Preparation method of trazodone dimer impurity

Abstract

The invention provides a preparation method of a trazodone dimer impurity, which comprises the following steps: S1) under the catalytic action of iodide, reacting m-chloroaniline with dimethyl sulfoxide in a solvent to obtain a first intermediate product; s2) heating bis (2-chloroethyl) amine hydrochloride and the first intermediate product in a solvent for reflux reaction to obtain a second intermediate product; s3) reacting 1-bromo-3-chloropropane with the second intermediate product in the presence of a solvent under alkaline conditions to obtain a third intermediate product; and S4) carrying out a reaction on pyridine triazolone and the third intermediate product in a solution of inorganic alkali and water to obtain the trazodone dimer impurity. The preparation method provided by the invention can be used for preparing the trazodone dimer impurity with high yield and high purity.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of a trazodone dimer impurity. Background Art

[0002] Trazodone hydrochloride has the chemical name of 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one, and the hydrochloride salt of trazodone is usually used in marketed products. Trazodone belongs to the triazolopyridine class of antidepressants, which was developed by Angelini Company in Italy and is now on the market in many countries. The structural formula of trazodone hydrochloride is shown as follows. It is a specific serotonin reuptake inhibitor and has α1-adrenergic antagonistic and antihistamine effects; clinically, it can be used to treat various types of depression, anxiety disorders accompanied by depressive symptoms, and mood disorders after drug addicts withdraw from drugs;

[0003]

[0004] 2,2'-(((Methylenebis(3-chloro-4,1-phenylene))bis(piperazine-4,1-diyl))bis(propane-3,1-diyl))bis([1,2,4]triazolo[4,3-a]pyridin-3(2H)-one) as shown in formula (IV) is an impurity generated by process transfer in the production process of trazodone raw materials. It is generated in the following process: in the first step, m-chloroaniline undergoes coupling at high temperature, and then it is transferred to the API through process transfer to form this polymer impurity. Currently, there are many reports on the synthesis routes of trazodone. Specifically: first, the key intermediate 1-(3-chlorophenyl)piperazine hydrochloride (II) is prepared, then it reacts with 1-chloro-3-bromopropane to generate 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride (III), and finally it reacts with pyridinetriazolone to obtain trazodone. The process route is as follows:

[0005]

[0006] In the above preparation process, during the preparation of compound (II), m-chloroaniline and bis(2-chloroethyl)amine hydrochloride react at high temperature. In this process, a side reaction occurs with the residual dichloromethane in the system to generate the core fragment of the dimer impurity: 4,4'-methylenebis(3-chloroaniline), which is not easy to remove and is transferred to the final product through the subsequent process route to form a dimer impurity. Therefore, this trazodone dimer is an inevitable process impurity in the preparation of trazodone.

[0007] In addition to being related to the pharmacological activity of the drug itself, the adverse reactions that occur during the clinical use of drugs are sometimes also greatly related to the impurities present in the drugs. Conducting impurity research in a standardized manner and controlling them within a safe and reasonable limit range will directly relate to the quality and safety of marketed drugs. So far, there has been no report on the preparation of this dimer impurity in the prior art. Therefore, providing a synthesis method for this impurity is of great significance for the preparation of impurity reference standards and the quality and impurity research of trazodone hydrochloride products. It can be used for the qualitative and quantitative analysis of impurities in the production of trazodone hydrochloride products, providing guarantee for drug use safety. Summary of the Invention

[0008] The technical problem solved by the present invention lies in providing a preparation method for trazodone dimer impurity, and the preparation method provided by this application can obtain trazodone dimer impurity with high yield and purity.

[0009] In view of this, this application provides a preparation method for trazodone dimer impurity as described in formula (IV), including the following steps:

[0010] S1) Under the catalysis of an iodide, react m-chloroaniline and dimethyl sulfoxide in a solvent to obtain a first intermediate product;

[0011] S2) Heat the bis(2-chloroethyl)amine hydrochloride and the first intermediate product to reflux in a solvent to obtain a second intermediate product;

[0012] S3) React 1-bromo-3-chloropropane and the second intermediate product in a solvent and under basic conditions to obtain a third intermediate product;

[0013] S4) React pyridinetriazolone and the third intermediate product in a solution of an inorganic base and water to obtain trazodone dimer impurity;

[0014]

[0015] Preferably, the iodide includes one or more of elemental iodine, sodium iodide, potassium iodide, and ammonium iodide;

[0016] And / or, the molar ratio of the m-chloroaniline to the iodide is 1:(1 - 3);

[0017] And / or, the solvent includes water;

[0018] And / or, the temperature of the reaction is 100 - 150 °C, and the time is 24 - 48 h.

