KR20140115085A - The preparation method for preparing paliperidone with higher yield and purity - Google Patents

Abstract

Disclosed is a new method for manufacturing paliperidone with high purity and high yield. According to the present invention palperidone with high purity of 99.85-99.9% and high yield of 85-90% can be manufactured and refined, and moreover, paliperidone having content of specific impurities controlled to be lower than 0.1%. Disclosed is a method for manufacturing paliperidone is characterized by comprising the steps of manufacturing crude paliperidone; manufacturing paliperidone hydrochloride; and conversing into paliperidone.

Description

TECHNICAL FIELD [0001] The present invention relates to a method for producing paliperidone of high purity at a high yield. BACKGROUND ART < RTI ID = 0.0 >

The present invention relates to a process for preparing paliperidone. More specifically, the present invention relates to a method for producing paliperidone at a higher purity and a higher yield as compared to the conventional method by preparing hydrochloride of paliperidone and converting it into paliperidone. More particularly, the present invention relates to a method for producing paliperidone having a high purity of 99.85 to 99.9% or more and a high yield of 85 to 90% or more as a method for purifying paliperidone, and a method for producing high-purity paliperidone having a specific impurity content of less than 0.1%.

Schizophrenia and paliperidone (Paliperidone) to be used for the bipolar affective disorder, that is, 9-hydroxy-risperidone represents an antagonistic action on dopamine and serotonin receptors in the brain as the major active metabolite of risperidone (Risperidone) α _1, α ₂ And Histamine (H ₁ ) receptors.

Schizophrenia is a general and incapacitating mental illness characterized by extreme disturbances in cognition and thinking, affecting language, perception, and sense of self. Schizophrenia is known to be caused by confusion (annular or hallucination) due to the overactive activity of neurotransmitters (mainly dopamine), which blocks dopamine and serotonin receptors to inhibit the excess activity of dopamine and regulates schizophrenia It is.

Patients with schizophrenia had two symptoms: benign symptoms (hallucinations, confusion, hostility) and negative symptoms (absence of emotion and lack of social skills). Compared with the less developed effects of antipsychotic drugs on negative symptoms , Paliperidone is effective on both symptoms and is known to be effective in improving depression, anxiety, and guilt.

Paliferidone is chemically synthesized from 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1- piperidinyl] ethyl] -6,7,8,9- Tetrahydro-9-hydroxy-2-methyl-4H-pyrido [l, 2-a] pyrimidin-4-one and has the following chemical structural formula (I).

[Chemical Formula 1]

With regard to the process for producing paliperidone, there is the following conventional literature.

Korean Patent No. 0146053 discloses paliperidone and a preparation method thereof. As can be seen from the following reaction formula,

Fluoro-3-piperidino-1,2-benzisoxazole hydrochloride (hereinafter referred to as " FPBI " in the present specification) According to the known N-alkylation method, an alkylating agent, specifically, 3- (2-chloroethyl) -6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [ -a] -pyrimidin-4-one (hereinafter referred to as " CMHTP "). However, this document does not specifically focus on yield and purity.

Korean Patent Application No. 10-2009-7003511 discloses a method for producing paliperidone using CMHTP while disclosing a method for synthesizing CMHTP and its intermediates. Specifically, a method is disclosed in which isolated or recovered CMHTP is condensed with FPBI to form paliperidone, wherein a mixture of CMHTP and FPBI, sodium carbonate and potassium iodide in DMF is heated, extracted with DCM in water and extracted from acetonitrile Crystallization method is used. However, also in this document, the final product can not be obtained at a high yield and the purity is also poor.

In addition, International Patent Publication No. WO2011 / 015936 discloses an improved preparation method of pure paliperidone, specifically, a process for producing 3- {2- [4- (6- Yl] -1-piperidinyl] -ethyl} -2-methyl-7,8-dihydro-6H-pyrido- [1,2- a] pyrimidine Discloses a method for purifying paliperidone by reacting CMHTP and FPBI under a closed system to inhibit the formation of -4,9-dione.

