WO2006046082A1

WO2006046082A1 - A process for the preparation of risperidone

Info

Publication number: WO2006046082A1
Application number: PCT/HU2005/000109
Authority: WO
Inventors: Tamás FODOR; György SZABÓ; Ádám DEMETER
Original assignee: Richter Gedeon Vegyészeti Gyár Rt.
Priority date: 2004-10-25
Filing date: 2005-10-10
Publication date: 2006-05-04
Also published as: HU0402163D0; HUP0402163A2

Abstract

The object of the invention is a process for the preparation of risperidone (chemical name: 3-[2-[4-(6-fluoro-l,2-benzisoxazole-3-yl)-l-piperidinyl]ethyl-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one) of the formula (I) by reacting 6-fluoro-3-(4-piperidinyl)- 1,2-benzisoxazole of the formula (II), and 3-(2-iodoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one of the formula (III).

Description

A PROCESS FOR THE PREPARATION OF RISPERIDONE

The invention relates to a process for the preparation of risperidone (chemical name: 3 -[2-[4-(6-fluoro- 1 ,2-benzisoxazole-3 -yl)- 1 -piperidinyl] ethyl-2-methyl-6,7, 8₅9-tetrahydro-4H- pyrido [ 1 ,2-a]pyrimidine-4-one) of the formula (I)

(I)

by reacting 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of the formula (II),

(II) and 3-(2-iodoethyl)-2-methyl-6₅7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidme-4-one of the formula (III)

(III)

The risperidone has combined serotonin (5-HT₂) and dopamine (D₂) receptor antagonist effects (it is an antipsychotic compound) and plays an important role in the. treatment of schizophrenia. For the preparation of the risperidone several chemical processes have been developed, in which the syntheses of using the 3-(2-substituted-ethyl)-2-methyl-6,7,S,9-tetrahydro-4H- pyrido[l,2-a]pyrimidine-4-one of the general formula (IV),

(IV)

-wherein X stands for a halogen atom-, reactive ester or, a sulfonyloxy-group and 6-fluoro-3- (4-piperidinyl)-l,2-benzisoxazole of the formula (II) are preferred for industrial application.

According to the HU 195,793 Hungarian patent specification (Janssen Pharmaceutica) although iodine-ethyl derivative as a potential intermediate of the risperidone synthesis is described but neither its production nor its use in the synthesis of risperidone are disclosed among the examples of the invention. The chloro- and bromo derivatives and also the preparation of risperidone reacting the 3-(2-chloro-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H- pyrido[l,2-a]pyrimidine-4-one of the formula (V) and the intermediate of the formula (II) are disclosed. This reaction is carried out in an inert solvent, such as dimethylformamide, in the presence of catalytic amount of sodium iodide and the crude product obtained is crystallized from a mixture of dimethylformamide and 2-propanol to give the product with a total yield of 46 %.

(V)

According to the EP 1280804 European patent specification (RPG Life Sciences) the same starting materials are reacted in water to give the risperidone with a yield of 72 %, but the synthesis of iodo-ethyl derivative or its using are not described either. While in the reaction application of the carcinogenic dimethylformamide is avoided, recrystallization of the crude product is carried out from dimethylformamide. When the reaction is performed in water, the reactant of the formula (II) may undergo hydrolysis in the alkaline aqueous medium forming a hydroxyethyl derivative of the formula (VI),

which appears as a considerable amount of contamination in the crude product. A further source of impurity (5%) is the starting benzisoxazole derivative of the formula (III), a part of which remains unreacted due to the hydrolytic loss of the compound (II). Another drawback of this process is that while both the starting material of the formula (II) and of the formula (III) are marketed as stable hydrochloride salts, they are used in the reaction in the form of bases which are susceptible to decomposition. That is the reason for, when performing the reaction in aqueous medium the base form of the compounds are strictly necessary to be used. In our experiments when the hydrochlorides of the compounds of the formula (II) and (III) were reacted in the presence of an alkali carbonate, a sticky mass was obtained which couldn't be stirred and was difficult-to-manage, particularly at industrial scale. Consequently, said hydrochloride salts should be converted first into the corresponding bases in an additional step which causes a substantial increase in the production costs. Besides these technological and economical problems there is also an environmental one: since the recrystallization is carried out from the carcinogenic dimethylformamide, the mother liquor obtained requires a special, environmentally acceptable work up.

