Preparation method of trazodone and hydrochloride thereof

Abstract

The invention relates to a preparation method of trazodone and hydrochloride thereof, and belongs to the field of pharmaceutical chemicals. Specifically, a compound shown as a formula IV or a salt thereof and 3-chloroaniline generate a compound shown as a formula V or a salt thereof in the presence of a catalyst, an organic alkali and an aprotic solvent. The invention provides a new preparation route of trazodone and hydrochloride thereof, and the preparation route is high in yield and high in product purity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a method for preparing trazodone and its hydrochloride salt. Background Art

[0002] Trazodone Hydrochloride is a 5 - hydroxytryptamine reuptake inhibitor and 5 - HT2 receptor antagonist, and is used for the treatment of depression with or without anxiety symptoms. Trazodone Hydrochloride was first marketed in Italy in 1972 and has been marketed in more than 50 countries and regions including China and the United States so far. It is an efficient and safe antidepressant drug and can be used for the treatment of mild and moderate depression.

[0003] Although some preparation routes of trazodone and its hydrochloride salt have been disclosed in the prior art such as US3381009A and GB1117068A, there is still an urgent need for a method for preparing trazodone and its hydrochloride salt with high yield and high purity. Summary of the Invention

[0004] The present invention provides a method for preparing a compound of formula V or its salt, which is characterized in that: a compound of formula IV or its salt and 3 - chloroaniline react in the presence of a catalyst, an organic base and an aprotic solvent to form a compound of formula V or its salt.

[0005]

[0006] In some embodiments of the present invention, the aprotic solvent is one solvent selected from toluene, xylene, chlorobenzene, N,N - dimethylformamide, dimethyl adipate, N - methylpyrrolidone, dioxane or a mixed solvent of two or more thereof; in some typical embodiments, the aprotic solvent is one solvent selected from toluene, xylene, chlorobenzene, N,N - dimethylformamide, N - methylpyrrolidone or a mixed solvent of two or more thereof; in some more typical embodiments, the aprotic solvent is one solvent selected from toluene, xylene, chlorobenzene or a mixed solvent of two or more thereof; in some most typical embodiments, the aprotic solvent is xylene.

[0007] In some embodiments of the present invention, the organic base is selected from one reagent or a mixed reagent of two or more of methylamine, ethylamine, propylamine, butylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, N,N-dimethylethanolamine, N-methylethanolamine, ethylenediamine, piperidine, quinoline, imidazole, benzimidazole, histidine, pyridine, methylpyridine, dimethylpyridine, 2,4,6-trimethylpyridine, morpholine, N-methylmorpholine, aniline, cyclohexylamine, diisopropylethylamine, diisopropylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, N,N-diisopropylethylamine; in some typical embodiments, the organic base is selected from one reagent or a mixed reagent of two or more of triethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, N,N-diisopropylethylamine; in some more typical embodiments, the organic base is N,N-diisopropylethylamine or triethylamine; in some most typical embodiments, the organic base is N,N-diisopropylethylamine.

[0008] In some embodiments of the present invention, the catalyst is a metal halide; in some typical embodiments, the catalyst is selected from one reagent or a mixed reagent of two or more of lithium iodide, sodium iodide, potassium iodide; in some more typical embodiments, the catalyst is sodium iodide.

[0009] In some embodiments of the present invention, the molar ratio of the compound of formula IV or its salt to 3-chloroaniline in the feed is 1:0.5 - 3; in some typical embodiments, the molar ratio of the compound of formula IV or its salt to 3-chloroaniline in the feed is 1:1 - 1.5; in some more typical embodiments, the molar ratio of the compound of formula IV or its salt to 3-chloroaniline in the feed is 1:1.05 - 1.2; in some most typical embodiments, the molar ratio of the compound of formula IV or its salt to 3-chloroaniline in the feed is 1:1.

[0010] In some embodiments of the present invention, the mass-to-volume ratio of the compound of formula IV or its salt to the aprotic solvent in the feed, calculated as the free base of the compound of formula IV, is 1 g:1 mL - 50 mL; in some typical embodiments, the mass-to-volume ratio of the compound of formula IV or its salt to the aprotic solvent in the feed, calculated as the free base of the compound of formula IV, is 1 g:2 mL - 20 mL; in some more typical embodiments, the mass-to-volume ratio of the compound of formula IV or its salt to the aprotic solvent in the feed, calculated as the free base of the compound of formula IV, is 1 g:3 mL - 12 mL; in some most typical embodiments, the mass-to-volume ratio of the compound of formula IV or its salt to the aprotic solvent in the feed, calculated as the free base of the compound of formula IV, is 1 g:8 mL - 12 mL.

