Preparation method of tandospirone citrate and application thereof in preparations

Abstract

The intermediate 1 is prepared by reacting compound I and compound II at low temperature in a solvent, and the intermediate 1 forms intermediate 2 (carboxylate) in an alkaline aqueous solution, and then an organic solvent immiscible with water is added to promote the conversion of intermediate 2 into tandospirone, and the generated tandospirone is then dissolved in the organic solvent, and the alkaline aqueous layer is separated. The organic layer is dried with a desiccant and then distilled under reduced pressure to obtain high-purity tandospirone, which is salted in a conventional manner to obtain tandospirone citrate. After the tandospirone citrate is mixed with the auxiliary materials, granulation, drying, granulation, total mixing, tableting, and coating are performed to obtain tandospirone citrate tablets.

Description

Technical Field

[0001] The invention relates to a preparation method of tandospirone citrate and belongs to the field of medicines. Background Art

[0002] Tandospirone citrate is an anti-anxiety drug developed by Sumitomo Pharma Co., Ltd. of Japan. It was first approved for marketing in Japan in 1996. The original formulation was tablets, and the domestic market specification was 10 mg (5 mg and 20 mg are not imported). The structural formula of Tandospirone citrate is: , which is the citrate salt of tandospirone.

[0003] The literature reports that there are three synthetic routes for tandospirone:

[0004] Route A: The literature Chem. Pharm. Bull. 39 (9) 2288-2300 (1991) uses compound III and compound IV to react in DMF with potassium carbonate and potassium iodide to prepare tandospirone.

[0005] . Compound III is a high-boiling oil, and dibromobutane is used in its synthesis. Since solid compound III cannot be obtained by conventional crystallization, and dibromobutane is also a high-boiling substance, the purification of compound III is relatively difficult.

[0006] Route B: Patent CN101362751 uses compound V and compound VI to react in DMF with potassium carbonate to prepare tandospirone.

[0007] .

[0008] The reaction temperature of this route is relatively high, which increases the requirements for industrial equipment, and the product color is darker. In post-treatment, activated carbon decolorization and acid dissolution and alkali precipitation are required to eliminate the product color, resulting in cumbersome production operations.

[0009] Route C: Patent US4507303 uses compound Ⅰ (cis-2,3-norbornane dicarboxylic anhydride) and compound Ⅱ (4-aminobutyl-1-(2-pyrimidinyl)-piperazine) to reflux in pyridine to prepare tandospirone.

[0010] .

[0011] This route uses pyridine to reflux for a long time at high temperature. After the reaction, the product is obtained by vacuum distillation and silica gel column purification. However, it has the disadvantages of pyridine odor, column purification is not conducive to industrialization, and low yield. Summary of the invention

[0012] Comprehensively analyzing the shortcomings of the above synthetic routes, we found that the problems existing in routes A and B are difficult to avoid, while in route C, the reaction of compound I and compound II first produces intermediate 1 (semi-amide compound), and the subsequent cyclization process is more difficult (as shown below), and the reaction time is long (US4507303). The cyclization process is the key step to determine whether the reaction is good or not;

[0013] .

[0014] In view of the problems existing in route C, the present invention adopts an innovative optimization route (as follows): compound I and compound II are reacted at low temperature in a solvent to obtain intermediate 1, intermediate 1 forms intermediate 2 (carboxylate) in an alkaline aqueous solution, and then an organic solvent immiscible with water is added to promote the conversion of intermediate 2 into tandospirone, and the generated tandospirone is then dissolved in the organic solvent, the alkaline aqueous layer is separated, the organic layer is dried with a desiccant, and then distilled under reduced pressure to obtain high-purity tandospirone. The tandospirone obtained by this route is salified with citric acid in a conventional manner reported in the literature to obtain tandospirone citrate with a purity of >99.9%;

[0015] .

