Process for preparation of intermediates of BCL-2 inhibitors

Abstract

The invention discloses a method for preparing an intermediate of a BCL-2 inhibitor, and particularly relates to a method for preparing 2-((1H-pyrrolo [2, 3-b] pyridine-5-yl) oxy)-4-(2-oxo-7-azaspiro [3.5] nonane-7-yl) methyl benzoate, and the method is high in yield, few in by-products and suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an intermediate of a Bcl-2 inhibitor. Background Art

[0002] The B-cell lymphoma 2 (BCL-2) gene family is a group of proteins homologous to the Bcl-2 protein, encoding more than 20 proteins that regulate the intrinsic apoptosis pathway. Many small molecule BH3 mimetics targeting Bcl-2 have been reported. The compound with formula (A) has also been described as an inhibitor of Bcl-2 wild type and Bcl-2 G101V mutation.

[0003]

[0004] The compound of formula (II) is an important intermediate for the production of the compound of formula (A), which is described in WO2019 / 210828A1. A new preparation method is needed to increase the yield of the compound of formula (II) to be suitable for large-scale industrial production.

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a new preparation method, which can increase the yield of the intermediate of the Bcl-2 inhibitor, that is, the yield of the compound of formula (II), so as to increase the yield of the raw material of the Bcl-2 inhibitor compound with formula (A).

[0007] According to the first aspect of the present invention, there is provided a method for preparing an intermediate of a Bcl-2 inhibitor, the method comprising the following steps: using the compound of formula (I) as a reaction raw material, and hydrolyzing in the presence of an acid to obtain the compound of formula (II), that is, the intermediate of the Bcl-2 inhibitor. The reaction route is as follows:

[0008]

[0009] The molar ratio of the compound of formula (I) to the acid catalyst is 1:0.6 - 2.8.

[0010] In one embodiment of the present invention, the molar ratio of the compound of formula (I) to the acid is 1:0.8 - 1.6, preferably 1:1 - 1.4, more preferably about 1:1.2.

[0011] In one embodiment of the present invention, the acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid or a combination of two of them or a combination of three of them, preferably hydrochloric acid.

[0012] In one embodiment of the present invention, the reaction is carried out in an organic solvent, which is dichloromethane, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, isopropyl acetate, ethyl acetate or a combination of two of them or a combination of three of them, preferably dichloromethane.

[0013] In one embodiment of the present invention, the reaction is carried out at a temperature of 10 - 40 °C, preferably 20 - 30 °C, more preferably about 25 °C.

[0014] In one embodiment of the present invention, the reaction is carried out for 5 - 10 hours, preferably 6 - 8 hours, more preferably about 7 hours.

[0015] As used herein, the term "about" means a range of ±20% of the value following it; in some alternative embodiments, the term "about" means a range of ±10% of the value following it; in some alternative embodiments, the term "about" means a range of ±5% of the value following it.

[0016] The molar ratio of the compound and the acid described herein represents the molar ratio of the compound and the hydrogen ions in the acid.

[0017] As used herein, w / w refers to the weight / weight ratio.

[0018] Advantages of the present invention

[0019] The product compound (II) of the present invention is unstable under acidic conditions and is easily hydrolyzed. Therefore, the amount of acid used in the reaction is particularly important. The present invention unexpectedly finds that by using a specific amount of acid, the reaction can proceed with a high yield, and the by-products of acid hydrolysis of compound (II) can be at a relatively low level. The entire preparation method has good repeatability, is suitable for large-scale industrial production, and has good economic value. Detailed embodiments

[0020] The preparation method of the compound of formula (II) of the present invention will be described in detail below.

[0021] The following aims to illustrate and emphasize the accuracy of the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations within the knowledge of those skilled in the art should be considered. Unless otherwise specified, the temperature is in °C. The reagents are purchased from commercial providers such as Sigma-Aldrich, Alfa Aesar or TCI, and can be used without further purification unless otherwise specified. If no specific conditions are specified below, they should be carried out according to conventional conditions or the conditions recommended by the manufacturer. For example, the room temperature described herein is 25 °C. All compounds not specifically synthesized below are synthesized according to conventional methods in the art or methods disclosed in the existing literature.