In a process disclosed in WO 02/14286 (TEVA) published international patent application the compounds of the formulae (II) and (III) are reacted in a solvent different from the above (acetonitrile, 2-propanol, isobutanol, methyl ethyl keton, etc.) and the crude product is then recrystallized. The yield, however, even at best is below 63 % and the product is rather contaminated. The iodo-ethyl derivative of formula (III) is not disclosed in this application either.

Our aim was to provide a process lacking the disadvantages of the previous processes, i. e. to obtain the end-product in good yield and in the required drug-purity. In the course of our experiments we dealt with the production of 3-(2-iodo ethyl)-2- methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one of the formula (III): 2-acetylbutyrolactone was reacted with 2-aminopyridine in the presence of polyphosphoric acid and the product obtained was catalytic hydrogenated. The solid product was added to a suspension by cooling which was made from triphenylphosphine and anhydrous acetonitrile and powdered iodine. The reaction gives the intermediate with a yield of 88 %; it can be identified by NMR-, MS- and IR-spectra (figures 1., 2., 3.). The purity of the compound quit unexpectedly is between 96-98 %, was determined by HPLC.

In the course of our further experiments we have surprisingly found that with the using of 3-(2-iodoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one of the formula (III) obtained for the synthesis of risperidone we get the risperidone in very high purity and yield. In our process according to this invention if the iodoethyl derivative of formula (III) and the intermediate of formula (II) are reacted in keton solvent, preferably in acetone, in the presence of alkaline or alkaline earth metal carbonate acid neutralizing agent, preferably potassium carbonate and water is added to the suspension, the crude product is obtained with a yield of 89.5 %. The product, which is optionally recrystallized from 2- propanol, has a very high purity: >99.8 % by HPLC.

The advantage of the process according to this invention is that it gives the product with a yield of 92 % and this yield remains 87.4 % even after recrystallization (on the contrary of known processes go with 46-73 % yields). The crude product is obtained after precipitation with water in very high purity (99.86 %); a possible recrystallization doesn't cause environmental problems, since no hazardous solvent is used. The object of the invention is a process for the preparation of risperidone (chemical name: 3-[2-[4-(6-fluoro-l,2-benzisoxazole-3-yl)-l-piperidinyl]ethyl-2-methyl- 6,7,8,9-tetrahydro-4H-ρyrido[l,2-a]pyrimidine-4-one) of the formula (I)

(I)

by reacting 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of the formula (II),

(H) and 3-(2-iodoethyl)-2-rnethyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one of the formula (III)

In a preferred embodiment of the invention the reaction is performed in keton solvent, in the presence of acid neutralizing agent; the crude product is precipitated by water and optionally recrystallized from alcohol. hi another preferred embodiment of the invention the reaction is performed in acetone, in the presence of alkaline or alkaline earth metal carbonate acid neutralizing agent, and the recrystallization optionally is carried out from 2-propanol.

In further preferred embodiment of the invention the reaction is performed in the presence of potassium carbonate acid neutralizing agent.

Attached are 4 figures showing spectra of 3-(2-iodoethyl)-2-methyl-6,7,8,9-tetrahydro-4H- pyrido[l,2-a]pyrimidine-4-one of the formula (III); namely In figure 1 and 2 ¹H and ¹³C NMR spectra of compound of formula (III) are shown.

Instrument: Varian ^mττγ INOVA NMR (¹H: 300 MHz) spectrometer

Solvent: CDCl₃

Temperature: 30 ⁰C

Reference: 6XM_S- 0,00 ppm

Abbreviations: s=singlet, d=duplet, t=triplet

¹H NMR: 1.82-2.02 m (4H) [H-7, H-8]; 2.31 s (3H) [H-Il]; 2.86 t (2H) [H-9]; 3.11 t

(2H) [H-12]; 3.37 1 (2H) [H-13], 3.92 1 (2H) [H-6].