[0019] Preferably, in step S1), after the reaction, it further includes:

[0020] The obtained product was extracted with ethyl acetate. The obtained organic phase was washed with saturated brine and then dried with inorganic sodium sulfate to obtain the crude product.

[0021] The crude product was purified by column chromatography to obtain the first intermediate product.

[0022] Preferably, in step S2), the molar ratio of the first intermediate product to bis(2-chloroethyl)amine hydrochloride is 1:(1-4).

[0023] Preferably, step S2) is specifically as follows:

[0024] Bis(2-chloroethyl)amine hydrochloride and the first intermediate product were mixed, xylene was added, heated to reflux of xylene, stirred for 24-72 h, cooled, isopropanol was added, heated to reflux of isopropanol, stirred for 5-10 h, and filtered after cooling to obtain the second intermediate product.

[0025] Preferably, in step S3), the molar ratio of the second intermediate product to 1-bromo-3-chloropropane is 1:(2-5);

[0026] And / or, the alkaline condition is provided by an aqueous sodium hydroxide solution; the molar ratio of the second intermediate product, 1-bromo-3-chloropropane and the aqueous sodium hydroxide solution is 1:(2-5):(6-12);

[0027] And / or, the solvent includes one or more of methyl isobutyl ketone, acetone, acetonitrile, dioxane and tetrahydrofuran.

[0028] Preferably, after step S3), it further includes:

[0029] The reaction solution was filtered, the obtained filtrate was allowed to stand, the obtained organic phase was washed with purified water, the washed organic phase was adjusted to pH 5-6 with concentrated hydrochloric acid, the filtrate obtained by filtration was adjusted to pH 1-2 again with concentrated hydrochloric acid, and the third intermediate product was obtained after crystallization.

[0030] Preferably, in step S4), the molar ratio of the third intermediate product to pyridinetriazolone is 1:(2-4).

[0031] Preferably, in step S4), the inorganic base includes one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide, and the molar ratio of the third intermediate product, pyridinetriazolone and the inorganic base is 1:(2-4):(4-8).

[0032] Preferably, after the reaction in step S4), it further includes:

[0033] The obtained reaction solution was stirred and then crystallized, followed by filtration. The obtained filter cake was slurried with a dilute alkali solution and filtered again. The obtained filter cake was rinsed with purified water to obtain the trazodone dimer impurity; the dilute alkali solution was an aqueous solution of an inorganic base with a concentration of 1.0 - 5.0%.

[0034] The present application provides a method for preparing a trazodone dimer impurity. Using m-chloroaniline as the starting material, through dimethyl sulfoxide carbon insertion coupling, a first intermediate product was obtained. Then, the first intermediate product and bis(2-chloroethyl)amine hydrochloride were refluxed to obtain a second intermediate product. Subsequently, the second intermediate product and 1-bromo-3-chloropropane were reacted under alkaline conditions to obtain a third intermediate product. Finally, the third intermediate product and pyridyltriazolone were reacted to obtain the trazodone dimer impurity. The preparation method provided by the present application can obtain a trazodone dimer impurity with a high yield and a relatively high purity, thus avoiding the workload of extracting impurities from trazodone and promoting the preparation of the trazodone dimer impurity reference standard and the quality of trazodone. Description of the Drawings

[0035] Figure 1 1H NMR spectrum of the trazodone dimer impurity prepared in Example 1 of the present invention;

[0036] Figure 2 13C NMR spectrum of the trazodone dimer impurity prepared in Example 1 of the present invention;

[0037] Figure 3 Mass spectrum of the trazodone dimer impurity prepared in Example 1 of the present invention;

[0038] Figure 4 HPLC chromatogram for the impurity localization of the trazodone dimer impurity prepared in the present invention in the trazodone product. Detailed Embodiments

[0039] To further understand the present invention, the preferred embodiments of the present invention will be described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention and not for limiting the claims of the present invention.

