A novel process for the preparation of lurasidone hydrochloride

Abstract

The application discloses a preparation method of lurasidone hydrochloride and belongs to the technical field of chemical synthesis. The method comprises the following steps: A: reacting (3aR,7aR)-4'-(benzo[d]isothiazol-3-yl) octahydrospiro[isoindol-2,1'-piperazine]-2-X ammonium with ronexiamine, toluene and potassium carbonate to generate an intermediate product shown in formula III (3aR,4R,7S,7aS)-2-((1R,2R)-2-(4-(benzo[d]isothiazol-3-yl)piperazine-1-methyl)cyclohexyl)methyl)-3a,4,7,7a-tetrahydro-1H-4,7-methylisoindol-1,3(2H)-dione; B: reacting the intermediate product shown in formula III with hydrogen and a catalyst Y to generate lurasidone, and reacting lurasidone with hydrochloric acid to generate lurasidone hydrochloride. The application avoids the use of a phase transfer catalyst, overcomes the defects of low separation yield, poor selectivity, low yield and high cost, and has great implementation value and social and economic benefits due to the following advantages: raw materials are easy to obtain, operation is simple, reaction conditions are mild, and waste is less.

Description

TECHNICAL FIELD

[0001] The present application relates to a new preparation method of lurasidone hydrochloride, belonging to the technical field of chemical synthesis. BACKGROUND

[0002] Lurasidone hydrochloride (trade name: Latuda) is a new antipsychotic drug developed by Sumitomo Pharmaceuticals Co., Ltd. of Japan. The effectiveness of lurasidone on schizophrenia is mediated by the combined antagonism of central dopamine (D2) and 5-hydroxytryptamine (5-HT2A) receptors. It contains 6 hand centers, and the chemical name is (3aR, 4S, 7R, 7aS)-2-{(1R, 2R)-2-[4-(1, 2-benzisothiazol-3-yl) piperazine-1-methyl] cyclohexylmethyl} hexahydro-4, 7-methylene-2H- isoindole-1, 3-dione hydrochloride, and its structural formula is as follows:

[0003]

[0004] According to the reported synthetic routes in the literature, there are mainly three routes, as follows:

[0005] Route 1: The synthetic route is first reported in Japanese patent JP2800953:

[0006]

[0007] The existing method for synthesizing lurasidone hydrochloride is to react cyclohexanedimethyl disulfonate and 3-piperazine-1, 2-benzisothiazole to form a quaternary ammonium salt intermediate, and then react with norbornanedimide to form lurasidone crude product, and then salt to obtain lurasidone hydrochloride. In this method, tetrabutylammonium bromide, crown ether and indole phase transfer catalysts must be used in the condensation reaction; the solvent used in the whole route is large in amount, various in type, complicated in operation, high in cost and not environmentally friendly.

[0008] Route 2: JP2003-17158 / JP2004-362561

[0009]

[0010] This route uses racemic trans-1,2-cyclohexanedicarboxylic acid to generate a diastereomeric salt with (1S,2R)-(+)-norephedrine, and (R,R)-1,2-cyclohexanedicarboxylic acid is obtained by crystallization and acidification with hydrochloric acid, and optically pure (R,R)-SM1 is obtained by a reduction reaction. The use of ester solvents (such as ethyl acetate) or ketone solvents (methyl isobutyl ketone) instead of the highly toxic chlorinated solvent chloroform. And (R,R)-1,2-bis(methylsulfonyloxymethyl)cyclohexane (INT1), 3-(1-piperazinyl)-1,2-benzisothiazole (SM2) and potassium carbonate are used in toluene under water reflux for 7 h to obtain a monosubstituted intermediate, then a phase transfer catalyst tetrabutylammonium hydrogen sulfate and potassium carbonate are added and refluxed for 7 h to obtain a toluene solution of quaternary ammonium salt ((INT2); then potassium carbonate, imine (SM3) are added to the toluene solution of INT2 under water reflux for 4 h, then a small amount of water is added and refluxed for 30 h, and lurasidone is obtained through extraction, concentration, recrystallization, drying and other operations, with a yield of 83% and a purity of 99.7%. In this process, optically pure starting materials are used, avoiding the disadvantages of low yield and large solvent consumption caused by chiral resolution.

[0011] Route three: US5532372

[0012]

[0013] In this route, INT1 reacts with SM2 to obtain a monosubstituted intermediate through a nucleophilic substitution, and then reacts with SM3 to obtain lurasidone. However, this intermediate is unstable and can continue to react with SM2 to generate a double-substituted byproduct, and therefore is not suitable for industrial production. SUMMARY

[0014] The technical problem to be solved by the present application is to avoid the use of tetrabutylammonium bromide, crown ether, indole and other phase transfer catalysts, reduce costs, and provide a new preparation method for lurasidone, which has the advantages of reasonable process, mild conditions, simple operation, high reaction yield, short production cycle and the like. The yield of each step is more than 90%, and the reduction and salt formation use a telescopic reaction, which is continuous and simple to operate.

