KR100671306B1 - Novel Making Process of the Risperidone - Google Patents

Abstract

The present invention relates to a novel process for preparing risperidone of formula (9), which is widely used as an antipsychotic, schizophrenia, and psychoanxiety agent, and includes aldehyde compounds of formula (5) and benzoylpiperidine compounds of formula (6) or salts of such compounds. And a reductive amination to prepare a ketone compound represented by the following formula (7), and by producing a final product through a novel intermediate product that implements the high-quality antipsychotics can be synthesized in a simple and high yield .

[Formula 9]

[Formula 5]

[Formula 6]

[Formula 7]

Pyrido [1,2-a] pyrimidin-4-one derivatives, risperidone

Description

Novel Making Process of the Risperidone

The present invention relates to a novel process for preparing risperidone of formula (9), which is widely used as an agent for treating psychosis, schizophrenia and psychoanxiety, wherein the aldehyde compound of formula 5 and the benzoylpiperidine compound of formula 6 or salts of such compounds The present invention relates to a method for providing Listeridon, including preparing an ketone compound of Formula 7 by amination.

[Formula 9]

A further embodiment of the invention is a compound of formula 7, 3- [2- [4- (2,4-difluorobenzoyl) -piperidin-1-yl] ethyl] -2-methyl-6,7 , 8,9-tetrahydro-4H-) pyrido [1,2-a] pyrimidin-4-one and 6,7,8,9-tetrahydro-2-methyl-3-vinyl Pyrido [1,2-a] pyrimidin-4-one, 3-bromo-6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyridine Midin-4-one and 6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one. These compounds are described in detail below as synthetic intermediates in the preparation of compounds of formula 9.

Risperidone is an antipsychotic agent belonging to the novel chemical class benzisoxazole derivatives. The chemical name is 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethyl] -6,7,8,9-tetrahydro -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one. This is a compound of formula (9) having a mixture of benzisoxazole and pyrimidine, and is an agent showing excellent therapeutic efficacy against schizophrenia. Looking at the prior art for producing risperidone so far as follows.

In U.S. Patent No. 4,804,663, 6-fluoro-3- (4-piperidinyl) -1,2-benzoisoxazole compound and 3- (2-chloroethyl) -2-methyl-6, Risperidone is prepared through a coupling reaction with a 7,8,9-tetrahydro-4H-pyrido- [1,2, a] pyrimidin-4-one compound. This reaction is performed by adding potassium carbonate under a dimethylformamide solvent, and the reaction yield is not very good, and has a disadvantage of using dimethylformamide (DMF), which is a solvent that is harmful to the human body and is very difficult to remove.

Scheme 1

International Patent Publication No. WO 01/85731 discloses hydrogenation of 3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2, a] pyrimidin-4-one with palladium as shown in Scheme 2 below. To give 3- (2-chloroethyl) -2-methyl-6,7,, 8,9-tetrahydro-4H-pyrido- [1,2, a] pyrimidin-4-one compound, Risperidone is synthesized from this compound and 6-fluoro-3- (4-piperidinyl) -1,2-benzoisoxazole compound using sodium hydroxide and a water solvent. However, this also increases the reaction yield slightly, but the reality is that it is difficult to purify due to the generation of impurities due to various addition reactions.

Scheme 2

Spanish Patent No. 2,074,966 discloses a process for preparing risperidone of Formula 1 by reacting an oxazole compound of Formula 9 with an amino pyrimidine compound of Formula 8, as shown in Scheme 3 below.

Scheme 3

However, the above process uses the intermediate 3- (6-fluorobenzo [d] isoxazol-3-yl) -5-idopentyl methanesulfonate and 3- (2-aminoethyl) -2-methyl-6 The method for synthesizing, 7,8,9-tetrahydropyrido [1,2, a] pyrimidin-4-one has complex and difficult problems.

EP 0196132 discloses 3-2- [4- (6-fluorobenzo (D) isoxazol-3-yl) -piperidin-1-yl] -ethyl-2-methyl-6,7, Another method for the preparation of 8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidin-4-one (I) is disclosed. The method is an intramolecular condensation reaction between different functional groups to provide a 2-methyl-6,7,8,9-tetrahydro-4H-pyrido- (1,2-a) pyrimidin-4-one system. Cyclization of other intermediates by Most of these processes involve the use of highly complex intermediates and the implementation of reactions that inevitably affect the overall cost of the final process at the final synthesis stage.