In addition, International Patent Publication No. WO2011 / 030224 discloses paliperidone or a pharmaceutically acceptable salt thereof substantially free from impurities. The preparation method disclosed in this document is a method of reacting CMHTP with FPBI using diisopropyl ethanolamine, tetrabutylammonium bromide, and sodium iodide, and using DMF, L (+) - tartaric acid, sodium dithionite / NH2 solution Lt; / RTI > However, yields are not very high when using this method.

Namely, although various methods for producing paliperidone are disclosed in the prior art, there is still a need for a method for producing paliperidone in high purity and high yield.

Korean Patent No. 156053 Korean Patent Application No. 10-2009-7003511 International Patent Publication No. WO2011 / 015936 International Patent Publication No. WO2011 / 030224

Accordingly, the present invention provides a method for producing and purifying paliperidone having a high purity and a high yield, more specifically, a high purity of 99.85 to 99.9% and a high yield of 85 to 90% or more as a method of purifying paliperidone having a specific impurity content of less than 0.1% And a method for manufacturing the same.

To this end, the present invention discloses the following means.

In a method for producing paliperidone in high yield and high purity,

1) alkylating the FPBI of formula II with a CMHTP of formula III to give a crude paliperidone of formula I, by alkylation with an N-alkylating agent in an inert solvent;

2) 0.1 to 0.61 wt% (w / v): 0.48 wt% (w / v) of methanol: hydrochloric acid: triethylamine on the basis of FPBI to the crude pyriperidone prepared in step 1) % (w / v) or less to produce paliperidone hydrochloride of formula (IV); And

3) converting paliperidone hydrochloride prepared in step 2) into paliperidone of formula (I) in water or an organic solvent or a mixed solvent thereof in the presence of a base in the presence of a base; ≪ / RTI >

Also disclosed is a process for the preparation of paliperidone, wherein the N-alkylating agent of step 1) is selected from the group consisting of diisopropylamine, isopropylethylamine.

Also disclosed is a process for the preparation of paliperidone, wherein the equivalent of the N-alkylating agent is 1.0 to 4.0 in the process.

Further, in the above method, a process for producing paliperidone is disclosed, wherein the process of step 2) is carried out at a pH of 3-6.

Further, in the above method, a process for producing paliperidone, which is characterized in that the process of step 2) is repeated once or several times.

Further, in the above method, a process for producing paliperidone in which the organic solvent in step 3) is selected from acetonitrile, acetone, and methanol is disclosed.

Further, in the above method, a process for producing paliperidone in which the base of step 3) is selected from sodium hydrogen carbonate, sodium carbonate, and sodium hydroxide is disclosed.

According to the present invention, paliperidone having a high purity of 99.85 to 99.9% and a high yield of 85 to 90% or more can be produced and purified, and paliperidone having a specific impurity content of less than 0.1% can be produced.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the SEM analysis results of the crystalline paliperidone prepared in Example 5. FIG.

Piperidone] ethyl] -7-hydroxy-4-methyl-1,5-dihydro- Diazabicyclo [4.4.0] deca-3,5-dien-2-one is a 5-HT antagonist belonging to the chemical class of benzisoxazole derivatives and racemic mixtures having the formula:

[Chemical Formula 1]

Paliperidone is a metabolite of risperidone. Palifuridone is marketed under the trade name Invega® and is licensed for treatment of schizophrenia in the United States. A method for the synthesis of paliperidone is described in U.S. Patent No. 5,158,952. A method of synthesizing a precursor of paliperidone, (3- (2-chloroethyl) -2-methyl-9-benzyloxy-4H-pyrido [1,2-a] -pyrimidin- . The resulting mixture of chemical reactions is rarely a single compound with sufficient purity to meet pharmaceutical criteria. Byproducts and by-products of the reaction and additional reagents used in the reaction will also be present in the product mixture in most cases. At a particular point in the API, paliperidone process, purity should generally be analyzed by HPLC, TLC or GC analysis to determine whether it is appropriate for the subsequent process and ultimately as a pharmaceutical product. The API does not have to be completely pure because complete purity is a theoretical ideal that is not generally available. Rather, the purity criteria are set to ensure that the API is as free of impurities as possible and is as safe as possible for clinical use. As noted above, in the United States, the Food and Drug Administration guidelines recommend that the amount of impurities be limited to less than 0.1%.