[0016] The temperature of the reaction of compound I and compound II can be controlled at -20°C to 30°C, preferably 0-25°C. The solvent used can be a commonly used solvent in synthesis, such as cyclic ethers (such as tetrahydrofuran, dioxane, etc.), nitrile (such as acetonitrile), chlorinated hydrocarbons (such as dichloromethane, chloroform, etc.), aromatic hydrocarbons (such as benzene, toluene, etc.), preferably cyclic ethers. This step replaces the pyridine used in the literature, eliminates the stench in the synthesis process and post-treatment, reduces the reaction temperature, and adopts low temperature to obtain high-yield, high-purity intermediate 1, which has obvious advantages over the preparation method reported in the literature.

[0017] It is difficult to directly cyclize intermediate 1 to amide. The reflux reaction in pyridine takes a long time. In addition, due to the high reaction temperature, the product purity is poor and column treatment is required, which is not suitable for industrial production. Therefore, there are relatively few literature reports using this route.

[0018] The conventional method of forming amides is to convert carboxylic acid into acid chloride or anhydride and then react with amine. However, there are few reports on the synthesis of amides using carboxylates and amines. The literature J. Org. Chem. 2014, 79, 3, 943–954 reported the condensation reaction of amides using carboxylates and amines, but a condensation agent such as HBTU was added. The carboxylates were first activated and then the amines were added for reaction. Since the condensation agent is expensive, this method is not easy to industrialize.

[0019] In the present invention, after a large number of experiments and explorations, it is unexpectedly found that: by adding intermediate 1 to an alkaline aqueous solution to form intermediate 2 (carboxylate), and then adding an organic solvent immiscible with water, tandospirone can be obtained almost quantitatively, with high purity and quickly. Adding an organic solvent immiscible with water is the key to the reaction conversion. If intermediate 2 is only dissolved in alkaline water alone, it will only exist in the form of carboxylate for a long time and will not be converted to tandospirone. At the same time, if the added solvent is miscible with water, intermediate 2 will not be converted to tandospirone.

[0020] The base used to prepare the intermediate 2 can be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and other alkaline substances commonly used in organic synthesis. The water-immiscible organic solvent that promotes the conversion of the intermediate 2 into tandospirone can be chlorinated hydrocarbons, esters, aromatic hydrocarbons, etc., preferably dichloromethane and ethyl acetate.

[0021] This process greatly simplifies the process of preparing tandospirone by amidation of intermediate 1. The materials used are simple, the reaction conditions are mild, the reaction time is short, the yield and purity are high, and it is easy to industrialize. Compared with the current conventional amidation method, it has obvious advantages and is of reference value for other amidation reactions other than tandospirone products.

[0022] The tandospirone citrate prepared by the process is mixed evenly with lactose monohydrate, corn starch and carboxymethylcellulose calcium, a hydroxypropyl methylcellulose aqueous solution is added to prepare a soft material, wet granules are obtained by passing through a 20-mesh sieve, and dried at about 50°C. The granules are sieved through a 20-mesh sieve, magnesium stearate is added, and the mixture is uniformly mixed and tableted, coated, and tandospirone citrate tablets are obtained. In addition to the 10 mg specification, the inventor also prepared tablets with a specification of 5 mg by adjusting the formula ratio. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Tandospirone H NMR spectrum;

[0024] Figure 2 Tandospirone C-NMR spectrum;

[0025] Figure 3 Single crystal X-ray diffraction of tandospirone;

[0026] Figure 4 HPLC chromatogram of tandospirone citrate. DETAILED DESCRIPTION

[0027] Example 1: 100g of compound I and 500ml of tetrahydrofuran were placed in a three-necked flask, cooled to 0-5°C, and a mixture of 141.6g of compound II and 800ml of tetrahydrofuran was added dropwise. About half an hour after the start of the dropwise addition, a white solid precipitated. The mixture was stirred at 0-5°C for 2.5 hours and filtered to obtain a wet intermediate 1 with a dry weight of 232g. The yield was 96% and the purity was >99%.

[0028] The wet intermediate 1 was added to a solution of 34.7 g of sodium hydroxide and 1000 ml of water, stirred at room temperature to dissolve, 500 ml of dichloromethane was added and stirred for 1 hour, the layers were separated, 500 ml of dichloromethane was added to the aqueous layer and stirred for 1 hour, the layers were separated, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain 217 g of tandospirone, with a yield of 98%, a purity of >99.8%, and a single impurity of <0.1%.

