Benzenesulfonate containing piperidine ring compound, preparation method therefor, and use thereof

Abstract

Disclosed in the present invention are a benzenesulfonate containing a piperidine ring compound, a preparation method therefor, and a use thereof. Specifically, provided in the present invention is compound 2. Compound 2 can exist stably, and by means of a step of salt preparation, the content of the isomer impurity shown in formula 1' can be significantly reduced.

Description

A benzenesulfonate salt containing a piperidine ring compound, its preparation method and application

[0001] This application claims priority to Chinese patent application CN202311584010X, filed on November 24, 2023. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a benzenesulfonate salt of a piperidine ring-containing compound, a preparation method and application thereof. Background Art

[0003] Compound 1 is a compound with antiplatelet activity. The compound can generate active metabolites of clopidogrel through the action of hydrolases in the body, thereby further irreversibly inhibiting platelet coagulation activity.

[0004] The crude product of Compound 1 obtained by the prior art preparation process contains an isomeric impurity represented by Formula 1' (referred to as impurity 1'). Impurity 1' cannot be removed by conventional purification methods such as recrystallization and column chromatography. Compound 1 also cannot form stable salts with conventional acids or bases, such as hydrochloric acid, sulfuric acid, and sodium hydroxide.

[0005] Impurity 1' characterization data: LCMS: [M+H] + =472.1; 1 H NMR: (400MHz, DMSO-d6)δ=12.52(br s,1H),7.53-7.44(m,2H),7.43-7.34(m,2H),5.66(s,1H),5.34(br d,J=2.8Hz,1H),5.27(d,J=12.1Hz,1H),5.10(d,J=12.1Hz,1H),4.82-4.70(m,2H),3.65(s,3H),3.45(d,J=12.1Hz,1H),3.10(br d,J=12.5Hz,1H),2.75-2.57(m,2H),2.11-1.98(m,1H),1.82(br dd,J=1.8,14.2Hz,1H), 1.22(dd,J=2.8,6.2Hz,6H). Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the drawback of the prior art that isomeric impurities such as those represented by Formula 1' are difficult to remove. In particular, the content of impurity 1' is reduced from approximately 2% to even lower. Thus, a benzenesulfonate salt of a piperidine ring-containing compound, a preparation method, and applications thereof are provided. The present invention unexpectedly discovered that compound 1 can form a salt with benzenesulfonic acid. By preparing this salt form, the aforementioned isomeric impurities can be removed. This step significantly reduces the content of the isomeric impurities represented by Formula 1'.

[0007] The present invention mainly solves the above technical problems through the following technical solutions.

[0008] The present invention provides a compound 2:

[0009] The present invention also provides a method for preparing the compound 2 as described above, comprising the following steps: mixing the compound 1 with benzenesulfonic acid in a solvent, wherein the solvent is an ether solvent, a mixed solvent of an ether solvent and ethanol, an ester solvent, or an alkane solvent;

[0010] In one embodiment, the method comprises the following steps: mixing a solution 1 containing compound 1 with a solution 2 containing benzenesulfonic acid for reaction; wherein the solvent of the solution 1 is an ether solvent, a mixed solvent of an ether solvent and ethanol, or an ester solvent; the solvent of the solution 2 is an ether solvent or an alkane solvent; the ether solvent may be isopropyl ether; the ester solvent may be ethyl acetate; and the alkane solvent may be n-heptane.

[0011] In the preparation method of the compound 2, the purity of the compound 1 can be 90%-99.6%, for example, 94.6% or 97.5%.

[0012] In one embodiment, the compound 1 is a crude product of the compound 1, which is a mixture of the compound 1 and an isomeric impurity represented by formula 1'; the mass ratio of the compound 1 to the isomeric impurity may be (10-100):1, for example, 23.47:1 or 42.03:1;

[0013] In one embodiment, in the preparation method of compound 2, when the solvent is a mixed solvent of an ether solvent and ethanol, the volume ratio of the ether solvent to the ethanol is (1-10):1, for example, 5:1.

[0014] In one embodiment, in the preparation method of the compound 2, the mass volume ratio of the compound 1 to the solvent of the solution 1 is 1:(1-10) g / ml, for example, 1:2.3 g / ml, 1:4 g / ml or 1:6 g / ml.