An object of the present invention is to solve the above problems and to prepare a methyl-3-vinylpyrido [1,2, a] pyrimidin-4-one derivative and pharmaceutically acceptable salt thereof in high yield and economically. To provide a method for producing risperidone.

The present invention provides 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethyl] -6,7,8,9 An alternative method is provided for preparing tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, the process of which is illustrated in Scheme 1 below.

Scheme 1

3- [2- [4- (2,4-difluorobenzoyl) -piperidin-1-yl] ethyl] -2-methyl-6,7,8,9-tetrahydro of formula 7 -4H-) pyrido [1,2-a] pyrimidin-4-one is a 2- (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [ 1,2-a] pyrimidin-3-yl) acetaldehyde from condensation with 4- (2,4-difluorobenzoyl) -piperidine of formula (6).

Subsequently, the reflux reaction of Chemical Formula 7 gave 3- [2- [4- (2,4-difluorophenyl) (hydroxyimino) methyl] piperidin-1-yl] ethyl] -2- in Chemical Formula 8. Methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one is obtained.

Finally, 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethyl] -6,7,8,9 of Formula 9 The formation of -tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one can be prepared with risperidone from the ring closure of the compound of Formula 8.

In addition, a further embodiment of the present invention is a synthetic intermediate for preparing the aldehyde compound of Formula 5 is shown in Scheme 2 below.

Scheme 2

2- (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde of formula 5 in the present invention Prepared from 6,7,8,9-tetrahydro-2-methyl-3-vinylpyrido [1,2-a] pyrimidin-4-one of 4, wherein the compound of formula 4 is 3- It is prepared from bromo-6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one, wherein the compound of Formula 3 is 6,7,8 of Formula 2 , 9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one, wherein the compound of formula 2 is 2-methyl-4H-pyrido [1,2- a] is formed from pyrimidin 4-one. Such compounds are previously unknown as synthetic intermediates in the preparation of compounds of formula 9 and form part of the present invention.

Specifically, the present invention is represented by the following formula (9) comprising preparing a ketone compound of formula (7) by reductive amination reaction of the aldehyde compound of formula (5) and the benzoylpiperidine compound of formula (6) or salts of these compounds It relates to a method for producing risperidone.

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 9]

Here, as a reducing reagent used in the reductive amination reaction, a reducing agent selected from sodium cyanoborohydride, zinc, palladium, sodium borohydride, sodium acetoxyborohydride and lithium aluminum hydride is used as a solvent. May be prepared using risperidone selected from methanol, water, alcohols, ethers, aromatic hydrocarbons and halogenated hydrocarbons.

As such, the first feature of the present invention is to prepare a ketone compound of formula (7) using an aldehyde compound of formula (5) and a benzoylpiperidine compound of formula (6), wherein the amount used when each compound is combined is a compound of the aldehyde compound of formula (5). It is used in an amount of 1.0 to 1.5g per 2.5g of benzoylpiperidine compound of 6, the reducing agent is used in an amount of 1.0 to 1.2g per 2.5g of benzoylpiperidine compound of Formula 6, and the solvent is benzoylpipe of Formula 6 A method of preparing risperidone using an amount of 10 ml per 2.5 g of ferridine compound.

Another feature of the present invention is 3- [2- [4- (2,4-difluorobenzoyl) -piperidin-1-yl] ethyl] -2-methyl-6,7,8,9 To give -tetrahydro-4H-) pyrido [1,2-a] pyrimidin-4-one:

[Formula 7]

2- (2-Methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde of Formula 5

[Formula 5]

And a condensation reaction with 4- (2,4-difluorobenzoyl) -piperidine of Formula 6 or any of its salts:

[Formula 6]

3- [2- [4- (2,4-difluorophenyl) (hydroxyimino) methyl] piperidine of the following formula (8) by refluxing with a compound of formula (7) in the presence of hydroxyamine hydrochloride and pyridine -1-yl] ethyl] -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one,

[Formula 8]

Then, 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperi of the formula (9) was subjected to the ring closure of the compound of the formula (8) in the presence of 30% aqueous potassium hydroxide solution. Din-1-yl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one It relates to a manufacturing method.

