Preparation method of vortioxetine

Abstract

The present application belongs to the field of pharmaceutical chemistry and relates to a method for preparing vortioxetine. After the salt of vortioxetine is treated with an organic solvent under the conditions of a solution of 1,2-propylenediamine, vortioxetine, a compound of formula I, is generated, which can efficiently and cost-effectively reduce palladium residues and impurities such as chloride and acetylated impurities in the prior art.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical chemistry and relates to a method for preparing vortioxetine. Background Art

[0002] Vortioxetine hydrobromide is a new drug for the treatment of depression, jointly developed by Lundbeck Pharmaceuticals of Denmark and Takeda Pharmaceuticals of Japan. It was approved for marketing by the US Food and Drug Administration (FDA) on September 30, 2013 under the trade name Brintellix, later renamed TRINTELLIX, for the treatment of major depression. It was officially launched in the European market in January 2014.

[0003] Example 19 of Chinese patent application CN101472906A discloses the use of palladium catalyst Pddba2 to catalyze the coupling reaction.

[0004]

[0005] Obviously, the palladium-catalyzed reaction in step 1 will undoubtedly lead to contamination of the reaction product, because palladium is difficult to separate from the target product. There are strict regulations on the acceptable limit of residual palladium content in drug approval, which usually needs to be strictly controlled below 20ppm, and even required to be controlled below 10ppm. On the other hand, the acceptable limit of chloride content in drug approval should be controlled below 0.05%.

[0006] The inventors of the present application repeated steps 1 to 3 of the prior art Chinese patent application CN101472906A and found that the palladium residue in the compound of formula I, vortioxetine, was as high as 33.56 ppm, and the chloride residue was 0.056%. If the reaction conditions of step 3 were changed to NaOH / methanol / ethyl acetate, it was found that the product vortioxetine contained about 10% of the acetylated impurities of the compound of formula II.

[0007]

[0008] In order to solve the problem of palladium residue in palladium catalytic reaction, the specification of Chinese patent application CN108191792A, pages 17-18, discloses "adding 28 mL of anhydrous methanol to a first refined product of vortioxetine hydrobromide, and removing palladium by adsorption with N-acetyl-L-cysteine ​​to obtain 4.49 g of a refined product of vortioxetine hydrobromide after palladium removal, with a yield of 90.3%. The palladium residue is 7 ppm". The palladium residue in the first refined product of vortioxetine hydrobromide is 25 ppm. After palladium removal by this technical solution, the residual palladium is still close to 10 ppm.

[0009]

[0010] Traditional palladium removal methods include column chromatography, 0.22 μm separation filter, palladium removal reagents, and activated carbon adsorption. Palladium removal reagents such as 2,4,6-trithiotriazinoic acid silica gel, macroporous polystyrene-2,4,6-trithiotriazinoic acid, sodium thiosulfate, sompex resin bonded silica gel, cellulose, 3-mercaptopropyl ethyl sulfide silica, 2-mercaptoethyl sulfide ethyl silica, triamine ethyl sulfide amide silica, N-acetyl-L-cysteine ​​ethyl ester silica, 2-aminoethyl ethyl sulfide silica, sulfide functional polysiloxane ( MP), methylthiourea thioether ethyl ethyl silica, ethylenediamine modified silica (BASF SA–FC Si-1), pentaerythritol 2-mercaptoethyl sulfide silica or pentamine sulfide ethyl amide silica. The above-mentioned resin palladium removal materials are expensive and not suitable for large-scale production, and the mercapto group is a toxic functional group. Activated carbon adsorption is cheap, but after removing palladium, the activated carbon particles are easy to adhere to the wall of the reactor, which is not easy to clean, and the effect of activated carbon on palladium removal is very limited.

[0011] Therefore, how to further efficiently and cost-effectively reduce palladium residues and impurities such as chlorides and acetylated impurities in the prior art still requires further improvement plans. Summary of the invention

[0012] The present invention provides a method for preparing vortioxetine, which comprises the following steps:

[0013] The salt of vortioxetine is treated in the solution of 1,2-propylenediamine and an organic solvent to generate vortioxetine, a compound of formula I.

