Preparation method of trazodone hydrochloride

Abstract

The invention relates to a preparation method of trazodone hydrochloride. The preparation method comprises the following steps: activating 1, 2, 4-triazolo [4, 3-a] pyridine-3 (2H)-ketone by using an inorganic strong base, adding an inorganic weak base as an acid-binding agent to react with 1-(3-chlorphenyl)-4-(3-chloropropyl) piperazine hydrochloride, filtering to remove inorganic salt after the reaction is finished, crystallizing to obtain trazodone free base, salifying to obtain a trazodone hydrochloride crude product, and purifying to obtain the trazodone hydrochloride. And finally, recrystallizing by using a mixed solvent of an organic solvent and water to obtain a trazodone hydrochloride finished product. The preparation method of trazodone hydrochloride provided by the invention is simple and efficient to operate, the product purity is high, genotoxic impurities and residue on ignition meet the requirements of laws and regulations, and the preparation method has obvious industrialization and commercialization advantages.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis and relates to a method for preparing trazodone hydrochloride. Background Art

[0002] Trazodone Hydrochloride chemical name: 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-α]pyridin-3(2H)-one hydrochloride, its structural formula is as follows:

[0003] Trazodone hydrochloride is a serotonin reuptake inhibitor and 5-HT 2 Receptor antagonists used to treat various types of depression and anxiety disorders accompanied by depressive symptoms, as well as mood disorders after withdrawal in drug addicts.

[0004] The original research company's patent US3381009 (A) discloses trazodone hydrochloride and its synthesis method: 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one (Formula II) and 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (Formula III) are refluxed in 1,4-dioxane solvent in the presence of sodium hydride for 20 hours to synthesize trazodone, and further salt is formed to obtain trazodone hydrochloride with a yield of 66.9%.

[0005]

[0006] Sodium hydride can react violently with water and lower alcohols, causing combustion or explosion, and there are safety hazards in industrial use. In addition, (Formula III) has a warning structure of chloroalkane genotoxic substances. In the standard of trazodone hydrochloride raw materials included in the United States Pharmacopoeia (USP), this impurity is named "trazodone-related compound F" and stipulates that it should not exceed 2.5ppm, and the above preparation method is difficult to control the impurity below 15ppm. In order to remove this impurity, Yuanyan Company has disclosed another patent CN101772490 (B): dissolve trazodone free base in an organic solvent, add an aqueous solution of alkali (such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc.), react in the presence of a phase transfer catalyst, and remove the halogenated alkane genotoxic impurities by the principle of hydrolysis. This method is cumbersome, not only loses the yield, but also introduces a new isobutyl ether impurity: 1-(3-chlorophenyl)-4-[3-(2-methylpropoxy)propyl]-piperazine (Formula IV).

[0007]

[0008] WO2015110883 discloses a method for preparing trazodone by reacting 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one sodium salt with 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine (or its hydrochloride) in the presence of a phase transfer catalyst or an antioxidant. 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one sodium salt is prepared by reacting (Formula II) with an aqueous sodium hydroxide solution using the method disclosed in US4465683 (A).

[0009]

[0010] 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one and 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride are key intermediates of trazodone hydrochloride, both of which are solid, stable in quality, and convenient for storage and transportation. The method of WO2015110883 not only requires the use of expensive phase transfer catalysts or antioxidants, but also requires the preparation of 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one sodium salt and 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine free base, which is complicated, time-consuming, and has high production costs.

[0011] Chinese patent CN105777745 (A) discloses a method for preparing trazodone hydrochloride: 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (Formula II), 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride (hydrochloride of Formula II), a base (such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc.), and a solvent (isopropanol) are simultaneously put into a reaction bottle for reflux reaction. After the reaction is completed, the inorganic salt is removed by filtering, and a sodium hydroxide aqueous solution is added to the filtrate for reflux reaction for hydrolysis to remove potential genotoxic impurities, thereby obtaining recrystallized trazodone free base. This method adds (Formula II), (hydrochloride of Formula II) and base to a reflux reaction. In actual experiments, an excess of strong base (sodium hydroxide) is added at one time. Since the reaction solution is in a strong alkaline environment, the reaction by-products water impurities (Formula V) and isopropyl ether impurities (Formula VI) are relatively large impurities, and the purity of the reaction solution is only 75.3%. Using a weak base (such as potassium carbonate) cannot trigger the reaction and almost no product is generated.