[0011] In some embodiments of the present invention, the molar ratio of the compound of formula IV or its salt to the organic base in the feed is 1:2 - 20; in some typical embodiments, the mass ratio of the compound of formula IV or its salt to the organic base in the feed is 1:3 - 10; in some more typical embodiments, the mass ratio of the compound of formula IV or its salt to the organic base in the feed is 1:3 - 5; in some most typical embodiments, the mass ratio of the compound of formula IV or its salt to the organic base in the feed is 1:4.

[0012] In some embodiments of the present invention, the molar ratio of the compound of formula IV or its salt to the catalyst in the feed is 1:0.02 - 7.08; in some typical embodiments, the molar ratio of the compound of formula IV or its salt to the catalyst in the feed is 1:0.02 - 1.18; in some more typical embodiments, the molar ratio of the compound of formula IV or its salt to the catalyst in the feed is 1:0.11 - 0.55; in some more typical embodiments, the molar ratio of the compound of formula IV or its salt to the catalyst in the feed is 1:0.45 - 0.49; in some most typical embodiments, the molar ratio of the compound of formula IV or its salt to the catalyst in the feed is 1:0.47.

[0013] In some embodiments of the present invention, the reaction of Route 1 occurs at 30°C - 180°C; in some typical embodiments, the reaction temperature is 50°C - 160°C; in some more typical embodiments, the reaction temperature is 100°C - 140°C; in some most typical embodiments, the reaction temperature is 120°C, 130°C, 135°C or 140°C.

[0014] In some embodiments of the present invention, the reaction time of Route 1 is 0.5 h - 24 h; in some typical embodiments, the reaction time of the reaction is in the range of 1 h - 16 h; in some most typical embodiments, the reaction time of the reaction is 1 h, 3 h, 5 h, 9 h, 11 h, 13 h or 16 h.

[0015] In some embodiments of the present invention, the prepared compound of formula V can optionally be further converted into its hydrochloride salt, which is characterized in that: at -20°C - 80°C, a hydrogen chloride ethanol solution is added to the organic solvent containing the compound of formula V.

[0016] In some embodiments of the present invention, the compound of formula IV or its salt can be the compound of formula IV or its hydrochloride salt; in some typical embodiments, the compound of formula IV or its salt is the hydrochloride salt of the compound of formula IV.

[0017] In some embodiments of the present invention, the hydrochloride salt of the compound of formula IV and 3-chloroaniline react in the presence of a catalyst, an organic base, and an aprotic solvent to form the compound of formula V or a salt thereof.

[0018] The present invention provides a method for preparing a compound of formula IV or a salt thereof, characterized in that: the compound of formula III or a salt thereof reacts with thionyl chloride in the presence of solvent A to form the compound of formula IV or a salt thereof.

[0019]

[0020] In some embodiments of the present invention, the molar ratio of the compound of formula III or a salt thereof to thionyl chloride in the feed is 1:2 - 10; in some typical embodiments, the molar ratio of the compound of formula III or a salt thereof to thionyl chloride in the feed is 1:2.5 - 5; in some more typical embodiments, the molar ratio of the compound of formula III or a salt thereof to thionyl chloride in the feed is 1:2.5 - 4; in some most typical embodiments, the molar ratio of the compound of formula III or a salt thereof to thionyl chloride in the feed is 1:4.

[0021] In some embodiments of the present invention, solvent A is selected from one solvent or a mixed solvent of two or more solvents among chloroform, N,N-dimethylformamide, dichloromethane, dichloroethane, toluene, isopropyl acetate, and xylene; in some typical embodiments, solvent A is chloroform, N,N-dimethylformamide, dichloromethane, dichloroethane, toluene, or xylene; in some most typical embodiments, solvent A is chloroform.

[0022] In some embodiments of the present invention, the mass-to-volume ratio of the compound of formula III or a salt thereof to solvent A in the feed is 1 g:1 mL - 20 mL; in some typical embodiments, the mass-to-volume ratio of the compound of formula III or a salt thereof to solvent A in the feed is 1 g:2 mL - 10 mL; in some more typical embodiments, the mass-to-volume ratio of the compound of formula III or a salt thereof to solvent A in the feed is 1 g:3 mL - 8 mL; in some most typical embodiments, the mass-to-volume ratio of the compound of formula III or a salt thereof to solvent A in the feed is 1 g:5 mL.

