SK15695A3 - Preparing method of 3{2-£4-(6-fluorobenzo £d|-isoxazole-3-yl piperidine-1-yl| ethyl}-2-methyl-6,7,8,9-tetrahydro-4-h-pyridole pyridole £1,2-a| pyrimidine-4-on - Google Patents

Abstract

Disclosed is a method for preparation of 3-{2-[4-(6-fluorine-benzo [d] isoxasol-3-yl) piperidine-1-yl]ethyl}-methyl-6,7,8,6-tetrahydro-4H- pyridol[1,2-a]pyrimindin-4-one of formula (I) by reaction 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido- [1,2-a]pyrimidin-4-one of formula (II) with compound of formula (III), wherein Y and Z are same or each other different releasing groups such is halogen or C1-6 alkyl or phenyl-sulphonyloxy group under the presence of dissolvent and alkali. Disclosed are also compounds of formula (II) and formula (III), wherein Z and Y are of the said meaning, as intermediates of the method for preparation of compound of formula (I).

Description

Preparation of 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] ethyl} -2-methyl-5,7,8,9-tetrahydro-4H-pyrido [i] 2-pyrimidin-4-one

Technical field

The present invention relates to a process for the preparation of 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one of formula I

which has a pharmaceutical utility due to its antipsychotic properties.

Similarly, the invention relates to 3- (2-aminoethyl) -2-methyl-6,7,8,9 tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one of Formula II and compounds of Formula III.

and

I!

F!

I

FROM

CII) CIII) wherein Y and Z are the same or different released groups, such as a halogen atom or an alkyl group or an arylsulfonyloxy group. Both of these groups are intermediates used in the process of the invention.

Compounds of formula II and formula III together with their precursors are not known in the art.

BACKGROUND OF THE INVENTION

EP 196123 describes four different methods of preparing 3- (2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] ethyl} -2-methyl-6,7 8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one Three of these methods are based on the formation of a 2-methyl-6,7,8,9-tetrahydro-4H-pyrido 1.1 system The fourth method is based on the K -alkylation of 6-fluoro-3- (4-piperidinyl) benzo [d] isoxazole, for example, 3- (2-chloroethyl) -2-pyrimidin-4-one. methyl 6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one with various released groups.

Spanish Patent Nos. 2006888 and 2006889 disclose a method based on various types of final cyclization of the isoxazole ring.

The construction of the N-alkylpiperidines or n-arylpiperidines on which the process according to the invention is based is described in the chemical literature by reaction of 1,5-dihalopentanes with primary amines (J). von Sraun, Chem., Ber. 37, 3210, 1904: 39, 4351, 1906: 40, 3914, and 3930, 1907; 42, 2048 and 2052, 1909), also by reacting 1-5-bis-alkylsulfonyloxypentanes or 1-5-bisarylsulfonyloxypentanes with primary amines (K). Reynolds, J. Amer. Chem. Soc. 72, p. 1597, 1950].

SUMMARY OF THE INVENTION

Process for preparing 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl] piperidin-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [ 1,2-a] pyrimidin-4-one of formula I

According to the invention, 3- (2-aminoethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one is reacted with a compound of formula II of formula III

wherein Y and Z are the same or different leaving groups, such as a halogen atom or an alkyl or arylsulfonyloxy group, in the presence of a solvent and a base.

The reaction is carried out according to the following reaction scheme

The reaction is carried out in a polar solvent such as a low molecular weight alcohol such as methanol, ethanol, isopropanol or n-butanol, preferably "ethanol" or in a polar aprotic solvent such as acetonitrile, Ν, Ν- dimethylformamide or N-methylpyrrolidone, preferably in acetonitrile, in the presence of an organic base such as triethylamine or in the presence of an inorganic base such as an alkali hydroxide, carbonate or bicarbonate at a temperature of 40 to 120 ° C, preferably about 80 ° C . The product of formula I obtained is isolated by known methods and purified by recrystallization.