[0012]

[0013] The methods disclosed in the above patents have a relatively complicated production process. For example, additional alkaline solution needs to be added for hydrolysis to remove genotoxic impurities, 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one sodium salt and 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine free base need to be prepared, and a phase transfer catalyst or antioxidant needs to be added for reaction. The production cycle is long, the production cost is high, and there are many process by-products. In addition, since a large amount of inorganic base is used in the process, the ignition residue in the final product is very likely to exceed the limit (the European Pharmacopoeia (EP11.0) stipulates that the ignition residue of trazodone hydrochloride raw materials shall not exceed 0.1%). Therefore, it is necessary to develop a method for preparing trazodone hydrochloride that is simpler, more efficient, industrially feasible, commercially beneficial, and of reliable quality. Summary of the invention

[0014] The invention provides a preparation method of trazodone hydrochloride, which comprises using a powdered inorganic strong base to activate 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one, and then adding fine particles or powdered inorganic weak base and 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride to react. After the reaction is completed, filtering and crystallizing to obtain trazodone free base, salting to obtain a crude trazodone hydrochloride product, and finally recrystallizing to obtain a finished trazodone hydrochloride product. The preparation method avoids the use of dangerous reagent sodium hydride, does not need to separate 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one sodium (potassium) salt and 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine free base, and does not need to use a phase transfer catalyst or an antioxidant. In addition, since the amount of inorganic strong base used to activate 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one is relatively small, the hydrolysis impurities (Formula V) and isopropyl ether impurities (Formula VI) are less, which effectively improves the yield.

[0015] The technical solution of the present invention: The present invention provides a method for preparing trazodone hydrochloride, and the steps of the preparation method are as follows: (1) adding 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one and an inorganic strong base to an organic solvent 1 for reaction; (2) adding an inorganic weak base and 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride, and heating to reflux for reaction; after the reaction is completed, filtering to remove the inorganic salt, and crystallizing to obtain trazodone free base; (3) dissolving trazodone free base in organic solvent 2, and adding hydrochloric acid dropwise to form a salt to obtain a crude trazodone hydrochloride product; (4) dissolving the crude trazodone hydrochloride in a mixed solvent of organic solvent 3 and water, decolorizing, filtering, adding organic solvent 3 to the filtrate, cooling and crystallizing, filtering, washing and drying to obtain the finished trazodone hydrochloride.

[0016] Furthermore, the organic solvent 1 in step (1) is one or a mixed solvent of two or more selected from the group consisting of acetonitrile, ethanol, isopropanol and isobutanol, and the preferred solvent is isopropanol or acetonitrile.

[0017] The inorganic strong base in step (1) is sodium hydroxide powder or potassium hydroxide powder, preferably potassium hydroxide powder.

[0018] The molar ratio of the inorganic strong base to 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride in step (1) is 0.5-1.5:1, preferably 1.0-1.2:1.

[0019] The potassium hydroxide powder described in step (1) has a purity greater than or equal to 90% and a particle size of 80 to 500 microns.

[0020] The reaction temperature of step (1) is 20-80°C, preferably 30-50°C, and the reaction time is 0.5-2 hours.

[0021] The inorganic weak base in step (2) is anhydrous sodium carbonate or anhydrous potassium carbonate, preferably anhydrous potassium carbonate.

[0022] The anhydrous potassium carbonate described in step (2) is in the form of fine particles or powder with a particle size of 80 to 500 microns.

[0023] The molar ratio of the inorganic weak base in step (2) to 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride is 0.5-2.4:1, preferably 0.5-1.0:1.

[0024] The crystallization method described in step (2) comprises: directly cooling the filtrate to crystallize to obtain trazodone free base; or concentrating the filtrate under reduced pressure and then adding an organic solvent to recrystallize to obtain trazodone free base.

