CN102911169B - Method for preparing lurasidone - Google Patents

Abstract

The invention discloses a preparation method of lurasidone as shown in formula I, which comprises the following steps: in a polar aprotic solvent, under the action of a base, compound II or compound III, and compound IV in The following reactions can be carried out at 50-150°C; the preparation method of lurasidone of the present invention has high yield, simple operation and low cost, is suitable for large-scale industrial production, and provides a new method for the preparation of lurasidone new way.

Description

A kind of preparation method of lurasidone

technical field

The invention relates to a preparation method of lurasidone.

Background technique

Mental illness is a common disease, affecting about one percent of the population. With the accelerated pace of life and frequent social interactions, mental illness has increasingly become a frequent disease, especially in cities with a relatively concentrated population. At present, antipsychotic drugs have annual sales of 16.2 billion US dollars in the global market, making them the fifth largest therapeutic category after cholesterol-lowering drugs.

Among the existing antipsychotic drugs, haloperidol, olanzapine and other drugs are likely to cause weight gain, and the extrapyramidal adverse reactions are serious; ziprasidone mesylate is effective in controlling the acute agitation symptoms of schizophrenia, and There were no adverse reactions of weight gain, but there were adverse reactions of cardiac QT prolongation.

Lurasidone hydrochloride, a new anti-schizophrenic drug launched in 2010, has a chemical name of (3aR, 4S, 7R, 7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazole -3-yl)piperazin-1-yl]methyl]cyclohexylmethyl}hexahydro-4,7-methylene-2H-isoindole-1,3-dione hydrochloride, its structural formula is as follows :

Its main features are faster onset of action, peak blood drug time of 1 to 3 hours, less intermittent impact on cardiac QTc, and a half-life of up to 18 hours, which can better control schizophrenia (see http://www. accessdata.fda.gov/drugsatfda_docs/nda/2010/200603Orig1s000SumR.pdf).

Lurasidone, the optically active (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-1- Piperazinylmethyl]-2,3-bicyclo[2.2.1]heptane-dicarboximide (Compound I) is the free base form of lurasidone hydrochloride used in the treatment of schizophrenia.

EP0464846 reports the preparation method of compound I. In the presence of potassium carbonate, compound II and compound IV are refluxed in xylene for 16 hours, but the yield of the reaction is not reported. This method needs to add phase transfer catalyst diphenyl-18-crown-6-ether, the cost is high, the reaction time is also long, and the pure product needs to be separated by column chromatography.

JP2006169155 also reported the preparation method of compound I. In the presence of fine granular (specific surface area 0.6m ² /g) potassium carbonate, compound II and compound IV were refluxed in toluene for 2 hours, and the yield was 89.5%. JP2006169154 reports that in the preparation method described in JP2006169155, adding a phase transfer catalyst helps to increase the reaction yield to 93.9%. The inventor finds through practice that the above-mentioned reaction is a heterogeneous reaction, and compound II is insoluble in toluene. Therefore, in the actual operation process, compound II cannot completely react, and the actual yield is lower than 65%; and when the amount of solvent exceeds At 1 L, during the reaction, compound II and potassium carbonate tend to agglomerate, resulting in a further reduction in the reaction rate to 30-40%.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the defects of long reaction time, incomplete reaction, high preparation cost, complicated post-treatment process and unsuitability for industrial large-scale preparation in the existing preparation method of lurasidone. And a preparation method of lurasidone is provided. The method has the advantages of high yield, simple operation and low cost, and is suitable for industrial large-scale production.