[Formula 9]

Another feature of the present invention is a method for producing risperidone as described above, wherein 6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyrido [1,2-a] To provide pyrimidine-3-carbaldehyde, 6,7,8,9-tetrahydro-2-methyl-3-vinylpyrido [1,2-a] pyrimidin-4-one of formula (4):

[Formula 4]

This is a method for preparing risperidone in which 9-borabicyclo [3,3,1] nonane is added to a tetrahydrofuran solvent and heated, followed by dichloromethane solvent and pyridinium chlorochromate.

In addition, to provide 6,7,8,9-tetrahydro-2-methyl-3-vinylpyrido [1,2-a] pyrimidin-4-one of Chemical Formula 4, 3- Bromo-6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one:

[Formula 3]

(X is a halogen atom.)

Is a method for producing risperidone using tributyl (vinyl) tin and tetrakistriphenylphosphinepallium as catalysts in a toluene solvent.

In addition, to provide 3-bromo-6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one of Chemical Formula 3, 6 , 7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one:

[Formula 2]

This is a method for producing risperidone in which bromine water is added under a chloroform solvent and reacted at room temperature.

Subsequently, in order to provide 6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one of Chemical Formula 2, 2-methyl-4H- of Chemical Formula 1 Pyrido [1,2-a] pyrimidin 4-one:

[Formula 1]

This is a method for preparing risperidone by adding 2-amino pyridine and methylaceto acetate in a toluene solvent and refluxing the reaction using para-toluene sulfonic acid as a catalyst.

Further, another feature of the present invention is a compound of formula (7), a compound of formula (4), a compound of formula (3) and the like which are used as a reaction intermediate in the synthesis for producing a compound of formula (9) according to the method for preparing risperidone as described above It relates to a compound of formula (2).

Hereinafter, the present invention will be described in detail.

First, Scheme 4 below is a process for preparing the compound of Formula 1. As in Scheme 4, 2-amino pyridine (left structural formula) and methylaceto acetate (middle structural formula) were reacted under a toluene solvent by adding para-toluene sulfonic acid as a catalytic amount to reflux the reaction of 2-methyl-4H-pyrido [1,2-a] pyrimidin 4-one (right structure) compound was prepared in a yield of at least 95%. This reaction is carried out using a conventional organic solvent toluene, benzene, zylene, etc., preferably carried out at 80 ~ 100 ℃, in place of the acid catalyst para-toluene sulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, etc. Eggplant acid catalyst can be used in various ways. Preferably acetic acid, para-toluene sulfonic acid, hydrochloric acid, etc. are used.

[Scheme 4] [Scheme 1]

,

,

Next, Reaction Scheme 5 is a process of preparing the compound of Formula 2 (right structure) from the compound of Formula 1 (left structure). In order to reduce the compound of Formula 1, 6,7,8,9-tetrahydro-2-methylpyri of Formula 2 was added by applying hydrogen pressure at 125 psi under 10% palladium / carbon and 6.0 normal hydrochloric acid solution as in Scheme 5. An optional compound, which is Fig. [1,2-a] pyrimidin-4-one, was obtained in 74% yield. As a reducing reagent, reagents such as palladium / carbon and platinum oxide are used, and the reaction solvent may be 6.0 normal hydrochloric acid aqueous solution, water, methanol, ethanol, isopropanol, or the like.

[Scheme 5] [Scheme 2]

,

,

Then, Scheme 6 below is a process for preparing the compound of formula 3 (right structure) from the compound of formula 2 (left structure). To carry out the bromination reaction to the compound of Formula 2, bromine water was added under a chloroform solvent as in Scheme 6 and reacted at room temperature for 4 hours to obtain the compound of Formula 3 in 73% yield. In formula (3), X is a halogen atom. In synthesizing Formula 3, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and the like are used as the reaction solvent.

[Scheme 6] [Scheme 3]

,

,

                                                       (X is a halogen atom.)

In addition, the following Reaction Scheme 7 is a process for preparing the compound of Formula 4 (right structure) from the compound of Formula 3 (left structure). Tributyl (vinyl) tin and tetrakistry using a stille reaction, a nomenclature reaction (Journal of the American Chemical Society. 100, 3636, 1978), as shown in Scheme 7, to carry out the coupling reaction to the compound of the formula (3). Reaction was carried out in a toluene solvent for 12 hours using phenylphosphinepallium as a catalyst in 6,7,8,9-tetrahydro-2-methyl-3-vinylpyrido [1,2-a] in 83% yield. ] Pyrimidin-4-one or acid addition salts thereof was prepared.

