Preparation method of anti-platelet drug intermediate

Abstract

The invention discloses a preparation method of an anti-platelet drug intermediate, and particularly provides a preparation method of a compound as shown in a formula 2, which is characterized by comprising the following steps: in the presence of a solvent, reacting a compound as shown in a formula 1 with hydrazine hydrate and triphenylphosphine to generate the compound as shown in the formula 2; the preparation method provided by the invention has the advantages of few generated impurities, high product purity and good reaction efficiency. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for preparing an antiplatelet drug intermediate. Background Art

[0002] WO2022022559 discloses an antiplatelet drug and a synthesis method thereof, which includes a method for preparing a compound of formula 2 from a compound of formula 1 as described below:

[0003] ;

[0004] In this method, compound 1 is dissolved in NH3 / MeOH (7M, 2.0 L) solution, and NaBH4 is used as a catalyst. The actual yield of the reaction is low, and more impurities are produced during the reaction, which is not conducive to the subsequent reaction process.

[0005] In order to overcome the above defects, CN116813532A replaced the NH3 / MeOH in the above method with hydrazine hydrate / acetonitrile, which greatly improved the product purity. However, this method will produce impurity compound 3, which is difficult to remove using conventional methods, and after being brought into the next step of the reaction, it will still participate in the reaction to produce new impurities, resulting in waste of raw materials and increased difficulty in purification.

[0006] . Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the defects of high impurity content and difficulty in removing impurities during the synthesis of antiplatelet drug intermediates in the prior art, and to provide a method for preparing an antiplatelet drug intermediate with less impurities, high product purity and good reaction efficiency.

[0008] The present invention solves the above technical problems through the following technical solutions:

[0009] The present invention provides a method for preparing a compound of formula 2, which comprises the following steps: in the presence of a solvent, reacting a compound of formula 1 with hydrazine hydrate and triphenylphosphine to generate a compound of formula 2;

[0010] .

[0011] The solvent is a conventional solvent for this type of reaction in the art, and is based on the ability to dissolve the components of the reaction system, preferably a nitrile solvent; for example, acetonitrile.

[0012] In some embodiments, the molar ratio of the compound of formula 1 to the triphenylphosphine is 1:(1-3); preferably 1:(1-2); for example 1:2 or 1:3.

[0013] In some embodiments, the mass-to-volume ratio of the compound of Formula 1 and the solvent is 1 g: (2-4) ml; for example, 1 g: 3 ml.

[0014] In some embodiments, the molar ratio of the compound of formula 1 to the hydrazine hydrate is 1:(0.8-2.5); preferably 1:(0.9-2.2); for example 1:1 or 1:2.

[0015] In some embodiments, the reaction temperature of the reaction is 20-40°C; for example, 30°C.

[0016] In some embodiments, the content of impurity compound 3 in the product of the reaction is less than 0.1% by molar ratio. .

[0017] In some embodiments, the reaction is carried out under protective gas, which is a conventional protective gas for this type of reaction in the art, such as nitrogen, helium or argon; preferably nitrogen.

[0018] In some embodiments, the reaction materials of the reaction consist of: the compound of Formula 1, the hydrazine hydrate and the solvent.

[0019] In some embodiments, the reaction further comprises the following post-treatment steps: after the reaction is completed, an aqueous solution of inorganic acid is added to adjust the pH to 6-7, followed by extraction, washing and concentration.

[0020] In some embodiments, in the post-treatment step, the aqueous mineral acid solution is an aqueous hydrochloric acid solution; for example, a 1 M hydrochloric acid solution.

[0021] In some embodiments, in the post-treatment step, the extraction solvent is n-heptane.

[0022] In some embodiments, in the post-treatment step, the concentration is concentrated under reduced pressure.

[0023] The positive and progressive effect of the present invention is that the preparation method of the antiplatelet drug intermediate provided by the present invention does not generate impurity compound 3, has a high yield, and has a high product purity, and is suitable for industrial production. DETAILED DESCRIPTION

[0024] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0025] As described in the examples of the present application, "V" represents the volume of the solution corresponding to 1 g of compound 1, such as "3V" represents that the volume of the solution corresponding to 1 g of compound 1 is 3 ml).

[0026] Example 1

[0027] ;

[0028] Compound 1 (100 g), acetonitrile (237 g, 3.0 V), and triphenylphosphine (118 g) were mixed at 30 ° C under nitrogen, and then hydrazine hydrate (21.47 g) was added dropwise thereto. After the addition was completed, the mixture was stirred at 30 ° C for 10 hours. 1N HCl aqueous solution (164 g, 1.6 V) was added to the reacted mixture to adjust the pH to 6-7. The mixture was then extracted with water / n-heptane, and the organic phase was washed with water 3 times. Concentrated under reduced pressure to obtain 76 g of compound 2 (yield 99%, purity 98%, impurity compound 3 content <0.1%). .