[0023] In some embodiments of the present invention, the reaction temperature of Route 2 is in the range of 20°C - 140°C; in some typical embodiments, the reaction temperature is in the range of 40°C - 100°C; in some most typical embodiments, the reaction temperature is in the range of 50°C - 80°C.

[0024] In some embodiments of the present invention, the reaction time of Route 2 is in the range of 0.5 h to 24 h; in some typical embodiments, the reaction time is in the range of 1 h to 16 h; in some most typical embodiments, the reaction time is 1 h, 2 h, 3 h, 5 h or 7 h.

[0025] The present invention provides a method for preparing a compound of Formula III, which is characterized in that: a compound of Formula II or a salt thereof reacts with 2,2'-dihydroxydiethylamine in the presence of a catalyst to form a compound of Formula III or a salt thereof.

[0026]

[0027] In some embodiments of the present invention, the mass-to-volume ratio of the compound of Formula II to 2,2'-dihydroxydiethylamine in the feed is 1 g: 1 mL - 10 mL; in some typical embodiments, the mass-to-volume ratio of the compound of Formula II to 2,2'-dihydroxydiethylamine in the feed is 1 g: 1 mL - 5 mL; in some more typical embodiments, the mass-to-volume ratio of the compound of Formula II to 2,2'-dihydroxydiethylamine in the feed is 1 g: 1.1 mL - 4 mL; in some most typical embodiments, the mass-to-volume ratio of the compound of Formula II to 2,2'-dihydroxydiethylamine in the feed is 1 g: 4 mL.

[0028] In some embodiments of the present invention, the molar ratio of the compound of Formula II or a salt thereof to the catalyst in the feed is 1:0.14.

[0029] The present invention provides a method for preparing a compound of Formula II, which is characterized in that: a compound of Formula I or a salt thereof reacts with 1-bromo-3-chloropropane in the presence of Solvent B to form a compound of Formula II or a salt thereof.

[0030]

[0031] In some embodiments of the present invention, the molar ratio of the compound of Formula I or a salt thereof to 1-bromo-3-chloropropane in the feed is 1:1 - 5; in some typical embodiments, the molar ratio of the compound of Formula I or a salt thereof to 1-bromo-3-chloropropane in the feed is 1:1.1 - 3; in some more typical embodiments, the molar ratio of the compound of Formula I or a salt thereof to 1-bromo-3-chloropropane in the feed is 1:1.1 - 1.5; in some most typical embodiments, the molar ratio of the compound of Formula I or a salt thereof to 1-bromo-3-chloropropane in the feed is 1:1.2.

[0032] In some embodiments of the present invention, solvent B is selected from one solvent of acetone, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, 1,4-dioxane, 2-butanone, N-methylpyrrolidone or a mixed solvent of two or more thereof; in some typical embodiments, solvent B is acetone, acetonitrile or 2-butanone; in some more typical embodiments, solvent B is acetone.

[0033] In some embodiments of the present invention, the reaction of Route 4 is carried out in the presence of an inorganic base or an organic base.

[0034] In some embodiments of the present invention, the inorganic base or organic base is one reagent of potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, lithium hydroxide or a mixed reagent of two or more thereof; in some typical embodiments, the organic base is one reagent of sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide or a mixed reagent of two or more thereof; in some typical embodiments, the inorganic base is one reagent of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or a mixed reagent of two or more thereof; in some more typical embodiments, the inorganic base is one reagent of potassium carbonate, sodium carbonate, sodium hydroxide or a mixed reagent of two or more thereof; in some most typical embodiments, the inorganic base is potassium carbonate.

[0035] In some embodiments of the present invention, the molar ratio of the compound of formula I or its salt to the inorganic base or organic base in the feed is 1:1 - 5; in some typical embodiments, the molar ratio of the compound of formula I or its salt to the inorganic base or organic base in the feed is 1:1 - 3; in some more typical embodiments, the molar ratio of the compound of formula I or its salt to the inorganic base or organic base in the feed is 1:1 - 2; in some most typical embodiments, the molar ratio of the compound of formula I or its salt to the inorganic base or organic base in the feed is 1:1.2.