The two potential impurities of paliperidone are:

R084852: 3- {2- [4- (4-Fluoro-2-hydroxy-benzoyl) -piperidin- l-yl] -ethyl} -9- 9-Tetrahydro-pyrido- [1,2-a] pyrimidin-4-one

[Formula V]

R125239: 3- {2- [4- (6-Fluor-1,2-benzisoxazole-3-yl) -Pyrido- [l, 2-a] pyrimidine-9,9-dione (9-keto impurity)

(VI)

These impurities remain in the final product. Accordingly, there is a need in the art for a purification process to obtain paliperidone having higher purity as well as this.

The present invention provides an improved method for producing paliperidone to obtain paliperidone having a purity of 99.85 to 99.9% or more at a high yield of 85 to 90% or more. As used herein, the term CMHTP refers to 3- (2-chloroethyl) -6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [ ] -Pyrimidin-4-one < / RTI >

[Formula (III)

As used herein, the term FPBI refers to 6-fluoro-3-piperidino-1,2-benzisoxazole hydrochloride of formula II:

[Formula II]

In the present specification, the term R084852 represents 3- {2- [4- (4-fluoro-2-hydroxy-benzoyl) -piperidin- l-yl] -ethyl} -9- -Methyl-6,7,8,9-tetrahydro-pyrido- [l, 2-a] pyrimidin-

[Formula V]

As used herein, the term R125239 refers to 3- {2- [4- (6-fluoro-1,2-benzisoxazole-3-yl) -1- piperidinyl] -7,8-dihydro-6H-pyrido- [l, 2-a] pyrimidine-4,9-

(VI)

As used herein, the term paliperidone hydrochloride refers to 3- {2- [4- (6-fluoro-benzo [d] isoxazol-3- yl) -piperidin- -9-hydroxy-2-methyl-6,7,8,9-tetrahydro-pyrido- [l, 2-a] pyrimidin-

[Formula IV]

As used herein, the term paliperidone refers to 3- {2- [4- (6-fluoro-benzo [d] isoxazol-3- yl) -piperidin- l-yl] Hydroxy-2-methyl-6,7,8,9-tetrahydro-pyrido- [l, 2-a] pyrimidin-

(I)

In the present invention, in relation to the process for preparing paliperidone represented by the general formula (I), the FPBI represented by the general formula (II) is reacted with the CMHTP represented by the general formula (III) and alkylated with the N-alkylating agent to obtain the crude paliperidone represented by the general formula Discloses a process for preparing crude paliperidone as a hydrochloride salt of paliperidone represented by the formula (IV), and then converting the paliperidone hydrochloride to paliperidone. Hereinafter, the present invention will be described in detail.

First, the step of preparing N-alkylation reaction of FPBI and CMHTP to prepare crude pyrrolidone is explained. The reaction of FPBI and CMHTP is carried out in an inert solvent in the presence of a base, and examples of the solvent include water; Aromatic hydrocarbon solvents (e.g., benzene, methine benzene, dimethyl benzene, chlorobenzene, methoxybenzene, etc.); C1-6 alkanols such as methanol, ethanol, 1-butanol and the like; Ketones such as 2-propanone, 4-methyl-2-pentanone, and the like; Esters (e.g., ethyl acetate,? -Butyrolactone and the like); Ethers such as 1,1'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; 1, 3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, 1, 3-dimethyl-2-imidazolidinone, 1,1,3,3-tetramethylurea, 1-methyl-2-pyrrolidinone, nitrobenzene, acetonitrile and the like); Or a mixture of these solvents. However, in the present invention, methanol is preferably used as the solvent.