[0029] Example 2

[0030] ;

[0031] Compound 1 (100 g), acetonitrile (237 g, 3.0 V), and triphenylphosphine (177 g) were mixed at 30 ° C under nitrogen, and then hydrazine hydrate (21.47 g) was added dropwise thereto. After the addition was completed, the mixture was stirred at 30 ° C for 10 hours. 1N HCl aqueous solution (164 g, 1.6 V) was added to the reacted mixture to adjust the pH to 6-7. The mixture was then extracted with water / n-heptane, and the organic phase was washed with water 3 times. Concentrated under reduced pressure to obtain 76 g of compound 2 (yield 99%, purity 98%, impurity compound 3 content <0.1%).

[0032] Comparative Example 1

[0033] ;

[0034] Acetonitrile (200 g, 3.1V) and compound 1 (166 g) were mixed at 30°C under nitrogen, and hydrazine hydrate (17.8 g) was then added dropwise thereto. After the addition was completed, the mixture was stirred at 30°C for 10 hours. 1N HCl aqueous solution (136 g, 1.6V) was added to the reacted mixture to adjust the pH to 6-7. The mixture was then extracted with water / n-heptane, and the organic phase was washed with water 3 times. Concentrated under reduced pressure to obtain 127 g of compound 2 (yield 99%, purity 95%, impurity compound 3 content 3%).

[0035] Comparative Example 2

[0036] ;

[0037] To a solution of compound 1 (263.0 g, 583.1 mmol) in NH3 / MeOH (7M, 2.0 L) was added NaBH4 (222 mg, 5.8 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 20 / 1) to give compound 2 (202 g, 100% yield, purity 60%) as a light yellow oil.

[0038] The comparison results show that the addition of triphenylphosphine in the preparation of compound 2 can improve the purity of the product without affecting the reaction yield, especially significantly reducing the content of the difficult-to-remove impurity compound 3, which is beneficial to the subsequent steps and suitable for industrial production.

[0039] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula 2, characterized in that: It includes the following steps: In the presence of a solvent, the compound of formula 1 reacts with hydrazine hydrate and triphenylphosphine to generate a compound of formula 2; 。 2. The preparation method according to claim 1, characterized in that It meets one or more of the following conditions: (1) The solvent is a nitrile solvent; (2) The mass-to-volume ratio of the compound of formula 1 and the solvent is 1 g: (2-4) ml; (3) The molar ratio of the compound of formula 1 to the hydrazine hydrate is 1:(0.8-2.5); (4) The molar ratio of the compound of formula 1 to the triphenylphosphine is 1:(1-3); (5) The reaction temperature of the reaction is 20-40°C; (6) The reaction is carried out under protective gas; (7) The reaction materials of the reaction are composed of the following: the compound of formula 1, the hydrazine hydrate, the triphenylphosphine and the solvent; (8) In the product of the reaction, the content of impurity compound 3 is less than 0.1% by molar ratio, 。 3. The preparation method according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The solvent is acetonitrile; (2) The mass-to-volume ratio of the compound of formula 1 and the solvent is 1 g:3 ml; (3) The molar ratio of the compound of formula 1 to the hydrazine hydrate is 1:(0.9-2.2); (4) The molar ratio of the compound of formula 1 to the triphenylphosphine is 1:(2-3); (5) The reaction temperature of the reaction is 30°C; (6) The protective gas is nitrogen, helium or argon.

4. The preparation method according to claim 3, characterized in that: It meets one or more of the following conditions: (1) The molar ratio of the compound of formula 1 to the hydrazine hydrate is 1:1 or 1:2; (2) The molar ratio of the compound of formula 1 to the triphenylphosphine is 1:2 or 1:3; (3) The protective gas is nitrogen.

5. The preparation method according to claim 1, characterized in that: The reaction further comprises the following post-treatment steps: after the reaction is completed, an inorganic acid aqueous solution is added to adjust the pH to 6-7, followed by extraction, washing and concentration.

6. The preparation method according to claim 5, characterized in that: The post-processing step satisfies one or more of the following conditions: (1) In the post-treatment step, the inorganic acid aqueous solution is a hydrochloric acid aqueous solution; (2) In the post-treatment step, the extraction solvent is n-heptane; (3) In the post-treatment step, the concentration is concentrated under reduced pressure.

7. The preparation method according to claim 6, characterized in that: The inorganic acid aqueous solution is a 1M hydrochloric acid aqueous solution.

Images