The compounds of formula (II) and formula (III) required for carrying out the process according to the invention are not known from the literature and the invention also relates to them.

3- (2-Aminoethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one of formula II can be prepared according to the following reaction scheme:

Reaction to replace the chlorine atom in 3- (2-chloroethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one of formula IV / Japanese Patent Specification JP 52005797; J. Fujita, Ann. Rep. Sankyo Res. Lab. 29, p. 75-97, 1977) with dibenzylamine to give 3- (2-dibenzylaminoethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one of formula V is carried out in a suitable solvent, for example in acetonitrile, in the presence of an inorganic base such as an alkali hydroxide, carbonate or bicarbonate, or in the presence of an organic base such as triethylamine at a temperature of 50 to 100 ° C, preferably 70 to 90 ° C.

x, ·

In addition, an alkali metal iodide may be added to the reaction mixture as a catalyst.

Hydrogenation of 3- (2-dibenzylaminoethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one of formula V to 3- (2-aminoethyl) -2 -methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one of formula II is carried out in an inert solvent such as methanol, ethanol, isopropyl alcohol or a mixture of these alcohols with water in in various proportions, at a temperature of 20 to 60 ° C, preferably 45 to 55 ° C and at a pressure of from 1 to 2 MPa, preferably at a pressure slightly higher than ambient pressure, in the presence of 5% by weight of palladium on carbon catalyst up to 15% based on the weight of the starting material of formula V. The compounds of formulas V and II are isolated by methods known per se and do not require subsequent purification.

Compounds of formula (III) may be obtained in a five-step process.

The 4-tetrahydropyranocarbonyl of formula VI / J is reacted. Gibson, J. Chem. Soc., P. 2525, 1930) and 1,3-difluorobenzene of formula VII in the presence of anhydrous aluminum chloride to give the Friedel-Crafts alkylating agent (2,4-difluorophenyl) tetrahydropyran-4-yl) methanone of formula VIII, either in a suitable solvent such as for example dichloromethane or 1,2-dichloroethane or with an excess of 1,3-difluorobenzene alone acting as solvent. The reaction is carried out at a temperature of 40 to 85 ° C, preferably at about 80 ° C. The product is isolated in a manner known per se and purified by recrystallization.

The oxime is obtained from a compound of formula VIII by reacting a compound of formula VIII with hydroxylamine hydrochloride by methods known per se (e.g., Advanced Organic Chemistry),

J. March, 4th edition, p. 406 /. A mixture of (75: 25) sin and anti isomers (2,4-difluorophenyl) tetrahydropyria-4-yl) methoxone: .delta. The compound of formula IX is isolated by methods known per se and can either be used directly in the next reaction step; without pre-separation of the isomers, or most of the sin oxime can be isolated by column chromatography on silica gel.

The procedure is as follows:

HO x i

wherein Y, Z are the same or different from each other and represent a chlorine, bromine or iodine atom, a CH 2 -SO 4 - or p-ch ₃ c ₆ h _{4 s 3 group} .

The cyclization of a mixture of oximes of formula IX or the corresponding sinisomer to 6-fluoro-3- (tetrahydropyran-4-yl) benzo [d] isoxazole of formula X is carried out in a suitable solvent such as methanol and ethanol in the presence of a base such as hydroxide, carbonate or an alkali metal bicarbonate, or tetrahydrofuran or dioxane and in the presence of an alkali metal hydroxide or alkoxide. The reaction is carried out at a temperature of 50 to 100 ° C, preferably at the boiling point of the reaction mixture. The product of formula X is isolated by methods known per se. It must be separated from the non-reactive isomer of the native oxime of formula IX by column chromatography on silica gel if a mixture of oximes is used as starting material.

