CN102746289B - The preparation method of a kind of lurasidone hydrochloride - Google Patents

Abstract

The invention discloses a preparation method of lurasidone hydrochloride as shown in formula (I), which comprises the following steps: mixing a water-miscible organic solvent and hydrochloric acid, treating compound (II) in A solution in a dialkyl ketone solvent with no more than 6 carbon atoms can be crystallized; the mass ratio of the water-miscible organic solvent to hydrochloric acid is 0.5:1 to 100:1; the The molar ratio of hydrogen chloride and compound II in hydrochloric acid is 10:1 to 0.9:1. The durability of the preparation method of the present invention is significantly improved, and the prepared lurasidone hydrochloride (compound I) has high purity, low residual acetone, high yield, is more economical, and is suitable for industrial production.

Description

A kind of preparation method of lurasidone hydrochloride

technical field

The present invention specifically relates to a preparation method of lurasidone hydrochloride.

Background technique

Lurasidone hydrochloride (lurasidonehydrochloride), also known as lurasidone hydrochloride, can be used for the treatment of mental diseases (such as schizophrenia). Its chemical structure is shown in structural formula I.

According to the report of patent document JP-A-5-17440 and its family of patents EP0464846, the above-mentioned compound I can be obtained by processing the acetone solution of its free base (compound II) with an isopropanol solution of hydrogen chloride, but the above-mentioned method is not suitable for large-scale industrialization Production.

According to the report of Chinese patent 200480022168.7, the acetone solution of compound II needs to be treated with 1.8% to 5.0% hydrochloric acid to obtain lurasidone hydrochloride (compound I) with low acetone residue, and the yield is low (85%). When using hydrochloric acid with a concentration greater than 5.0% to prepare compound I according to the method described in this patent, the acetone residue of the obtained compound I is greater than 0.5%. According to the "Technical Guidelines for Research on Residual Solvents in Chemical Drugs" promulgated by the Drug Evaluation Center of the State Food and Drug Administration, the limit of acetone residues in chemical drugs is 0.5%. When compound I was prepared according to the method described in this patent with a concentration of 1.8% hydrochloric acid, the yield of compound I was only 65%. Therefore, when the above method is applied to large-scale industrial production, it has limitations.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the defect of lurasidone hydrochloride with low acetone residue, high purity and high yield in the existing preparation method of lurasidone hydrochloride, which requires harsher conditions, A method for preparing lurasidone hydrochloride with high durability is provided. The lurasidone hydrochloride (compound I) obtained by the preparation method of the present invention has high purity, low residual acetone, high yield, is more economical, and is suitable for industrial production.

Therefore, the present invention provides a kind of preparation method of lurasidone hydrochloride as shown in formula (I), it comprises the following steps: with the mixture that can be mixed with water organic solvent and hydrochloric acid composition, process compound (II) The solution in a hydrophilic solvent can be crystallized; the mass ratio of the water-miscible organic solvent to hydrochloric acid is 0.5:1 to 100:1; the hydrogen chloride in the hydrochloric acid and the compound II The molar ratio is from 10:1 to 0.9:1;

Wherein, the described organic solvent miscible with water is: methanol, ethanol, isopropanol, n-propanol, n-butanol, sec-butanol, isobutanol, ethylene glycol, 1,2-propanediol, 1 , 3-propanediol, 1,4-butanediol, 2,3-butanediol, 1,5-pentanediol, 1,6-hexanediol, glycerin, acetone, butanone, acetonitrile, tetrahydrofuran and 2- One or more of methyl tetrahydrofuran and the like. The preferred water-miscible organic solvent is: one or more of acetone, butanone, ethanol, isopropanol, n-propanol, sec-butanol, acetonitrile and tetrahydrofuran. More preferred water-miscible organic solvents are: one or more of acetone, butanone and ethanol.

Wherein, the hydrophilic solvent includes one or more of ketone solvents, alcohol solvents, ether solvents and nitrile solvents, preferably ketone solvents and/or alcohol solvents, more preferably ketone solvents . The ketone solvent is preferably a dialkyl ketone containing no more than 6 carbon atoms, such as one of acetone, methyl ethyl ketone (also known as methyl ethyl ketone) and 4-methyl-2-pentanone, etc. one or more species. Preferred ketone solvents are acetone and/or butanone, most preferably acetone. The alcoholic solvent can be an alcohol containing no more than 6 carbon atoms, such as one or more of isopropanol, ethanol, methanol and ethylene glycol, preferably isopropanol and/or ethanol. The ether solvent may be an ether containing no more than 6 carbon atoms, such as tetrahydrofuran and/or 2-methyltetrahydrofuran. The nitrile solvent can be a nitrile containing no more than 6 carbon atoms, such as one or more of acetonitrile, butyronitrile and succinonitrile.