[0040] In view of the fact that in the prior art, the trazodone dimer impurity shown in formula (IV) will be generated during the preparation process of trazodone, and due to the need for quality control of the trazodone hydrochloride product, the present application provides a preparation method for the trazodone dimer impurity. Starting from m-chloroaniline, the first intermediate is obtained through carbon insertion coupling with dimethyl sulfoxide (DMSO). Then, the first intermediate reacts with bis(2-chloroethyl)amine hydrochloride to form the second intermediate. Further, the second intermediate reacts with 1-bromo-3-chloropropane to obtain the third intermediate, and finally reacts with pyridinetriazolone to obtain the trazodone dimer impurity. The preparation method provided by the present application can synthesize the trazodone dimer impurity with high yield and high purity, which can be applied to the reference substance research in trazodone products and is of great significance for ensuring the quality of trazodone. Specifically, the embodiments of the present invention disclose a preparation method for the trazodone dimer impurity as described in formula (IV), including the following steps:

[0041] S1) Under the catalysis of an iodide, m-chloroaniline and dimethyl sulfoxide are reacted in a solvent to obtain a first intermediate;

[0042] S2) Bis(2-chloroethyl)amine hydrochloride and the first intermediate are heated to reflux in a solvent to obtain a second intermediate;

[0043] S3) 1-bromo-3-chloropropane and the second intermediate are reacted in a solvent and under basic conditions to obtain a third intermediate;

[0044] S4) Pyridinetriazolone and the third intermediate are reacted in a solution of an inorganic base and water to obtain the trazodone dimer impurity;

[0045]

[0046] In the preparation method of the trazodone dimer impurity provided by the present application, the first intermediate is first prepared, that is, under the catalysis of an iodide, m-chloroaniline and dimethyl sulfoxide are reacted in a solvent to obtain the first intermediate; during this process, the iodide is used as a catalyst, which includes one or more of elemental iodine, sodium iodide, potassium iodide, and ammonium iodide. Specifically, the iodide is selected from elemental iodine, sodium iodide, potassium iodide, or ammonium iodide. More specifically, the iodide is selected from ammonium iodide. The molar ratio of the m-chloroaniline to the iodide is 1:(1-3). Specifically, the molar ratio of the m-chloroaniline to the iodide is 1:1. The solvent includes water. The temperature of the reaction is 100-150°C, and the time is 24-48h. Specifically, the temperature of the reaction is 120-140°C, and the time is 24h. After the reaction, purification is also included, specifically:

[0047] The obtained product was cooled to room temperature and then poured into water. The aqueous phase was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine and then dried with anhydrous sodium sulfate to obtain the crude product.

[0048] The crude product was purified by column chromatography to obtain the first intermediate.

[0049] The reaction formula for preparing the first intermediate is as follows:

[0050]

[0051] In this application, bis(2-chloroethyl)amine hydrochloride and the first intermediate were then heated to reflux in a solvent to obtain the second intermediate; during this process, the molar ratio of the first intermediate to bis(2-chloroethyl)amine hydrochloride was 1:(1-4). Specifically, the molar ratio of the first intermediate to bis(2-chloroethyl)amine hydrochloride was 1:1, 1:2, 1:3, or 1:4. The above reflux reaction was specifically as follows:

[0052] Bis(2-chloroethyl)amine hydrochloride and the first intermediate were mixed, xylene was added, and the mixture was heated to reflux of xylene and stirred for 24-72 h. After cooling, isopropanol was added, and the mixture was heated to reflux of isopropanol and stirred for 5-10 h. After cooling, filtration was carried out to obtain the second intermediate.