The opening of the tetrahydropyranol ether to the 6-fluoro-3 (tetrahydropyran-4-yl) benzo [c] isoxazole of formula X is carried out using various reagents according to the nature of the groups Y and Z desired in the compound of formula III. For example, phosphorus tribromide in the presence of hydrobromic acid or phosphoric acid at 140 ° C / P can be used. Volynskii, Izv. Akad. SSSP Teaching Ser. Chim. 11, p. 2528, 1979, C.A. 92, 1234341 (1980) (directly yielding a compound of formula III (Y = Z = Br)). Treatment of the compound of formula X with either acetyl bromide in the presence of zinc chloride as catalyst (V). N. Odinov, Chim. Acc. Soedin. 2, p. 272-276, 1989] or anhydrous magnesium bromide in acetic anhydride (D). J. Goldsmith, J. Org. Chem. 40, p. 3571, 1975] and subsequent saponification of the obtained bromoacetate with potassium carbonate in methanol at ambient temperature affords the bromo alcohol of formula XI (Y = Br). Similarly, a compound of formula XI (Y = 1) is obtained by treating the compound of formula X with acetyl iodide in acetonitrile at the reflux temperature of the reaction mixture (A, Oku, Tetrahedron Lett). 23, p. 682, 1982) and by saponification of the iodoacetate obtained as an intermediate.

The haloalcohols of formula (XI) are converted to the dihalogenated products of formula (III) by treatment with classical alcohol halide dehydrating agents such as thionyl chloride, phosphorus trichloride and phosphorus trichloride) trichloride-phosphorus trioxide or phosphorus tribromide (e.g. Advanced Organic Chemistry, J. March, / Publication, p. 433 /. Similarly, treatment of the haloalcohols of formula XI with an alkyl halide or an arylsulfonyl compound, for example mptenesulfonyl chloride or p-toluenesulfonyl chloride, affords the corresponding halomethanesulfonate or halo-p-toluenesulfonate III.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3- (2-Dibenzylaminoethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one (V) compound (g) (0.1666 mol) sodium bicarbonate; and 24 g (0.1218 mol) of dibenzylamine is added to a solution of 25 g (0.1104 mol) of 3- (2-chloroethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one in 125 ml acetonitrile. The reaction mixture was refluxed for 16 hours, cooled to 5 ° C and shaken for 30 minutes at 5 ° C. The solid was suspended in 125 mL of water and the mixture was heated to 60 ° C with shaking for one hour. The suspension was allowed to o ^_ cooled to room temperature and shaken for 30 minutes. The solid is filtered off, suctioned off and dried under vacuum at 40 ° C to give 35.7 g of 3- (2-dibenzylaminoethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1]. , 2-apyrimidin-4-one as a white solid with a yield of 84% ·

Mp 110-111 ° C.

IR (KBr / cm &^lt; -1 > ⁾ : 3020, 2980-2800, 1655, 1588, 1533, 1444, 1188, 744, 694.

RNM (CDCl 3), δ (ppm): 7.40-7.15 (sc, 10H); aromat./

3.80 / t J = 6.2, 2H; CH ₂ pyridopyrimidone /

3.65 / s, 4H; CH ₂ benzyl /

2.85 / t J = 6.2, 2H; CH ₂ pyridopyrimidone /

2.70 ./sc, 2E; CH ₂ ethylene /

2.60 / sc, 2H; CPI ₂ ethylene /

2.10 / s, 3H; Ch ^T 3 /

1.90 / sc, 4K; CH ₂ pyridopyrimidone /

Elemental analysis for ^C 25 ^H 29 ^N 3 ° (MW: 387.53).

calculated (%): C 77.49 K 7.54 N 10.87 found: C 77.36 K 7.59 N 10.77

Example 2

3- (2-Aminoethyl) -2-methyl-6,7,5,9-tetrahydro-4K-ppyrido [1,2-a] pyrimidin-4-one (compound of formula II)

To a suspension of 20 g (0.0517 mol) of 3- (2-dibenzylaminoethyl) -2-methyl-6,7,8,9-tetrahydro-4K-pyrido [1,2-a] pyrimidin-4-one in 100 ml of ethanol is added 2 g of 10% palladium on carbon with a moisture content of 50%. The mixture is hydrogenated at 45-50 ° C until 2.7 liters of hydrogen are consumed. The mixture was allowed to cool to ambient temperature, the catalyst was filtered off over decalitr, and the solvent was removed in vacuo to give an oily residue which was recrystallized and treated with heptane. The product is dried under vacuum at ambient temperature to give 9.3 g of 3- (2-amino-ethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one; in the form of a white solid with a yield of.