¹³C NMR: 3.0 [C-13], 19.1 [C-8], 21.5 [C-Il], 21.8 [C-7], 31.0 [C-12], 31.4 [C-9], 42.6

[C-6], 119.8 [C-3], 156.5 [C-10], 158.9 [C-2], 162.0 [C-4]. In figure 3 IR spectrum of compound of formula (III) is shown.

Instrument: PERKIN-ELMER 1000 spectrophotometer

Phase: KBr pellet

Resolution: 4 cm^"1

The most characteristic infrared absorption bands of the compound are as follows: C=O 1648 cm ^'1

CH₂-I 495 cm ^"1

Other significant absorption bands (cm ^"*): 2954, 2881, 1586, 1538, 1409, 1250, 774, 702, 602 hi figure 4 MS spectrum of compound of formula (III) is shown.

Instrument: MAT 95

Ionisation method: EI

Electron energy: 70 eV

Source temperature: 140 ⁰C m/z (rel. int %): 318 (6.8); 191 (100); 177(17); 110(5.7); 83 (12)

M= 318

According to the analytical results 3-(2-iodoethyl)-2-methyl-6,7,8,9-tetrahydro-4H- pyrido[l,2-a]pyrimidine-4-one of the formula (III) was identified.

1. The purity of the 3-(2-iodoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2- a]pyrimidine-4-one of the formula was determined by HPLC as follows: Column: Chromolit RPlδe 100x4,6mm Eluent: A: water

B_.: acetonitrile Gradient:

Detection: 274 nm Temperature: 10 ⁰C Injected volume: 3 μl Sampling: 4 mg/ml, acetone Approximate retention time: 20.17 min

2. The purity of the risperidone (chemical name: 3-[2-[4-(6-fluoro-l,2-benzisoxazole-3-yl)-l- piperidinyl]ethyl-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[ 1 ,2-a]pyrirnidine-4-one) of the formula (I) was determined by HPLC as follows:

Column: Hypersil BDS Cl 8, 100 x 4.6 mm ID, 3 μm Eluent: A: 70% 5.0 g/1 NH₄OAc + 30% methanol B: 100% methanol Gradient:

Detection: 260 nm, 30 min

Temperature: 25 °C

Injected volume: 10 μl

Sampling: 10 mg/ml, methanol

Approximate retention time: 10 min (risperidone)

The invention is illustrated by following non-limiting Examples

Example 1

Preparation of 3-(2-iodoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l ,2-a]pyrimidine-4-one of the formula (III).

T St step: Production of 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H- pyrido [ 1 ,2-a]pyrimidine-4-one:

The mixture of 25.6 g (0.2 mol) of 2-acetylbutyrolactone, 18.8 g (0.2 mol) 2-aminopyridine and 4 g of polyphosphoric acid is placed into an oil-bath preheated to 160 °C and stirred for 5 hours. The mixture is cooled to 100 ⁰C, poured into ice-water then the pH of the mixture is adjusted to 8 with 4N sodium hydroxyde solution. The mixture is extracted 6 x 50 ml of chloroform, chloroform is distilled off. The residue is dissolved in 80 ml of hot methanol, clarified, filtrated and crystallized. The solution is stirred at 0 °C for 3 hours, the crystals obtained is filtrated, washed with 2 x 20 ml methanol at 0 ⁰C and dried at 60 °C. Dry weight: 14.3-17 g (36-42 %). Melting point: 168-170 °C. TLC: Rf=0.34.

