Preparation method of Venoclara intermediate

Abstract

The invention provides a preparation method of a Venoclara intermediate. The preparation method comprises the following steps: (1) carrying out nucleophilic substitution reaction on a compound shown as a formula (I) and methanol under the catalysis of a copper reagent to obtain a compound shown as a formula (II); and (2) reducing methyl in the compound of the formula (II) under the action of Lewis acid to obtain a compound of a formula (III). In the methyl reduction step, the aluminum trichloride is selected for methyl reduction under the acidic condition, the aluminum trichloride is very low in cost, few in reaction byproduct impurities and high in yield, the use of boron tribromide is avoided, and the boron tribromide is easy to volatilize, high in toxicity and high in cost. And industrial production is not easy to realize. By-product impurities are few, the operation difficulty in industrial production is greatly reduced, and the yield of the whole reaction is improved. The impurities in each step of the reaction are less, the separation difficulty and cost are obviously reduced, and the method is more suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drug synthesis, and particularly relates to a preparation method of a venetoclax intermediate. Background Art

[0002] Venetoclax, CAS registration number: 1257044-40-8, chemical name: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)–N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide, and its structural formula is:

[0003]

[0004] Venetoclax was approved by the FDA for marketing on April 11, 2016. It is the first BCL-2 inhibitor approved by the US FDA and is currently approved by the US FDA for the treatment of the following diseases:

[0005] 1. Chronic lymphocytic leukemia (CLL) with chromosome 17p deletion abnormality;

[0006] 2. Second-line treatment of chronic lymphocytic leukemia / small lymphocytic lymphoma (SLL) in combination with rituximab;

[0007] 3. First-line treatment of acute myeloid leukemia not suitable for standard induction treatment in combination with azacitidine / decitabine / cytarabine.

[0008] Venetoclax is the world's first BCL-2 (B-cell lymphoma-2 gene) inhibitor, a selective anti-apoptotic protein and an orally bioavailable small molecule inhibitor. It is highly active in chronic lymphocytic leukemia and was initially approved by the FDA for chromosome 17p deletion or relapsed / refractory chronic lymphocytic leukemia (CLL). Currently, venetoclax has been marketed in more than 50 countries / regions around the world.

[0009] Venetoclax has cytotoxic activity in tumor cells overexpressing BCL-2. Venetoclax selectively inhibits the anti-apoptotic protein BCL-2, which is overexpressed in chronic lymphocytic leukemia (CLL) cells and acute myeloid leukemia (AML) cells. BCL-2 mediates tumor cell survival and is associated with chemotherapy resistance. Venetoclax directly binds to the BCL-2 protein, displaces pro-apoptotic proteins and restores the apoptotic process.

[0010] The original research patent reported a synthesis method of venetoclax. This route uses 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine and 5-hydroxy-7-azaindole as starting materials, and venetoclax is prepared through substitution, hydrolysis, and condensation reactions. The synthesis route is as follows:

[0011]

[0012] Among them, 5-hydroxy-7-azaindole is a key intermediate for the preparation of venetoclax, and its market supply price is very high. The cost of this key intermediate determines the cost of venetoclax API. Currently, in the synthesis method of 5-hydroxy-7-azaindole reported in the literature, a large amount of DMF is used in the methoxy substitution bromine reaction. DMF has a high boiling point and is difficult to remove. In the demethylation step, boron tribromide is used. Boron tribromide is volatile, highly toxic, and has a high cost. The post-treatment of the process is cumbersome, not convenient for industrial scale-up operation, difficult to obtain a high-purity target product, and has problems such as low yield and high cost. Due to the limitations of the preparation process, its large-scale production is restricted, and a new synthesis process is needed to solve the deficiencies in the existing technology. Summary of the Invention

[0013] The present invention provides a preparation method of a venetoclax intermediate to solve the problems of high cost, poor safety, cumbersome post-treatment of the process, inconvenient industrial scale-up operation, difficult to obtain a high-purity target product, low yield, and high cost when using boron tribromide in the synthesis of 5-hydroxy-7-azaindole at present. The present invention provides a brand-new preparation method of 5-hydroxy-7-azaindole.