[0053] The reaction formula for preparing the second intermediate is as follows:

[0054]

[0055] According to the present invention, the third intermediate was then prepared by reacting 1-bromo-3-chloropropane with the second intermediate under solvent and basic conditions to obtain the third intermediate; during the above process, the molar ratio of the second intermediate to 1-bromo-3-chloropropane was 1:(2-5), and the basic conditions were provided by an organic base aqueous solution, specifically provided by a sodium hydroxide aqueous solution. The molar ratio of the second intermediate, 1-bromo-3-chloropropane, and the sodium hydroxide aqueous solution was 1:(2-5):(6-12). Specifically, the molar ratio of the second intermediate, 1-bromo-3-chloropropane, and the sodium hydroxide aqueous solution was 1:(3-4):(8-10). The solvent included one or more of methyl isobutyl ketone, acetone, acetonitrile, dioxane, and tetrahydrofuran. Specifically, the solvent included methyl isobutyl ketone; it could be used as both a solvent and an extractant. After the above reaction, purification was also included, and the purification was specifically as follows:

[0056] Filter the reaction solution, let the obtained filtrate stand still and separate into layers. Extract the aqueous layer with methyl isobutyl ketone, wash the obtained organic phase with purified water, adjust the pH of the washed organic phase to 5 - 6 with concentrated hydrochloric acid, and then adjust the pH of the filtered filtrate to 1 - 2 with concentrated hydrochloric acid again. After crystallization, the third intermediate product is obtained.

[0057] The reaction formula for preparing the third intermediate product is as follows:

[0058]

[0059] Based on the above preparation of the third intermediate product, the present application finally obtains trazodone dimer impurity, that is, reacting pyridinetriazolone with the third intermediate product in a solution obtained from an inorganic base and water to obtain trazodone dimer impurity; during this process, the molar ratio of the third intermediate product to the pyridinetriazolone is 1:(2 - 4); the inorganic base provides an alkaline environment for the reaction, and the inorganic base includes one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide. Specifically, the inorganic base is selected from sodium hydroxide; the molar ratio of the third intermediate product, the pyridinetriazolone, and the sodium hydroxide is 1:(2 - 4):(4 - 8). Specifically, the molar ratio of the third intermediate product, the pyridinetriazolone, and the sodium hydroxide is 1:(3 - 4):(5 - 6). After the reaction, it also includes:

[0060] Stir the obtained reaction solution to room temperature and then crystallize, then filter. Pulp the obtained filter cake with a dilute alkali solution and filter again. Wash the obtained filter cake with purified water to obtain trazodone dimer impurity; the dilute alkali solution is an aqueous solution of an inorganic base with a concentration of 1.0 - 5.0%, and the dilute alkali solution exemplified can be selected from an aqueous solution of sodium bicarbonate.

[0061] The reaction formula for preparing trazodone dimer impurity is as follows:

[0062]

[0063] The synthesis method of trazodone dimer impurity provided by the present invention can conveniently obtain a relatively large amount of trazodone dimer impurity with high purity, avoiding the huge workload of extracting impurities from production samples, and plays a promoting role in the preparation of trazodone dimer impurity reference standards and the quality control of trazodone products, and can be widely promoted on a large scale.

[0064] To further understand the present invention, the following examples are used to illustrate in detail the preparation method of trazodone dimer impurity provided by the present invention. The protection scope of the present invention is not limited by the following examples.

[0065] The raw materials in the following examples are all commercially available products.

[0066] Example 1

[0067] Step 1: Synthesize the first intermediate: methylene bisaniline compound

[0068] In a 500 mL three-necked flask, 8.0 g of m-chloroaniline (63 mmol, 1.0 eq.) was mixed with DMSO (80 mL) and water (80 mL), then 9.1 g of ammonium iodide (63 mmol, 1.0 eq.) was added. After sealing, it was heated to about 140 °C and stirred for 24 hours. The temperature was lowered, diluted with purified water, extracted three times with ethyl acetate, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain a crude product of brown oily substance. After column purification, a yellow oily liquid first intermediate was obtained: 13.5 g, yield: 80%;

[0069] Step 2: Synthesize the second intermediate: bis(2-chloro-4-(piperazin-1-yl)phenyl)methane hydrochloride

[0070] In a 100 mL three-necked flask, 10.7 g of the first intermediate of methylene bisaniline (40 mmol, 1.0 eq.) and 14.3 g of bis(2-chloroethyl)amine hydrochloride (80 mmol, 2.0 eq.) were mixed, xylene was added, heated to reflux of xylene, and stirred for 48 hours. The temperature was lowered, isopropanol was added, heated to reflux of isopropanol, and stirred for 8 hours. After cooling, it was filtered to obtain a white solid second intermediate: 15.0 g, yield: 75%;