Among the present invention, described hydrochloric acid is the aqueous solution of hydrogen chloride (HCl), and its concentration is expressed in mass fraction (massfraction), refers to the ratio (w/w) of hydrogen chloride (solute) mass and hydrochloric acid (solution) mass, expressed in percentage . The concentration of the hydrochloric acid has no special requirements, and can be a low concentration to a saturated solution, such as 0.3% to a saturated concentration, preferably 14% to 38%, more preferably 30% to 38%.

In the present invention, the mass ratio of the water-miscible organic solvent to hydrochloric acid is preferably 1:1 to 60:1, more preferably 2:1 to 30:1.

In the present invention, the molar ratio of hydrogen chloride to compound II in the hydrochloric acid is preferably 3:1 to 1:1, more preferably 1.3:1 to 1:1.

In the present invention, the solution of compound II in a dialkyl ketone containing no more than 6 carbon atoms is a solution formed by completely dissolving compound II in a dialkyl ketone containing no more than 6 carbon atoms, The compound II can be ensured to be dissolved in the dialkyl ketone containing not more than 6 carbon atoms by conventional methods in the art, such as dissolving the compound II by heating (preferably heating to reflux). The mass ratio of the compound II to the dialkyl ketone containing no more than 6 carbon atoms may be 1:5 to 1:60, preferably 1:6 to 1:25. The dialkyl ketones containing not more than 6 carbon atoms are preferably acetone and/or methyl ethyl ketone.

In the present invention, the mixture of a water-miscible organic solvent and hydrochloric acid, the method of processing the solution of compound (II) in a hydrophilic solvent, that is, the mixture of a water-miscible organic solvent and hydrochloric acid, The method of mixing with the solution of Compound II in a hydrophilic solvent is not particularly limited. For example, a mixture of a water-miscible organic solvent and hydrochloric acid can be added to a solution of Compound II in a hydrophilic solvent; a solution of Compound II in a hydrophilic solvent can also be added to a water-miscible in a mixture of dissolved organic solvents and hydrochloric acid.

The time required for mixing the "mixture of a water-miscible organic solvent and hydrochloric acid" and the "solution of Compound II in a hydrophilic solvent" is not particularly limited. For example, the two can be mixed rapidly all at once, or one can be slowly added to the other. Slow mixing is preferred. In this case, the time required is from 1 minute to 6 hours, preferably from 3 minutes to 3 hours, more preferably from 10 minutes to 1 hour.

In the present invention, the operation method of the crystallization is not particularly limited, and the technical means commonly used in the art are usually adopted to ensure sufficient crystallization, such as cooling and stirring to promote crystal precipitation. The cooling rate of cooling and crystallization does not need to be specially specified, and it may be rapid cooling or programmed temperature reduction, preferably programmed temperature reduction. The obtained crystals of lurasidone hydrochloride (I) can be separated by common means, such as filtration. Before filtering, the temperature of the crystallization reaction slurry is usually kept at -20-65°C, preferably at -10-30°C, more preferably at 10-25°C.

The isolated lurasidone hydrochloride can be dried to remove the solvent. There is no special requirement on the drying method, for example, it can be dried under reduced pressure, under normal pressure, by flowing an inert gas such as nitrogen or by air. The drying temperature is not particularly required, for example, it can be 0-100°C, preferably 40-70°C.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive and progressive effect of the present invention is that: the preparation of lurasidone hydrochloride (I) by the method of the present invention has achieved unexpected remarkable and excellent effects. The residual acetone of lurasidone hydrochloride (I) obtained is less than 0.2%. The high-performance liquid chromatography (HPLC) purity of the obtained lurasidone hydrochloride (I) is greater than 99.85%, and the maximum single impurity is less than 0.1%; and the preparation method of the present invention can achieve the effect of high yield. In particular, compared with the prior art, the preparation method of the present invention has significantly improved durability, does not require harsh conditions, improves process stability and reliability, and is more suitable for industrial production.

detailed description

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples. For the experimental methods that do not specify specific conditions in the following examples, select according to conventional methods and conditions, or according to the product instructions.

Example 1

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (Compound II) (5 g) was dissolved in acetone (53 g) with heating. Under reflux state, dropwise add the acetone (12g) solution of 36% hydrochloric acid (1.13g), reflux and stir for 2h after dropwise addition, after cooling to room temperature, filter, obtain lurasidone hydrochloride (5.16g) after vacuum drying at 60°C. g, yield 96%): HPLC purity 99.86%, the largest single impurity 0.06%, acetone residue 0.13%.