[0014]

[0015] In some embodiments, the salt of vortioxetine includes salts made from inorganic acids. In some embodiments, the inorganic acid includes hydrochloric acid, hydrobromic acid, trifluoroacetic acid. In some embodiments, the inorganic acid is hydrochloric acid.

[0016] In some embodiments, the solution of 1,2-propylenediamine can be an aqueous solution, a methanol solution, an ethanol solution, a dichloromethane solution, or an ethyl acetate solution.

[0017] In some embodiments, the organic solvent may be one of ethyl acetate, dichloromethane, and chloroform.

[0018] In some embodiments, the organic solvent is ethyl acetate.

[0019] In some embodiments, the solvent is dichloromethane.

[0020] In some embodiments, the solvent is chloroform.

[0021] In some embodiments, after the 1,2-propylenediamine aqueous solution reacts with vortioxetine hydrochloride for a period of time, ethyl acetate is added for reaction.

[0022] In some embodiments, after the reaction of the methanol solution of 1,2-propylenediamine and vortioxetine hydrochloride is completed, the solution is concentrated under reduced pressure to remove methanol, and then ethyl acetate and water are added for extraction.

[0023] In some embodiments, after the reaction of the dichloromethane solution of 1,2-propylenediamine and vortioxetine hydrochloride is completed, purified water is added for extraction.

[0024] In some embodiments, the molar ratio of the salt of vortioxetine to 1,2-propylenediamine is 1:5-15.

[0025] In some embodiments, the molar ratio of the salt of vortioxetine to 1,2-propylenediamine is 1:10.

[0026] The preparation method of vortioxetine provided in the present application can obtain vortioxetine by reacting the salt of vortioxetine, and can simultaneously free vortioxetine and remove palladium. The results show that the chloride is as low as 0.004%, the acetylated impurities are as low as 0.03%, and the palladium residue is as low as 0.28ppm, which is much lower than 10ppm. Compared with the prior art, the technical solution of first obtaining vortioxetine hydrobromide and then removing palladium has fewer operation steps and a good palladium removal effect, which is suitable for industrial production. DETAILED DESCRIPTION

[0027] The vortioxetine hydrochloride used in the following examples was prepared by the method of Example 19 of Chinese patent application CN101472906A.

[0028] Example 1

[0029]

[0030] Under stirring, add 300mL purified water and 75mL 1,2-propylenediamine (873.25mmol) in a 1000mL three-necked flask, control the temperature at 0-20℃, and then slowly add 30.0g vortioxetine hydrochloride (89.58mmol), and stir for 1 hour. Add 450mL ethyl acetate, stir for 2 hours, and stand for separation. The organic layer is washed with 300mL brine × 2 times and 300mL purified water × 2 times. Dry with anhydrous sodium sulfate, filter, collect the filtrate, add 1.5g activated carbon, stir and decolorize for 1 hour, and then filter. Collect the filtrate and concentrate under reduced pressure until no liquid flows out. Add 240mL acetonitrile, heat to 70-80℃ and stir to dissolve, add 1.5g activated carbon, stir and decolorize for 1 hour, and filter while hot. The filtrate is slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered, and the filter cake is collected. The filter cake was dried under reduced pressure at 50±5°C to obtain 18.3 g of vortioxetine, with a palladium residue of 0.28 ppm, a chloride residue of 0.004%, and an acetylated impurity of 0.03%.