[0071] Step 3: Synthesize the third intermediate bis(2-chloro-4-(4-(3-chloropropyl)piperazin-1-yl)phenyl)methane hydrochloride

[0072] In a 250 mL three-necked flask, 12.0 g of the second intermediate of bis(2-chloro-4-(4-(3-chloropropyl)piperazin-1-yl)phenyl)methane (25 mmol, 1.0 eq.) and 7.9 g of 1-bromo-3-chloropropane (50 mmol, 2.0 eq.) were mixed, methyl isobutyl ketone was added, stirred to dissolve, and an aqueous sodium hydroxide solution (6.0 g of NaOH, 150 mmol, 6.0 eq.) was added dropwise for reaction. After the reaction was completed, the organic phase was separated and collected by liquid separation. The aqueous phase was extracted with methyl isobutyl ketone. After combining the organic phases, it was washed with purified water. For the washed organic phase, the pH value was adjusted to 5 with hydrochloric acid aqueous solution for the first time, and the filtrate was collected by filtration; for the second time, the pH was adjusted to 1 with hydrochloric acid aqueous solution and stirred at room temperature for 2 hours for crystallization to obtain a white third intermediate: 12.6 g, yield: 80%.

[0073] Step 4 Synthesis of Trazodone Dimer Impurity - 2,2'-(((Methylenebis(3-chloro-4,1-phenylene))bis(piperazine-4,1-diyl))bis(propane-3,1-diyl))bis([1,2,4]triazolo[4,3-a]pyridin-3(2H)-one)

[0074] In a 200 mL three-necked flask, 12.6 g of the third intermediate bis(2-chloro-4-(4-(3-chloropropyl)piperazin-1-yl)phenyl)methane hydrochloride (20 mmol, 1.0 eq.), 5.4 g of pyridinetriazolone (40 mmol, 2.0 eq.), and 3.2 g of sodium hydroxide (80 mmol, 4.0 eq.) were mixed, purified water was added and stirred to dissolve, and the mixture was heated for reaction; after the reaction was completed, it was stirred at room temperature for crystallization, filtered, the filter cake was slurried with 3.0% aqueous sodium bicarbonate solution, filtered, the filter cake was collected, the filter cake was rinsed with purified water, and the obtained filter cake was dried to obtain the trazodone dimer impurity: 11.3 g, yield: 75%, purity: 85%.

[0075] The 1H NMR spectrum of the trazodone dimer impurity prepared in this example is as follows: 1 H NMR(CDCl3)δ(ppm):7.75(d,2H,Ar-H),7.05 - 7.10(m,4H,Ar-H),6.86 - 6.89(m,4H,Ar-H),6.68 - 6.69(m,2H,Ar-H),6.46 - 6.49(m,2H,Ar-H),4.07 - 4.10(m,4H,-CH2-),3.99(s,2H,-CH2-),3.10 - 3.12(m,8H,-CH2-),2.56 - 2.58(m,8H,-CH2-),2.48 - 2.51(m,4H,-CH2-),2.04 - 2.07(m,4H,-CH2-): as Figure 1 shown;

[0076] The 13C NMR spectrum: 13 C NMR(CDCl3)δ(ppm):150.6,148.6,141.5,134.7,130.9,129.8,123.7,116.5,115.4,114.4,110.5,55.5,53.0,48.8,44.4,35.0,26.0; as Figure 2 shown;

[0077] The mass spectrum: MS-ESI(m / z)[M + H] + 755.3110; as Figure 3 shown.