Examples of the base (N-alkylating agent) which can be used include alkali metal or alkaline earth metal carbonates, hydrogencarbonates, hydroxides, oxides, carboxylates, alkoxide hydrides or amides such as sodium carbonate, sodium hydrogencarbonate, potassium carbonate , Sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide and the like), or tertiary amines such as N, N-diethylethanamine, N- (1-methylethyl) -2- propanamine , 4-ethylmorpholine, 1,4-diazabicyclo [2,2,2] octane, pyridine, etc.) can be added to absorb the acid liberated during the course of the reaction. In some cases it may be appropriate to add an iodide salt, preferably an alkali metal iodide, or a crown ether, for example 1,4,7,10,13,16-hexaoxa-cyclooctadecane or the like have. Stirring and a slight elevated temperature can promote the rate of reaction, more particularly the reaction can be carried out at the reflux temperature of the reaction mixture. It may also be advantageous to carry out said N-alkylation under an inert atmosphere such as, for example, oxygen-free argon or nitrogen gas. In addition, the N-alkylation can be performed by applying a phase transfer catalysis reaction known in the art. Wherein the reaction conditions are such that the reactants are reacted with a suitable phase transfer catalyst such as trialkylphenylmethylammonium, tetraalkylammonium, tetraalkylphosphonium, tetraarylphosphonium halide, hydroxide, hydrogen sulphide, etc., optionally under the aforementioned inert atmosphere Lt; / RTI > in the presence of a suitable base.

However, in the present invention, diisopropylamine and diisopropylethylamine are used in particular, and the amount of the base used is preferably 1.0 to 4.0 equivalents.

Through the above reaction, FBPI and CMHTP react with each other to produce paliperidone. However, the result produced in this step is a state in which various byproducts are mixed with paliperidone, i.e., untreated paliperidone, and therefore, it is not preferable to directly use this as a raw material for pharmaceuticals. Accordingly, in the present invention, an intensive study for obtaining higher yield and higher purity of paliperidone from the crude paliperidone was continued. As a result, it was found that the crude paliperidone was prepared as paliperidone hydrochloride, It has been found that paliperidone can be produced and purified at a very high yield and at a high purity as compared with the conventional method. Hereinafter, the step of preparing the hydrochloride of paliperidone in the crude paliperidone will be described.

To prepare the hydrochloride of paliperidone in the crude paliperidone, a solvent such as a C1 to C4 alcohol, a C1 to C4 ketone, a halogenated hydrocarbon and the like may be used together with hydrochloric acid. However, in the present invention, methanol, hydrochloric acid and triethylamine are added to the crude paliperidone in an amount of 2.5 to 15 wt% (w / v), 0.15 to 0.61 wt% (w / v), and 0.48 wt% w / v) or less to prepare a hydrochloride salt of paliperidone. Thus, the preparation of paliperidone through the hydrochloride salt of paliperidone greatly affects high yield and high purity.

That is, the technical feature of the present invention is to produce paliperidone in high yield and high purity. For this purpose, the reaction system defined above, that is, the material to be used and the content ratio are particularly important. That is, when the methanol content is less than 2.5% by weight, the reaction product is not stirred, and when the methanol content is more than 15% by weight, the final yield of paliperidone is remarkably decreased. When the content of hydrochloric acid is less than 0.15% by weight, the crude paliperidone is not completely converted to paliperidone hydrochloride. When the content of hydrochloric acid is more than 0.61% by weight, the amount of hydrochloric acid which is actually reacted is exceeded. In addition, when the triethylamine content is 0.48 wt% or more, there is a possibility of conversion from paliperidone hydrochloride to base, resulting in an increase in the content of the flux and a significant reduction in the final yield of paliperidone.

Furthermore, the reaction is preferably carried out at a pH of 3 to 6, and this step may be performed once or repeatedly several times.

Next, a method of converting the hydrochloride of paliperidone to paliperidone will be described.

Conversion of paliperidone hydrochloride to paliperidone is accomplished by reacting the crystalline form of paliperidone hydrochloride or paliperidone hydrochloride with an alkaline solution. That is, it is converted into paliperidone by liberating the hydrochloride salt in the presence of a base in water or an organic solvent or a mixed solvent thereof. As the base material, sodium hydrogen carbonate, sodium hydroxide, sodium carbonate, calcium hydroxide, calcium carbonate and the like can be used, but it is preferably selected from sodium hydrogen carbonate, sodium carbonate or sodium hydroxide. The organic solvent is preferably selected from acetonitrile, acetone, and methanol.