[0036] The present invention provides a method for preparing trazodone hydrochloride, which is characterized in that at -20°C - 80°C, a hydrogen chloride ethanol solution is added to an organic solvent containing a compound of formula V.

[0037] In some embodiments of the present invention, the reaction temperature in the method for preparing trazodone hydrochloride is -10°C - 30°C; in some typical embodiments, the reaction temperature is -5°C - 10°C; in some more typical embodiments, the reaction temperature is 0°C - 10°C.

[0038] In some embodiments of the present invention, the method for preparing trazodone hydrochloride optionally further includes a stirring operation.

[0039] In some embodiments of the present invention, the preparation method of trazodone hydrochloride optionally further includes a filtration operation.

[0040] In some embodiments of the present invention, the preparation method of trazodone hydrochloride optionally further includes a drying operation.

[0041] The present invention provides a preparation method of trazodone hydrochloride, characterized in that the preparation method comprises the preparation method shown in the foregoing Route 1.

[0042] The present invention provides a preparation method of trazodone hydrochloride, characterized in that the preparation method simultaneously comprises the preparation methods shown in the foregoing Route 1 and Route 2.

[0043] The present invention provides a preparation method of trazodone hydrochloride, characterized in that the preparation method simultaneously comprises the preparation methods shown in the foregoing Route 1, Route 2 and Route 3.

[0044] The present invention provides a preparation method of trazodone hydrochloride, characterized in that the preparation method simultaneously comprises the preparation methods shown in the foregoing Route 1, Route 2, Route 3 and Route 4.

[0045] In some embodiments of the present invention, the route reaction is optionally carried out under nitrogen protection; in some typical embodiments, the Route 1 reaction is carried out under nitrogen protection.

[0046] The present invention provides a high-purity trazodone hydrochloride, characterized in that the total mass percentage of the compound of Formula A, the compound of Formula B and / or the compound of Formula C contained in the trazodone hydrochloride is not higher than 0.15%.

[0047] Compound of Formula A:

[0048]

[0049] Compound of Formula B:

[0050]

[0051] Compound of Formula C:

[0052]

[0053] In some typical embodiments, the purity of trazodone hydrochloride is above 99%, and the total mass percentage of the compound of formula A, the compound of formula B, and / or the compound of formula C in the total mass is not higher than 0.1%; in some more typical embodiments, the purity of trazodone hydrochloride is above 99.5%, and the total mass percentage of the compound of formula A, the compound of formula B, and / or the compound of formula C in the total mass is not higher than 0.05%; in some more typical embodiments, the purity of trazodone hydrochloride is above 99.9%, and the total mass percentage of the compound of formula A and / or the compound of formula B in the total mass is not higher than 33 ppm; in some more typical embodiments, the purity of trazodone hydrochloride is above 99.9%, and the total mass percentage of the compound of formula A and / or the compound of formula B in the total mass is not higher than 16 ppm; in some most typical embodiments, the purity of trazodone hydrochloride is above 99.92%, and the total mass percentage of the compound of formula A and / or the compound of formula B in the total mass is not higher than 2.5 ppm.

[0054] In the present invention, the compound of formula I can be obtained by purchase or prepared according to the prior art, and the prior art includes but is not limited to EP0025603A1, US20090209550A1, "Design, synthesis and pharmacological activities of 2-substituted 4-phenylquinolines as potential antidepressant drugs", "Microwave-assisted N-debenzylation of amides with triflic acid"; in the present invention, 1-bromo-3-chloropropane, 2,2'-dihydroxydiethylamine, and 3-chloroaniline can be obtained by purchase or prepared according to the prior art, and the prior art includes but is not limited to DE2253075A1, EP456183A2, EP678494A1, US3313848, DE1914606A1, US3683025A, DE2105682A1, US3726877A.

[0055] In the present invention, the purity of the compound of formula II, the compound of formula III, the compound of formula IV, and the compound of formula V can be measured by liquid chromatography, and the specific detection conditions are shown in Table 1:

[0056] Table 1

[0057]

[0058] The contents of the compound of formula V, the compound of formula A, the compound of formula B and the compound of formula C can be measured by liquid chromatography-mass spectrometry, and the specific detection conditions are shown in Table 2:

[0059] Table 2

[0060]

[0061]

[0062] The present invention provides a preparation method of trazodone and its hydrochloride, and the product prepared by this method has a low content of by-products and good yield and purity.