[0078] Example 2

[0079] The preparation method is basically the same as that of Example 1, except that: in Step 1, the selection and dosage of the iodide are adjusted, and the obtained first intermediate product, the yield of the first intermediate product, and the purity of the first intermediate product are shown in Table 1;

[0080] Table 1 Data table of the selection and dosage of iodide and the relevant data of the first intermediate product

[0081] Iodide Dosage First intermediate Yield Purity Sodium iodide 9.4 g (1.0 eq.) 12.6g 75％ 97％ Potassium iodide 10.5 g (1.0 eq.) 12.1g 72％ 98％ Elemental iodine 16.0 g (1.0 eq.) 13.1g 78％ 96％

[0082] Example 3

[0083] The preparation method is basically the same as that of Example 1, except that: in Step 2, the molar dosage ratio of the first intermediate product to bis(2-chloroethyl)amine hydrochloride is adjusted, and the obtained second intermediate product, the yield of the second intermediate product, and the purity of the second intermediate product are shown in Table 2;

[0084] Table 2 Data table of the raw material molar ratio and the relevant data of the second intermediate product

[0085]

[0086]

[0087] Example 4

[0088] The preparation method is basically the same as that of Example 1, except that: in Step 3, the molar ratio of the second intermediate product to 1-bromo-3-chloropropane is adjusted, specifically:

[0089] In a 250 mL three-necked flask, 12.0 g of bis(2-chloro-4-(4-(3-chloropropyl)piperazin-1-yl)phenyl)methane second intermediate product (25 mmol, 1.0 eq.) and 19.8 g of 1-bromo-3-chloropropane (125 mmol, 5.0 eq.) were mixed, methyl isobutyl ketone was added, stirred and dissolved, and an aqueous sodium hydroxide solution (12.0 g NaOH, 300 mmol, 12.0 eq.) was added dropwise for reaction; after the reaction was completed, the organic phase was collected by liquid separation, the aqueous phase was extracted with methyl isobutyl ketone, the organic phases were combined and then washed with purified water, the obtained organic phase was first adjusted to pH 6 with an aqueous hydrochloric acid solution, and the filtrate was collected by filtration; the second time, the pH was adjusted to 2 with an aqueous hydrochloric acid solution, and the mixture was stirred at room temperature for 2 hours for crystallization to obtain 11.5 g of white intermediate product 4, and the yield was: 73%.

[0090] Example 5

[0091] The preparation method is basically the same as that of Example 1, except that: in Step 4, the molar ratio of the third intermediate product to pyridinetriazolone is adjusted, specifically:

[0092] Step 4: Synthesis of Trazodone Dimer Impurity - 2,2'-(((Methylenebis(3-chloro-4,1-phenylene))bis(piperazine-4,1-diyl))bis(propane-3,1-diyl))bis([1,2,4]triazolo[4,3-a]pyridin-3(2H)-one)

[0093] In a 200 mL three-necked flask, 12.6 g of the third intermediate bis(2-chloro-4-(4-(3-chloropropyl)piperazin-1-yl)phenyl)methane hydrochloride (20 mmol, 1.0 eq.), 10.8 g of pyridinetriazolone (80 mmol, 4.0 eq.), and 6.4 g of sodium hydroxide (160 mmol, 8.0 eq.) were mixed. Purified water was added and stirred to dissolve, and then heated for reaction. After the reaction was completed, the mixture was stirred at room temperature for crystallization, filtered, and the filter cake was slurried with 1.0% aqueous sodium bicarbonate solution, filtered, and the filter cake was collected. The filter cake was washed with purified water and then dried to obtain 10.5 g of trazodone dimer impurity, with a yield of 70%.

[0094] Or,

[0095] Step 4: Synthesis of Trazodone Dimer Impurity - 2,2'-(((Methylenebis(3-chloro-4,1-phenylene))bis(piperazine-4,1-diyl))bis(propane-3,1-diyl))bis([1,2,4]triazolo[4,3-a]pyridin-3(2H)-one)

[0096] In a 200 mL three-necked flask, 12.6 g of the third intermediate bis(2-chloro-4-(4-(3-chloropropyl)piperazin-1-yl)phenyl)methane hydrochloride (20 mmol, 1.0 eq.) and 8.1 g of pyridinetriazolone (60 mmol, 3.0 eq.), 4.8 g of sodium hydroxide (120 mmol, 6.0 eq.) were mixed. Purified water was added and stirred to dissolve, and then heated for reaction. After the reaction was completed, the mixture was stirred at room temperature for crystallization, filtered, and the filter cake was slurried with 5.0% aqueous sodium bicarbonate solution, filtered, and the filter cake was collected. The filter cake was washed with purified water and then dried to obtain 11.0 g of trazodone dimer impurity, with a yield of 73%.