Melting point 126 ° C.

IR / KBr / cm &^lt; ^-1 >: 3322, 2944, 1655, 1588, 1527, 1322, 1194,

RNM (CDCl 3), δ T (ppm): 3.90 (t J = 6); CH ₂ pyridopyrimidone /

3.85 / t J = 7; CH 2 pyridopyrimidone and CH ₂ ethylene /

2.70 / t J = 7; 2H; CH ₂ ethylene /

2.30 / s, 3H; CHy

1.90 / sc, 4H; CH ₂ pyridopyrimidone /

1.70 / s, 2H; NH ₂ deut./

Elemental analysis for / molecular weight:

207,28 /.

calc. /% /: C 63.74 H 8.27 N 20.27 found /% /: C 63.69 H 8.26 N 20.35

Example 3 (2,4-Difluorophenyl) - (tetrahydropyran-4-yl) methanone (compound of formula VIII)

34.1 g (0.229 mol) of 4-tetrahydropyrancarbonyl chloride is added dropwise to a shaken suspension of 61.3 g (0.460 mol) of anhydrous aluminum chloride in 113 ml of 1,3-difluorobenzene. The mixture was refluxed for 20 hours, allowed to cool? The reaction mixture is poured into a mixture of 500 g of ice and 50 ml of concentrated hydrochloric acid. The mixture is extracted three times with 200 ml of dichloromethane each time. The organic phases are combined, washed with a saturated aqueous salt solution and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give a salt which crystallized. The salt was recrystallized from heptane to give 41.1 g of (2,4-difluorophenyl) - (tetrahydropyran-4-yl) methanone as a white solid in 80% yield.

Mp 50-51 ° C.

IR (KBr / cm < -1 >): 3054, 2964, 2845, 1680, 1605, 1485, 1421,

1,093th

RNM (CDCl 3) (δ vpm): 7.85 (dod, 1H); aromat./

6.80 / m, 2H; aromat./

4.05 (dt, 2H, H-eq -O-THP)

3.50 / m, 2K; Ax-H-R-H-TKP /

3.30 / m, 1 H; CH-C-O /

1.85 / sc, 4H; THP /

Anal., Calcd for ^ -) 2 ^ 12 ^ 2 ^ 2 / ^mo ^ ^e ^ ^s ^ ^ul weight: 226.22 / Calculated /% /: C 63.71 H 5.35 N 16.80 Found /% /: C 63.65 K 5.38 N 16.75 ·

EXAMPLE 4 (2,4-Difluorophenyl) - (tetrahydro-pyran-4-yl) -methoxyxime (compound of formula · IX)

To a solution of 31 g (0.137 mol) of (2,4-difluorophenyl) - (tetrahydro-pyran-4-yl) -methanone in 100 ml of ethanol is added 10 g (0.144 mol) of hydroxylamine hydrochloride dissolved in 50 ml of water and 20 ml. ml (0.147 mol) of sodium acetate trihydrate. The resulting solution was refluxed for 10 hours. The mixture was cooled and the ethanol was evaporated in vacuo. 100 ml of water are added and the suspension obtained is cooled to 5 ° C and the solid is filtered off, washed with ice water and dried at 40 ° C. 32 £ give 4 g (2,4-difluorophenyl) - (tetrahydropyran-4-yl) methanone oxime as a white solid, which is-: .zmesou / 3 and 1 / sin / anti oxime with a yield of 93 ^L,

The desired sin oxime was separated from its isomers by chromatography on silica gel using heptane / ethyl acetate (7: 3) as eluent.