Therefore, the present invention relates to a preparation method of lurasidone as shown in formula I, which comprises the following steps: in a polar aprotic solvent, under the action of a base, compound II or compound III, and compound IV Carry out the following reaction at 50-150°C;

Wherein, the polar aprotic solvent is preferably N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMAC), six One or more of methylphosphoric triamide (HMPA) and N,N-dimethylethanolamine (DMEA); more preferably N,N-dimethylformamide (DMF). The amount of the polar aprotic solvent can be the conventional amount used in this type of reaction in the art; preferably, the volume-mass ratio of the polar aprotic solvent to compound II or compound III is 3-100ml/g; More preferably 10-30ml/g; best 10-20ml/g. The base may be a conventional base for this type of reaction in the art, such as an inorganic base and/or an organic base. The inorganic base is preferably one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate and sodium bicarbonate; preferably potassium carbonate. The organic base is preferably pyridine and/or tertiary amine; the tertiary amine is preferably triethylamine and/or diisopropylethylamine. The amount of the base can be the conventional amount of this type of reaction in the art; preferably, the molar ratio of the base to compound II or compound III is 1:5 to 1:0.2; more preferably 1:1 ~1:0.5. The amount of the compound IV can be the conventional amount of this type of reaction in the art; preferably, the molar ratio of the compound IV to the compound II or the compound III is 1:0.8～1:2; more preferably 1 : 1～1: 1.1. The temperature of the reaction is preferably 100-150°C. The reaction time is preferably until the completion of the detection reaction, generally 2-24 hours, preferably 5-10 hours.

In the present invention, the compound II and compound III can be prepared from commercially available trans-cycloadipic acid with reference to the method in EP464846; the compound IV can be obtained with reference to Bioorganic & Medicinal Chemistry 12 (2004) 4565-4573 and The method among EP0261688, is made from commercially available exo-norbornene anhydride.

Unless otherwise specified, the raw materials or reagents described in the present invention are commercially available.

The positive and progressive effects of the present invention are: the preparation method of lurasidone of the present invention has high yield, simple operation and low cost, is suitable for industrial large-scale production, and provides a new way for the preparation of lurasidone.

Detailed ways

The present invention is further illustrated below with examples, but the present invention is not limited thereto.

Unless otherwise specified, the raw materials or reagents used in the examples are commercially available.

Compound II and Compound III described in the examples were prepared from commercially available trans-cycloadipic acid with reference to the method in EP464846; described Compound IV was prepared with reference to Bioorganic & Medicinal Chemistry 12 (2004) 4565-4573 and EP0261688 Method, prepared from commercially available exo-norbornene anhydride.

Comparative Example Compound I was prepared according to the method in JP2006169154

Put 30.0g of compound II and 10.9g of potassium carbonate in a reaction flask, add 560ml of toluene, stir, then add 11.9g of compound IV, heat to 110°C, and react for 2 hours, but the reaction is not complete. 0.8 g of tetra-n-butylammonium bisulfate was added, and the reaction was continued for 4 hours. After the reaction is over, add 320ml of water, stir, all the solids are dissolved, filter, remove a little floc, separate the layers of the filtrate, wash the aqueous phase with 150ml of toluene, combine the toluene layers, wash with water (150ml×2), and then wash with 150ml of toluene Wash with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, remove the desiccant, and concentrate under reduced pressure to obtain 12.2 g of compound I as a pale yellow solid with a yield of 35%.

Example 1 Preparation of Compound I

5g (11.8mmol) compound II, 2.2g (13.3mmol) compound IV and 1.9g (13.7mmol) potassium carbonate were placed in the reaction flask, added 100ml N, N-dimethylformamide (DMF), heated to 130 °C, react for 4 hours. After the reaction, 100ml of water was added, stirred at room temperature for 2 hours, a large amount of solid was precipitated, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 5.25g after drying, with a yield of 90%.

Its structural identification data are as follows:

¹ H NMR (DMSO-d ₆ ) δ: ppm 1.1-1.2 (3H, d), 2.0-2.1 (2H, m), 2.5-2.6 (1H, dd), 2.8-2.9 (2H, t), 2.96- 3.0(1H,dd), 3.3-3.5(3H,m), 3.5-3.7(4H,m), 4.2-4.3(2H,t), 4.3-4.4(2H,t), 4.6-4.7(2H,m ), 4.8-5.2 (1H, br), 6.9-7.15 (6H, m), 7.3-7.4 (2H, m), 8.0-8.1 (2H, m).