[0015] In one embodiment, in the preparation method of the compound 2, the molar ratio of the benzenesulfonic acid to the compound 1 can be (0.3-1):1, for example, 0.5:1, 0.98:1 or 1:1.

[0016] In one embodiment, in the preparation method of compound 2, the mass volume ratio of the benzenesulfonic acid to the solvent of solution 2 is 1:(0.1-10) g / ml, for example, 1:0.15 g / ml, 1:0.7 g / ml or 1:10 g / ml.

[0017] In one embodiment, the preparation method of compound 2 further includes the operation of mixing with a solvent 3; the solvent 3 is a mixed solvent of an ether solvent and acetonitrile, or an alkane solvent, the ether solvent is isopropyl ether; the alkane solvent is n-heptane; when the solvent 3 is an ether solvent and acetonitrile, the volume ratio of the ether solvent to the acetonitrile can be (13-20):1, for example, 15:1.

[0018] In one embodiment, in the preparation method of the compound 2, the mass volume ratio of the compound 1 to the solvent 3 is 1:(3-45) g / ml, for example, 1:6 g / ml, 1:17.85 g / ml or 1:27 g / ml.

[0019] In one embodiment, the method for preparing compound 2 may further include adding solution 2 containing benzenesulfonic acid to solution 1 containing compound 1, and the addition rate may be 1-10 V / h, for example, 4 V / h.

[0020] In one embodiment, the method for preparing compound 2 may further include adding solvent 3 to a mixed solution of solution 1 containing compound 1 and solution 2 containing benzenesulfonic acid, and the addition rate may be 0.1-3 V / h, for example, 1.5 V / h.

[0021] In one embodiment, in the method for preparing compound 2, the mixing temperature is a conventional temperature for this type of reaction in the art, such as 25°C.

[0022] In one embodiment, in the preparation method of compound 2, the mixing reaction time is 5-100 hours, for example, 9.3 hours, 22 hours or 73 hours.

[0023] In a certain embodiment, the preparation method of compound 2 includes Scheme A or Scheme B:

[0024] Scheme A: A solution 1 containing compound 1 is mixed with a solution 2 containing benzenesulfonic acid for reaction; the solvent of solution 1 is a mixed solvent of isopropyl ether and ethanol (for example, the volume ratio of isopropyl ether to ethanol is 5:1); the solvent of solution 2 is isopropyl ether; further, after the mixing reaction, the operation of mixing with solvent 3 is included; the solvent 3 is a mixed solution of isopropyl ether and acetonitrile (for example, the volume ratio of isopropyl ether to ethanol is 15:1);

[0025] Scheme B: Solution 1 containing compound 1 and solution 2 containing benzenesulfonic acid are mixed and reacted; the solvent of solution 1 is ethyl acetate; the solvent of solution 2 is n-heptane.

[0026] In a certain scheme, a solution 1 containing compound 1 is mixed with a solution 2 containing benzenesulfonic acid for reaction; wherein the solvent of the solution 1 is an ether solvent, a mixed solvent of an ether solvent and ethanol, or an ester solvent; the solvent of the solution 2 is an ether solvent or an alkane solvent; the ether solvent is isopropyl ether; the ester solvent is ethyl acetate; the alkane solvent is n-heptane; the purity of the compound 1 is 90%-99.6%; the compound 1 is a crude product of the compound 1, which is a mixture of the compound 1 and the isomeric impurities represented by formula 1'; the mass ratio of the compound 1 to the isomeric impurities is (1 0-100):1; the mass volume ratio of the compound 1 to the solvent of the solution 1 is 1:(1-10) g / ml; the molar ratio of the benzenesulfonic acid to the compound 1 is (0.3-1):1; the mass volume ratio of the benzenesulfonic acid to the solvent of the solution 2 is 1:(0.1-10) g / ml; further, it can also include an operation of mixing with a solvent 3; the solvent 3 is a mixed solvent of an ether solvent and acetonitrile, or an alkane solvent, the ether solvent is isopropyl ether; the alkane solvent is n-heptane; the mass volume ratio of the compound 1 to the solvent 3 is 1:(3-45) g / ml.

[0027] The purity of the compound 2 prepared by the method for preparing the compound 2 is above 98.5%, for example, 98.9% or 99%.

[0028] In the product prepared by the method for preparing compound 2, the content of impurity 1' is less than 1%, for example, 0.8% or less than 0.1%.