When the above method is adopted, it is possible to produce paliperidone with high yield and high purity. In particular, the content of certain impurities (R084852 and R125239) can be minimized.

Hereinafter, the present invention will be described by way of examples. The following examples illustrate specific embodiments of the present invention and are not to be construed as limiting the technical scope of the present invention, and it should be noted that various modifications of the following embodiments may exist as long as they are included in the following claims.

Example

HPLC method:

Column and packing: Agilent ZORBAX Eclipse Plus C18 4.6 * 100mm particle size 3.5㎛

Buffer: 9.5 g of tetrabutylammonium hydrogen sulphide dissolved in 1 L of purified water

Eluent A: 90% buffer: 10% methyl alcohol

Eluent B: 100% methyl alcohol

inclination:

time Eluent A% Eluent B% 0 100 0 5 100 0 35 85 15 36 100 0 45 100 0

Flow: 0.9 mL / min

Operating time: 35 minutes

Equilibration time: 10 minutes

Sample volume: 10 μL

Detector: 275 nm

Column temperature: 40 ° C

Diluent 1: Precisely weigh 0.71 g of disodium hydrogenphosphate and 0.62 g of sodium hydrogen phosphate, place in a 1000-mL volumetric flask and mix well with purified water.

Diluent 2: (Diluent 1: methyl alcohol = 50: 50)

Sample solution: Approximately 2 g of paliperidone is added to the mixer or induction for 1-2 minutes and ground. Weigh accurately about 100.00 mg of this product (± 5.00 mg) into a 200-mL volumetric flask, add 100 mL of methyl alcohol, shake vigorously for 30 minutes, and fill well with the diluent. Shield for 1 hour and stabilize at room temperature.

Calculation:

Pr * r _i * q _r * G 1

Calculation method:% content = S * ------------------- * ----- * 100

* R * _r * Fr Qth q _s RRF

S = correction factor = 1

Pr = purity of the active ingredient

Fr = 1.000 = corrected salt / base coefficient

r _i = peak area of the flexible substance in the sample solution

r _r = average peak area 5 times due to system compatibility of the standard product

G = Fr = 1.000 = salt / base coefficient of API

qs = the amount of active ingredient in the test solution (in mg)

qr = the amount of active ingredient in the standard solution (in mg)

Qth = 1 (main component)

RRF = relative response factor (T002026, T001492, R084852 = 1.000, R125239 = 0.581, unidentified flexible substance = 1.000)

Material name Relative retention time Detection limit% Relative response coefficient T002026 (CMHTP) 0.57 0.03 0.834 T001492 (FPBI) 0.83 0.03 0.827 R076477 (paliperidone) 1.00 0.03 1,000 R084852 1.11 0.03 0.877 R125239 1.27 0.03 0.581

Comparative Example 1:

100 ml of methyl alcohol is added to the reaction tank and stirred. 10 g of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole hydrolchloride (FPBI) and 13.7 ml of diisopropylamine were added thereto. 11.3 g of 7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a] -pyrimidin-4-one (CMHTP) . When the reaction is complete, the reaction mixture is concentrated. It is dissolved in trichloromethane and washed with water. The organic layer is dried and filtered. Concentrated and the residue was purified by using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as the eluent and then using a mixture of trichloromethane and ammonia saturated methanol (95: 5 by volume) And purified twice by column chromatography on silica gel. The pure fractions were collected, concentrated and crystallized with 2-propanone. After cooling, the precipitate was filtered to give 3- {2- [4- (6-fluoro-benzo [d] isoxazol-3- yl) -piperidin- l-yl] -ethyl} -9- 3.6 g (yield: 21.6%) of 2-methyl-6,7,8,9-tetrahydro-pyrido [1,2-a] pyrimidin-

Example 1:

1-yl] -ethyl} -9-hydroxy-2-methyl-6,7-dihydro-isoquinolin- , 8,9-tetrahydro-pyrido [1,2-a] pyrimidin-4-one hydrochloride

