Preparation method of intermediate of BCL-2 inhibitor

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 specifically 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 apoptotic pathway. Many small molecule BH3 mimetics targeting Bcl-2 have been reported. Compounds having the formula (A) have also been described as inhibitors of Bcl-2 wild type and Bcl-2 G101V mutants.

[0003]

[0004] The compound of formula (II) is an important intermediate for the production of the compound of formula (A), as 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, namely the compound of formula (II), thereby increasing the yield of the compound raw material of the Bcl-2 inhibitor having the formula (A).

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

[0008]

[0009] In one embodiment of the present invention, the phosphoric acid raw material used in the reaction step is 85%

[0010] (w / w) phosphoric acid.

[0011] The concentration of phosphoric acid in the final reaction medium is 40%-55% (w / w), preferably 45%-50% (w / w), more preferably about 47% (w / w).

[0012] In one embodiment of the present invention, the solvent medium of the reaction includes methanol, acetone, water or a combination of two or three of them, preferably water.

[0013] In one embodiment of the present invention, the reaction is carried out at 5 - 30 °C, preferably 8 - 20 °C, more preferably about 10 °C.

[0014] As used herein, the term "about" means a range of ±20% of the value that follows; in some alternative embodiments, the term "about" means a range of ±10% of the value that follows; in some alternative embodiments, the term "about" means a range of ±5% of the value that follows.

[0015] As used herein, w / w refers to the weight / weight ratio.

[0016] Advantages of the present invention

[0017] The inventors of the present invention attempted to use the compound of formula (I) as a reaction raw material and hydrolyze it in the presence of different types of acids to obtain the compound of formula (II). The inventors found that the type of acid and the choice of reaction solvent greatly affect the purity and yield of the product; the present invention unexpectedly found that by using a specific type of acid and reaction medium, the reaction can not only proceed with a high yield, but also keep the by-products at a low level. The entire preparation method has good repeatability, is suitable for large-scale industrial production, and has good economic value. Detailed implementation manners

[0018] The preparation method of the compound of formula (II) of the present invention will be described in detail below.

[0019] The following is intended 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.

[0020] HPLC conditions: 1) Waters high performance liquid chromatography (ultraviolet detector); 2) Mobile phase A: water with 0.025% TFA, mobile phase B: acetonitrile with 0.025% TFA; 3) Chromatographic column: Waters CORTECS C18, 100mm * 4.6mm, 2.7um,; Ghost-Sniper column, 50mm * 4.6mm, Chromasir,; 4) Elution is carried out using the gradient method as shown in the following table, flow rate: 1.0 mL / min.

[0021] Time (minutes) A(％) B(％) 0 90 10 19 50 50 28 10 90 28.1 90 10 33 90 10

[0022] Example 1

[0023]

[0024] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.5 8 .1 6 tetradecan-11-yl)methyl benzoate (0.3 g, 0.65 mmol, prepared by the method described in PCT / CN2022 / 142314) was added to a mixed medium composed of methanol (0.9 mL) and pure water (2.1 mL) (i.e., 30% v / v methanol aqueous solution), and phosphoric acid (H3PO4, 2.0 mL, 32.5 mmol) with a concentration of 85% (w / w) was added to obtain a mixed solution. The mixed solution was stirred at 10 °C for 2 hours. Samples were taken for HPLC detection, and the results are recorded in Table 1.

[0025] Comparative Example 1

[0026]

[0027] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.5 8 .1 6 tetradecan-11-yl)methyl benzoate (0.3 g, 0.65 mmol) was added to a mixed medium composed of methanol (0.9 mL) and pure water (2.1 mL) (i.e., 30% v / v methanol aqueous solution), and trifluoroacetic acid (TFA, 2.0 mL, 26.9 mmol) was added to obtain a mixed solution. The mixed solution was stirred at 10 °C for 2 hours. Samples were taken for HPLC detection, and the results are recorded in Table 1.

[0028] Comparative Example 2

[0029]

[0030] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.5 8 .1 6Methyl (tetradecan-11-yl)benzoate (0.3 g, 0.65 mmol) was added to a mixed medium composed of methanol (0.9 mL) and pure water (2.1 mL) (i.e., 30% v / v aqueous methanol solution), and trifluoromethanesulfonic acid (2.0 mL, 25.0 mmol) was added. The mixed solution was stirred at 10 °C for 2 hours. Samples were taken for HPLC detection, and the results are recorded in Table 1.