Mp 115-116 ° C.

IE / KBr / cm ¹ : 3323, 2936, 2850, 1617, 1505, 1421, 1110, 969, 845.

ENM (CDCl 3), δ (ppm): 8.10 (s, 1H); N-OH, deut./

7.15 / ddd, 1H; aromat./

6.95 / m, 2H; aromat./

4.00 / dt, 2H; K-eq - '- O-TKP /

3.40 / M 2H; H-ax - <* - 0-THP / 2.70 / M 1 H; CH-C-O / 1, 70 / M 4H; THP / Elementary analysis away. 13 ^N0 / molecular weight: 241.22 / calculated j (%): C 59.56 H 5 42 F 13.24> N, 5.80 found /% / C 59.61 H 55. 48 F 13.19 N, 5.82

Example 5

6-Fluoro-3- (tetrahydro-ydropyran-4-yl) benzo [d] isoxazole (compound of formula X)

To a solution of 3 g (0.0444 mol) of potassium hydroxide, 85%, in 100 ml of ethanol, 10 g (0.0415 mol) of sin-oxime (2,4-difluorophenyl} - (tetrahydropyran-4-yl) methanone) was added. The reaction mixture was refluxed for 1 hour, cooled to ambient temperature and the solvent was evaporated to dryness, water (50 ml) was added, the suspension was shaken for 15 minutes, the solid was filtered off and washed thoroughly with water. 40 ° C to give 9.0 g of 6-fluoro-3- (tetrahydropyran-4-yl) benzofedisoxazole in 98% yield, mp 86-87 ° C.

IR (KBr / cm &^lt; -1 &gt; ⁾ : 2926, 2858, 1612, 1498, 1240, 1123, 840.

ENM (CDCl3) (ppm): 7.65 (dd, 1H); aromat./

7.25 / dd, 1 H; aromat./ ··

7.05 / ddd, 1H; aromat./

4.10 / dt, 2H; H-eq-ck-O-THP (3.60) ddd, 2H; Ax-H-C <-O-TKP /

3.35 / m, 1 H; CH-C-N / 2.10 / m, 4K; THP / Elemental analysis for [delta] H . pFNOp / molecular weight; 221.23 / (%): C 65.15 K 8.59 F 8.59 N 6.33 found (%): C 65.22 H 8.52 F 8.65 N 6.29.

Example 6

3- [6-Fluorobenzo [d] isoxazol-3-yl? -5-iodopentan-1-ol- (compound of formula XI, X = 1)

To a solution of 3.4 g (0.0154 mol) of 6-fluoro-3- (tetrahydropyran-4-yl) benzo [d] isoxazole in 20 ml of dry acetonitrile is added successively 8.147 g (0.054 mol) of sodium iodide and 3.3 ml (0.1 ml). 0462 mol / acetyl chloride. The mixture was refluxed under dry nitrogen for 8 hours. The reaction mixture was allowed to cool to ambient temperature and poured into 20 g of sodium metabisulphite solution and 60 ml of water. The acetonitrile is evaporated off under vacuum and the residue is extracted three times with 50 ml of dichloromethane each time. The organic phases are combined, washed with 50 ml of a saturated aqueous salt solution and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the oily residue was dissolved in 20 ml of methanol. Anhydrous potassium carbonate (2.13 g, 0.0154 mol) was added and the mixture was shaken at ambient temperature for 30 minutes.

7.8 ml of 3N hydrochloric acid are added, the methanol is evaporated off under vacuum and the residue is partitioned between 20 ml of water and 20 ml of dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo to dryness to give 3.54 g of 3- (6-fluoro-benzo [dj isoxazol-3-yl) 5-iodo-pentane-l "^ ⁰ as an oil (compound of formula XI, X = 1) in 66% yield.

