FIELD OF THE INVENTION

The present invention relates to a new process for the preparation of crystalline 1- [4-[3-[4-(6-fluoro- 1 ,2-benzisoxazol-3-yl)- 1 -piperidinyl]propoxy]-3-methoxyphenyl]- ethanone (Iloperidone).

The synthetic process comprises the reaction between 3-[l-(3-chloropropyl)-4- piperidinyl]-6-fluoro-l,2-benzisoxazole and 3-methoxy-4-hydroxy-acetophenone.

BACKGROUND OF THE INVENTION

Iloperidone, whose chemical structure is shown bellow, is a neuroleptic and 5- hydroxytryptamine 2A antagonist to be used for the treatment of schizophrenia and general psychosis.

Iloperidone

The product is protected by the patents US 5364866, US RE 39198 E and EP 402644 B l .

The first reported synthetic method for Iloperidone is described in patent EP 402644 Al.

In this document, the last step for the synthesis is the SN2 reaction between the nitrogen from the piperidine cycle and the halogen from the alkyl aryl ether, as is shown in Schema I. Schema I

The yield of purified product obtained for this reaction is 58 %. Several patents were published after, describing essentially the same synthetic way such as US 5364866 and US 5663449.

SUMMARY OF THE INVENTION

In accordance with the invention, a convenient manufacturing process is presented that has advantages over the known previous one.

The process is characterized by the reaction between 3-[l-(3-chloropropyl)-4- piperidinyl]-6-fluoro-l,2-benzisoxazole and 3-methoxy-4-hydroxy-acetophenone in an organic solvent or water in the presence of a base, as is shown in schema 2.

Schema 2

This is actually a Williamson reaction between a phenol, acting as a nucleophilic reagent and an alkyl chloride to yield the corresponding ether. Besides the different substances involved into the reaction with regard to the published one, the present process shows some advantages.

• Its yield (75 %) is significantly higher than the published one (58 %).

• Obtained Iloperidone is colourless instead of beige.

• It employs a friendlier and not so toxic solvent.

• It employs an excess of a cheaper reagent (3-methoxy-4-hydroxy-acetophenone) instead of l-[4-(2-chloroethoxy)-3-methoxyphenyl] ethanone.

DESCRIPTION OF THE DRAWINGS

FIG.l shows an X-ray power diffractogram of crystalline Iloperidone.

DETAILED DESCRIPTION OF THE INVENTION

Iloperidone is prepared by a novel and advantageous method.

In accordance with the method of the present invention, it is characterized by the reaction of 3-[l-(3-chloropropyl)-4-piperidinyl]-6-fluoro-l,2-benzisoxaz ole with 3- methoxy-4-hydroxy-acetophenone in the presence of a base.

The organic solvent(s) which may be used includes at least one solvent selected from the group consisting of tetrahydrofurane, dioxane, acetonitrile, water, toluene, methyl ethyl ketone, methyl isopropyl ketone, dimethylacetamide and dimethylformamide.

Methyl ethyl ketone, acetone and methyl isopropyl ketone are the most preferred.

The reaction of the present invention may be carried out at a temperature in the range of 20 ⁰ C to the boiling point of the solvent during 30 minutes to 24hours, preferably 60 to 120 ⁰ C during 4 to 30 hours.

The base employed may be an organic or inorganic one, including one of the following: sodium hydroxide, carbonate o bicarbonate, potassium hydroxide carbonate or bicarbonate, lithium hydroxide, trimethyl amine, triethyl amine, pyridine, piperidine and DBU (1,8-diazabicyclo [5.4.0] undec-7-ene).

Potassium or sodium carbonates are the most preferred. Examples

The following examples are for illustrative purposes only and are not to be construed as limiting the invention. All temperatures are given in degrees Centigrade ( ⁰ C) unless indicated otherwise.

Preparation of l-[4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]pr opoxy]-3- methoxyphenyl]-ethanone

(A) Synthesis of 3-[l-(3-chloropropyl)-4-piperidinyl]-6-fluoro-l,2-benzisoxaz ole

In a 250 ml round bottomed flask equipped with a cool bath and magnetic stirrer, containing dimethylformamide (DMF) (180 ml); 3-(4-piperidinyl)-6-fluoro-l,2- benzisoxazole hydrochloride (10 g; 39 mM) and potassium carbonate (10.8 g; 77.9 mM) are added, giving rise to a suspension.

A solution of 1,3-bromochloropropane (6.0 ml; 61 mM) in DMF (7 ml) is dropped into the vigorously stirred suspension in a period of 30 minutes.

Stirring is continued for 17 hours at room temperature.

The resulting suspension is poured into water (120 ml) and extracted with ethyl acetate (120 ml).

The aqueous phase is extracted four additional times with 50 ml of ethyl acetate each time.

The joined organic phases are washed three times with a saturated sodium chloride solution and two additional times with water.

