A method for preparing a piperidine compound having antiplatelet activity

Abstract

The present invention provides a method for preparing a piperidine compound having antiplatelet activity. The present invention discloses a method for preparing a compound as shown in Formula I: in a solvent, under the condition that the pH of the reaction system is 11 to 13, a compound as shown in Formula Ia is subjected to a hydrolysis reaction to obtain a compound as shown in Formula I. The method can obtain a single product with good selectivity or yield, and the method is simple to operate, has mild reaction conditions, and is safe and environmentally friendly.

Description

Technical Field

[0001] The invention relates to a method for preparing a piperidine compound with antiplatelet activity. Background Art

[0002] Clopidogrel is the most widely used and best-selling anticoagulant in the world. Clopidogrel is a prodrug that produces a clopidogrel metabolite in the human body as shown in formula (a).

[0003] (a)

[0004] Compound (a) has 4 isomers. Among them, only the compound shown in formula (I) has the activity of inhibiting platelets in the human body, that is, the in vivo activity of clopidogrel mainly comes from this compound. This compound has irreversible inhibitory ability on the coagulation activity of platelets. In addition, compound I also plays an important role in various industrial production and scientific research. For example, it plays a role in clopidogrel-related metabolic experiments and can be used in the stability research of drugs such as clopidogrel.

[0005] (I)

[0006] In the prior art, the preparation method of compound I is mainly to obtain compound I by clopidogrel through enzyme catalysis. However, the cost of the enzyme required in this method is relatively high, and since the enzyme in this process has high requirements for reaction conditions, the production cost is further increased. Scott A. Shaw, Balu Balasubramanian and others disclosed a method for chemically synthesizing compound I, but the steps of this method are relatively complicated, and the product obtained is a mixture of four stereoisomers of the compound of formula a. In order to obtain pure compound I, it still needs to be separated and purified by means such as chiral columns, which is difficult to apply to large-scale production.

[0007] Therefore, further development of methods for producing compound I is still needed. Summary of the invention

[0008] The technical problem to be solved by the present invention is to provide a method for preparing a piperidine compound with antiplatelet activity in order to overcome the problems of high cost, strict reaction conditions, and difficulty in separating the obtained products in the prior art. The preparation method of the present invention can obtain a single product with good selectivity or yield, and the method is simple to operate, mild reaction conditions, and safe and environmentally friendly.

[0009] The present invention provides a method for preparing a piperidine compound having antiplatelet activity, which comprises the following steps:

[0010] In a solvent, under the condition that the pH of the reaction system is 11-13, the compound represented by formula Ia is hydrolyzed to obtain the compound represented by formula I;

[0011] .

[0012] In one embodiment, the reaction pH of the hydrolysis reaction is 11, 12 or 13, preferably 12.

[0013] In a certain embodiment, the solvent is an organic solvent, water or a mixed solvent of an organic solvent and water, preferably a mixed solvent of an organic solvent and water; the organic solvent is an alcohol solvent and / or an ether solvent.

[0014] The alcohol solvent is conventional in the art, such as methanol or ethanol.

[0015] The ether solvent is conventional in the art, for example, ethylene glycol dimethyl ether.

[0016] The volume ratio of the organic solvent to water is conventional in the art, preferably (5-1):1, such as 2:1.

[0017] In one embodiment, the solvent is a mixed solution of methanol and water, preferably a mixed solution of methanol and water in a volume ratio of 2:1.

[0018] In one embodiment, the mass volume ratio of the compound of formula Ia to the solvent is 10-50 mg / mL, for example 30 mg / mL.

[0019] In one embodiment, the hydrolysis reaction is preferably carried out in the presence of an inorganic base.

[0020] The inorganic base is preferably an alkali metal hydroxide, more preferably sodium hydroxide.

[0021] The molar ratio of the compound of formula Ia to the inorganic base is preferably 1:(1-5), more preferably 1:(1.5-2.3), for example 1:2.1.

[0022] In one embodiment, the temperature of the hydrolysis reaction is 35-50°C, preferably 40°C.