The product can be purified by silica gel column chromatography using heptane / ethyl acetate as eluent

4- 15 reagents (7: 3).

IR / KBr / cm ^1: 3400, 3100, 2950, 1615 ₅ 1500, 1280, 1120, 1050 _5960, 840 _

RMM (CDCl3) (ppm): 7.75 (dd, 1H); aromat./

7.25 / sss, 1H; aromat./

7.10 / ddc, 1H; aromat./

3.65 / sc, 3H; CH-C = N and CH ₂ -OH /

3.15 / m, 2H; CH ₂ -I /

2.40 / m, 2H; CH ₂ -CH ₂ -OH /

2.10 / m, 2H; Ch ^T 2 -CH ₂ -I /

1.70 / s, 1H; -OH, deut./

Elemental analysis for &lt; RTI ID = 0.0 &gt; 2H-FINC2 _&lt; / RTI & gt _; (molecular weight: 349.14 (calculated /%)): C 41.23 H 3.75 F 5.44 I 36.35 K 4.01 found (%) 32 H 3.82 F 5.39 I 36.24 N 3.95

Example 7

3- (6-Fluorobenzo [d] isoxazol-3-yl) -4-isopentyl methanesulfonate (compound of formula III, X = 1, Y = -O-SO 2 -CH 2)

2 ml (0.0143 mol) of triethylamine a are successively added

1.1 ml (0.0143 mol) of methanesulfonyl chloride in 1C ml of dichloromethane to a solution of 3.533 g (0.01 mol) of 3- (6-fluorobenzoEd] isoxazol-3-yl) -4-iodopentan-1-ol in 20 ml of dry of dichloromethane pre-cooled to 0 ° C. The mixture was shaken at 0-5 ° C for 1 hour. 20 ml of water are added, the liquid is decanted and the aqueous phase is extracted twice with 20 ml of dichloromethane. The combined organic phases are washed successively with 20 ml of 1N hydrochloric acid and 20 ml of saturated aqueous salt solution. It was dried over anhydrous sodium sulfate and the solvent was evaporated to dryness to give 3.48 g of 3- (6-fluorobenzo [d] isoxazol-3-yl) 4-isopentyl methanesulphenate as an oil in 81% yield.

IR (K. Br) cis / n-1. 3090, 2.930, 1615, 1350, 1175, p Ϊ55. - 820. RNN (COCl), δ (pprn): 7.7 5 (dd, 1k; arcistat ·) 7.30 (dd, 1H; aromatic) 7.15 (ddd, 1H; arom.) 4.20 (m, 2H, _CH2 ~ 0 _and 5) 3.60 (m, 1H; C-C-N) 3.15 (m, 2.H; CH 2 -J) 2.95 (s, 3H; CH 3 -SO 3 -) 2.35 (sc, 4H; CH 2 -CH 2 -J a i CH ₂ -CK2-O3S-) Elementary analysis for C. H. rPINO, / molecular mass 426.73 / calculated / %: C, 36.59 H 3.54 F 4.45 J 29.74 N. 3.28 found /% /: S 7.51 C, 36.62 H 3.60 F 4.50 J 29.69 N QO O S, 7.60

Example 8

3- {2- [4- (6-Fluoro-benzo [d] isoxazol-3-yl) -piperidin-1-yl] -ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine- 4-one (compound of formula 1)

20 g (0.08 mol) of 3- (2-eminoethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one is dissolved and 34.2 g (0.08 mol) of 2- (6-fluorobenzothiazolazol-3-yl) 4-isopentyl methanesulfonate in 300 ml of acetonitrile. Sodium bicarbonate (17 g, 0.2 mol) was added and the product obtained was heated to reflux for 6 hours. The reaction mixture was cooled to ambient temperature and the solvent was evaporated in vacuo. 300 ml of water are added and the suspension is heated to boiling for 30 minutes without shaking.

