CN102746289A - Preparation method for lurasidone hydrochloride - Google Patents
Preparation method for lurasidone hydrochloride Download PDFInfo
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Abstract
The present invention discloses a preparation method for lurasidone hydrochloride represented by a formula (I). The method comprises the following steps: adopting a mixture to treat a solution formed by dissolving a compound (II) in a dialkyl ketone solvent having carbon number not more than 6, and carrying out crystallization to obtain the product of the present invention, wherein the mixture comprise an organic solvent capable of mixing and dissolving with water and hydrochloric acid, a mass ratio of the organic solvent to the hydrochloric acid is 0.5:1-100:1, a molar ratio of hydrogen chloride in the hydrochloric acid to the compound II is 10:1-0.9:1. The preparation method of the present invention has the following advantages that: durability is significantly improved, the prepared lurasidone hydrochloride (the compound I) has characteristics of high purity, low residual acetone, and high yield, and the method is economical and is suitable for industrial production.
Description
Technical field
The preparation method who relates to a kind of hydrochloric acid Lu Laxi ketone that the present invention is concrete.
Background technology
Hydrochloric acid Lu Laxi ketone (lurasidone hydrochloride) is claimed hydrochloric acid Lu Laxi ketone again, can be used for the treatment of Psychiatric disorders (like schizophrenia).Its chemical structure is shown in structural formula I.
According to the report of patent documentation JP-A-5-17440 and patent families EP0464846 thereof, the acetone soln that above-claimed cpd I can use the aqueous isopropanol of hydrogenchloride to handle its free alkali (compound I I) makes, but aforesaid method is not suitable for large-scale industrial production.
In addition according to the report of Chinese patent 200480022168.7, need just can obtain the low residual hydrochloric acid Lu Laxi ketone (compound I) of acetone, yield lower (85%) with the acetone soln of 1.8% to 5.0% salt s.t. compound I I.When with concentration greater than 5.0% hydrochloric acid, when preparing compound I by the said method of this patent, the acetone of gained compound I is residual greater than 0.5%.Evaluate " the chemicals residual solvent investigative technique governing principle " that issue at the center according to State Food and Drug Administration's medicine, the limit of acetone residual quantity is 0.5% in the chemicals.When using concentration is 1.8% hydrochloric acid, and when preparing compound I by the said method of this patent, the yield of gained compound I is merely 65%.Therefore, when aforesaid method is applied to large-scale industrial production, has limitation.
Summary of the invention
Technical problem to be solved by this invention is among the preparation method who overcomes existing hydrochloric acid Lu Laxi ketone; Need can make just that low acetone is residual than severe condition, the defective of the hydrochloric acid Lu Laxi ketone of high purity, high yield, and the preparation method of the high hydrochloric acid Lu Laxi ketone of a kind of wearing quality is provided.Hydrochloric acid Lu Laxi ketone (compound I) purity that preparation method of the present invention obtains is high, acetone residual low, yield is high, and is more economical, is suitable for suitability for industrialized production.
Therefore; The invention provides a kind of preparation method suc as formula the hydrochloric acid Lu Laxi ketone shown in (I), it comprises the following step: the mixture that can form with miscible organic solvent of water and hydrochloric acid, handle the solution of compound (II) in hydrophilic solvent; Crystallization gets final product; Described can be 0.5: 1 to 100: 1 with the miscible organic solvent of water and the mass ratio of hydrochloric acid; The mol ratio of hydrogenchloride in the described hydrochloric acid and compound I I is 10: 1 to 0.9: 1;
Wherein, Describedly can be: methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, sec-butyl alcohol, isopropylcarbinol, terepthaloyl moietie, 1,2-Ucar 35,1, ammediol, 1 with the miscible organic solvent of water; 4-butyleneglycol, 2; 3-butyleneglycol, 1,5-pentanediol, 1, one or more in 6-pinakon, glycerine, acetone, butanone, acetonitrile, THF and the 2-methyltetrahydrofuran etc.Preferably can be: one or more in acetone, butanone, ethanol, Virahol, n-propyl alcohol, sec-butyl alcohol, acetonitrile and the THF with the miscible organic solvent of water.Preferredly can be: one or more in acetone, butanone and the ethanol with the miscible organic solvent of water.