[0031] Example 2

[0032]

[0033] Under stirring, add 300mL purified water and 75mL 1,2-propylenediamine (873.25mmol) in a 1000mL three-necked flask, control the temperature at 0-20℃, and add 450mL ethyl acetate. Then slowly add 30.0g vortioxetine hydrochloride (89.58mmol), stir for 3 hours, and stand for separation. The organic layer is washed with 300mL of saline solution × 2 times and 300mL of purified water × 2 times. Dry with anhydrous sodium sulfate, filter, collect the filtrate, add 1.5g of activated carbon, stir and decolorize for 1 hour, and then filter. Collect the filtrate and concentrate under reduced pressure until no liquid flows out. Add 240mL acetonitrile, heat to 70-80℃ and stir to dissolve, add 1.5g of activated carbon, stir and decolorize for 1 hour, and filter while hot. The filtrate is slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered, and the filter cake is collected. The filter cake was dried under reduced pressure at 50±5°C to obtain 18.3 g of vortioxetine, with residual palladium of 0.30 ppm, residual chloride of 0.005%, and acetylated impurities of 0.04%.

[0034] Embodiment 3:

[0035]

[0036] Add 200mL of 3moL / L sodium hydroxide solution to a 1000mL three-necked flask under stirring, control the temperature at 0-10℃, slowly add 20.0g of vortioxetine hydrochloride (59.72mmoL), continue to control the temperature and stir to react for 4 hours, then add 300mL of ethyl acetate and stir for 1 hour. Let stand for separation, collect the organic phase, wash with 300mL of saline solution × 2 times, and wash with 300mL of purified water × 2 times. Dry with anhydrous sodium sulfate and filter. Collect the filtrate, add 1g of activated carbon and stir to decolorize for 30 minutes, filter by suction, collect the filtrate, and concentrate under reduced pressure until there is no liquid. Add 160mL of acetonitrile, heat to 70-80℃ and stir to dissolve, add 1g of activated carbon, stir to decolorize for 1 hour, and filter by suction while hot. The filtrate is then slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered by suction, and the filter cake is collected. The filter cake is dried under reduced pressure at 50±5℃ to obtain 12.5g of vortioxetine. The palladium residue was 33.56 ppm, the chloride residue was 0.056%, and the acetylated impurity was 0.04%.

[0037] Embodiment 4:

[0038]

[0039] Add 50mL of dichloromethane and 2.5mL of 1,2-propylenediamine (29.11mmol) to a 100mL three-necked flask under stirring, control the temperature at 0-20℃, and then slowly add 5.0g of vortioxetine hydrochloride (14.93mmol). After addition, control the temperature at 20-30℃ and stir for 3 hours. Wash 50mL with purified water × 3 times. Dry with anhydrous sodium sulfate, filter with suction, collect the filtrate, add 0.25g of activated carbon, stir and decolorize for 30 minutes, and then filter with suction. Collect the filtrate and concentrate under reduced pressure until no liquid flows out. Add 40mL of acetonitrile, heat to 70-80℃ and stir to dissolve, add 0.25g of activated carbon, stir and decolorize for 1 hour, and filter with suction while hot. The filtrate is slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered with suction, and the filter cake is collected. The filter cake is dried under reduced pressure at 50±5℃ to obtain 2.7g of vortioxetine. The palladium residue was 10.79 ppm, the chloride residue was 0.083%, and the acetylated impurity was 0.05%.

[0040] Embodiment 5:

[0041]

[0042] Add 50mL of dichloromethane and 6.4mL of 1,2-propylenediamine (74.52mmol) to a 100mL three-necked flask under stirring, control the temperature at 0-20℃, and then slowly add 5.0g of vortioxetine hydrochloride (14.93mmol). After the addition, control the temperature at 20-30℃ and stir for 3 hours. Wash with purified water 50mL×3 times. Dry with anhydrous sodium sulfate, filter with suction, collect the filtrate, add 0.25g of activated carbon, stir and decolorize for 30 minutes, and then filter with suction. Collect the filtrate and concentrate under reduced pressure until no liquid flows out. Add 40mL of acetonitrile, heat to 70-80℃ and stir to dissolve, add 0.25g of activated carbon, stir and decolorize for 1 hour, and filter with suction while hot. The filtrate is then slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered with suction, and the filter cake is collected. The filter cake is dried under reduced pressure at 50±5℃ to obtain 2.6g of vortioxetine. The palladium residue was 7.32 ppm, the chloride residue was 0.019%, and the acetylated impurity was 0.03%.