[0025] The crystallization solvent in step (2) is one or two of isopropanol, isobutanol, anhydrous ethanol, ethyl acetate, n-heptane, acetone, etc.

[0026] The organic solvent 2 described in step (3) is isopropanol, anhydrous ethanol, acetone, acetonitrile, toluene, ethyl acetate, etc.

[0027] The hydrochloric acid described in step (3) is concentrated hydrochloric acid, ethanol hydrochloric acid, ethyl hydrochloric acid, isopropanol hydrochloric acid, etc.

[0028] The organic solvent 3 in step (4) is one of acetone, tetrahydrofuran, ethanol, methanol and acetonitrile.

[0029] The ratio of the volume of the mixed solvent organic solvent 3, the volume of water and the weight of the crude trazodone hydrochloride product in step (4) is: 有机溶剂 :V 水 :w 盐酸曲唑酮粗品=(1~5):(0.5~2):1, the unit is ml:ml:g.

[0030] The ratio of the volume of the organic solvent 3 added in step (4) to the weight of the crude trazodone hydrochloride is: 有机溶剂 :w 盐酸曲唑酮粗品 = (1~10): 1, unit is ml:g.

[0031] The present invention also provides a method for refining trazodone hydrochloride, which comprises: dissolving a crude trazodone hydrochloride product in a mixed solvent of an organic solvent 3 and water, decolorizing, filtering, adding the organic solvent 3 to the filtrate, cooling for crystallization, filtering, washing, and drying to obtain a finished trazodone hydrochloride product.

[0032] Preferably, the organic solvent 3 is one of acetone, tetrahydrofuran, ethanol, methanol and acetonitrile.

[0033] The ratio of the volume of the mixed solvent organic solvent 3, the volume of water and the weight of the crude trazodone hydrochloride product is: 有机溶剂 :V 水 :w 盐酸曲唑酮粗品 =(1~5):(0.5~2):1, the unit is ml:ml:g.

[0034] The ratio of the volume of the added organic solvent 3 to the weight of the crude trazodone hydrochloride product is: 有机溶剂 :w 盐酸曲唑酮粗品 = (1~10): 1, unit is ml:g.

[0035] The preparation method and purification method of trazodone hydrochloride provided by the present invention are simple and efficient in operation, the product purity is high, the genotoxic impurities and the ignition residue meet the regulatory requirements, and the product has obvious industrialization and commercialization advantages. Implementation

[0036] In order to better understand the content of the present invention, the present invention is further described below in conjunction with comparative examples and embodiments, but does not constitute any limitation to the present invention.

[0037] Comparative Example 1: Trazodone was synthesized with reference to the method of WO2015110883.

[0038] 8.88 g (0.222 mol) of sodium hydroxide was added to a 250 ml reaction bottle, and 170 ml of purified water was stirred to dissolve. 30.00 g (0.222 mol) of 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one was added, and the temperature was raised to 80°C and stirred to dissolve. The temperature was lowered to 5°C and the reaction was allowed to proceed overnight. The mixture was filtered and dried under reduced pressure to obtain 37.63 g of 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one sodium salt with a yield of 90.2%.

[0039] In a 500 ml reaction bottle, 50.0 g (0.161 mol) of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride, 26.64 g (0.170 mol) of 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one sodium salt, 42.4 g (0.307 mol) of anhydrous potassium carbonate, 2.5 g (0.0078 mol) of tetrabutylammonium bromide and 300 ml of isopropanol were added. The temperature was raised to reflux for reaction for 20 hours. The reaction solution was sampled for HPLC detection, with a purity of 38.7% and a residual 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine of 40.3%.

[0040] Experimental results: Referring to WO2015110883, a phase transfer catalyst was added, but 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride was not freed, the reaction could not proceed smoothly, and a large amount of raw materials remained.

[0041] Comparative Example 2: Synthesis of trazodone according to the method of CN105777745 (A) In a 1000 ml reaction bottle, 50.0 g (0.161 mol) of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride, 26.18 g (0.194 mol) of 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one, 14.86 g (0.372 mol) of sodium hydroxide and 750 ml of isopropanol were added. The temperature was raised to reflux for reaction for 26 hours. The reaction solution was sampled for HPLC detection.