[0015] The technical scheme of the present application is: a synthesis method of lurasidone hydrochloride, characterized in that it comprises the following steps:

[0016]

[0017] Step A: (3aR,7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piperazin]-2-x ammonium as shown in formula I reacts with riloxacin, toluene, potassium carbonate as shown in formula II to generate intermediate product as shown in formula III (3aR,4R,7S,7aS)-2-((1R,2R)-2-(4-(benzo[d]isothiazol-3-yl)piperazin-1- methyl)cyclohexyl)methyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione;

[0018] Step B: intermediate product as shown in formula III reacts with hydrogen gas, catalyst Y to generate lurasidone, lurasidone reacts with hydrochloric acid to generate lurasidone hydrochloride;

[0019] Further, X in formula I in step A is one of methanesulfonic acid anion, p-toluenesulfonic acid anion or bromide;

[0020] Further, the molar ratio of compound (I) to potassium carbonate in step A is 1:1.5~2.2;

[0021] Further, the molar ratio of compound (I) to riloxacin in step A is 1:1.1~1.3;

[0022] Further, potassium carbonate in step A is light potassium carbonate and the particle size D90 of potassium carbonate is 100~350μm;

[0023] Further, catalyst Y in step B is platinum carbon, palladium carbon or platinum dioxide;

[0024] Further, the pressure range of hydrogenation reaction in step B is 0.01~0.2MPa;

[0025] Further, the temperature of hydrogenation reaction in step B is 10~40℃;

[0026] Further, the amount of catalyst used in step B is 1%~10% of the weight of compound III;

[0027] Further, the solvent used in step B is a mixed solvent of toluene and methanol, ethanol or isopropanol;

[0028] Further, the molar ratio of hydrochloric acid to compound III in step B is 1:1.1~1.3.

[0029] The beneficial effects of the present application compared with the prior art mainly lie in that a novel method for synthesizing lurasidone hydrochloride by taking (3aR, 7aR)-4'-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1'-piperazin]-2-x ammonium shown as formula I and rionexim shown as formula II as starting materials, and then performing ring-opening substitution, hydrogenation reduction and salt formation, is invented, which is original. The use of phase transfer catalyst is avoided, and the disadvantages of low resolution yield, poor selectivity, low yield and high cost are overcome. The raw materials required in the method are easy to obtain, the operation is simple, the reaction conditions are mild, and the amount of waste is less, so the method has great implementation value and social and economic benefits. DETAILED DESCRIPTION

[0030] The technical solutions of the present application are described below with specific examples, but the protection scope of the present application is not limited thereto.

[0031] Step A Example 1

[0032] A 3000ml three-necked flask was charged with I (methanesulfonate) 100g (236.1mmol), rionexim (II) 42.37g (259.7mmol), potassium carbonate 48.95g (354.1mmol, D90=136μm), toluene 400ml, and the mixture was stirred to be heated to 110℃ and refluxed for 8h. After cooling, 500ml of distilled water was added twice, and the mixture was stirred and separated to obtain an organic phase. The organic phase was evaporated under reduced pressure to obtain a light yellow oil. 2000ml of anhydrous ethanol was added, and the mixture was stirred to be heated to reflux and dissolved. After cooling, the mixture was stirred at room temperature for 2h, and then white solid III was obtained by suction filtration. The white solid was dried at 50℃, and 107.27g of white solid was obtained with a yield of 92.6%. Example 2

[0033] A 3000ml three-necked flask was charged with I (methanesulfonate) 100g (236.1mmol), rionexim (II) 42.37g (259.7mmol), potassium carbonate 48.95g (354.1mmol, D90=136μm), toluene 400ml, and the mixture was stirred to be heated to 110℃ and refluxed for 8h. After cooling, 500ml of distilled water was added twice, and the mixture was stirred and separated to obtain an organic phase. The organic phase was evaporated under reduced pressure to obtain a light yellow oil. 2000ml of anhydrous ethanol was added, and the mixture was stirred to be heated to reflux and dissolved. After cooling, the mixture was stirred at room temperature for 2h, and then white solid III was obtained by suction filtration. The white solid was dried at 50℃, and 107.27g of white solid was obtained with a yield of 92.6%. Example 3

[0034] Into a 3000ml three-necked flask, add compound I (bromide salt) 100.0g (244.9mmol), noracime (II) 47.94g (293.8mmol), potassium carbonate 60.93g (440.8mmol, D90=346μm), toluene 400ml, stir to warm to 110℃ reflux for 8h, stir to cool, add distilled water 500ml x2, stir to separate into organic phase, evaporate the organic phase under reduced pressure to obtain a light yellow oil, add anhydrous ethanol 2000ml, stir to warm to reflux to dissolve, stir to cool, the ester crystallizes at room temperature for 2h, suction filtration to obtain white solid III, 50℃ air-drying to obtain white solid 109.95g, yield: 91.5%. Example 4

[0035] Into a 3000ml three-necked flask, add compound I (bromide salt) 100.0g (244.9mmol), noracime (II) 47.94g (293.8mmol), potassium carbonate 60.93g (440.8mmol, D90=346μm), toluene 400ml, stir to warm to 110℃ reflux for 8h, stir to cool, add distilled water 500ml x2, stir to separate into organic phase, evaporate the organic phase under reduced pressure to obtain a light yellow oil, add anhydrous ethanol 2000ml, stir to warm to reflux to dissolve, stir to cool, the ester crystallizes at room temperature for 2h, suction filtration to obtain white solid III, 50℃ air-drying to obtain white solid 109.95g, yield: 91.5%.