[Scheme 7] [Scheme 4]

,

,

(X is a halogen atom.)

Next, Reaction Scheme 8 is a process of preparing the compound of Formula 5 (right structure) from the compound of Formula 4 (left structure). As shown in Scheme 8, 9-borabicyclo [3,3,1] nonane was heated in tetrahydrofuran solvent, followed by heating with dichloromethane solvent and pyridinium chlorochromate. The same aldehyde compound was obtained in 53% yield. In order to obtain an aldehyde compound, a boron compound was prepared by using compounds such as 9-borabicyclo [3,3,1] nonane, borane-methyl sulfide complex, and borane tetrahydrofuran complex using an anti-markonicope reaction. It can be oxidized to pyridinium chlorochromate to form an aldehyde compound, or to a vinyl compound using chromylchloride and zinc to form an aldehyde.

[Scheme 8] [Scheme 5]

,

,

In addition, the following Reaction Scheme 9 is a process for preparing the compound of Formula 7 (right structure) from the condensation reaction of the compound of Formula 5 (middle structural formula) and the compound of Formula 6 (left structural formula). 4- (2,4-difluorobenzoyl) piperidine hydrochloride, a compound of Formula 6, was prepared according to a conventional preparation method, and reacted with a methanol solvent to react with a compound of Formula 5, as shown in Scheme 9. Sodium cyanoborohydride was added to give the compound of Formula 7 in 88% yield.

Scheme 9

    [Formula 6] [Formula 5] [Formula 7]

In Scheme 9, a reducing agent selected from zinc, palladium, sodium borohydride, sodium acetoxyborohydride, and lithium aluminum hydride, instead of sodium cyanoborohydride as a reducing reagent as a reducing amination reaction, is used as water. All organic solvents selected from among methanol, alcohol, ether and aromatic hydrocarbons can be used in various ways.

Subsequently, the following Reaction Scheme 10 is a process for preparing the compound of Formula 8 (right structure) from the compound of Formula 7 (left structure). The compound of Formula 7 was added with hydroxylamine hydrochloride in a pyridine solvent as in Scheme 10, and refluxed for 5 hours to prepare a compound of Formula 8 in 64% yield.

Scheme 10

                                                   [Formula 8]

In addition, Scheme 11 is a process of preparing the compound of formula 9 (right structure) from the compound of formula 8 (left structure). The compound of Formula 8 was subjected to a ring-closure reaction at 90 ° C. for 12 hours in an aqueous 30% potassium hydroxide solution as shown in Scheme 11 to give the final compound risperidone- (3- [2- [4- (6) in 85% yield. -Fluoro-1,2-benzisoxazol-3-yl) piperidin-1-yl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2- a] pyrimidin-4-one) was obtained in 89% yield. In the following Reaction Scheme 11, as the alkali reagent, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide and mixtures thereof may be used.

Scheme 11

[Formula 9]

Hereinafter, the present invention will be described in more detail with reference to the examples, which are only intended to help understanding the structure and operation of the present invention and the scope of the present invention is not limited to these examples.

Example 1 Preparation of 2-methyl-4H-pyrido [1,2-a] pyrimidin 4-one (Formula 1) (Scheme 4)

4.0 g of 2-amino pyridine, 5.4 g of methyl aceto acetate, and 0.2 g of paratoluene sulfonic acid were added to a 20 mL toluene and 100 mL reactor, a water separator and a reflux condenser were installed and reacted at reflux for 12 hours, followed by cooling. . 50 mL of toluene was added to the cooled reaction solution, and the mixture was washed with saturated sodium bicarbonate. The upper toluene layer was dried over magnesium sulfate, filtered and concentrated to give 6.5 g of 2-methyl-4H-pyrido [1,2-a] pyrimidin 4-one (yield 95%).