[0042] Reaction solution test results: Example 1

[0043] Add 600ml of acetonitrile, 48.0g (0.355 mol) of 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one, and 7.11g (0.178 mol) of sodium hydroxide powder to a 1000ml reactor, and stir at 50-60°C for 1 hour. Add 68.5g (0.646 mol) of anhydrous sodium carbonate and 100.0g (0.323 mol) of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride, and heat to reflux for 15 hours. Sample the reaction solution for HPLC detection (see Table 2 below for the detection results). After the reaction is completed, cool to 20-30°C, filter, wash with 100ml of acetonitrile, and concentrate the filtrate under reduced pressure until it stops. Add 400 ml of anhydrous ethanol, heat to reflux, stir and dissolve, cool to 0-5°C for crystallization for 2 hours, filter, wash with 100 ml of anhydrous ethanol, and dry under reduced pressure at 50°C to obtain 109.3 g of trazodone free base with a yield of 91.0% and a purity of 99.18%.

[0044] The trazodone free base was transferred into a 1000 ml reaction bottle, 600 ml of ethanol was added, the temperature was raised to reflux for dissolution, 30% hydrochloric acid ethanol was added dropwise to adjust the pH to 1-3, the temperature was lowered by 0-10 ° C for crystallization for 2 hours, and the filter cake was washed with 100 ml of ethanol and dried under reduced pressure at 60 ° C to obtain 110.0 g of crude trazodone hydrochloride, with a total yield of 83.4%, a purity of 99.90%, and 0.80 ppm of trazodone-related compound F.

[0045] Reaction solution test results: Example 2

[0046] Add 20 kg of isopropanol, 1.75 kg (12.95 moles) of 1,2,4-triazolo[4,3-a]pyridine-3(2H)-one, and 0.80 kg (content ≥ 90%, 12.83 moles) of potassium hydroxide powder to a 30L reactor, and stir at 20-30°C for 1 hour. Add 1.79 kg (12.95 moles) of anhydrous potassium carbonate and 4.00 kg (12.92 moles) of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride, and heat to reflux for 20 hours. Take samples for HPLC detection. The detection results are shown in Table 3 below. After the reaction is completed, cool to 20-30°C, filter, wash with 2 kg of isopropanol, transfer the filtrate to a 30L reaction solution, and crystallize at 0-10.0°C for 2 hours. The product was filtered and the filter cake was washed with 2 kg of isopropanol to obtain 4.42 kg of trazodone free base with a yield of 92.0% and a purity of 99.20%.

[0047] Trazodone free base was transferred into a 30L reactor, 20.0kg of acetone was added, the temperature was raised to reflux for dissolution, 1.31kg (12.93 mol) of concentrated hydrochloric acid was added dropwise to adjust the pH to 1-3, the temperature was lowered by 0-10°C for crystallization for 2 hours, the filter cake was washed with 2.0kg of acetone, and the filter cake was dried under reduced pressure at 60°C to obtain 4.60kg of crude trazodone hydrochloride, with a total yield of 87.3%, a purity of 99.89%, and a trazodone-related compound F of 0.59ppm.

[0048] Reaction solution test results: Example 3

[0049] 80 g of crude trazodone hydrochloride (prepared in Example 1 above), 240 ml of tetrahydrofuran, and 40 ml of purified water were added to a 500 ml reaction bottle, and the temperature was raised to 60-66° C. and stirred to dissolve. 2.4 g of activated carbon was added for decolorization for 30 minutes, filtered, and the filtrate was transferred to a 1000 ml reaction bottle, 240 ml of tetrahydrofuran was added dropwise at 50-65° C., the temperature was lowered to 0-10° C. for crystallization for 2 hours, filtered, and dried at 50° C. to obtain 72.4 g of trazodone hydrochloride product, with a yield of 90.5%, a purity of 99.97%, 0.02 ppm of trazodone-related compound F, and 0.014% of ignition residue. Example 4

[0050] 4.50 kg of crude trazodone hydrochloride (prepared in Example 2 above), 9 L of acetone, and 2.3 L of purified water were added to a 30 L reactor, and the temperature was raised to 55-57 ° C and stirred to dissolve. 225 g of activated carbon was added for decolorization for 30 minutes. Filter, transfer the filtrate to a 50 L reactor, add 13.5 L of acetone dropwise, cool to 0-10 ° C for crystallization for 2 hours. Filter, wash with acetone, and dry under reduced pressure at 50 ° C to obtain 4.15 kg of trazodone hydrochloride, with a yield of 92.2%, a purity of 99.95%, 0.01 ppm of trazodone-related compound F, and 0.010% residue on ignition.