[0097] Application Example

[0098] Preparation Method of Trazodone

[0099] In the first step, 15 - 20 g of bis(2-chloroethyl)amine hydrochloride and 10 - 15 g of m-chloroaniline were added to a glass bottle, dispersed with xylene, and heated to reflux for reaction. After the reaction was completed, the temperature was lowered and isopropanol was added and stirred under reflux. Filtered and dried to obtain a white solid, which is Intermediate 1, 15 - 19 g, with a yield of about 50 - 70%;

[0100] In the second step, add 25 - 30 g of 1 - bromo - 3 - chloropropane and 70 - 100 ml of methyl isobutyl ketone into a glass bottle, and dropwise add sodium hydroxide solution; after dropping, add Intermediate I in batches; after adding, react at room temperature; after the reaction is completed, filter, extract the aqueous layer with methyl isobutyl ketone; combine the organic phases, wash with purified water; adjust the pH value of the organic phase with concentrated hydrochloric acid, and stir to crystallize at room temperature; filter, wash the filter cake with methyl isobutyl ketone; add the filter cake to dichloromethane and stir to make a slurry; filter, wash the filter cake with dichloromethane; dry the filter cake to obtain an off - white solid, namely Intermediate II, 14 - 18 g, with a yield of about 50 - 85%;

[0101] In the third step, add 6 - 8 g of pyridinetriazolone, 12 - 15 g of Intermediate II, purified water, and 8 - 10 g of solid sodium bicarbonate into a glass reaction kettle, and heat to react; after the reaction is completed, stir and cool to room temperature to crystallize; filter, wash with purified water; add the filter cake to a sodium bicarbonate solution and stir to make a slurry at room temperature; filter, wash the filter cake with purified water; dry the filter cake; obtain about 12 - 15 g of crude product, then add it to ethanol and heat to stir until dissolved; after dissolution, add activated carbon and stir at a constant temperature for adsorption; filter, crystallize the filtrate at room temperature; then slowly cool to crystallize; filter, wash the filter cake with ethanol; dry the filter cake to obtain about 8 - 12 g of Intermediate III, with a yield of about 50 - 70.%;

[0102] In the fourth step, add 8 - 12 g of Intermediate III and acetone into a flask, stir and heat to dissolve, then cool to room temperature, add activated carbon, and stir for adsorption at room temperature; filter the activated carbon, wash the filtrate with acetone; adjust the pH value of the filtrate by dropwise adding concentrated hydrochloric acid and stir to crystallize at room temperature; filter, wash the filter cake with acetone; vacuum - dry the filter cake; weigh the filter cake, about 8 - 11 g, add n - propanol and purified water, stir and heat to dissolve; filter, let the filtrate stand and crystallize at room temperature, wash the filter cake with n - propanol; then wash with acetone; add the filter cake to acetone and stir to make a slurry at room temperature; filter, wash the filter cake with acetone; dry the filter cake to obtain 8 - 10 g of crude product, with a yield of 60 - 90%.

[0103] Trazodone impurity localization method:

[0104] Related substances are determined by high - performance liquid chromatography (General Chapter 0512, Volume IV, Chinese Pharmacopoeia 2020 Edition).

[0105] Diluent: Mix mobile phase A (0.01% aqueous triethylamine solution) and mobile phase B (0.01% triethylamine acetonitrile solution) in a volume ratio of 4:1;

[0106] Test solution: Take about 100 mg of this product, accurately weigh, place it in a 100 - ml volumetric flask, dissolve and dilute to the mark with the diluent, and shake well;

[0107] Reference solution: Accurately measure 1 ml of the test solution, transfer it to a 100-ml volumetric flask, dilute it to the mark with the diluent, mix well, accurately measure 1 ml and transfer it to a 10-ml volumetric flask, dilute it to the mark with the diluent, and mix well;

[0108] System suitability solution: Weigh appropriate amounts of trazodone hydrochloride and the dimer impurity reference substance, dissolve and dilute with the diluent to prepare a solution containing about 0.1 mg of trazodone hydrochloride and 1 μg of each dimer impurity per 1 ml;

[0109] Sensitivity solution: Accurately measure 5 ml of the reference solution, transfer it to a 10-ml volumetric flask, dilute it to the mark with the diluent, and mix well;

[0110] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel (XBridge C18 75×4.6 mm, 3.5 μm or equivalent in performance) as the filler; use 0.01% aqueous triethylamine solution as mobile phase A; 0.01% triethylamine acetonitrile solution as mobile phase B, the column temperature is 25°C, the flow rate is 2 ml per minute, the detection wavelength is 254 nm; the injection volume is 10 μl.