Wherein, described hydrophilic solvent comprises one or more in ketones solvent, alcoholic solvent, ether solvent and the nitrile solvents, preferred ketones solvent and/or alcoholic solvent, more preferably ketones solvent.Ketones solvent preferable for containing the dialkyl ketone of no more than 6 carbon atoms, like in acetone, butanone (being called methyl ethyl ketone again) and the 4-methyl-2 pentanone etc. one or more.Preferred ketones solvent is acetone and/or butanone, and most preferred is acetone.Alcoholic solvent can be the alcohol that contains no more than 6 carbon atoms, like in Virahol, ethanol, methyl alcohol and the terepthaloyl moietie etc. one or more, and preferred Virahol and/or ethanol.Ether solvent can be the ether that contains no more than 6 carbon atoms, like THF and/or 2-methyltetrahydrofuran.Nitrile solvents can be the nitrile that contains no more than 6 carbon atoms, like in acetonitrile, butyronitrile and the succinonitrile one or more.
Among the present invention, described hydrochloric acid is the aqueous solution of hydrogenchloride (HCl), and its concentration refers to the ratio (w/w) of hydrogenchloride (solute) quality and hydrochloric acid (solution) quality all with massfraction (mass fraction) expression, representes with percentage ratio.The concentration of described hydrochloric acid does not have particular requirement, can for lower concentration to saturated solution, such as 0.3% to saturation concentration, be preferably 14% to 38%, more preferably 30% to 38%.
Among the present invention, described can with preferred 1: 1 to 60: 1 of the mass ratio of miscible organic solvent of water and hydrochloric acid, more preferably 2: 1 to 30: 1.
Among the present invention, the mol ratio of hydrogenchloride in the described hydrochloric acid and compound I I is preferably 3: 1 to 1: 1, more preferably 1.3: 1 to 1: 1.
Among the present invention; The solution of described compound I I in the dialkyl ketone that contains no more than 6 carbon atoms is that compound I I is dissolved in the solution that forms in the dialkyl ketone that contains no more than 6 carbon atoms fully; Can guarantee that compound I I is dissolved in the dialkyl ketone that contains no more than 6 carbon atoms through the conventional method in this area, as compound I I being dissolved through heating (preferably being heated to backflow).Said compound I I can be 1: 5 to 1: 60 with the mass ratio that contains the dialkyl ketone of no more than 6 carbon atoms, is preferably 1: 6 to 1: 25.Said preferred acetone of dialkyl ketone and/or the butanone that contains no more than 6 carbon atoms.
Among the present invention; The mixture that can form with miscible organic solvent of water and hydrochloric acid; Handle the mode of the solution of compound (II) in hydrophilic solvent; The mixture that just can form with miscible organic solvent of water and hydrochloric acid does not have special qualification with the hybrid mode of the solution of compound I I in hydrophilic solvent.For example, can be with being added in the solution of compound I I in hydrophilic solvent with the mixture that miscible organic solvent of water and hydrochloric acid are formed; Also can the solution of compound I I in hydrophilic solvent be added in the mixture that can form with miscible organic solvent of water and hydrochloric acid.
Mixing " mixture that can form with miscible organic solvent of water and hydrochloric acid " and " solution of compound I I in hydrophilic solvent " required time does not have special qualification.For example, can both disposable short mix also can slowly be added to a kind of material in the another kind of material.The slow blended mode of preferred employing, in this case, the time that needs is 1 minute to 6 hours, and is preferably between 3 minutes to 3 hours, preferred between 10 minutes to 1 hour.
Among the present invention, described crystalline working method does not have special restriction, takes this area technique means commonly used to guarantee that crystallization is abundant usually, as promoting crystal to separate out through operations such as cooling and stirrings.The speed of cooling of cooling crystallization need not special appointment, can cool off or programmed cooling the preferable procedure cooling fast.Gained hydrochloric acid Lu Laxi ketone (I) crystallization can separate through common means, as filtering.Before the filtration, the temperature of crystallization reaction slurries remains on-20～65 ℃ usually, and is preferably at-10～30 ℃, preferred at 10～25 ℃.
Separate the hydrochloric acid Lu Laxi ketone that obtains can be through the dry solvent of removing.Drying mode also has no special requirements, for example, can drying under reduced pressure, constant pressure and dry, through rare gas element or dry airs such as circulation nitrogen.Drying temperature also has no special requirements, for example, can be at 0～100 ℃, preferred 40～70 ℃.
On the basis of this area general knowledge, above-mentioned each optimum condition, but arbitrary combination promptly get each preferred embodiment of the present invention.
Agents useful for same of the present invention and raw material are all commercially available to be got.