[0051] The detection conditions of HPLC are as follows: Chromatographic conditions: Chromatographic column: C18 250mm×4.6mm 5μm Mobile phase A: 0.01 mol / L potassium dihydrogen phosphate (1 mol / L potassium hydroxide solution adjusted to pH 6.6) Mobile phase B: acetonitrile Column flow rate: 1.0ml / min Detection wavelength: 254nm Injection volume: 10 μl Column temperature: 35°C Diluent: water-acetonitrile = 8:2 Elution gradient:

[0052] The detection method of trazodone-related compound F refers to the LC-MS method of trazodone hydrochloride in the United States Pharmacopoeia (USP-NF 2023 Issue 1).

Claims

1. A method for preparing trazodone hydrochloride, characterized in that: The steps include: (1) adding 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one and an inorganic strong base to an organic solvent 1 for reaction; (2) adding an inorganic weak base and 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride, and heating to reflux for reaction; after the reaction is completed, filtering to remove the inorganic salt, and crystallizing to obtain trazodone free base; (3) dissolving trazodone free base in organic solvent 2, adding hydrochloric acid dropwise to form a salt, and obtaining a crude trazodone hydrochloride product; (4) dissolving the crude trazodone hydrochloride in a mixed solvent of organic solvent 3 and water, decolorizing, filtering, adding organic solvent 3 to the filtrate, cooling and crystallizing, filtering, washing and drying to obtain the finished trazodone hydrochloride.

2. The preparation method according to claim 1, wherein: In step (1), the organic solvent 1 is one or a mixed solvent of two or more selected from acetonitrile, ethanol, isopropanol and isobutanol. Preferably, the organic solvent 1 is isopropanol or acetonitrile; and / or the inorganic strong base is sodium hydroxide powder or potassium hydroxide powder. Preferably, it is potassium hydroxide powder. More preferably, the potassium hydroxide powder has a purity of greater than or equal to 90% and a particle size of 80 to 500 μm.

3. The preparation method according to claim 1, wherein: The molar ratio of the inorganic strong base to 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride in step (1) is 0.5-1.5:1, preferably 1.0-1.2:

1.

4. The preparation method according to claim 1, wherein: The reaction temperature in step (1) is 20-80° C., preferably 30-50° C.; and / or the reaction time is 0.5-4 hours.

5. The preparation method according to claim 1, wherein: The inorganic weak base in step (2) is sodium carbonate or potassium carbonate, preferably potassium carbonate; more preferably, potassium carbonate is in the form of fine particles or powder with a particle size of 80 to 500 microns.

6. The preparation method according to claim 1, wherein: The molar ratio of the inorganic weak base to 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride in step (2) is 0.5-2.4:1, preferably 0.5-1.0:

1.

7. The preparation method according to any one of claims 1 to 6, wherein: The organic solvent 3 in step (4) is one of acetone, tetrahydrofuran, ethanol, methanol and acetonitrile.

8. The preparation method according to any one of claims 1 to 6, wherein: The ratio of the volume of the organic solvent 3, the volume of water and the weight of the crude trazodone hydrochloride in the mixed solvent described in step (4) is: (1-5): (0.5-2):

1.

9. The preparation method according to any one of claims 1 to 6, wherein: The ratio of the volume of the organic solvent 3 added in step (4) to the weight of the crude trazodone hydrochloride is (1-10):

1.

10. The preparation method according to any one of claims 1 to 9, wherein: In step (3), the organic solvent 2 is one or two of isopropanol, isobutanol, anhydrous ethanol, ethyl acetate, n-heptane, acetone, etc.

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