Example 2

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (Compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux state, dropwise add the acetone (6.5g) solution of 18% hydrochloric acid (0.91g), reflux and stir 2h after dropwise addition, after cooling to room temperature, filter, obtain lurasidone hydrochloride ( 2.14 g, yield 99%): HPLC purity 99.83%, the maximum simplex 0.06%, acetone residue 0.21%.

Example 3

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, add 14.4% hydrochloric acid (1.13g) in acetone (6.5g) dropwise. After the dropwise addition, stir at the same temperature for 2 hours. After cooling to room temperature, filter, and vacuum dry at 60°C to obtain lurazil hydrochloride Ketone (1.95 g, yield 95%): HPLC purity 99.83%, maximum simplex 0.07%, residual acetone 0.051%.

Example 4

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, add 7.2% hydrochloric acid (2.26g) in acetone (6.5g) solution dropwise, after the dropwise addition, add the same temperature and stir for 2h, after cooling to room temperature, filter, and vacuum dry at 60°C to obtain lurazil hydrochloride Ketone (1.94 g, yield 90%): HPLC purity 99.81%, maximum simplex 0.07%, residual acetone 0.097%.

Example 5

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, add 25% hydrochloric acid (0.65g) in acetone (6.5g) solution dropwise, after the dropwise addition, add the same temperature and stir for 2h, after cooling to room temperature, filter, and vacuum dry at 60°C to obtain lurazil hydrochloride Ketone (2.04 g, yield 95%): HPLC purity 99.88%, max. simple 0.04%, residual acetone 0.22%.

Example 6

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, add dropwise a solution of 36% hydrochloric acid (0.45g) in acetone (12g). After the dropwise addition, stir at the same temperature for 2 hours. After cooling to room temperature, filter and vacuum dry at 60°C to obtain lurasidone hydrochloride. (2.05g, yield 95%): HPLC purity 99.87%, the maximum simplex 0.06%, acetone residue 0.24%.

Example 7

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, add dropwise a solution of 36% hydrochloric acid (0.45g) in ethanol (7g). After the dropwise addition, stir at the same temperature for 2 hours. After cooling to room temperature, filter, and vacuum dry at 60°C to obtain lurasidone hydrochloride (1.95 g, yield 91%): HPLC purity 99.76%, the maximum simple impurity 0.11%, acetone residue 0.10%.

Example 8

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, add dropwise 36% hydrochloric acid (0.45g) in butanone (6.5g) solution, after the dropwise addition, add the same temperature and stir for 2h, after cooling to room temperature, filter, and vacuum dry at 60°C to obtain Lula hydrochloride Citron (2.07 g, yield 96%): HPLC purity 99.87%, maximum unmixed 0.07%, residual acetone 0.38%.

Example 9

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, add dropwise a solution of 36% hydrochloric acid (0.45g) in acetone (12g). After the dropwise addition, stir at the same temperature for 2 hours. After cooling to room temperature, filter and vacuum dry at 60°C to obtain lurasidone hydrochloride. (2.09g, yield 97%): HPLC purity 99.90%, the maximum simplex 0.06%, acetone residue 0.067%.

Example 10

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, add dropwise a solution of 36% hydrochloric acid (0.45g) in acetone (12g). After the dropwise addition, stir at the same temperature for 2 hours. After cooling to room temperature, filter and vacuum dry at 60°C to obtain lurasidone hydrochloride. (2.06g, yield 96%): HPLC purity 99.84%, maximum simplex 0.05%, residual acetone 0.078%.

Example 11

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, add 36% hydrochloric acid (0.9g) (2.2 equivalents) in acetone (12g) solution dropwise, after the dropwise addition, add the same temperature and stir for 2h, after cooling to room temperature, filter, and vacuum dry at 60°C to obtain hydrochloric acid Lurasidone (2.29 g, yield 100%): HPLC purity 99.71%, the maximum simple impurity 0.09%, acetone residue 0.21%.

Example 12

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, add 36% hydrochloric acid (3.6g) (8.8 equivalents) in acetone (12g) solution dropwise, after the dropwise addition, add the same temperature and stir for 2h, after cooling to room temperature, filter, and vacuum dry at 60°C to obtain hydrochloric acid Lurasidone (2.14 g, yield 99%): HPLC purity 99.77%, the maximum monotonicity 0.11%, acetone residue 0.069%.