100 ml of methyl alcohol is added to the reaction tank and stirred. 10 g of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole hydrolchloride (FPBI) and 13.7 ml of diisopropylamine were added thereto. 11.3 g of 7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a] -pyrimidin-4-one (CMHTP) are introduced. The temperature is raised to 66.7 占 폚 and stirring is performed for 12 hours or more. Concentrate when the reaction is complete. 10 ml of acetonitrile is added and the mixture is concentrated (repeated twice). 100 ml of acetonitrile is added and stirred. Cool to 0 ~ -5 ℃ and stir. Filtration and washing with 10 ml of acetonitrile. wet solid into the reaction tank. 75 ml of methyl alcohol is added and stirred. Add 1.5 ml of hydrochloride, cool to 0 ~ -5 ℃ and stir. Filtered, washed with 10 ml of acetonitrile and dried under reduced pressure at 40 [deg.] C or lower for more than 8 hours to give 3- {2- [4- (6-fluoro-benzo [d] isoxazol-3- yl) -piperidin- 16.3 g (Yield: 90.5% / [l, 2-a] pyrimidin- Purity [HPLC qualitative analysis]: 99.8%).

Example 2:

1-yl] -ethyl} -9-hydroxy-2-methyl-6,7-dihydro-isoquinolin- , 8,9-tetrahydro-pyrido [1,2-a] pyrimidin-4-one hydrochloride

100 ml of methyl alcohol is added to the reaction tank and stirred. 10 g of 6-fluoro-3- (4-piperidinyl) -1,2-benzisoxazole hydrolchloride (FPBI) and 13.7 ml of diisopropylamine were added thereto. 11.3 g of 7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a] -pyrimidin-4-one (CMHTP) are introduced. The temperature is raised to 66.7 占 폚 and stirring is performed for 12 hours or more. Concentrate when the reaction is complete. 10 ml of acetonitrile is added and the mixture is concentrated (repeated twice). 100 ml of acetonitrile is added and stirred. Cool to 0 ~ -5 ℃ and stir. Filtration and washing with 10 ml of acetonitrile. wet solid into the reaction tank. 75 ml of methyl alcohol is added and stirred. 6.1 ml of hydrochloric acid was added to dissolve it. 4.8 ml of triethylamine is added to crystallize. Cool to 0 ~ -5 ℃ and stir. Filtered, washed with 10 ml of acetonitrile and dried under reduced pressure at 40 [deg.] C or lower for more than 8 hours to give 3- {2- [4- (6-fluoro-benzo [d] isoxazol-3- yl) -piperidin- 16.2 g (Yield: 90.1% / (2-a) pyridin-2-yl) Purity [HPLC qualitative analysis]: 99.78%).

Example 3:

1-yl] -ethyl} -9-hydroxy-2-methyl-6,7-dihydro-isoquinolin- , 8,9-tetrahydro-pyrido [1,2-a] pyrimidin-4-one hydrochloride

Except that 16.9 ml (2.5 eq) of diisopropylethylamine was used instead of diisopropylamine (13.7 ml) as a base. Ethyl-9-hydroxy-2-methyl-isoxazole-3-carboxylic acid was prepared from 3- {2- [4- (6-Fluoro-benzo [d] isoxazol- 15.2 g (yield: 84.3% / purity [HPLC qualitative analysis]: 99.70%) of 6,7,8,9-tetrahydro-pyrido [1,2- a] pyrimidin-4-one hydrochloride was obtained.

Example 4:

1-yl] -ethyl} -9-hydroxy-2-methyl-6,7-dihydro-isoquinolin- , 8,9-tetrahydro-pyrido [1,2-a] pyrimidin-4-one hydrochloride

Except that 16.9 ml (2.5 eq) of diisopropylethylamine was used instead of diisopropylamine (13.7 ml) as a base. Ethyl-9-hydroxy-2-methyl-isoxazole-3-carboxylic acid was prepared from 3- {2- [4- (6-Fluoro-benzo [d] isoxazol- 15.3 g (yield: 84.9% / purity [HPLC qualitative analysis]: 99.73%) of 6,7,8,9-tetrahydro-pyrido [1,2- a] pyrimidin-4-one hydrochloride was obtained.