The washed organic phase is dried over sodium sulphate, filtered and the solvent eliminated under reduced pressure.

The oily residue, when treated with water (2.5 ml) yields, after half an hour, an off white crystalline solid.

After 1 hour in an ice bath, the suspension is filtered, washed with water and dried.

It yields 9.2 g (80 %) of the desired product.

This crude product is employed as it is for the next step.

Anyway, a small portion of this crude product was purified by flash chromatography eluted with ethyl acetate. The residue obtained from the best fractions, was crystallized from isopropanol to yield a colourless crystalline product. Melting point:69.2-70.2 ⁰ C.

¹ H NMR (CDCl ₃ ) δ 1.99 (m, 2H, ClCH ₂ CH ₂ CH ₂ ), 2.03-2.21 (m, 6H, piper-3H, - 5H, -2H _ax , -6H _3x ,), 2.55 (t, J= 7 Hz, 2H, ClCH ₂ CH ₂ CH ₂ ), 3.02-3.1 1 (m, 3Η, piper-2H _eq , - 6H _eq , -4H), 3.64 (t, J= 6.5 Hz, 2H, ClCH ₂ CH ₂ CH ₂ ), 7.03-7.08 (m, IH, benzisox-5H), 7.24 (dd, J= 2 Hz and 8.5 Hz, IH, benzisox-7H), 7.70 (dd, J= 5 Hz and 8.5 Hz, IH, benzisox- 4H).

¹³ C NMR (CDCl ₃ ) 6 30.1 and 30.6 (ClCH ₂ CH ₂ CH ₂ piper-3C and -5C), 34.6 (piper-4C), 43.3 (ClCH ₂ CH ₂ CH ₂ ), 53.6 (piper-2C and-6C), 55.7 (ClCH ₂ CH ₂ CH ₂ ), 97.5 (d, J= 26 Hz, benzisox-7C), 1 12.3 (d, J= 25 Hz, benzisox-5C), 1 17.3 (benzisox-3aC), 122.6 (d, J= 1 1 Hz, benzisox-4C), 161.1 (benzisox-3C), 163.9 (d, J= 14 Hz, benzisox-7aC), 164.1 (d, J = 250 Hz, benzisox-6C)

IR (KBr) (cm- ¹ ) Absorption at: 3046, 2824, 2776, 2743, 1615, 1514, 1499, 1472, 1447, 1416, 1379, 1352, 1271, 1256, 1235, 1 123, 1030, 993, 980, 955, 893, 847, 814, 774, 640, 584, 530, 475 and 442.

(B) Synthesis of l-[4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]pr opoxy]- 3-methoxyphenyl]-ethanone (Iloperidone)

In al50 ml round bottomed flask, equipped with a heating bath, a reflux condenser and magnetic stirring, containing methyl ethyl ketone (MEK) (45 ml), 4-hydroxy-3- methoxy acetophenone (3.36 g; 20.22 itiM) and potassium carbonate (2.8 g; 20.22 mM) are added.

The obtained suspension is stirred and heated under reflux; 3-[l-(3-chloropropyl)-4- piperidinyl]-6-fluoro-l,2-benzisoxazole (5.0 g; 16.85 mM) is added and the suspension is heated under reflux (78-80 ⁰ C) overnight.

The reaction mixture is cooled at room temperature, and to the pale brown suspension, water (30 ml) is added giving rise to two phases.

The whole is evaporated under reduced pressure in order to eliminate MEK.

The resultant aqueous suspension is extracted with ethyl acetate (180 ml). The organic phase is washed four times with a 10 % sodium hydroxide solution (4 x 20 ml) and then twice with a saturated sodium chloride solution acidified with 10 % (v/v) of HCL O.l N.

The organic phase is then washed with water (3 x 10 ml) and the solvent eliminated under reduced pressure.

A pale brown solid is obtained (6.65 g; 92.5%) which is crystallized from ethanol (9ml).

It yields 5.84 g (81.3 %) of beige crystals with melting point 1 14-1 19 ⁰ C.

1.5 g of this product are recrystallized from ethanol (3.5 ml) giving 1.38 g (92 %) of a colourless crystalline product with melting point 119.5-122 ⁰ C.

IR (KBr) (cm- ¹ ) Absorption at: 3033, 2950, 2822, 1669, 1615, 1594, 1586, 151 1, 1462, 1449, 1416, 1381, 1314, 1264, 1221, 1179, 1 150, 1 125, 1078, 1044, 1032, 997, 986, 957, 886, 876, 853, 812, 781, 644, 612, 569, 475.

X-ray diffraction pattern expressed in terms of d-spacing (2 θ), said diffraction pattern includes peaks at about 7.17, 10.18, 12.67, 14.37, 16.75, 17.13, 17.24, 17.60, 18.18, 18.31, 20.32, 20.41, 20.70, 21.60, 22.14, 23.64, 23.98, 26.40, 28.97, 30.78.