.
  • a preferred dosage form is a solid dosage form for oral administration such as a tablet or capsule.
  • the pH of the reaction mass was adjusted to 5.5-6.0 with 20% NaOH at 25-30°C.
  • the reaction mass was stirred for 15-20 minutes at 25-30°C.
  • the reaction mass was allowed to settle, and the layers were separated.
  • the aqueous layer was extracted with 150 ml of methylene chloride.
  • the organic layers were combined and washed with 250 ml of water.
  • the combined organic layers were then subjected to vacuum distillation at 35°C.
  • To the resulting oily mass was added 50 ml acetone, and the resulting solution was distilled atmospherically. Again, 50 ml acetone was added, and the reaction mixture was heated to reflux for 15-20 minutes.
  • Example 4 The process of Example 2 was followed using the compound of formula IV instead of the compound of formula VI to obtain the compound of formula II (compound of formula V, ⁇ 10% by HPLC analysis, Purity of compound of formula II > 85%).
  • Example 4
  • the layers were again separated, and the aqueous layer was extracted with 28 ml of methylene chloride.
  • the organic layers were combined and washed thrice with 42 ml water.
  • the washed organic layer was treated with 3.5 g silica.
  • the treated organic layer was subjected to atmospheric distillation to remove methylene chloride at 25-30°C.
  • Methanol 280 ml was added to the concentrated mass and distilled off atmospherically.
  • Acetone 70 ml
  • Acetone was distilled up to 35 ml at atmospheric pressure.
  • the slurry was cooled to 0-5°C and maintained for 45-60 minutes.
  • the reaction mass was filtered, and the solid was washed twice with (2x14 ml) chilled acetone.
  • the solid was transferred to a flask and refluxed with 75 ml acetone for 20-30 minutes.
  • the reaction mixture was cooled to 25-30°C and maintained for 30 minutes.
  • the solid was filtered and washed twice with 15 ml acetone to obtain 11.5 g pure paliperidone.
  • Paliperidone (2 g) was slurried in acetone (80 ml). The temperature was raised to 55- 57°C and maintained for 1 hour. The suspension was cooled to 25-30°C. The product was filtered and dried at 70°C.
  • Paliperidone (1.5 g) was dissolved in toluene (45 ml) at 90-95°C. Hexane (90 ml) was added to the solution. The suspension was cooled to 25-30°C and stirred for 30 minutes.
  • the product was filtered and dried at 70°C.
  • reaction mixture was cooled to 20-30°C, stirred for 30 minutes and then filtered.
  • the solid filtrate was collected, combined with 250 ml of water and stirred for 30 minutes, filtered and washed twice with water (2 x 100 ml) followed by acetone (50ml) to obtain 59.6 g. paliperidone with an HPLC purity of 98.04% and 9-oxo impurity level of 0.04%.
  • Stage - II Preparation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrido[l,2-a] pyrimidin-4-one from 3-(2-chloroethyl)-9-hydroxy-2-methyl- 4H-pyrido[l,2-a] pyrimidin-4-one
  • Stage - 1 Stage - 1 1 Raw-material:
  • Stage III Preparation of 3-[2-[4-(6-fluoro-l, 2-benxisoxazol-3-yl)-l-piperidinyl] ethyl]- 6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one from 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrido [ 1 ,2-a] pyrimidin-4-one.

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Abstract

La présente invention concerne un procédé pour la préparation et la purification de 3-[2-[4-(6- fluoro-1,2-benzisoxazol-3-yl)-1-pipéridinyl]éthyl]-6,7,8,9-tétrahydro-9-hydroxy-2-méthyl-4H-pyrido[1,2-a]pyrimidin-4-one, également appelée palipéridone ou 9-hydroxy-rispéridone.
PCT/US2011/030302 2011-03-29 2011-03-29 Procédé amélioré pour la préparation de palipéridone Ceased WO2012134445A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20140115085A (ko) * 2013-03-20 2014-09-30 신풍제약주식회사 고순도의 팔리페리돈을 고수율로 제조하는 방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009130710A2 (fr) * 2008-04-21 2009-10-29 Glenmark Generics Limited Procédé pour la fabrication d'intermédiaires de palipéridone
US20100267954A1 (en) * 2009-04-21 2010-10-21 Dipharma Francis S.R.L. Process for the purification of paliperidone
US20100311969A1 (en) * 2008-02-05 2010-12-09 Watson Pharma Private Limited Process For Preparation of Paliperidone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100311969A1 (en) * 2008-02-05 2010-12-09 Watson Pharma Private Limited Process For Preparation of Paliperidone
WO2009130710A2 (fr) * 2008-04-21 2009-10-29 Glenmark Generics Limited Procédé pour la fabrication d'intermédiaires de palipéridone
US20100267954A1 (en) * 2009-04-21 2010-10-21 Dipharma Francis S.R.L. Process for the purification of paliperidone

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20140115085A (ko) * 2013-03-20 2014-09-30 신풍제약주식회사 고순도의 팔리페리돈을 고수율로 제조하는 방법
KR102049091B1 (ko) 2013-03-20 2019-11-26 신풍제약주식회사 고순도의 팔리페리돈을 고수율로 제조하는 방법

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