2^nd step: Production of 3-(2-hydroxy-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H- pyrido [ 1 ,2-a]pyrimidin-4-one

27.5 g (0.135 mol) of product obtained in the 1. step is dissolved in the mixture of 150 ml of water and 150 ml of methanol; to this solution a suspension of 2.5 g of Palladium 5 wt% on activated carbon and 20 ml of water is added and the mixture is hydrogenated under 5-6 bar and at 25-30 °C. After 5 hours the catalyst is filtered out, the solvent is distilled off. Further 2 xlOO ml of 2-propanol is added to the solution, then it is distilled off, the solid product obtained is stirred with 50 ml of 2-propanol for 3 hours at 0 ⁰C, filtrated, washed with 30 ml of 2-propanol of -10 °C, dried at 50 °C. Dry weight: 20 g (71.7 %). Melting point: 133-134 °C. The mother liquor is concentrated to 20 ml and stirred for 3 hours at 0 °C. The crystals are filtered out, washed with 2-propanol (20 ml) of 10 ⁰C. Dry weight 5,1 g (18.2 %). Meltingpoint: 133-134 °C. Yield 90 %. TLC: Rf=0.27.

3^rd step: production of 3-(2-iodoethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2- a]pyrimidine-4-one 15 g (0.0594 mol) powdered iodine is added during stirring to the suspension of 15.5 g (0.0594 mol) triphenylphosphine in 100 ml of anhydrous acetonitrile and cooled to 0 °C.

The suspension is stirred at 0 °C for 90 minutes and then the product obtained in the 2^nd step is added to this suspension. The cooling is shutting off and then the suspension is stirred for 16 hours and then the solvent is distilled off under reduced pressure (30 mbar, 40 ⁰C water-bath). 100 ml of ethyl acetate and 60 ml of water are added to the residue and after stirring and decantation, water layer is separated, the organic layer is extracted with 4x40 ml of water and 40 ml of IN HCl. The collected water layers are extracted with 20 ml of ethyl acetate. 60 ml of dichloromethane is added to the water layer and the pH of the solution is adjusted to 7 with 10 % Of NaHCO₃ solution at 10-15 °C. Phases are separated and the water layer is extracted with 2x40 ml of dichloromethane. The collected organic layers are dried with 30 g of anhydrous Na₂SO₄, filtrated and then the solvent is distilled off under reduced pressure (30 mbar, 40 °C water-bath). Dry weight: 15.1 g (88%).

Melting point: 60-62 ⁰C. Purity: 96-98 % (determined by HPLC)

The product obtained from this procedure can be used in the synthesis of risperidone directly. Example 2

Production of risperidone of formula (I) from 3-(2-iodoethyl)-2-methyl-6,7,8,9-tetrahydro-4H- pyrido [ 1 ,2-a]pyrimidine-4-one

2.56 g (10 mmol) of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole HCl, 2.56 g (10 mmol) 3-(2-iodoemyl)-2-memyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidme-4- one, 2.76 g (20 mmol) of potassium carbonate and 50 ml of acetone are added into a distilling flask equipped with reflux condenser. The suspension is boiled for 6 hours during stirring and then 100 ml of water is added to the suspension and the acetone is distilled off under reduced pressure. The suspension is cooled down to 20 °C and stirred for 1 hour, filtered, washed with 50 ml of water, dried at 60 ⁰C. 3.77 g (92 %) product is obtained which is recrystallized from 2-propanol.

Dry weight: 3.58 g (87.4%). Melting point: 171-172 ⁰C. Purity: 99.86 % (determined by HPLC).

Claims

1. A process for the preparation of risperidone (chemical name: 3-[2-[4-(6-fluoro-l,2- benzisoxazole-3-yl)-l-piperidinyl]ethyl-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2- a]pyrirnidine-4-one) of the formula (I)

(I)

from 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of the formula (II),

(H) characterized in that the reaction is carried out with 3-(2-iodoethyl)-2-methyl-6,7,8,9- tetrahydro-4H-pyrido[l,2-a]pyrimidine-4-one of the formula (III).

(HI)

2. A process according to claim 1, characterized in that the reaction is performed in keton solvent, in the presence of acid neutralizing agent; the crude product is precipitated by water and optionally recrystallized from alcohol.

3. A process according to claim 2, characterized in that the reaction is performed in acetone, in the presence of alkaline or alkaline earth metal carbonate acid neutralizing agent, and the recrystallization optionally is carried out from 2-propanol.

4. A process according to claim 3, characterized in that the reaction is performed in the presence of potassium carbonate acid neutralizing agent.