Positive progressive effect of the present invention is: adopt method of the present invention to prepare hydrochloric acid Lu Laxi ketone (I), obtained beyond thought remarkable excellent results.The acetone of the hydrochloric acid Lu Laxi ketone (I) of gained is residual less than 0.2%.Performance liquid chromatography (HPLC) purity of the hydrochloric acid Lu Laxi ketone (I) of gained is greater than 99.85%, and is maximum single assorted less than 0.1%; And preparation method of the present invention can reach the high effect of yield.Especially, preparation method of the present invention compares the prior art wearing quality and significantly improves, and need not severe condition, has improved the stability and the safety of technology, is more suitable for suitability for industrialized production.
Embodiment
Mode through embodiment further specifies the present invention below, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
Embodiment 1
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (5g) heating for dissolving in acetone (53g).Under reflux state, drip acetone (12g) solution of 36% hydrochloric acid (1.13g), dropwise back refluxing and stirring 2h; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (5.16g, yield 96%) after 60 ℃ of vacuum-dryings: HPLC purity 99.86%; Maximum list mixes 0.06%, acetone residual quantity 0.13%.
Embodiment 2
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip acetone (6.5g) solution of 18% hydrochloric acid (0.91g), dropwise back refluxing and stirring 2h; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (2.14g, yield 99%) after 60 ℃ of vacuum-dryings: HPLC purity 99.83%; Maximum list mixes 0.06%, acetone residual quantity 0.21%.
Embodiment 3
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip acetone (6.5g) solution of 14.4% hydrochloric acid (1.13g), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (1.95g, yield 95%) after 60 ℃ of vacuum-dryings: HPLC purity 99.83%; Maximum list mixes 0.07%, acetone residual quantity 0.051%.
Embodiment 4
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip acetone (6.5g) solution of 7.2% hydrochloric acid (2.26g), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (1.94g, yield 90%) after 60 ℃ of vacuum-dryings: HPLC purity 99.81%; Maximum list mixes 0.07%, acetone residual quantity 0.097%.
Embodiment 5
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip acetone (6.5g) solution of 25% hydrochloric acid (0.65g), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (2.04g, yield 95%) after 60 ℃ of vacuum-dryings: HPLC purity 99.88%; Maximum list mixes 0.04%, acetone residual quantity 0.22%.
Embodiment 6
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip acetone (12g) solution of 36% hydrochloric acid (0.45g), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (2.05g, yield 95%) after 60 ℃ of vacuum-dryings: HPLC purity 99.87%; Maximum list mixes 0.06%, acetone residual quantity 0.24%.
Embodiment 7
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip ethanol (7g) solution of 36% hydrochloric acid (0.45g), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (1.95g, yield 91%) after 60 ℃ of vacuum-dryings: HPLC purity 99.76%; Maximum list mixes 0.11%, acetone residual quantity 0.10%.
Embodiment 8
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip butanone (6.5g) solution of 36% hydrochloric acid (0.45g), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (2.07g, yield 96%) after 60 ℃ of vacuum-dryings: HPLC purity 99.87%; Maximum list mixes 0.07%, acetone residual quantity 0.38%.
Embodiment 9
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip acetone (12g) solution of 36% hydrochloric acid (0.45g), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (2.09g, yield 97%) after 60 ℃ of vacuum-dryings: HPLC purity 99.90%; Maximum list mixes 0.06%, acetone residual quantity 0.067%.
Embodiment 10
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip acetone (12g) solution of 36% hydrochloric acid (0.45g), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (2.06g, yield 96%) after 60 ℃ of vacuum-dryings: HPLC purity 99.84%; Maximum list mixes 0.05%, acetone residual quantity 0.078%.
Embodiment 11
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip acetone (12g) solution of 36% hydrochloric acid (0.9g) (2.2 equivalent), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (2.29g, yield 100%) after 60 ℃ of vacuum-dryings: HPLC purity 99.71%; Maximum list mixes 0.09%, acetone residual quantity 0.21%.
Embodiment 12
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip acetone (12g) solution of 36% hydrochloric acid (3.6g) (8.8 equivalent), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (2.14g, yield 99%) after 60 ℃ of vacuum-dryings: HPLC purity 99.77%; Maximum list mixes 0.11%, acetone residual quantity 0.069%.
Embodiment 13
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2kg) heating for dissolving in acetone (21.2kg).Under reflux state, drip acetone (12kg) solution of 36% hydrochloric acid (450g), add synthermal stirring 2h after dropwising; Behind the cool to room temperature; Filter, promptly get hydrochloric acid Lu Laxi ketone (2.1kg, yield 97%) after 60 ℃ of vacuum-dryings: HPLC purity 99.89%; Maximum list mixes 0.05%, acetone residual quantity 0.047%.