Example 5:

1-yl] -ethyl} -9-hydroxy-2-methyl 6,7-dihydro- Preparation of 8,9-tetrahydro-pyrido [1,2-a] pyrimidin-4-one (paliperidone)

50 ml of purified water is added to the reaction tank and stirred. 1-yl] -ethyl} -9-hydroxy-2-methyl-6,7-dihydro-isoquinolin- , 8,9-tetrahydro-pyrido [1,2-a] pyrimidin-4-one hydrochloride are added. 50 ml of acetonitrile is added to dissolve. 0.5 g of activated carbon is added. Filter with activated charcoal and wash with 5 ml of purified water. 45 ml of purified water and 4 g of sodium hydrogencarbonate are mixed and dissolved. Stir and cool to 0 ~ 5 ℃ and stir. Filtered and washed with 10 ml of purified water and dried under reduced pressure at 40 [deg.] C or lower to give 3- {2- [4- (6-fluoro-benzo [d] isoxazol-3- yl) -piperidin- -9-hydroxy-2-methyl-6,7,8,9-tetrahydro-pyrido [1,2-a] pyrimidin- ]: 99.9%).

Example 6:

1-yl] -ethyl} -9-hydroxy-2-methyl 6,7-dihydro- Preparation of 8,9-tetrahydro-pyrido [1,2-a] pyrimidin-4-one (paliperidone)

The procedure of Example 5 was repeated except that 50 ml of methanol was used instead of 50 ml of acetonitrile as an organic solvent. Ethyl-9-hydroxy-2-methyl-isoxazole-3-carboxylic acid was prepared from 3- {2- [4- (6-Fluoro-benzo [d] isoxazol- 8.5 g (yield: 92.0% / purity [HPLC qualitative analysis]: 99.83%) of 6,7,8,9-tetrahydro-pyrido [1,2- a] pyrimidin-

Example 7:

1-yl] -ethyl} -9-hydroxy-2-methyl 6,7-dihydro- Preparation of 8,9-tetrahydro-pyrido [1,2-a] pyrimidin-4-one (paliperidone)

Except that 5 g of sodium carbonate was used instead of 4 g of sodium hydrogencarbonate as a base. Ethyl-9-hydroxy-2-methyl-isoxazole-3-carboxylic acid was prepared from 3- {2- [4- (6-Fluoro-benzo [d] isoxazol- 8.3 g (yield: 90.1% / purity [HPLC qualitative analysis]: 99.88%) of 6,7,8,9-tetrahydro-pyrido [1,2- a] pyrimidin-

Claims (7)

In a method for producing paliperidone in high yield and high purity,
1) alkylating the FPBI of formula II with a CMHTP of formula III to give a crude paliperidone of formula I, by alkylation with an N-alkylating agent in an inert solvent;
2) 0.1 to 0.61 wt% (w / v): 0.48 wt% (w / v) of methanol: hydrochloric acid: triethylamine on the basis of FPBI to the crude pyriperidone prepared in step 1) % (w / v) or less to produce paliperidone hydrochloride of formula (IV); And
3) converting paliperidone hydrochloride prepared in step 2) into paliperidone of formula (I) in water or an organic solvent or a mixed solvent thereof in the presence of a base in the presence of a base; ≪ / RTI > 2. Process according to claim 1, characterized in that the N-alkylating agent of step 1) is selected from the group consisting of diisopropylamine, isopropylethylamine. The process for producing paliperidone according to claim 2, wherein the equivalence of the N-alkylating agent is 1.0 to 4.0. The process according to claim 1, wherein the step of step 2) is carried out at a pH of 3-6. The method according to claim 4, wherein the step of step 2) is repeated once or several times. The process according to claim 1, wherein the organic solvent of step 3) is selected from acetonitrile, acetone, methanol. 7. The process according to claim 6, wherein the base of step 3) is selected from sodium hydrogen carbonate, sodium carbonate and sodium hydroxide.

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