The reaction mixture was cooled to ambient temperature, the light ocher-colored solid was filtered off, washed with water and

4 · dried at 50 ° C. Recrystallization from ethanol gave 26.3 g of 3- {2 - [[4- (6-fluorobenzo [d] isoxezol-3-yl) piperidin-1-yl] ethyl} 2-methyl-6,7,8,9-tetrahydro -4H-pyrido [1,2-a] pyrimidin-4-one as a white solid in 80% yield. Melting point 170 ° C.

IR. (cure) cm -1: 3060, 2944 RNM (COCl ₃ ), δ (pprn): 7.75 , 2300, 1650, 1527, 1122. (dd, 1 H; · Oromo) 7.25 (dd, 1 H; aromatic). 7.05 (ddd, 1 H ; aroidat-) 3.95 (t. 2'ri; CH 2 pyrldopyrimidine) 3.15 (sc, 3H; pypfôľ) 2.35 (t, 2H; CH in pyridcipyrimidine) 2.75 (sc, 2H; ethylene,) 2.55 (sc, 2H; ethylene) 2.30 (s, 3K; CH 3) 2.10 (sc, 4H; P y p er -. P y r d 0 p y r x m -) 1.90 (sc, 6H; PyPer-, PyridcPyrim-) Elemental analysis for C C- ^HryryFN ^O O / molecular weight: 41 0,49 / Calc'd (?): c 67.30 H, 6.63 F 4.63 J 13.65 J • found (%): 0 66.16 K 6.70 F 4.57 J 13.72 J Industrial applications

A novel process for the preparation of 3- [2- [4- (6-fluorobenzophidisoxazol-3-yl) piperidin-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] Pyrimidin-4-one having pharmaceutical utility due to its antipsychotic properties, starting from 3- (2-aminoethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyridof1,2-a] pyrimidine- 4-one.

Claims (7)

PATENT CLAIMS Process for the preparation of 3- {2- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H- pyrido [1,2-a] pyrimidin-4-one of formula I characterized by 3- (2-aminoethyl) -2-methyl-6 [1,2-a] pyrimidin-4-one of formula II, The reaction is carried out by reacting the compound 7,8,9-tetrahydro-4H-p-yridoso with a general compound NH ₂ dl) wherein Y and Z are the same or different leaving groups, such as halogen or alkyl or arylsulfonyloxy in the presence of a solvent and a base. The process according to claim 1, characterized in that the reaction is carried out in a polar solvent such as a low molecular weight alcohol such as methanol, ethanol, isopropyl alcohol or n-butanol, preferably ethanol or polar aprotic. a solvent such as acetonitrile, N, N-dimethylformamide or N-methylpyrrolidone, preferably in acetonitrile. I - 19 Process according to claims 1 and 2, characterized in that the reaction is carried out in the presence of an organic base, such as a tertiary or heterocyclic amine, preferably in triethylamine, or in the presence of an inorganic base, such as hydroxide, carbonate or an alkali metal bicarbonate or mixture thereof, preferably in the presence of sodium bicarbonate. 4. A method according to claim 1, 2 and 3. that the reaction is carried out at a temperature of 40 to 120 ° C, preferably at a temperature of about 80 ° C; 5. The process according to claim 1, 2, 3, and 4, wherein a compound of formula III is reacted, wherein the Y and Z groups released are preferably iodine and methanesulfonyloxy. 6. 3- (2-Aminoethyl) -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one of formula II, a reactive intermediate for the preparation of 3- {2 - [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [2-a] pyrimidin-4 -one of formula I according to claims 1 to 5. 7. A compound of formula m wherein Y is Y ^; a. From the same or different loosened ones; groups such as -, a halogen atom or an alkyl or arylsulfonyloxy group, a reactive intermediate for the preparation of 3- [2- [4- (6-fluorobeazo [d] isoxazol-3-yl) piperidin-1-yl] ethyl} -2 - methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one of the formula I as claimed in claims 1 to 5;