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.05 (d, 1H), 7.75 (m, 1H), 7.62 (d, 1H), 7.15 (m, 1H), 2.48 (s, 3H) MS ( FAB); 159 (M ⁺ + H ⁺ )

Example 2 Preparation of 6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one (Formula 2) (Scheme 5)

To 30 g of 2-methyl-4H-pyrido [1,2-a] pyrimidin 4-one prepared in Example 1, 2.0 g of 20% 10% palladium carbon solution of 6N hydrochloric acid was added, and hydrogen pressure of 125 psi at room temperature. The hydrogenation reaction was carried out for 18 hours. The reaction solution was filtered through Celite, 20 mL of 50% sodium hydroxide solution was added to the filtrate, and extracted three times with 200 mL of dichloromethane. The extracted dichloromethane layer is dried and filtered with anhydrous sodium sulfate. The filtrate was concentrated to give 18.0 g (yield 74%) of 6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 6.17 (s, 1H), 3.93 (t, 2H, J = 5.82 Hz), 2.92 (t, 2H, J = 6.6 Hz), 2.24 (s, 3H ), 1.97-1.86 (m, 4H) MS (FAB); 163 (M ⁺ + H ⁺ )

Example 3: Preparation of 3-bromo-6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one (Formula 3) (Scheme 6)

100 mL of chloroform was added to 30.0 g of 6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one prepared in Example 2, and the temperature of the reactor was adjusted to 0 ° C. . 31.6 g of bromine water was diluted in 100 mL of 150 mL of chloroform and added dropwise while maintaining the temperature for 1 hour. After completion of the dropwise stirring, the temperature is gradually raised to room temperature for 3 hours. After completion of stirring, the residue was filtered, the filtrate was washed with 20% sodium thiosulfate aqueous solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 3-bromo-6,7,8,9-tetrahydro-2-methyl. 32.5 g (yield 73%) of pyrido [1,2-a] pyrimidin-4-ones were obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 3.99 (t, 2H, J = 12.36 Hz), 2.87 (t, 2H, J = 13.24 Hz), 2.44 (s, 3H, J = 9.01 Hz), 1.98-1.88 (m, 4H) MS (FAB); 241 (M ⁺ + H ⁺ )

Example 4: Preparation of 6,7,8,9-tetrahydro-2-methyl-3-vinylpyrido [1,2-a] pyrimidin-4-one (Formula 4) (Scheme 7)

3-bromo-6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidine-4- prepared in Example 3 after installing a reflux condenser in a 50 mL reactor under nitrogen stream. On 1.0g, 1.3 g of tributyl (vinyl) tin and 0.08g of tetrakistriphenylphosphinepalladium were added, 20 mL of toluene was added and refluxed for 15 hours. The reaction solution is cooled and then concentrated by filtration through celite. The concentrate was purified by silica gel chromatography to obtain 0.78 g of 6,7,8,9-tetrahydro-2-methyl-3-vinylpyrido [1,2-a] pyrimidin-4-one as a target compound. Yield 83%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 6.63 (t, 1H, J = 13.38 Hz), 6.25 (d, 1H, J = 17.95), 5.49 (d, 1H, J = 12.94 Hz), 3.96 (t, 2H, J = 5.97), 2.88 (t, 2H, J = 6.56 Hz), 2.36 (s, 3H), 1.95-1.88 (m, 4H) MS (FAB); 189 (M ⁺ + H ⁺ )

Example 5 2- (2-Methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde 5) Preparation (Scheme 8)

A reflux condenser was installed in a 100 mL reactor under a nitrogen stream, and 3-bromo-6,7,8,9-tetrahydro-2-methyl-3-vinylpyrido [1,2-a] pyrile prepared in Example 4 was prepared. 20 mL of anhydrous tetrahydrofuran solvent was added to 1.3 g of midin-4-one, and 6.2 mL of borabycyclo [3,3,1] nonane dissolved in 0.5 mol tetrahydrofuran was added thereto, followed by heating at 60 ° C for 3 hours. The reaction solution was cooled to room temperature and added dropwise to a reactor containing 50 mL of dichloromethane and 5.0 g of pyridinium chlorochromate prepared separately. Heated for 3 hours after the addition was completed. After cooling the reaction solution, the concentrated residue of the black residue was purified by silica gel chromatography under reduced pressure to obtain 2- (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2 -a] pyrimidin-3-yl) acetaldehyde (0.74 g) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 9.58 (s, 1H), 3.81 (t, 2H), 3.53 (s, 2H), 7.15 (m, 1H), 2.78 (t, 2H), 2.10 (s, 3H), 1.90-1.88 (m, 4H) MS (FAB); 159 (M ⁺ + H ⁺ )

Example 6: 3- [2- [4- (2,4-Difluorobenzoyl) -piperidin-1-yl] ethyl] -2-methyl-6,7,8,9-tetrahydro Preparation of -4H-pyrido [1,2-a] pyrimidin-4-one (Scheme 7) (Scheme 9)

1.2 g of 2- (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde prepared in Example 5 2.5 g of 4- (2,4-difluorobenzoyl) -piperidine was dissolved in 10 mL of methanol at room temperature, and then 1.1 g of sodium cyanoborohydride and 0.1 mL of acetic acid were added with stirring, followed by stirring for 6 hours. 1.0 mL of water was added to the reaction, the reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel chromatography to obtain 3- [2- [4- (2,4-difluorobenzoyl) -piperidin-1-yl. 2.3 g (yield 88%) of] ethyl] -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one were obtained.