[0043] Embodiment 6:

[0044]

[0045] Add 50mL of dichloromethane and 19.2mL of 1,2-propylenediamine (223.55mmol) to a 100mL three-necked flask under stirring, control the temperature at 0-20℃, and then slowly add 5.0g of vortioxetine hydrochloride (14.93mmol). After the addition, control the temperature at 20-30℃ and stir for 3 hours. Wash 50mL with purified water × 3 times. Dry with anhydrous sodium sulfate, filter with suction, collect the filtrate, add 0.25g of activated carbon, stir and decolorize for 30 minutes, and then filter with suction. Collect the filtrate and concentrate under reduced pressure until no liquid flows out. Add 40mL of acetonitrile, heat to 70-80℃ and stir to dissolve, add 0.25g of activated carbon, stir and decolorize for 1 hour, and filter with suction while hot. The filtrate is slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered with suction, and the filter cake is collected. The filter cake is dried under reduced pressure at 50±5℃ to obtain 2.4g of vortioxetine. The palladium residue was 3.22 ppm, the chloride residue was 0.010%, and the acetylated impurity was 0.04%.

[0046] Embodiment 7:

[0047]

[0048] Add 50mL methanol and 2.5mL 1,2-propylenediamine (29.11mmol) to a 250mL three-necked flask under stirring, control the temperature at 0-20℃, and then slowly add 5.0g vortioxetine hydrochloride (14.93mmol). After addition, control the temperature at 20-30℃ and stir for 3 hours. Concentrate under reduced pressure until there is no liquid, add 50mL ethyl acetate, and wash 50mL × 3 times with purified water. Dry with anhydrous sodium sulfate, filter with suction, collect the filtrate, add 0.25g activated carbon, stir and decolorize for 30 minutes, and then filter with suction. Collect the filtrate and concentrate under reduced pressure until no liquid flows out. Add 40mL acetonitrile, heat to 70-80℃ and stir to dissolve, add 0.25g activated carbon, stir and decolorize for 1 hour, and filter while hot. The filtrate is slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered with suction, and the filter cake is collected. The filter cake is dried under reduced pressure at 50±5℃ to obtain 2.6g vortioxetine. The palladium residue was 0.33 ppm, the chloride residue was 0.054%, and the acetylated impurity was 0.03%.

[0049] Embodiment 8:

[0050]

[0051] Under stirring, add 50mL methanol and 6.4mL 1,2-propylenediamine (74.52mmol) to a 250mL three-necked flask, control the temperature at 0-20℃, and then slowly add 5.0g vortioxetine hydrochloride (14.93mmol). After addition, control the temperature at 20-30℃ and stir for 3 hours. Concentrate under reduced pressure until there is no liquid, add 50mL ethyl acetate, and wash 50mL × 3 times with purified water. Dry with anhydrous sodium sulfate, filter with suction, collect the filtrate, add 0.25g activated carbon, stir and decolorize for 30 minutes, and then filter with suction. Collect the filtrate and concentrate under reduced pressure until no liquid flows out. Add 40mL acetonitrile, heat to 70-80℃ and stir to dissolve, add 0.25g activated carbon, stir and decolorize for 1 hour, and filter with suction while hot. The filtrate is slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered with suction, and the filter cake is collected. The filter cake is dried under reduced pressure at 50±5℃ to obtain 2.7g vortioxetine. The palladium residue was 0.35 ppm, the chloride residue was 0.024%, and the acetylated impurity was 0.02%.