[0029] The present invention also provides a use of the aforementioned compound 2 in the preparation of the aforementioned compound 1;

[0030] The present invention also provides a method for purifying compound 1, which comprises the following steps:

[0031] S1: the preparation method of compound 2 as described in any of the previous schemes;

[0032] S2: Compound 2 is hydrolyzed to obtain compound 1.

[0033] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0034] The reagents and raw materials used in the present invention are commercially available.

[0035] The present invention provides a positive improvement in that the piperidine ring-containing compound is difficult to form salts with other acids or bases and has no impurity-removing effect. The present invention provides a benzenesulfonate salt of a piperidine ring-containing compound, a preparation method, and applications thereof. The benzenesulfonate salt is stable and, through the salt preparation step, significantly reduces the content of isomeric impurities such as those represented by Formula 1'. DETAILED DESCRIPTION

[0036] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0037] Abbreviation table:

[0038] The test methods involved in the following embodiments are as follows:

[0039] High Performance Liquid Chromatography (HPLC)

[0040] The detailed parameters are as follows:

[0041] Example 1 Preparation of Compound 1

[0042] Compound 1 was prepared according to the protocol described in Example 1 of patent WO2022022559. The resulting compound 1 contained an impurity content of approximately 4%-6%. Purification of this compound 1 by column chromatography (EA / PE = 1:10) reduced the impurity 1' content to 2.5%-3%, but this could not be further reduced.

[0043] Example 2 Preparation of benzenesulfonate

[0044] At 25°C, compound 1 (2 g, 94.6% purity, including 4.21% impurity 1') was dissolved in 6 V of IPE / EtOH solution (5:1 by volume). A solution of benzenesulfonic acid (335 mg) in IPE (335 mL, 10 wt%) was added to the mixture at a rate of 4 V / h, and the mixture was stirred for 1 h. After stirring, 6 V of IPE / ACN solution (15:1 by volume) was added to the mixture, and stirring was continued for 4 days. The resulting mixture was filtered, and the filter cake was dried under vacuum at 30°C to obtain compound 1 benzenesulfonate salt with a purity of 98.9% and an impurity 1' content of 0.8%.

[0045] Example 3 Preparation of benzenesulfonate

[0046] At 25°C, compound 1 (2 g, purity 97.5%, of which the impurity 1' content was 2.32%) was added to ethyl acetate (4V) and stirred for 10 minutes. Then, benzenesulfonic acid (0.98eq) and n-heptane (0.15V) were added thereto, stirred for 9 hours, filtered and the filter cake was washed with (2V) ethyl acetate, and dried at 25°C for 20 hours to obtain compound 1 benzenesulfonate with a purity of 99.0%, of which the impurity 1' content was 0.7%.

[0047] Comparative Example 1: Salt type screening

[0048] 25 mg of compound 1 prepared in Example 1 was dissolved in 0.5 mL of each solvent. Acid or base (0.55-1.1 eq) was then added to the solution at room temperature to allow the reaction to proceed. Conventional crystallization methods (antisolvent method, solvent evaporation method, cooling crystallization, etc.) failed to induce solid precipitation. The salt formation and impurity removal effects of the products are listed in the table below:

[0049] The corresponding situations are as follows:

[0050] Note: “None” in the table means no impurity removal effect.

[0051] As can be seen from the above, compound 1 can form salts with some acids or bases, but the physical form of these salts is oily and cannot remove the isomer impurities shown in Formula 1'.

Claims

1. A compound 2:

2. A preparation method of compound 2 as described in claim 1, characterized in that, it comprises the following steps: In a solvent, Compound 1 is mixed with benzenesulfonic acid, and the solvent is an ether solvent, a mixed solvent of an ether solvent and ethanol, an ester solvent or an alkane solvent; 3. The preparation method of compound 2 as described in claim 2, characterized in that, it comprises the following operations: mixing and reacting solution 1 containing compound 1 with solution 2 containing benzenesulfonic acid; wherein, the solvent of the solution 1 is an ether solvent, a mixed solvent of an ether solvent and ethanol, or an ester solvent; the solvent of the solution 2 is an ether solvent or an alkane solvent.

4. The preparation method of compound 2 as described in any one of claims 2-3, characterized in that, it satisfies one or more of the following conditions: (1) The ether solvent is isopropyl ether; (2) The ester solvent is ethyl acetate; and (3) The alkane solvent is n-heptane.