[0031] Comparative Example 3

[0032]

[0033] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.5 8 .1 6 Methyl (tetradecan-11-yl)benzoate (0.3 g, 0.65 mmol) was added to a mixed medium composed of methanol (0.9 mL) and pure water (2.1 mL) (i.e., 30% v / v aqueous methanol solution), and p-toluenesulfonic acid (2.0 g, 11.6 mmol) was added to obtain a mixed solution. The mixed solution was stirred at 10 °C for 2 hours. Samples were taken for HPLC detection, and the results are recorded in Table 1.

[0034] Comparative Example 4

[0035]

[0036] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxa-11-azadispiro[5.1.58.16]tetradecan-11-yl)benzoate (0.3 g, 0.65 mmol) was added to a mixed medium composed of methanol (0.9 mL) and pure water (2.1 mL) (i.e., 30% v / v aqueous methanol solution), and acetic acid (2.0 mL, 35.0 mmol) was added. The mixed solution was stirred at 25 °C for 2 hours. Samples were taken for HPLC detection, and the results are recorded in Table 1.

[0037] Table 1. HPLC detection results

[0038]

[0039] From the results in Table 1, it can be concluded that under the phosphoric acid conditions of Example 1, Reactant I reacted more completely, the yield of Product II was high, and the by-products were the least; the reaction conditions of Example 1 could not only ensure the reaction proceeded with a high yield but also keep the by-products at a relatively low level, which was suitable for large-scale industrial production.

[0040] Example 2

[0041]

[0042] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxo-11-azadispiro[5.1.5 8 .1 6 tetradecan-11-yl)methyl benzoate (0.3 g, 0.65 mmol) was added to a mixed medium composed of acetone (0.9 mL) and pure water (2.1 mL) (i.e., 30% v / v aqueous acetone solution), and 85% phosphoric acid (H3PO4, 2.0 mL, 32.5 mmol) was added. The mixed solution was stirred at 10 °C for 2 hours. Samples were taken for HPLC detection, and the results are recorded in Table 2.

[0043] Example 3

[0044]

[0045] 2-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(1,5-dioxo-11-azadispiro[5.1.58.16]tetradecan-11-yl)methyl benzoate (10 g, 21.6 mmol) was added to pure water (100 mL), and 85% phosphoric acid (H3PO4, 66.7 mL, 1084 mmol) was added. The mixed solution was stirred at 10 °C for 2 hours. Samples were taken for HPLC detection, and the results are recorded in Table 2.

[0046] Table 2. HPLC Detection Results

[0047]

[0048] ND: Not detected.

[0049] The inventors further screened the reaction solvents. From the results in Table 2, it can be seen that using an aqueous methanol solution as the reaction solvent in Example 1 would produce by-product II, using an aqueous acetone solution as the reaction solvent in Example 2 had a lower product purity, while using pure water as the reaction solvent in Example 3, by-product II was not detected, and the obtained product II had the highest purity.

[0050] Therefore, under the condition of phosphoric acid as the catalyst, simultaneously selecting pure water as the reaction solvent can further ensure that the reaction proceeds with a high yield and can also keep the by-products at a relatively low level, which is suitable for large-scale industrial production.

[0051] In the foregoing, the present invention has been described in detail through general descriptions, 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 phosphoric acid to obtain the compound of formula (II), and the reaction route is as follows:

2. The preparation method according to claim 1, wherein The phosphoric acid is 85% phosphoric acid (w / w).

3. The preparation method according to any one of claims 1-2, characterized in that, The concentration of phosphoric acid in the final reaction medium is 40%-55% (w / w), preferably 45%-50% (w / w), more preferably about 47% (w / w).

4. The preparation method according to any one of claims 1 to 3, characterized in that, The solvent medium for the reaction includes methanol, acetone, water, or a combination of two of them or a combination of three of them, preferably water.

5. The preparation method according to any one of claims 1-4, characterized in that, The reaction is carried out at 5-30 °C, preferably 8-20 °C, more preferably about 10 °C.

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