¹ H NMR (300MHz, D ₂ 0) δ (ppm): 7.85 ~ 8.0 (m, 1H), 7.05 ~ 7.20 (m, 2H), 4.0 (t, 2H), 3.85 (m, 2H), 3.65 (m , 1H), 3.20 to 3.35 (m, 4H), 3.20 (t, 2H), 2.90 to 3.10 (m, 2H), 2.45 (s, 3H), 2.20 to 2.40 (m, 2H), 1.80 to 2.10 (m , 6H) MS (FAB); 414 (M ⁺ + H ⁺ )

Example 7 3- [2- [4- (2,4-Difluorophenyl) (hydroxyimino) methyl] piperidin-1-yl] ethyl] -2-methyl-6,7, Preparation of 8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one (Scheme 8) (Scheme 10)

3- [2- [4- (2,4-Difluorobenzoyl) -piperidin-1-yl] ethyl] -2-methyl-6,7,8,9-tetrahydro prepared in Example 6 2.1 g of -4H-pyrido [1,2-a] pyrimidin-4-one, 1.6 hydroxyamine hydrochloride and 20 mL of pyridine were added thereto, and the mixture was stirred under reflux for 8 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The concentrate was diluted with 100 mL with dichloromethane and washed with 20.0 mL of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain 3- [2- [4- (2,4-difluorophenyl) (hydroxyimino) methyl] piperidine 1.4 g (yield 64%) of -1-yl] ethyl] -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one were obtained. .

¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 10.80 (s, 1H), 7.20 (m, 1H), 6.90 (m, 2H), 3.90 (t, 2H), 3.10 (m, 2H), 3.65 (m, 1H), 2.80 (t, 2H), 2.70 (m, 2H), 2.20 (m, 3H), 1.70-2.10 (m, 10H) MS (FAB); 429 (M ⁺ + H ⁺ )

Example 8 Risperidone (3- [2- [4- (6-fluoro-1,2-benzisooxazol-3-yl) piperidin-1-yl] ethyl] -6,7,8 Preparation of 9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one) (Scheme 11)

3- [2- [4- (2,4-difluorophenyl) (hydroxyimino) methyl] piperidin-1-yl] ethyl] -2-methyl-6,7 prepared in Example 7 1.4 g of 8,9-tetrahydro-4H-pyrido [1,2, a] pyrimidin-4-one was added to a 30% aqueous potassium hydroxide solution and stirred at 120 ° C. for 5 hours. The temperature of the reaction solution was cooled to room temperature, and dichloromethane 200mL was extracted three times. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperidine. 1.4 g (yield 89.8%) of -1-yl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one were obtained. .

¹ H NMR (300MHz, CDCl ₃ ) δ (ppm): 7.65∼7.61 (m, 1H), 7.18∼7.14 (m, 1H), 7.00∼6.94 (m, 1H) 3.87∼3.83 (m, 2H), 3.42 ~ 3.07 (m, 2H), 2.97-3.02 (m, 1H), 2.81-2.76 (m, 2H), 2.71-2.66 (m, 2H), 2.48-2.43 (m, 1H), 2.23 (s, 3H) , 2.34-2.19 (m, 2H), 2.05-2.01 (m, 4H), 1.87-1.79 (m, 4H) MS (FAB); 409 (M ⁺ + H ⁺ )

As described above, the process of preparing risperidone using a methyl-3-vinylpyrido [1,2, a] pyrimidin-4-one derivative and a pharmaceutically acceptable salt thereof according to the present invention is carried out according to the present invention. It combines simplicity and compliance with cost, safety and ecological requirements in the production of the active substance risperidone. Chemical processes are easily reproducible on a large scale through simple, high-yield synthesis steps that lead to quality end products.