5. The preparation method of compound 2 as described in any one of claims 2-3, characterized in that, it satisfies one or more of the following conditions: (1) The purity of the compound 1 is 90%-99.6%; (2) The compound 1 described is the crude product of compound 1, and the crude product of compound 1 is a mixture of compound 1 and an isomeric impurity represented by Formula 1'; the mass ratio of the compound 1 to the isomeric impurity is (10 - 100):1; (3) When the solvent is a mixed solvent of an ether solvent and ethanol, the volume ratio of the ether solvent to the ethanol is (1-10):1; (4) The molar ratio of the benzenesulfonic acid to the compound 1 is (0.3-1):1; (5) The preparation method of the compound 2 further comprises an operation of mixing with solvent 3; the solvent 3 is a mixed solvent of an ether solvent and acetonitrile, or an alkane solvent; (6) The mixing temperature is 25°C; (7) The mixing reaction time is 5-100h; (8) The purity of the compound 2 prepared by the preparation method of the compound 2 is above 98.5%; and (9) In the product prepared by the preparation method of the compound 2, the content of impurity 1' is less than 1%.

6. The preparation method of compound 2 as described in claim 5, characterized in that, it satisfies one or more of the following conditions: (1) The purity of the compound 1 is 94.6% or 97.5%; (2) The compound 1 described is the crude product of compound 1, and the crude product of compound 1 is a mixture of compound 1 and an isomeric impurity represented by formula 1'; the mass ratio of the compound 1 to the isomeric impurity is 23.47:1 or 42.03:1; (3) When the solvent is a mixed solvent of an ether solvent and ethanol, the volume ratio of the ether solvent to the ethanol is 5:1; (4) The molar ratio of the benzenesulfonic acid to the compound 1 is 0.5:1, 0.98:1 or 1:1; (5) When the solvent 3 is a mixed solvent of an ether solvent and acetonitrile, the volume ratio of the ether solvent to the acetonitrile is (13-20):1, such as 15:1; (6) The mass-volume ratio of the compound 1 to the solvent 3 is 1:(3-45) g / ml, such as 1:6 g / ml, 1:17.85 g / ml or 1:27 g / ml; (7) The mixing reaction time is 9.3h, 22h or 73h; (8) The purity of the compound 2 prepared by the preparation method of the compound 2 is 98.9% or 99%; and (9) In the product prepared by the preparation method of the compound 2, the content of impurity 1' is 0.8% or less than 0.1%.

7. The preparation method of compound 2 as described in claim 3, characterized in that, it satisfies one or more of the following conditions: (1) The mass-volume ratio of the compound 1 to the solvent of the solution 1 is 1:(1 - 10) g / ml; for example, 1:2.3 g / ml, 1:4 g / ml, or 1:6 g / ml; (2) The mass-volume ratio of the benzenesulfonic acid to the solvent of the solution 2 is 1:(0.1 - 10) g / ml; for example, 1:0.15 g / ml, 1:0.7 g / ml, or 1:10 g / ml; and (3) Add the solution 2 containing benzenesulfonic acid to the solution 1 containing compound 1, and the addition rate is 1 - 10 V / h, for example, 4 V / h.

8. The preparation method of the compound 2 as described in claim 2, characterized in that, it includes Scheme A or Scheme B: Scheme A: Mix and react the solution 1 containing compound 1 with the solution 2 containing benzenesulfonic acid; the solvent of the solution 1 is a mixed solvent of isopropyl ether and ethanol (for example, the volume ratio of isopropyl ether to ethanol is 5:1); the solvent of the solution 2 is isopropyl ether; further, after the mixing reaction, it also includes the operation of mixing with solvent 3; the solvent 3 is a mixed solution of isopropyl ether and acetonitrile (for example, the volume ratio of isopropyl ether to ethanol is 15:1); Scheme B: Mix and react the solution 1 containing compound 1 with the solution 2 containing benzenesulfonic acid; the solvent of the solution 1 is ethyl acetate; the solvent of the solution 2 is n-heptane.

9. Use of a compound 2 as described in claim 1 in the preparation of the compound 1; 10. A purification method for Compound 1, the purification method comprising the following operating steps: S1: The preparation method of the compound 2 as described in any one of claims 2 - 8; S2: The compound 2 undergoes a hydrolysis reaction to prepare the compound 1.

Images