[0036] Step B Example 1

[0037] Hydrogenation: Into a 2000ml hydrogenation kettle, add compound III (200g, 407.6mmol), 5% palladium on carbon 2g, toluene 600ml, methanol 200ml, replace with N2 three times, replace with H2 three times, maintain temperature at 10℃, maintain hydrogen pressure at 0.01MPa, until no more hydrogen is absorbed, continue to react for 30min, sample control compound 3≤0.10%, stop the reaction, filter, the filter cake is rinsed with 50ml toluene

[0038] Salification: transfer the filtrate to a 2000ml four-necked flask, warm to 40~60℃, dropwise add 30% hydrochloric acid methanol 54.49g (448.4mmol), after dropping, cool to 20~30℃, crystallize for 4h, suction filtration, air-dry at 50℃ for 6h, collect the white solid hydrochloric acid lurasidone 201.02g, yield: 93.2%. Example 2

[0039] Hydrogenation: Into a 2000ml hydrogenation kettle, add compound III (200g, 407.6mmol mmol), 5% platinum on carbon 20g, toluene 600ml, ethanol 200ml, replace with N2 for three times, replace with H2 for three times, maintain temperature at 40℃, maintain hydrogen pressure at 0.05MPa, until no more hydrogen is absorbed, continue to react for 30min, take sample to control compound 3≤0.10%, stop the reaction, filter, wash the filter cake with 50ml toluene

[0040] Salification: Transfer the filtrate to a 2000ml four-necked flask, warm up to 40~60℃, drop in 30% hydrochloric acid methanol 59.44g (489.12mmol), after dropping, cool down to 20~30℃, keep for 4h, filter, dry at 50℃ for 6h, get white solid lurasidone hydrochloride 204.04g, yield 94.6%. Example 3

[0041] Hydrogenation: Into a 2000ml hydrogenation kettle, add III (200g, 407.6mmol mmol), platinum dioxide 10g, toluene 600ml, isopropyl alcohol 200ml, replace with N2 for three times, replace with H2 for three times, maintain temperature at 30℃, maintain hydrogen pressure at 0.1MPa, until no more hydrogen is absorbed, continue to react for 30min, take sample to control compound 3≤0.10%, stop the reaction, filter, wash the filter cake with 50ml toluene

[0042] Salification: Transfer the filtrate to a 2000ml four-necked flask, warm up to 40~60℃, drop in 30% hydrochloric acid methanol 64.40g (529.88mmol), after dropping, cool down to 20~30℃, keep for 4h, filter, dry at 50℃ for 6h, get white solid lurasidone hydrochloride 204.89g, yield 95.0%. Example 4

[0043] Hydrogenation: Into a 2000ml hydrogenation kettle, add III (200g, 407.6mmol mmol), 5% palladium on carbon 10g, toluene 600ml, methanol 200ml, replace with N2 for three times, replace with H2 for three times, maintain temperature at 30℃, maintain hydrogen pressure at 0.2MPa, until no more hydrogen is absorbed, continue to react for 30min, take sample to control compound 3≤0.10%, stop the reaction, filter, wash the filter cake with 50ml toluene

[0044] Salification: Transfer the filtrate to a 2000ml four-necked flask, warm up to 40~60℃, drop in 30% hydrochloric acid methanol 61.92g (509.5mmol), after dropping, cool down to 20~30℃, keep for 4h, filter, dry at 50℃ for 6h, get white solid lurasidone hydrochloride 200.15g, yield 92.8%.

Claims

1. A process for the preparation of lurasidone hydrochloride, characterized in that The method comprises the following steps: Step A: reacting the renoxin of formula I with toluene and potassium carbonate to generate the intermediate of formula III, wherein the particle size D90 of the potassium carbonate is 100-350 μm; Step B: reacting the intermediate of formula III with hydrogen and catalyst Y to generate lurasidone, and reacting the lurasidone with hydrochloric acid to generate lurasidone hydrochloride; 。 2. The method of claim 1, wherein: In step A, the molar ratio of formula I: renoxin: potassium carbonate is 1:(1.1-1.3):(1.5-2.2).

3. The method of claim 1, wherein: In step B, the catalyst Y is platinum carbon, palladium carbon or platinum dioxide.

4. The method of claim 1, wherein: In step B, the pressure range of the hydrogenation reaction is 0.01-0.2 MPa.

5. The method of claim 1, wherein: In step B, the temperature of the hydrogenation reaction is 10-40 ℃.

6. The method of claim 1, wherein: In step B, the amount of the catalyst is 1%-10% of the weight of formula III.

7. The method of claim 1, wherein: In step B, the solvent used is a mixed solvent of toluene and methanol, ethanol or isopropyl alcohol.

8. The method of claim 1, wherein: In step B, the molar ratio of hydrochloric acid to formula III is 1:1.1-1.

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