[0063] It is easy for those skilled in the art to understand that the error range of the parameters listed in the present invention also belongs to the protection scope of the present invention, and the error range includes but is not limited to the expected experimental error, technical error and instrument error degree of the given technology for measuring this value.

[0064] It is easy for those skilled in the art to understand that the judgment of the reaction end point can be achieved based on the experience of those skilled in the art, experimental phenomena, technical means monitoring, etc.; the "technical means monitoring" includes but is not limited to thin layer chromatography, high performance liquid chromatography, ultraviolet spectrophotometer, etc.

[0065] Unless otherwise specified, the following terms have the following meanings:

[0066] The ratio of the mobile phase in HPLC is a volume ratio.

[0067] LC-MS refers to a liquid chromatography-mass spectrometry instrument.

[0068] "H2O" refers to pure water.

[0069] "MeOH" refers to methanol.

[0070] "h" refers to hour.

[0071] "min" refers to minute.

[0072] "propylamine" refers to n-propylamine or isopropylamine.

[0073] "butylamine" refers to n-butylamine or 2-butylamine.

[0074] "xylene" refers to one or a mixture of two or more of o-xylene, m-xylene and p-xylene, such as commercially available xylene. Detailed Description of the Invention

[0075] For clarity, the present invention will be further described in detail below in conjunction with the embodiments, but it should be understood that the embodiments do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0076] Example 1 Preparation of 2-(3-chloropropyl)-1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula II)

[0077] Under nitrogen protection, 50 g of 1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula I), 69.9 g of 1-bromo-3-chloropropane, 500 mL of acetone, and 61.4 g of potassium carbonate were added to a reaction flask, stirred, heated to reflux, and reacted for 17 h. The reaction solution was cooled to 25 °C - 30 °C, filtered, and concentrated to obtain 81 g of a solid. The obtained solid was added to 500 mL of ethyl acetate and 200 mL of water, stirred for 30 min, separated, and the ethyl acetate layer was concentrated until no obvious distillate remained. The concentrated solid was stirred with 500 mL of n-hexane for 1 h and then filtered, and the filter cake was rinsed with a small amount of n-hexane. The filter cake was dried under vacuum at 35 °C for 16 h to obtain 63.06 g of the title compound (purity 92.2%).

[0078] Example 2 Preparation of 2-[3-[bis(2-hydroxyethyl)amino]propyl]-1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula III)

[0079] Under nitrogen protection, 20 g of 2-(3-chloropropyl)-1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula II), 80 mL of 2,2'-dihydroxydiethylamine, and 2 g of sodium iodide were added to a reaction flask, stirred, heated to 100 °C, and kept reacting for 16 h. The reaction solution was cooled to 25 °C - 30 °C, 400 mL of water, 140 g of saturated sodium chloride water, and 800 mL of dichloromethane were added, and 8 g of sodium hydroxide was added for extraction and separation. The organic layers were combined and the solvent was evaporated to dryness to obtain 24.2 g of the title compound (purity 95.4%).

[0080] Example 3 Preparation of hydrochloride of 2-[3-[bis(2-chloroethyl)amino]propyl]-1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula IV)

[0081] Under nitrogen protection, 24.2 g of 2-[3-[bis(2-hydroxyethyl)amino]propyl]-1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula III) and 125 mL of chloroform were added to a reaction flask, stirred, and thionyl chloride was added dropwise during the stirring process, with a total of 41.08 g added dropwise. After the addition was complete, the temperature was raised to reflux and kept reacting for 2 h. The reaction solution was cooled to 30 °C - 35 °C and concentrated until no obvious distillate remained to obtain 28 g of the title compound (purity 96.4%).

[0082] Example 4 Preparation of 1,2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula V)

[0083] Under nitrogen protection, 50 g of 2-[3-[bis(2-chloroethyl)amino]propyl]-1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula IV) hydrochloride, 18.1 g of 3-chloroaniline, 500 mL of xylene, 73.2 g of N,N-diisopropylethylamine, and 10 g of sodium iodide were added to a reaction flask, stirred, heated to 135 °C, and kept reacting for 16 h. The reaction solution was concentrated until no obvious distillate remained, 125 mL of methyl tert-butyl ether was added and stirred. After filtering the solid, it was dried under vacuum at 35 °C for 16 h to obtain 45 g of the title compound (purity 98.27%), and the mass spectrometry data was 372.2 m / z.