[0023] In one embodiment, the hydrolysis reaction requires stirring, and the stirring speed is 300-500 rpm, preferably 400 rpm.

[0024] The progress of the hydrolysis reaction is detected by conventional monitoring methods in the art, and generally the disappearance or no-reaction of the reactants is taken as the end point of the reaction. In a certain embodiment, the hydrolysis reaction time is 1 to 5 hours, preferably 3 hours.

[0025] In one embodiment, the hydrolysis reaction preferably includes the following addition sequence: adding an inorganic base to a mixture of the compound represented by Formula Ia and a solvent;

[0026] Wherein, the inorganic base is preferably added to the above mixture in the form of an inorganic base aqueous solution.

[0027] The concentration of the aqueous solution of the inorganic base is preferably 5-15 mol / L, for example 10 mol / L.

[0028] The concentration of the inorganic base in the reaction system is 0.1-0.3 mol / L, preferably 0.1-0.2 mol / L, for example 0.15 mol / L.

[0029] In one embodiment, the hydrolysis reaction is preferably carried out under the protection of a protective gas, and the protective gas may be nitrogen or a rare gas, such as nitrogen.

[0030] In a certain embodiment, the reaction pH is 11-13; the solvent is a mixed solution of methanol and water; the mass volume ratio of the compound of formula Ia to the solvent is 10-50 mg / mL; the hydrolysis reaction is carried out in the presence of an inorganic base; the molar ratio of the compound of formula Ia to the inorganic base is 1:(1-5); the temperature of the hydrolysis reaction is 35-50°C; and the time of the hydrolysis reaction is 1-5h.

[0031] In a certain embodiment, in the hydrolysis reaction, the reaction pH is 13; the solvent is a mixed solution of methanol and water in a volume ratio of 2:1; the mass volume ratio of the compound of formula Ia to the solvent is 30 mg / mL; the hydrolysis reaction is carried out in the presence of sodium hydroxide; the molar ratio of the compound of formula Ia to the inorganic base is 1:(1.5~2.3); the temperature is 40°C; the hydrolysis reaction time is 3h; and the protective gas is nitrogen.

[0032] In a certain embodiment, before the hydrolysis reaction, the process further includes: mixing the compound represented by Formula Ia with the solvent, and the mixing method is preferably ultrasonic vortex.

[0033] In a certain embodiment, the mixing is based on complete dissolution, and preferably the mixing time is 1 to 5 minutes, such as 1 minute.

[0034] In one embodiment, after the hydrolysis reaction is completed, the following post-treatment steps are also included: adjusting the pH of the reaction system to 3-4 and preparing liquid phase purification.

[0035] In one embodiment, the pH of the reaction system is adjusted by adding acid to the reaction system.

[0036] In one embodiment, the acid is an inorganic acid, preferably concentrated sulfuric acid or concentrated hydrochloric acid, such as concentrated hydrochloric acid.

[0037] The concentration of the acid is preferably 10-15 mol / L, for example 12 mol / L.

[0038] In a certain embodiment, in the post-treatment, the mobile phase A in the liquid phase is a formic acid aqueous solution, and the mobile phase B is acetonitrile;

[0039] The detection wavelength of the liquid phase is 214 nm;

[0040] The mobile phase flow rate of the liquid phase is 30 ml / min;

[0041] The elution gradient of the liquid phase is

[0042] Taking the total volume of the mobile phase as 100%;

[0043] The first stage: from 0 to 0.2 min, the volume of the mobile phase A is maintained at 60%, and the volume of the mobile phase B is maintained at 40%; from 0.2 to 8.0 min, the volume of the mobile phase A is gradually reduced from 60% to 45%, and the volume of the mobile phase B is gradually increased from 40% to 55%;

[0044] The second stage: from 8.0 to 8.5 min, the volume of the mobile phase A is gradually reduced from 45% to 5%, and the volume of the mobile phase B is gradually increased from 55% to 95%; from 8.5 to 10.0 min, the volume of the mobile phase A is maintained at 5%, and the volume of the mobile phase B is maintained at 95%;

[0045] The third stage: from 10.0 to 10.3 min, the volume of the mobile phase A increased from 5% to 60%, and the volume of the mobile phase B decreased from 95% to 40%; from 10.3 to 13.0 min, the volume of the mobile phase A was maintained at 60%, and the volume of the mobile phase B was maintained at 40%;

[0046] Right now

[0047]

[0048] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0049] The reagents and raw materials used in the present invention are commercially available.

