CN103450172A - Preparation method of antipsychotic drug lurasidone - Google Patents

Abstract

The invention relates to preparation methods of (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazole-3-yl)piperazinyl-1-methyl]cyclohexyl methyl}hexahydro-1H-4,7-methano-isoindole-1,3-dione (a compound represented by a formula I) and intermediates thereof. A hydrochloride (lurasidone hydrochloride) of the compound represented by the formula (I) can be used as a drug for treatment of psychosis.

Description

A kind of preparation method of antipsychotics Lurasidone

Technical field

The present invention relates to a kind of (3aR, 4S, 7R, 7aS)-2-{ (1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-methyl] cyclohexyl methyl } six hydrogen-1H-4,7-methyl isoindole-1, the preparation method of 3-diketone (formula I compound) and intermediate thereof.

Background technology

Lurasidone HCl (Lurasidone hydrochloride, commodity are called Latuda) be that it is to serotonin 2A(5-HT2A by the antipsychotic agent with dual function of SUMITOMO CHEMICAL drugmaker exploitation) and d2 dopamine receptor all there is high affinity.The insane positive and recessive symptom are all had to obvious curative effects.Reported the synthetic route of formula (I) in JP 2006169155, with (1R, 2R)-1, 2-cyclohexanedimethanol two methanesulfonates formula (III) compounds are starting raw material, in toluene, reflux obtains methylsulfonic acid quaternary ammonium salt formula V, the quaternary ammonium salt obtained and (3aR, 4S, 7R, 7aS)-4, 7-methylene radical-1H-isoindole-1, 3-2H-bis-keto-acids (VI) reaction, make alkali in reflux in toluene with salt of wormwood, obtain target product (3aR, 4S, 7R, 7aS)-2-{ (1R, 2R)-2-[4-(1, 2-benzisothiazole-3-yl) piperazine-1-methyl] cyclohexyl methyl } six hydrogen-1H-4, 7-methyl isoindole-1, 3-diketone (formula I compound).But this method solvent for use toxicity is larger, unfriendly to environment, while easy generating portion by product when synthetic target product is done alkali in reflux in toluene with salt of wormwood, the existence of by product makes the purifying of target product be not easy operation, after making with extra care accordingly, to productive rate, can have a great impact, at US 2011263848A1, US2011263847A1 has carried out corresponding optimization to the problem existed, but still have by product to exist, and experimental implementation is more loaded down with trivial details, is difficult for carrying out suitability for industrialized production.

Summary of the invention

The problem existed for above prior art, the invention provides a kind of (3aR for preparing, 4S, 7R, 7aS)-2-{ (1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-methyl] cyclohexyl methyl } six hydrogen-1H-4,7-methyl isoindole-1, the method for 3-diketone (formula I compound).The method is than the prior art easy handling, the experiment condition gentleness, and reaction product is easy to purifying, and productive rate is high, and product purity is good, is easy to realize the characteristics such as suitability for industrialized production.

The method comprises the following steps

By (1R, 2R)-1,2-CHDM formula (II) and methylsulfonyl chloride reaction, in methylene dichloride ,-20 ° of C ~ 20 ° C, react 5 ~ 24h, obtains formula (III) compound.

Formula (III) compound obtains methylsulfonic acid quaternary ammonium salt formula V compound with 3-(1-piperazinyl)-1,2 benzisothia triazole hydrochloride (formula IV compound) under heating condition.

By methylsulfonic acid quaternary ammonium salt formula V compound and (3aR, 4S, 7R, 7aS)-4,7-methylene radical-1H-isoindole-1,3-2H-bis-keto-acids (VI) reaction, obtain formula (I) compound.

As seen from the above technical solution, principal feature of the present invention is:

1. synthetic marketable material (1R, the 2R)-1,2-CHDM of choosing of formula (III) compound is starting raw material, and raw material is easy to get, and the reaction conditions gentleness of synthesis type (III) compound is easy to control, and productive rate is high, is easy to purifying.

2. methylsulfonic acid quaternary ammonium salt formula V compound is synthetic, and selecting acetonitrile is solvent, and reaction conditions is than the toluene gentleness, simple to operate.Obtain product purity high.

3. the synthetic employing DMF of formula (I) is excellent, and the purity of resulting product is high, productive rate is high, the needs of applicable suitability for industrialized production simple to operate, and selected solvent is environmentally friendly, on experiment operator, impact does not almost have, and toluene has great toxicity.

Embodiment

Following examples are to describe in detail the present invention, and unrestricted the present invention.

1. (1R, 2R)-1,2-CHDM two methanesulfonates formulas (III)

Add 500.0g (1R, 2R)-1,2-CHDM in the 10L there-necked flask, the 7500ml methylene dichloride adds triethylamine 1052.5g successively, methylsulfonyl chloride 835.0g, and after adding, reaction 8h.Add 3750ml purified water agitator treating in reaction system, separatory discards water layer, and organic phase is washed with dilute hydrochloric acid, then successively with saturated sodium bicarbonate washing, saturated common salt water washing, separatory, organic phase anhydrous sodium sulfate drying.The filtering anhydrous sodium sulphate, be evaporated to dry.Add wherein ether, suction filtration, 60 ℃ of lower forced air dryings of filter cake obtain off-white color solid 889.4g, yield: approximately 85.4%.