Embodiment 2 preparation compound I

Put 5g of compound II, 2.2g of compound IV and 1.9g of potassium carbonate in a reaction flask, add 100ml of N,N-dimethylformamide (DMF), heat to 50°C, and react for 24 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 3.4g after drying, and the yield was 60%. The structural identification data was the same as in Example 1.

Example 3 Preparation of Compound I

Put 5g of compound II, 2.2g of compound IV and 1.9g of potassium carbonate in a reaction flask, add 100ml of N,N-dimethylformamide (DMF), heat to 150°C, and react for 3 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 5.0g after drying, with a yield of 86%, and its structural identification data was the same as in Example 1.

Example 4 Preparation of Compound I

Put 3g of compound II, 1.4g of compound IV and 1.2g of potassium carbonate in a reaction flask, add 100ml of dimethylsulfoxide (DMSO), heat to 130°C, and react for 4 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 3.1g after drying, with a yield of 88%, and its structural identification data was the same as in Example 1.

Example 5 Preparation of Compound I

Put 1.0g of compound II, 0.44g of compound IV and 0.40g of potassium carbonate in a reaction flask, add 20ml of N,N-dimethylethanolamine (DMEA), heat to 130°C, and react for 4 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 0.98g after drying, and the yield was 85%. The structural identification data was the same as in Example 1.

Example 6 Preparation of Compound I

Put 1.0g of compound II, 0.44g of compound IV and 0.40g of potassium carbonate in a reaction flask, add 20ml of N,N-dimethylacetamide (DMAC), heat to 130°C, and react for 4 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 1.02g after drying, with a yield of 88%, and its structural identification data was the same as in Example 1.

Example 7 Preparation of Compound I

Put 5g of compound II, 2.2g of compound IV and 1.9g of potassium carbonate in a reaction flask, add 100ml of hexamethylphosphoric triamide (HMPA), heat to 130°C, and react for 4 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 5.2g after drying, and the yield was 89%. The structural identification data was the same as in Example 1.

Example 8 Preparation of Compound I

Put 2.0g of compound II, 0.88g of compound IV and 0.56g of triethylamine in a reaction flask, add 40ml of N,N-dimethylformamide, heat to 80°C, and react for 8 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 1.6g after drying, with a yield of 70%. The structural identification data was the same as in Example 1.

Example 9 Preparation of Compound I

Put 2g of compound II, 0.88g of compound IV and 0.56g of diisopropylethylamine in a reaction flask, add 40ml of N,N-dimethylformamide, heat to 110°C, and react for 6 hours. After the reaction, add 100ml of water, stir at room temperature for 2 hours, precipitate a large amount of solid, filter, wash the filter cake with water to obtain a white solid, dry 1.7g, yield 73%, its structural identification data are the same as in Example 1.

Example 10 Preparation of Compound I

Put 2.0g of compound II, 0.88g of compound IV and 0.24g of sodium hydroxide in a reaction flask, add 40ml of N,N-dimethylformamide, heat to 130°C, and react for 4 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 1.2g after drying, with a yield of 52%, and its structural identification data was the same as in Example 1.

Example 11 Preparation of Compound I

Put 2g of compound II, 0.88g of compound IV and 0.32g of potassium hydroxide in a reaction flask, add 40ml of N,N-dimethylformamide, heat to 130°C, and react for 4 hours. After the reaction, add 100ml of water, stir at room temperature for 2 hours, separate out a large amount of solid, filter, wash the filter cake with water to obtain a white solid, weigh 1.2g after drying, yield 52%, its structural identification data is the same as in Example 1.

Example 12 Preparation of Compound I

Put 2g of compound II, 0.88g of compound IV and 0.16g of lithium hydroxide in a reaction flask, add 40ml of N,N-dimethylformamide, heat to 130°C, and react for 4 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 1.3g after drying, and the yield was 56%.