Claims (14)

A method for preparing risperidone represented by the following formula (9) comprising preparing a ketone compound of the following formula (7) by reducing amination of an aldehyde compound of formula (5) and a benzoylpiperidine compound of formula (6) or salts of such a compound. [Formula 5]

[Formula 6]

[Formula 7]

[Formula 9]

The method of claim 1, wherein the reductive amination reaction uses a reducing agent selected from sodium cyanoborohydride, zinc, palladium, sodium borohydride, sodium acetoxyborohydride and lithium aluminum hydride as a reducing reagent. , As a solvent, a method for producing risperidone, characterized in that a solvent selected from methanol, water, alcohol, ether, aromatic hydrocarbon and halogenated hydrocarbon is used. The method for preparing risperidone according to claim 1 or 2, wherein the aldehyde compound of the formula (5) is used in an amount of 1.0 to 1.5 g per 2.5 g of the benzoylpiperidine compound of the formula (6). The method for preparing risperidone according to claim 2, wherein the reducing agent is used in an amount of 1.0 to 1.2 g per 2.5 g of the benzoylpiperidine compound represented by Chemical Formula 6. The method for preparing risperidone according to claim 2, wherein the solvent is used in an amount of 10 ml per 2.5 g of the benzoylpiperidine compound represented by Chemical Formula 6. 3- [2- [4- (2,4-Difluorobenzoyl) -piperidin-1-yl] ethyl] -2-methyl-6,7,8,9-tetrahydro-4H To give pyrido [1,2-a] pyrimidin-4-one: [Formula 7]

2- (2-Methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) acetaldehyde of Formula 5 [Formula 5]

And a condensation reaction with 4- (2,4-difluorobenzoyl) -piperidine of Formula 6 or any of its salts: [Formula 6]

3- [2- [4- (2,4-difluorophenyl) (hydroxyimino) methyl] piperidine of the following formula (8) by refluxing with a compound of formula (7) in the presence of hydroxyamine hydrochloride and pyridine -1-yl] ethyl] -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one, [Formula 8]

Then, 3- [2- [4- (6-fluoro-1,2-benzisoxazol-3-yl) piperi of the formula (9) was subjected to the ring closure of the compound of the formula (8) in the presence of 30% aqueous potassium hydroxide solution. Din-1-yl] ethyl] -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one Manufacturing method. [Formula 9]

The compound of claim 6, wherein 2- (2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-3-yl) To provide acetaldehyde, 6,7,8,9-tetrahydro-2-methyl-3-vinylpyrido [1,2-a] pyrimidin-4-one of formula (4): [Formula 4]

To 9-borabicyclo [3,3,1] nonane in a tetrahydrofuran solvent is heated, and then added to the dichloromethane solvent and pyridinium chloro chromate and reheating the method of producing risperidone. According to claim 7, to provide 6,7,8,9-tetrahydro-2-methyl-3-vinylpyrido [1,2-a] pyrimidin-4-one of Formula 4, 3-Bromo-6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one of 3: [Formula 3]

(X is a halogen atom.) Tributyl (vinyl) tin and tetrakistriphenylphosphinepallium as catalysts in a toluene solvent. The method according to claim 8, to provide 3-bromo-6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one of Formula 3, 6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one of Formula 2: [Formula 2]

The method for producing risperidone, wherein bromine water is added under a chloroform solvent and reacted at room temperature. 10. The method according to claim 9, to provide 6,7,8,9-tetrahydro-2-methylpyrido [1,2-a] pyrimidin-4-one of Chemical Formula 2, Methyl-4H-pyrido [1,2-a] pyrimidin 4-one: [Formula 1]

The method for producing risperidone, wherein 2-amino pyridine and methylaceto acetate are added in a toluene solvent, followed by reflux reaction using para-toluene sulfonic acid as a catalyst. The compound of formula (7), characterized in that the reaction intermediate used in the synthesis reaction for producing the compound of formula (9) according to the preparation method of risperidone of claim 6. [Formula 7]

According to the method for preparing risperidone of claim 7, the compound of formula 4, characterized in that the reaction intermediate used in the synthesis reaction for producing the compound of formula (9). [Formula 4]

The compound of formula 3, characterized in that the reaction intermediate used in the synthesis reaction for producing the compound of formula 9 according to the method for preparing risperidone of claim 8. [Formula 3]

(X is a halogen atom.) (delete)