[0084] Example 5 Preparation of Trazodone Hydrochloride

[0085] Under nitrogen protection, 45.0 g of 1,2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula V) and 900 mL of ethanol were added to a reaction flask. Under the condition of 0 °C - 10 °C, 35% hydrogen chloride ethanol solution was added dropwise, with a total of 25 g added dropwise. A solid precipitated, and it was kept stirring for 1 h. After filtering the solid, it was dried under vacuum at 35 °C for 16 h to obtain 48 g of trazodone hydrochloride (purity 99.94%).

[0086] Example 6 Screening of the Reaction System for the Preparation of 1,2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula V)

[0087] Operating procedure for Reaction System 1: Under nitrogen protection, 50 g of 2-[3-[bis(2-chloroethyl)amino]propyl]-1,2,4-triazolo[4,3-a]pyridin-3-one (Compound of Formula IV) hydrochloride, 500 mL of ethylene glycol monoethyl ether, and 5 g of NaI were added to a reaction flask, stirred, heated to 120 °C, and kept reacting for 16 h.

[0088] Referring to the operating procedure of Reaction System 1, the following process parameters were replaced respectively (as shown in Table 3) to form Reaction Systems 2, 3, 4, and 5. The contents of 3-chloroaniline, Compound of Formula IV, Compound of Formula A, Compound of Formula B, Compound of Formula C, and Compound of Formula V in each reaction system were determined using the liquid chromatography - mass spectrometry conditions shown in Table 2, and the detection results are shown in Table 4.

[0089] Table 3

[0090]

[0091] "-" indicates not added.

[0092] Table 4

[0093]

[0094] "ND" indicates not detected.

[0095] 3-chloro-aniline: retention time 0.304 min.

[0096] Compound of formula IV: retention time 0.933 min.

[0097] Compound of formula A: retention time 1.607 min.

[0098] Compound of formula B: retention time 1.639 min.

[0099] Compound of formula C: retention time 2.213 min.

[0100] Compound of formula V: retention time 1.966 min.

[0101] Compound of formula A:

[0102]

[0103] Compound of formula B:

[0104]

[0105] Compound of formula C:

[0106]

[0107] The above-described embodiments merely represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula V or a salt thereof, characterized in that: The compound of formula IV or its salt and 3-chloroaniline are reacted in the presence of a catalyst, an organic base and an aprotic solvent to generate a compound of formula V or its salt.

2. The preparation method according to claim 1, wherein the aprotic solvent is a solvent selected from toluene, xylene, chlorobenzene, N,N-dimethylformamide, dimethyl adipate, N-methylpyrrolidone, and dioxane, or a mixed solvent of two or more thereof; the organic base is a reagent selected from methylamine, ethylamine, propylamine, butylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, N,N-dimethylethanolamine, N-methylethanolamine, ethylenediamine, piperidine, quinoline, imidazole, benzimidazole, histidine, pyridine, picoline, lutidine, 2,4,6-trimethylpyridine, morpholine, N-methylmorpholine, aniline, cyclohexylamine, diisopropylethylamine, diisopropylamine, 1,8-diazacyclo[5,4,0]undecene-7, and N,N-diisopropylethylamine, or a mixed reagent of two or more thereof; and the catalyst is Metal halide, preferably, the aprotic solvent is a solvent selected from toluene, xylene, chlorobenzene, N,N-dimethylformamide, N-methylpyrrolidone or a mixed solvent of two or more, the organic base is selected from triethylamine, 1,8-diazacyclo[5,4,0]undecene-7, N,N-diisopropylethylamine or a mixed reagent of two or more, the catalyst is a metal halide, more preferably, the aprotic solvent is a solvent selected from toluene, xylene, chlorobenzene or a mixed solvent of two or more, the organic base is N,N-diisopropylethylamine or triethylamine, the catalyst is selected from lithium iodide, sodium iodide, potassium iodide or a mixed reagent of two or more, most preferably, the aprotic solvent is xylene, the organic base is N,N-diisopropylethylamine, and the catalyst is sodium iodide.

3. According to the preparation method according to any one of claims 1-2, the mass volume ratio of the compound of formula IV or its salt to the aprotic solvent is 1g:1mL-50mL, calculated as the free base of the compound of formula IV. Preferably, the mass volume ratio of the compound of formula IV or its salt to the aprotic solvent is 1g:2mL-20mL, more preferably, the mass volume ratio of the compound of formula IV or its salt to the aprotic solvent is 1g:3mL-12mL, most preferably, the mass volume ratio of the compound of formula IV or its salt to the aprotic solvent is 1g:8mL-12mL.