2. (3aR, 7aR)-4'-(1,2-benzisothiazole-3-yl) octahydro spiral shell [2H-isoindole-2,1'-piperazine] mesylate formula V

Add 885.0g (1R in the 20L reaction flask, 2R)-1,2-cyclohexanedimethanol two methanesulfonates formulas (III), 717.7g 3-(1-piperazinyl)-1,2 benzisothia triazole hydrochlorides (formula IV), 775.6g salt of wormwood, the 13.3L acetonitrile is heated with stirring to reflux and starts to reflux, stirring reaction.After reacting completely, filtered while hot, filter cake acetonitrile drip washing, filtrate decompression is concentrated into dry, obtains off-white color solid 1045.9g, yield approximately 88%.HPLC purity is greater than 99%.

3.(3aR, 4S, 7R, 7aS)-2-{ (1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-methyl] cyclohexyl methyl } six hydrogen-1H-4,7-methyl isoindole-1,3-diketone (formula I compound)

The 10L there-necked flask adds 625.0g (3aR, 7aR)-4'-(1,2-benzisothiazole-3-yl) octahydro spiral shell [2H-isoindole-2, the 1'-piperazine] mesylate, 248.6g (3aR, 4S, 7R, 7aS)-4,7-methylene radical-1H-isoindole-1,3-2H-bis-keto-acids (VI), 611.8g salt of wormwood, 6250ml DMF, stirring heating heats up, 100 ° of C ~ 130 ° C of temperature control, reaction 36h.Stopped reaction, filtered while hot, filter cake DMF drip washing, filtrate is chilled to room temperature, drips wherein while stirring the 9375ml purified water, continues to stir 2h.Filter, filter cake is dry to the greatest extent with being evacuated to after purified water drip washing, and 55 ℃ of lower vacuum-dryings, obtain the 646g target product, yield 89%, and HPLC is greater than 95%.

Claims (9)

1. one kind prepares (3aR, 4S, 7R, 7aS)-2-{ (1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-methyl] cyclohexyl methyl } six hydrogen-1H-4,7-methyl isoindole-1, the method for 3-diketone (formula I compound)

The method comprises the following steps

By the reaction of (1R, 2R)-1,2-CHDM formula (II) and methylsulfonyl chloride, in methylene dichloride-20 ℃ ~ 20 ℃, react 5 ~ 24h, obtain formula (III) compound

Formula (III) compound obtains methylsulfonic acid quaternary ammonium salt formula V compound with 3-(1-piperazinyl)-1,2 benzisothia triazole hydrochloride (formula IV compound) under heating condition

By methylsulfonic acid quaternary ammonium salt formula V compound and (3aR, 4S, 7R, 7aS)-4,7-methylene radical-1H-isoindole-1,3-2H-bis-keto-acids (VI) reaction, obtain formula (I) compound

。

2. according to the described method of right 1, it is characterized in that at synthesis type (III) solvent for use be methylene dichloride, alkali used is triethylamine or DIPEA.

3. according to the described method of right 2, the consumption of triethylamine or DIPEA be 2.2 ~ 5 equivalents with respect to compound formula (I), preferably 2.5 ~ 4.

4. according to the described method of right 2, the consumption of methylsulfonyl chloride be 1.9 ~ 3 equivalents with respect to compound formula (I), preferably 1.9 ~ 2.5.

5. according to the described method of right 1, it is characterized in that synthesis type (III) temperature of reaction-20 ℃ ~ 20 ℃, preferably-10 ℃ ~ 5 ℃, reaction times 5 ~ 24h, preferably 12 ~ 16h.

6. according to the described method of right 1, it is characterized in that at synthetic formula V solvent for use be acetonitrile, dimethylbenzene, DMF, the mixed solvent of N,N-dimethylacetamide or above solvent.

7. according to the described method of right 1, it is characterized in that at synthetic formula V alkali used be salt of wormwood, sodium carbonate, magnesiumcarbonate, 60 ℃ ~ 150 ℃ of temperature of reaction, preferably 80 ℃ ~ 120 ℃, reaction times 24h ~ 120h, preferably 60h ~ 96h.

8. according to the described method of right 1, it is characterized in that at synthesis type (I) solvent for use be DMF, N,N-dimethylacetamide, dioxane, the trimethyl carbinol, propyl carbinol, the mixed solvent of Virahol or above solvent.

9. according to the described method of right 1, it is characterized in that at synthesis type (I) alkali used be salt of wormwood, sodium carbonate, magnesiumcarbonate, calcium hydroxide, 60 ℃ ~ 150 ℃ of temperature of reaction, preferably 100 ℃ ~ 140 ℃.