Example 13 Preparation of Compound I

Put 5g of compound II, 2.2g of compound IV and 1.5g of sodium carbonate in a reaction flask, add 100ml of N,N-dimethylformamide, heat to 130°C, and react for 4 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 4.9g after drying, with a yield of 84%, and its structural identification data was the same as in Example 1.

Example 14 Preparation of Compound I

Put 5g (11.8mmol) of compound II, 14.7mmol of compound IV and 2.36mmol of potassium hydroxide in a reaction flask, add 15ml of N,N-dimethylformamide (DMF), heat to 100°C, and react for 14 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 3.8g after drying, and the yield was 65%. The structural identification data was the same as in Example 1.

Example 15 Preparation of Compound I

Put 5g (11.8mmol) of compound II, 5.9mmol of compound IV and 59mmol of pyridine into a reaction flask, add 500ml of N,N-dimethylformamide (DMF), heat to 150°C, and react for 2 hours. After the reaction, add 100ml of water, stir at room temperature for 2 hours, separate out a large amount of solid, filter, wash the filter cake with water to obtain a white solid, weigh 3.9g after drying, yield 66%, its structural identification data is the same as in Example 1.

Example 16 Preparation of Compound I

5g (11.8mmol) of compound II, 2.2g (13.3mmol) of compound IV and 13.7mmol of sodium bicarbonate were placed in a reaction flask, and 100ml of N,N-dimethylformamide (DMF) was added, heated to 130°C, and reacted 4 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 4.4g after drying, with a yield of 75%, and its structural identification data was the same as in Example 1.

Example 17 Preparation of Compound I

5g (11.8mmol) of compound III, 2.2g (13.3mmol) of compound IV and 13.7mmol of sodium carbonate were placed in a reaction flask, and 100ml of N,N-dimethylformamide (DMF) was added, heated to 130°C, and reaction 4 Hour. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 4.5g after drying, with a yield of 78%, and its structural identification data was the same as in Example 1.

Example 18 Preparation of Compound I

5g (11.8mmol) of compound II, 2.2g (13.3mmol) of compound IV and 13.7mmol of lithium hydroxide were placed in a reaction flask, and 100ml of N,N-dimethylformamide (DMF) was added, heated to 130°C, and reacted 4 hours. After the reaction was finished, add 100ml of water, stir at room temperature for 2 hours, a large amount of solids were separated out, filtered, and the filter cake was washed with water to obtain a white solid, which weighed 4.5g after drying, with a yield of 78%, and its structural identification data was the same as in Example 1.

Claims (8)

1. A preparation method of lurasidone as shown in formula I, characterized in that it comprises the following steps: in a polar aprotic solvent, under the action of a base, compound II or compound III, and compound IV in The following reaction can be carried out at 100-130°C; the polar aprotic solvent is N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, hexamethyl One or more of phosphoric triamide and N,N-dimethylethanolamine; 2. The preparation method according to claim 1, characterized in that: the volume-to-mass ratio of the polar aprotic solvent to compound II or compound III is 3-100 ml/g. 3. preparation method as claimed in claim 1 is characterized in that: described alkali is inorganic alkali and/or organic alkali: described inorganic alkali is potassium hydroxide, sodium hydroxide, lithium hydroxide, salt of wormwood, One or more of sodium carbonate and sodium bicarbonate; the organic base is pyridine and/or tertiary amine. 4. The preparation method according to claim 3, characterized in that: said tertiary amine is triethylamine and/or diisopropylethylamine. 5. The preparation method according to claim 1, characterized in that: the molar ratio of the base to compound II or compound III is 1:5-1:0.2. 6. The preparation method according to claim 1, characterized in that: the molar ratio of compound IV to compound II or compound III is 1:0.8-1:2. 7. The preparation method according to claim 1, characterized in that: the time of the reaction is to detect the completion of the reaction. 8. The preparation method according to claim 7, characterized in that: the reaction time is 2 to 24 hours.