[0050] The positive and progressive effects of the present invention are that the preparation method of the present invention can obtain a single product with good selectivity or yield, and the method is simple to operate, has mild reaction conditions, and is safe and environmentally friendly. DETAILED DESCRIPTION

[0051] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0052] The preparation of compound Ia of the present application is prepared by referring to the preparation method of compound Ib-2 in Example 1 in patent WO2022 / 022559A1.

[0053] Example 1 Preparation of Compound I

[0054]

[0055] 300 mg of compound Ia was added to 6 mL of MeOH and 3 mL of H2O, and ultrasonic vortexed for 1 min until completely dissolved. Then 130 μL of 10N NaOH aqueous solution was added to the mixture to adjust the pH to 12, and the mixture was reacted for 3 h under nitrogen, 40°C water bath and 400 rpm stirring, followed by the addition of 130 μL of concentrated HCl (12N) to adjust the pH to 3-4. The obtained mixture was purified by preparative liquid phase to obtain compound I. (yield 85%, purity 96%, ee value 100%)

[0056] 1 H NMR (601 MHz, CDCl3): 7.61-7.56 (m, 1H), 7.43-7.39 (m, 1H), 7.32-7.23 (m, 2H), 5.60 (s, 1H), 5.27 (t, J = 5.0 Hz, 1H), 4.82 (s, 1H), 3.72 (s,3H), 3.63 (d, J = 12.7 Hz, 1H), 3.21 (d, J = 13.0 Hz, 1H), 2.73-2.64 (m, 2H), 2.24-2.15 (m, 1H), 2.13 (d, J = 6.1 Hz, 1H), 1.78 (dq, J = 14.2, 2.0 Hz, 1H);

[0057] Preparation liquid parameters

[0058] Instrument: Waters liquid phase preparation instrument

[0059] Preparative column: Welch Xtimate C18

[0060] Mobile phase: A: 0.1% FA H2O (0.1% formic acid in water), B: CAN (acetonitrile)

[0061] Wavelength: 214nm

[0062] Flow rate: 30ml / min

[0063] gradient:

[0064]

[0065] Comparative Example 1 Preparation of Compound I

[0066]

[0067] 300 mg of compound Ia was added to 6 mL of MeOH and 3 mL of H2O, and ultrasonic vortexed for 1 min until completely dissolved. Then, 10 N NaOH aqueous solution was added to the mixture to adjust the pH to the value in the table below, and the mixture was reacted for 3 h under nitrogen, 40 ° C water bath and 400 rpm stirring, and then concentrated HCl (12 N) was added to adjust the pH to 3-4. The presence of raw materials and products in the obtained mixture was detected by thin layer chromatography (developing solvents were PE and EA), as shown in the following table:

[0068]

[0069] It can be seen from the table that when the pH value is low, the reaction is difficult to proceed; when the pH value is high, neither the raw material nor the product exists, indicating that the positions other than the sulfur atom in the raw material also undergo hydrolysis reactions, resulting in no product being obtained.

Claims

1. A method for preparing a compound as shown in formula I, characterized in that: It includes the following steps: In a solvent, the compound represented by formula Ia is subjected to a hydrolysis reaction under the condition that the pH of the reaction system is 12 to obtain a compound represented by formula I; ， The hydrolysis reaction is carried out in the presence of an inorganic base; The solvent is a mixed solvent of an organic solvent and water, wherein the organic solvent is methanol; The temperature of the hydrolysis reaction is 35-50°C.

2. The preparation method according to claim 1, characterized in that It meets one or more of the following conditions: (1) The mass volume ratio of the compound of formula Ia to the solvent is 10-50 mg / mL; (2) The hydrolysis reaction time is 1 to 5 hours; (3) The order of adding materials in the hydrolysis reaction is to add the inorganic base to the mixture formed by the compound represented by Formula Ia and the solvent; (4) The hydrolysis reaction is carried out under the protection of a protective gas, wherein the protective gas is nitrogen or a rare gas.

3. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The volume ratio of the organic solvent to water in the mixed solvent of the organic solvent and water is (5-1):1; (2) The molar ratio of the compound of formula Ia to the inorganic base is 1:(1-5); (3) The mass volume ratio of the compound of formula Ia to the solvent is 30 mg / mL; (4) The temperature of the hydrolysis reaction is 40°C; (5) The hydrolysis reaction time is 3 hours; (6) The hydrolysis reaction is carried out under the protection of a protective gas, wherein the protective gas is nitrogen.

4. The preparation method according to claim 3, characterized in that: The volume ratio of the organic solvent to water in the mixed solvent of the organic solvent and water is 2:

1.

5. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The inorganic base is an alkali metal hydroxide; (2) The molar ratio of the compound of formula Ia to the inorganic base is 1:(1.5-2.3); (3) The concentration of the inorganic base in the reaction system is 0.1-0.3 mol / L.

6. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The molar ratio of the compound of formula Ia to the inorganic base is 1:2.1; (2) The concentration of the inorganic base in the reaction system is 0.1-0.2 mol / L.

7. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The solvent is a mixed solution of methanol and water in a volume ratio of 2:1; (2) The concentration of the inorganic base in the reaction system is 0.15 mol / L.

8. The preparation method according to claim 1, characterized in that The hydrolysis reaction comprises the following steps: adding an inorganic base to a mixture of the compound represented by formula Ia and a solvent; the concentration of the inorganic base in the reaction system is 0.1-0.2 mol / L.

9. The preparation method according to claim 8, characterized in that: The inorganic base is added to the above mixture in the form of an inorganic base aqueous solution, wherein the concentration of the inorganic base aqueous solution is 5-15 mol / L.

10. The preparation method according to claim 1, characterized in that: The reaction pH is 12; the solvent is a mixed solution of methanol and water; the mass volume ratio of the compound of formula Ia to the solvent is 10-50 mg / mL; the hydrolysis reaction is carried out in the presence of an inorganic base; the molar ratio of the compound of formula Ia to the inorganic base is 1:(1-5); the temperature of the hydrolysis reaction is 35-50° C.; and the time of the hydrolysis reaction is 1-5 hours.

11. The preparation method according to claim 1, characterized in that: It meets one or both of the following conditions: (1) Before the hydrolysis reaction, the method further comprises: mixing the compound represented by Formula Ia with the solvent; (2) After the hydrolysis reaction is completed, the following post-treatment steps are also included: adjusting the pH of the reaction system to 3-4 and preparing liquid phase purification, Wherein, the conditions for liquid phase purification are that mobile phase A is 0.1% formic acid aqueous solution, and mobile phase B is acetonitrile; The detection wavelength of the liquid phase is 214 nm; The mobile phase flow rate of the liquid phase is 30 ml / min; The elution gradient of the liquid phase is: Taking the total volume of the mobile phase as 100%; The first stage: from 0 to 0.2 min, the volume of the mobile phase A is maintained at 60%, and the volume of the mobile phase B is maintained at 40%; from 0.2 to 8.0 min, the volume of the mobile phase A is gradually reduced from 60% to 45%, and the volume of the mobile phase B is gradually increased from 40% to 55%; The second stage: from 8.0 to 8.5 min, the volume of the mobile phase A is gradually reduced from 45% to 5%, and the volume of the mobile phase B is gradually increased from 55% to 95%; from 8.5 to 10.0 min, the volume of the mobile phase A is maintained at 5%, and the volume of the mobile phase B is maintained at 95%; The third stage: from 10.0 to 10.3 min, the volume of the mobile phase A increased from 5% to 60%, and the volume of the mobile phase B decreased from 95% to 40%; from 10.3 to 13.0 min, the volume of the mobile phase A was maintained at 60%, and the volume of the mobile phase B was maintained at 40%.

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