Experimental data and the result of table 1 embodiment 1～13 gather
HPLC purity in the table 1 and maximum single impurity adopt the high performance liquid chromatograph of configuration anti-phase ODS post and UV detector to measure.Acetone is residual then to be to utilize the gas chromatograph for determination have capillary column and hydrogen ion flame detector.
Comparative example 1
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-dione compounds II (30g), the dissolving of acetone (350g) reflux.55 ℃ drip 36% hydrochloric acid (6.78g) in 15min in above-mentioned system, add 60 ℃ of insulated and stirred 1h after dropwising.Cooling reaction to 0 ℃, the synthermal 1h that stirs down filters, 60 ℃ of vacuum-dryings, hydrochloric acid Lu Laxi ketone (31.5g, yield 98%): HPLC purity 99.06%, maximum single assorted 0.29%, the acetone residual quantity: 1.850%, product is defective.
Comparative example 2
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-dione compounds II (30g), the dissolving of acetone (350g) reflux.55 ℃ drip 18% hydrochloric acid (13.56g) in 15min in above-mentioned system, add 60 ℃ of insulated and stirred 1h after dropwising.Cooling reaction to 0 ℃, the synthermal 1h that stirs down filters, 60 ℃ of vacuum-dryings, hydrochloric acid Lu Laxi ketone (31.5g, yield 97.7%): HPLC purity 99.15%, maximum single assorted 0.18%, the acetone residual quantity: 1.650%, product is defective.
Comparative example 3
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-dione compounds II (30g), the dissolving of acetone (350g) reflux.55 ℃ drip 14.4% hydrochloric acid (16.95g) in 15min in above-mentioned system, add 60 ℃ of insulated and stirred 1h after dropwising.Cooling reaction to 0 ℃, the synthermal 1h that stirs down filters, 60 ℃ of vacuum-dryings, hydrochloric acid Lu Laxi ketone (31.0g, yield 96.2%): HPLC purity 99.47%, single impurity is less than 0.16%, the acetone residual quantity: 1.550%, product is defective.
Comparative example 4
Will (3aR, 4S, 7R, 7aS)-2-[(1R, 2R)-2-[4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl] cyclohexyl methyl] six hydrogen-1H-4,7-methyl isoindole 1,3-diketone (compound I I) (2g) heating for dissolving in acetone (21.2g).Under reflux state, drip 3.6% hydrochloric acid (4.52g).Add 60 ℃ of insulated and stirred 1h after dropwising.Cooling reaction to 0 ℃, the synthermal 1h that stirs down filters, 60 ℃ of vacuum-dryings, hydrochloric acid Lu Laxi ketone (1.64g, yield 76%): HPLC purity 99.85%, maximum single assorted 0.05%, acetone residual quantity 0.050%.Yield is low.
Claims (15)
1. preparation method suc as formula the hydrochloric acid Lu Laxi ketone shown in (I); It is characterized in that comprising the following step: the mixture that can form with miscible organic solvent of water and hydrochloric acid; Handle the solution of compound (II) in containing the dialkyl ketone solvent of no more than 6 carbon atoms, crystallization gets final product; Described can be 0.5: 1 to 100: 1 with the miscible organic solvent of water and the mass ratio of hydrochloric acid; The mol ratio of hydrogenchloride in the described hydrochloric acid and compound I I is 10: 1 to 0.9: 1;
2. preparation method as claimed in claim 1; It is characterized in that: describedly can be: methyl alcohol, ethanol, Virahol, n-propyl alcohol, propyl carbinol, sec-butyl alcohol, isopropylcarbinol, terepthaloyl moietie, 1,2-Ucar 35,1, ammediol, 1 with the miscible organic solvent of water; 4-butyleneglycol, 2; 3-butyleneglycol, 1,5-pentanediol, 1, one or more in 6-pinakon, glycerine, acetone, butanone, acetonitrile, THF and the 2-methyltetrahydrofuran.
3. preparation method as claimed in claim 2 is characterized in that: describedly can be with the miscible organic solvent of water: one or more in acetone, butanone, ethanol, Virahol, n-propyl alcohol, sec-butyl alcohol, acetonitrile and the THF.
4. preparation method as claimed in claim 3 is characterized in that: describedly can be with the miscible organic solvent of water: one or more in acetone, butanone and the ethanol.
5. preparation method as claimed in claim 1 is characterized in that: the described dialkyl ketone that contains no more than 6 carbon atoms is one or more in acetone, butanone and the 4-methyl-2 pentanone.
6. preparation method as claimed in claim 1 is characterized in that: the concentration of described hydrochloric acid is that 0.3% (w/w) is to saturation concentration.