[0029] Tandospirone is added to a solvent and heated to dissolve, and citric acid is added to obtain tandospirone citrate. This step has been reported in many literatures and will not be described in detail.

[0030] Example 2: 100g of compound I and 500ml of acetonitrile were placed in a three-necked flask, cooled to 0-5°C, and a mixture of 141.6g of compound II and 800ml of acetonitrile was added dropwise. About half an hour after the start of the addition, a white solid precipitated. The mixture was stirred at 0-5°C for 2.5 hours and filtered to obtain a wet intermediate 1 with a dry weight of 222g. The yield was 92% and the purity was >99%.

[0031] The wet intermediate 1 was added to a solution of 87.9 g of sodium carbonate and 1000 ml of water, and the solution was dissolved by stirring at room temperature. 500 ml of ethyl acetate was added and stirred for 1 hour. The layers were separated. 500 ml of ethyl acetate was added to the aqueous layer and stirred for 1 hour. The layers were separated, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to obtain 208 g of tandospirone with a yield of 98%, a purity of >99.8%, and a single impurity of <0.1%.

[0032] Example 3: Preparation of the pharmaceutical composition of the present invention

[0033] Tandospirone Citrate 5.0Kg

[0034] Lactose monohydrate 31.5Kg

[0035] Corn starch 1.55Kg

[0036] Carboxymethylcellulose calcium 1.2Kg

[0037] Hydroxypropyl methylcellulose 0.6Kg

[0038] Magnesium stearate 0.15Kg

[0039] 1.2Kg of coating powder.

[0040] Specification (10mg) Preparation process of tandospirone citrate tablets: Tandospirone citrate is evenly mixed with lactose monohydrate, corn starch and carboxymethylcellulose calcium, and a hydroxypropyl methylcellulose aqueous solution is added to prepare a soft material, which is passed through a 20-mesh sieve to obtain wet granules, which are dried at about 50°C, sieved through a 20-mesh sieve, and magnesium stearate is added. After mixing evenly, the granules are compressed into tablets and coated. A total of 500,000 tablets are prepared.

[0041] Example 4: Preparation of the pharmaceutical composition of the present invention

[0042] Tandospirone Citrate 2.5Kg

[0043] Lactose monohydrate 34.0Kg

[0044] Corn starch 1.55Kg

[0045] Carboxymethylcellulose calcium 1.2Kg

[0046] Hydroxypropyl methylcellulose 0.6Kg

[0047] Magnesium stearate 0.15Kg

[0048] 1.2Kg of coating powder.

[0049] Specification (5mg) Preparation process of tandospirone citrate tablets: Tandospirone citrate is evenly mixed with lactose monohydrate, corn starch and carboxymethylcellulose calcium, and a hydroxypropyl methylcellulose aqueous solution is added to prepare a soft material, which is passed through a 20-mesh sieve to obtain wet granules, which are dried at about 50°C, sieved through a 20-mesh sieve, and magnesium stearate is added. After mixing evenly, the granules are pressed into tablets and coated. A total of 500,000 tablets are prepared.

Claims

1. A method for preparing tandospirone citrate, characterized in that: The steps include: ， (1) Compound Ⅰ and compound Ⅱ react in a solvent to prepare intermediate 1; (2) intermediate 1 is reacted in an alkaline aqueous solution to form intermediate 2, and then dichloromethane or ethyl acetate immiscible with water is added to promote the conversion of intermediate 2 into tandospirone, wherein the alkali metal M in intermediate 2 is potassium or sodium; (3) Tandospirone forms a salt with citric acid in a solvent.

2. The preparation method according to claim 1, characterized in that: The solvent used in the reaction in step (1) is tetrahydrofuran, dioxane, acetonitrile, dichloromethane, chloroform, or toluene.

3. The preparation method according to claim 1, characterized in that: The reaction temperature in step (1) is -20°C to 30°C.

4. The preparation method according to claim 1, characterized in that: The base used in step (2) is sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

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