4. The preparation method according to any one of claims 1 to 3, wherein the molar ratio of the compound of formula IV or its salt to the organic base is 1:2-20, preferably, the mass ratio of the compound of formula IV or its salt to the organic base is 1:3-10, more preferably, the mass ratio of the compound of formula IV or its salt to the organic base is 1:3-5, and most preferably, the mass ratio of the compound of formula IV or its salt to the organic base is 1:

4.

5. The preparation method according to any one of claims 1 to 4, wherein the molar ratio of the compound of formula IV or its salt to the catalyst is 1:0.02-7.08, preferably, the molar ratio of the compound of formula IV or its salt to the catalyst is 1:0.02-1.18, more preferably, the molar ratio of the compound of formula IV or its salt to the catalyst is 1:0.11-0.55, preferably, the molar ratio of the compound of formula IV or its salt to the catalyst is 1:0.45-0.49, most preferably, the molar ratio of the compound of formula IV or its salt to the catalyst is 1:0.

47.

6. A method for preparing trazodone hydrochloride, characterized in that: The preparation method includes the preparation method shown in the aforementioned route 1; preferably, the preparation method includes the preparation methods shown in the aforementioned route 1 and route 2 at the same time, more preferably, the preparation method includes the preparation methods shown in the aforementioned route 1, route 2 and route 3 at the same time, and most preferably, the preparation method includes the preparation methods shown in the aforementioned route 1, route 2, route 3 and route 4 at the same time.

7. The preparation method according to claim 6, characterized in that: The preparation method further comprises adding a hydrogen chloride ethanol solution to an organic solvent containing the compound of formula V at -20°C to 80°C.

8. The preparation method according to any one of claims 6 to 7, characterized in that: The preparation method shown in route 2 is that a compound of formula III or a salt thereof reacts with thionyl chloride in the presence of solvent A to generate a compound of formula IV or a salt thereof. Preferably, the molar ratio of the compound of formula III or a salt thereof to thionyl chloride is 1:2-10, preferably, the molar ratio of the compound of formula III or a salt thereof to thionyl chloride is 1:2.5-5, preferably, the molar ratio of the compound of formula III or a salt thereof to thionyl chloride is 1:2.5-4, preferably, the molar ratio of the compound of formula III or a salt thereof to thionyl chloride is 1:

4.

9. The preparation method according to claim 8, wherein solvent A is selected from chloroform, N,N-dimethylformamide, dichloromethane, dichloroethane, toluene, isopropyl acetate, and xylene, or a mixed solvent of two or more thereof, and the mass volume ratio of the compound of formula III or its salt to solvent A is 1g:1mL-20mL. Preferably, solvent A is chloroform, N,N-dimethylformamide, dichloromethane, dichloroethane, toluene or xylene, and the mass volume ratio of the compound of formula III or its salt to solvent A is 1g:2mL-10mL. Preferably, solvent A is chloroform, and the mass volume ratio of the compound of formula III or its salt to solvent A is 1g:3mL-8mL. Preferably, solvent A is chloroform, and the mass volume ratio of the compound of formula III or its salt to solvent A is 1g:5mL.

10. The present invention provides a high-purity trazodone hydrochloride, characterized in that The sum of the mass of the compound of formula A, the compound of formula B and / or the compound of formula C contained in the trazodone hydrochloride accounts for no more than 0.15% of the total mass, wherein the compound of formula A is: Compound of formula B: Compound of formula C: Preferably, the purity of the trazodone hydrochloride is 99% or more, and the sum of the masses of the compounds of formula A, formula B and / or formula C accounts for no more than 0.1% of the total mass. Preferably, the purity of the trazodone hydrochloride is 99.5% or more, and the sum of the masses of the compounds of formula A, formula B and / or formula C accounts for no more than 0.05% of the total mass. Preferably, the purity of the trazodone hydrochloride is 99.9% or more, and the sum of the masses of the compounds of formula A and / or formula B accounts for no more than 33 ppm of the total mass. Preferably, the purity of the trazodone hydrochloride is 99.9% or more, and the sum of the masses of the compounds of formula A and / or formula B accounts for no more than 16 ppm of the total mass. Preferably, the purity of the trazodone hydrochloride is 99.92% or more, and the sum of the masses of the compounds of formula A and / or formula B accounts for no more than 2.5 ppm of the total mass.

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