7. preparation method as claimed in claim 6 is characterized in that: the concentration of described hydrochloric acid is 14% to 38% (w/w).
8. preparation method as claimed in claim 7 is characterized in that: the concentration of described hydrochloric acid is 30% to 38% (w/w).
9. preparation method as claimed in claim 1 is characterized in that: described can be 1: 1 to 60: 1 with the miscible organic solvent of water and the mass ratio of hydrochloric acid.
10. preparation method as claimed in claim 9 is characterized in that: described can be 2: 1 to 30: 1 with the miscible organic solvent of water and the mass ratio of hydrochloric acid.
11. preparation method as claimed in claim 1 is characterized in that: the mol ratio of hydrogenchloride in the described hydrochloric acid and compound I I is 3: 1 to 1: 1.
12. preparation method as claimed in claim 11 is characterized in that: the mol ratio of hydrogenchloride in the said hydrochloric acid and compound I I is 1.3: 1 to 1: 1.
13. preparation method as claimed in claim 1 is characterized in that: the solution of described compound I I in the dialkyl ketone that contains no more than 6 carbon atoms is dissolved in compound I I in the dialkyl ketone that contains no more than 6 carbon atoms through heating and obtains.
14. preparation method as claimed in claim 13 is characterized in that: said compound I I is 1: 5 to 1: 60 with the mass ratio that contains the dialkyl ketone of no more than 6 carbon atoms.
15. preparation method as claimed in claim 14 is characterized in that: said compound I I is 1: 6 to 1: 25 with the mass ratio that contains the dialkyl ketone of no more than 6 carbon atoms.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911170A (en) * | 2012-11-15 | 2013-02-06 | 苏州第壹制药有限公司 | Method for preparing imide compound hydrochloride |
| CN103539794A (en) * | 2013-10-17 | 2014-01-29 | 常州大学 | Salifying method of lurasidone hydrochloride |
| CN104031041A (en) * | 2013-03-06 | 2014-09-10 | 江苏恩华药业股份有限公司 | New crystal forms of lurasidone hydrochloride and preparation method thereof |
| CN106146486A (en) * | 2015-04-21 | 2016-11-23 | 上海医药集团股份有限公司 | A kind of method preparing high-purity high-yield Lurasidone |
| CN106496218A (en) * | 2016-10-20 | 2017-03-15 | 中国药科大学 | Based on the Lurasidone HCl nanocrystal preparation method that solubility relies on pH properties |
| US20170246165A1 (en) * | 2014-10-14 | 2017-08-31 | Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) | An improved process for the preparation of lurasidone hydrochloride |
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| EP0464846A1 (en) * | 1990-07-06 | 1992-01-08 | Sumitomo Pharmaceuticals Company, Limited | Imide derivatives, and their production and use |
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2012
- 2012-04-28 CN CN201210131007.8A patent/CN102746289B/en not_active Expired - Fee Related
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102911170A (en) * | 2012-11-15 | 2013-02-06 | 苏州第壹制药有限公司 | Method for preparing imide compound hydrochloride |
| CN104031041A (en) * | 2013-03-06 | 2014-09-10 | 江苏恩华药业股份有限公司 | New crystal forms of lurasidone hydrochloride and preparation method thereof |
| CN105524057A (en) * | 2013-03-06 | 2016-04-27 | 江苏恩华药业股份有限公司 | Lurasidone hydrochloride new crystal form and preparation method thereof |
| CN109705112A (en) * | 2013-03-06 | 2019-05-03 | 江苏恩华药业股份有限公司 | The preparation method of the novel crystal forms of Lurasidone HCl |
| CN103539794A (en) * | 2013-10-17 | 2014-01-29 | 常州大学 | Salifying method of lurasidone hydrochloride |
| US20170246165A1 (en) * | 2014-10-14 | 2017-08-31 | Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) | An improved process for the preparation of lurasidone hydrochloride |
| US10426770B2 (en) | 2014-10-14 | 2019-10-01 | Jubilant Generics Limited | Process for the preparation of Lurasidone hydrochloride |
| CN106146486A (en) * | 2015-04-21 | 2016-11-23 | 上海医药集团股份有限公司 | A kind of method preparing high-purity high-yield Lurasidone |
| CN113185508A (en) * | 2015-04-21 | 2021-07-30 | 上海医药集团股份有限公司 | Method for preparing lurasidone with high purity and high yield |
| CN106496218A (en) * | 2016-10-20 | 2017-03-15 | 中国药科大学 | Based on the Lurasidone HCl nanocrystal preparation method that solubility relies on pH properties |
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|---|---|
| CN102746289B (en) | 2016-06-08 |
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