[0111] As Figure 4 can be seen, Figure 4 is the HPLC chromatogram of the trazodone dimer impurity reference substance for impurity localization. As can be seen from the figure, the trazodone dimer impurity prepared by this application can be used to determine the impurities in the trazodone product.

[0112] The description of the above embodiments is only used to help understand the method and its core idea of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

[0113] The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be obvious to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but will be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing a trazodone dimer impurity as described in formula (IV), comprising the following steps: S1) reacting m-chloroaniline and dimethyl sulfoxide in a solvent under the catalytic action of iodide to obtain a first intermediate product; S2) heating bis(2-chloroethyl)amine hydrochloride and the first intermediate product in a solvent to reflux for reaction to obtain a second intermediate product; S3) reacting 1-bromo-3-chloropropane and the second intermediate product under a solvent and alkaline conditions to obtain a third intermediate product; S4) reacting pyridinetriazolone and the third intermediate product in a solution of an inorganic base and water to obtain a trazodone dimer impurity; 2. The preparation method according to claim 1, characterized in that: The iodide includes one or more of elemental iodine, sodium iodide, potassium iodide and ammonium iodide; and / or, the molar ratio of the m-chloroaniline to the iodide is 1:(1-3); and / or, the solvent comprises water; And / or, the reaction temperature is 100-150° C. and the reaction time is 24-48 hours.

3. The preparation method according to claim 1, characterized in that: In step S1), the reaction further comprises: The obtained product was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine and then dried with inorganic sodium sulfate to obtain a crude product; The crude product was purified by column to obtain the first intermediate product.

4. The preparation method according to claim 1, characterized in that: In step S2), the molar ratio of the first intermediate product to the bis(2-chloroethyl)amine hydrochloride is 1:(1-4).

5. The preparation method according to claim 1, characterized in that: Step S2) is specifically: Mix bis(2-chloroethyl)amine hydrochloride and the first intermediate product, add xylene, heat to xylene reflux, stir for 24 to 72 hours, add isopropanol after cooling, heat to isopropanol reflux, stir for 5 to 10 hours, cool and filter to obtain a second intermediate product.

6. The preparation method according to claim 1, characterized in that: In step S3), the molar ratio of the second intermediate product to the 1-bromo-3-chloropropane is 1:(2-5); and / or, the alkaline condition is provided by a sodium hydroxide aqueous solution; the molar ratio of the second intermediate product, the 1-bromo-3-chloropropane and the sodium hydroxide aqueous solution is 1:(2-5):(6-12); And / or, the solvent includes one or more of methyl isobutyl ketone, acetone, acetonitrile, dioxane and tetrahydrofuran.

7. The preparation method according to claim 1, characterized in that: Step S3) also includes: The reaction solution is filtered, the obtained filtrate is allowed to stand, the obtained organic phase is washed with purified water, the washed organic phase is adjusted to pH 5-6 with concentrated hydrochloric acid, the filtered filtrate is again adjusted to pH 1-2 with concentrated hydrochloric acid, and the third intermediate product is obtained after crystallization.

8. The preparation method according to claim 1, characterized in that: In step S4), the molar ratio of the third intermediate product to the pyridinetriazolone is 1:(2-4).

9. The preparation method according to claim 1, characterized in that: In step S4), the inorganic base includes one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide, and the molar ratio of the third intermediate product, the pyridinetriazolone and the inorganic base is 1:(2-4):(4-8).

10. The preparation method according to claim 1, characterized in that: In step S4), the reaction further comprises: The obtained reaction solution is stirred and then crystallized, and then filtered. The obtained filter cake is slurried with a dilute alkali solution, filtered again, and the obtained filter cake is rinsed with purified water to obtain trazodone dimer impurities; the dilute alkali solution is an aqueous solution of an inorganic base with a concentration of 1.0 to 5.0%.

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