[0052] Embodiment 9:

[0053]

[0054] Under stirring, add 50mL methanol and 19.2mL 1,2-propylenediamine (223.55mmol) to a 250mL three-necked flask, control the temperature at 0-20℃, and then slowly add 5.0g vortioxetine hydrochloride (14.93mmol). After addition, control the temperature at 20-30℃ and stir for 3 hours. Concentrate under reduced pressure until there is no liquid, add 50mL ethyl acetate, and wash 50mL × 3 times with purified water. Dry with anhydrous sodium sulfate, filter, collect the filtrate, add 0.25g activated carbon, stir and decolorize for 30 minutes, and then filter. Collect the filtrate and concentrate under reduced pressure until no liquid flows out. Add 40mL acetonitrile, heat to 70-80℃ and stir to dissolve, add 0.25g activated carbon, stir and decolorize for 1 hour, and filter while hot. The filtrate is slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered, and the filter cake is collected. The filter cake is dried under reduced pressure at 50±5℃ to obtain 2.5g vortioxetine. The palladium residue was 0.32 ppm, the chloride residue was 0.018%, and the acetylated impurity was 0.05%.

[0055] Embodiment 10:

[0056]

[0057] Under stirring, add 50mL ethyl acetate and 2.5mL 1,2-propylenediamine (29.11mmol) to a 250mL three-necked flask, control the temperature at 0-20℃, and then slowly add 5.0g vortioxetine hydrochloride (14.93mmol). After addition, control the temperature at 20-30℃ and stir for 3 hours. Wash with purified water 50mL×3 times. Dry with anhydrous sodium sulfate, filter with suction, collect the filtrate, add 0.25g activated carbon, stir and decolorize for 30 minutes, and then filter with suction. Collect the filtrate and concentrate under reduced pressure until no liquid flows out. Add 40mL acetonitrile, heat to 70-80℃ and stir to dissolve, add 0.25g activated carbon, stir and decolorize for 1 hour, and filter with suction while hot. The filtrate is slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered with suction, and the filter cake is collected. The filter cake is dried under reduced pressure at 50±5℃ to obtain 2.0g vortioxetine. The palladium residue was 0.25 ppm, the chloride residue was 0.066%, and the acetylated impurity was 0.04%.

[0058] Embodiment 11:

[0059]

[0060] Add 1200mL methanol and 28.7g sodium hydroxide (717.50mmoL) to a 2000mL three-necked flask under stirring, slowly add 60.0g vortioxetine hydrochloride (179.15mmoL), and stir at room temperature for 3 hours. Add 3g activated carbon, stir and decolorize for 30 minutes, filter, collect the filtrate, and concentrate under reduced pressure until there is no liquid. Add 900mL ethyl acetate and 450m purified water, stir and separate. Take the organic layer and wash 450mL with brine × 3 times. Dry with sodium sulfate, filter, collect the filtrate, add 3g activated carbon, stir and decolorize for 30 minutes and filter. Collect the filtrate and concentrate under reduced pressure until there is no liquid outflow. Add 480mL acetonitrile, heat to 70-80℃ and stir to dissolve, add 3g activated carbon, stir and decolorize for 1 hour, and filter while hot. The filtrate is slowly cooled to 10-15℃ and stirred for crystallization for 4 hours, filtered, and the filter cake is collected. The filter cake was dried under reduced pressure at 50±5°C to obtain 29.0 g of vortioxetine and 10.09% of acetylated impurities.

Claims

1. A method for preparing vortioxetine, characterized in that: include: The salt of vortioxetine is treated with an organic solvent in the presence of 1,2-propylenediamine to generate vortioxetine, a compound of formula I. Wherein, the solution of 1,2-propylenediamine is one of an aqueous solution, a methanol solution, and an ethyl acetate solution; The salt of vortioxetine is a salt made from an inorganic acid, and the inorganic acid is one of hydrochloric acid, hydrobromic acid and trifluoroacetic acid.

2. The preparation method according to claim 1, characterized in that The inorganic acid is hydrochloric acid.

3. The preparation method according to claim 1 or 2, characterized in that: The organic solvent is one of ethyl acetate, dichloromethane and chloroform.

4. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the salt of vortioxetine to 1,2-propylenediamine is 1:5-12.

5. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the salt of vortioxetine to 1,2-propylenediamine is 1:10.

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