Example 13

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2kg) was heated and dissolved in acetone (21.2kg). Under reflux state, dropwise add the acetone (12kg) solution of 36% hydrochloric acid (450g), after dropwise addition, add and stir at the same temperature for 2h, after cooling to room temperature, filter, obtain lurasidone hydrochloride after vacuum drying at 60°C ( 2.1kg, yield 97%): HPLC purity 99.89%, the maximum simplex 0.05%, acetone residue 0.047%.

The experimental data and result summary of table 1 embodiment 1～13

The HPLC purity and the largest single impurity in Table 1 were determined by a high-performance liquid chromatograph configured with a reversed-phase ODS column and a UV detector. Acetone residues were determined using a gas chromatograph with a capillary column and a hydrogen ion flame detector.

Comparative example 1

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione compound II (30g) and acetone (350g) were heated under reflux to dissolve. Add 36% hydrochloric acid (6.78g) dropwise to the above system in 15 minutes at 55°C, and after the dropwise addition, add 60°C and keep stirring for 1 hour. Cool the reaction to 0°C, stir at the same temperature for 1 h, filter, and dry in vacuo at 60°C to obtain lurasidone hydrochloride (31.5 g, yield 98%): HPLC purity 99.06%, maximum simplex 0.29%, residual acetone: 1.850%, the product is unqualified.

Comparative example 2

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione compound II (30g) and acetone (350g) were heated under reflux to dissolve. 18% hydrochloric acid (13.56 g) was added dropwise to the above system in 15 minutes at 55° C. After the dropwise addition was completed, add 60° C. and keep stirring for 1 hour. Cool the reaction to 0°C, stir at the same temperature for 1 h, filter, and dry in vacuo at 60°C to obtain lurasidone hydrochloride (31.5 g, yield 97.7%): HPLC purity 99.15%, maximum simplex 0.18%, residual acetone: 1.650%, the product is unqualified.

Comparative example 3

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione compound II (30g) and acetone (350g) were heated under reflux to dissolve. Add 14.4% hydrochloric acid (16.95 g) dropwise to the above system in 15 minutes at 55° C. After the dropwise addition, add 60° C. and keep stirring for 1 hour. Cool the reaction to 0°C, stir at the same temperature for 1 hour, filter, and dry in vacuo at 60°C to obtain lurasidone hydrochloride (31.0 g, yield 96.2%): HPLC purity 99.47%, single impurity less than 0.16%, residual acetone: 1.550%, the product is unqualified.

Comparative example 4

(3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexyl Methyl]hexahydro-1H-4,7-methylisoindole 1,3-dione (compound II) (2 g) was heated and dissolved in acetone (21.2 g). Under reflux, 3.6% hydrochloric acid (4.52 g) was added dropwise. After the dropwise addition was completed, add 60°C and keep stirring for 1h. Cool the reaction to 0°C, stir at the same temperature for 1 h, filter, and dry in vacuo at 60°C to obtain lurasidone hydrochloride (1.64 g, yield 76%): HPLC purity 99.85%, maximum simplex 0.05%, residual acetone 0.050 %. The yield is low.

Claims (6)

1. a preparation method of lurasidone hydrochloride as shown in formula (I), it is characterized in that comprising the following steps: with the mixture that water-miscible organic solvent and hydrochloric acid are formed, process compound (II) in containing A solution in a dialkyl ketone solvent with no more than 6 carbon atoms can be crystallized; the mass ratio of the water-miscible organic solvent to hydrochloric acid is 2:1 to 30:1; the The water-miscible organic solvent is: one or more of acetone, butanone and ethanol; the described dialkyl ketone containing no more than 6 carbon atoms is acetone; the concentration of the hydrochloric acid is 14% to 38% (w/w); the molar ratio of hydrogen chloride and compound II in the hydrochloric acid is 3:1 to 1:1; 2. The preparation method according to claim 1, characterized in that: the concentration of the hydrochloric acid is 30% to 38% (w/w). 3. The preparation method according to claim 1, characterized in that: the molar ratio of hydrogen chloride and compound II in the hydrochloric acid is 1.3:1 to 1:1. 4. The preparation method according to claim 1, characterized in that: the solution of the compound II in a dialkyl ketone containing no more than 6 carbon atoms is dissolved by heating the compound II in a dialkyl ketone containing no more than 6 carbon atoms. obtained from dialkyl ketones with 2 carbon atoms. 5. The preparation method according to claim 4, characterized in that the mass ratio of the compound II to the dialkyl ketone containing no more than 6 carbon atoms is 1:5 to 1:60. 6. The preparation method according to claim 5, characterized in that the mass ratio of the compound II to the dialkyl ketone containing no more than 6 carbon atoms is 1:6 to 1:25.