[0022] HPLC conditions: 1) Agilent high performance liquid chromatography (ultraviolet detector); 2) Mobile phase A: water with 0.05% trifluoroacetic acid, mobile phase B: acetonitrile with 0.05% trifluoroacetic acid; 3) Chromatographic column: Ascentis Express C 18 , 150 mm * 4.6 mm, 2.7 μm; 4) Gradient elution was performed as shown in the following table, flow rate: 0.9 mL / min.

[0023] Time (minutes) A(％) B(％) 0 95 5 12 25 75 15 5 95 18 5 95 18.10 95 5 23 95 5

[0024] Example 1

[0025]

[0026] To a solution of methyl 2 - ((1H - pyrrolo[2,3 - b]pyridin - 5 - yl)oxy)-4-(2,2 - dimethoxy - 7 - azaspiro[3.5]nonan - 7 - yl)benzoate (1.0 g, 2.2 mmol, prepared by the method described in WO2019 / 210828A1) in dichloromethane (15 mL) was added 1.0 mol / L hydrochloric acid (2.7 mL, 2.7 mmol). The mixed solution was stirred at 25 °C for 18 hours. Samples were taken for HPLC detection, and the results are recorded in Table 1.

[0027] Comparative Example 1

[0028]

[0029] To a solution of methyl 2 - ((1H - pyrrolo[2,3 - b]pyridin - 5 - yl)oxy)-4-(2,2 - dimethoxy - 7 - azaspiro[3.5]nonan - 7 - yl)benzoate (1.0 g, 2.2 mmol) in dichloromethane (15 mL) was added 1.0 mol / L hydrochloric acid (6.2 mL, 6.2 mmol). The mixed solution was stirred at 25 °C for 18 hours. Samples were taken for HPLC detection, and the results are recorded in Table 1.

[0030] Comparative Example 2

[0031]

[0032] To a solution of methyl 2 - ((1H - pyrrolo[2,3 - b]pyridin - 5 - yl)oxy)-4-(2,2 - dimethoxy - 7 - azaspiro[3.5]nonan - 7 - yl)benzoate (28.0 g, 62 mmol) in dichloromethane (300 mL) was added 1.0 mol / L hydrochloric acid (35 mL, 35 mmol). The mixed solution was stirred at 25 °C for 20 hours. Samples were taken for HPLC detection, and the results are recorded in Table 1.

[0033] Table 1. HPLC Detection Results

[0034]

[0035] It can be concluded from Table 1 that under the condition that the molar ratio of Reactant I to HCl in Example 1 is about 1:1.2, Reactant I reacts more completely, the yield of Product II is high, and the by-products are the least; the reaction conditions of Example 1 can not only ensure the reaction proceeds with a high yield, but also make the by-products of the acid hydrolysis of Product II at a relatively low level, which is suitable for large-scale industrial production.

[0036] In the foregoing, the present invention has been described in detail by general description, specific examples and tests. Modifications or improvements made without departing from the spirit of the present invention fall within the protection scope of the present invention. The scope of the present invention is intended to be defined by the appended claims and their equivalents.

Claims

1. A method for preparing a compound of formula (II), comprising the following steps: Using the compound of formula (I) as a reaction raw material, it is hydrolyzed in the presence of an acid to obtain the compound of formula (II), and the reaction route is as follows: It is characterized in that: the molar ratio of the compound of formula (I) to the acid is 1:0.6 - 2.

8.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the compound of formula (I) to the acid is 1:0.8 - 1.6, preferably 1:1 - 1.4, and more preferably about 1:1.

2.

3. The preparation method according to any one of claims 1-2, characterized in that, The acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid or a combination of two of them or a combination of three of them, preferably hydrochloric acid.

4. The preparation method according to any one of claims 1-3, characterized in that, The reaction is carried out in an organic solvent, and the organic solvent is dichloromethane, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, toluene, isopropyl acetate, ethyl acetate or a combination of two of them or a combination of three of them, preferably dichloromethane.

5. The preparation method according to any one of claims 1-4, characterized in that, The reaction is carried out at 10 - 40 °C, preferably 20 - 30 °C, and more preferably about 25 °C.

6. The preparation method according to any one of claims 1-5, characterized in that, The reaction is carried out for 5 - 10 hours, preferably 6 - 8 hours, and more preferably about 7 hours.

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