[0014] In order to achieve the object of the present invention, the inventors of the present invention obtained the following technical solutions through a large number of experimental studies:

[0015]

[0016] The present invention provides a preparation method of a venetoclax intermediate, which is characterized by including the following steps:

[0017] (1): The compound of formula (Ⅰ) undergoes a nucleophilic substitution reaction with methanol under the catalysis of a copper reagent to obtain the compound of formula (Ⅱ);

[0018] (2): The compound of formula (Ⅱ) reduces the methyl group under the action of a Lewis acid to obtain the compound of formula (Ⅲ).

[0019] The reaction temperature of step (1) is 90 °C, the reaction time is 2 hours, and the molar ratio of cuprous bromide to the compound of formula (Ⅰ) is 1.05:1 - 1.20:1.

[0020] Preferably, ethylene glycol dimethyl ether is used as the solvent in this step.

[0021] The reaction temperature in step (2) is 40 °C, the reaction time is 2 hours, the molar ratio of anhydrous aluminum trichloride to the compound of formula (II) is 1.5:1 - 2.5:1, and the molar ratio of trimethylamine hydrochloride to the compound of formula (II) is 3.00:1 - 4.00:1.

[0022] Preferably, dichloromethane is used as the solvent in this step.

[0023] Through the step design of the technical solution of the present invention, problems in the prior art such as the use of a large amount of DMF and boron tribromide, difficult product purification, and high production costs are avoided. In the step of reducing the methyl group in the present invention, aluminum trichloride is selected to reduce the methyl group under acidic conditions. Aluminum trichloride has a very low cost, few by-products and impurities in the reaction, high yield, and the use of boron tribromide is avoided. Boron tribromide is volatile, toxic, and costly, and is not easy to be industrially produced. The by-products and impurities in the present invention are few, greatly reducing the operation difficulty in industrial production and increasing the yield of the whole reaction. Each step of the above reaction has fewer impurities, and the separation difficulty and cost are significantly reduced, making it more suitable for industrial production. Description of the Drawings

[0024] Figure 1 : Liquid phase spectrum of the compound of formula (II)

[0025] Figure 2 : Liquid phase spectrum of the compound of formula (III)

[0026] Figure 3 : Of the compound of formula (III) 1 1H-NMR spectrum Detailed Description of the Invention

[0027] The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention to the scope of the described examples.

[0028] The reagents used in the present invention can all be purchased from the market or can be prepared by the methods described in the present invention.

[0029] 1. Synthesis of (II): Add 400 ml of ethylene glycol dimethyl ether to a 1000 ml three-necked reaction flask, add 80.0 g of (I), add 64 g of cuprous bromide, cool down to 0 °C, add 230 g of sodium methoxide, stir for 1 hour, then slowly drop 200 ml of methanol into the reaction flask, and heat up to 90 °C and stir for 2 hours. After the reaction is completed, concentrate DME, add 2000 ml of ethyl acetate, stir for 1 hour, and let it stand for liquid separation. Concentrate the organic layer to dryness at 45 °C, add 90 ml of toluene to the system, heat to 110 °C to dissolve, stir for 2 hours, then naturally cool to 20 °C, filter, wash the filter cake with 10 ml * 2 of toluene, and dry the filter cake in a blast dryer at 60 °C to obtain 49.3 g of a pale yellow solid with a purity of 98.89% and a yield of 82%.

[0030] 2. Synthesis of (Ⅲ): Add 200 ml of dichloromethane and 36 g of anhydrous aluminum trichloride into a 500-ml three-necked reaction flask. Cool the system to below 10 °C, add 42 g of trimethylamine hydrochloride and stir to mix. Control the temperature below 10 °C, and dropwise add a solution of 20 g of (Ⅱ) dissolved in 100 ml of dichloromethane. After the addition, warm the system to 40 °C and stir for 2 hours. After the reaction is completed, slowly pour the reaction solution into an ice-water bath, stir, separate the organic phase, collect the aqueous phase, add 30 g of sodium bicarbonate to the aqueous phase to adjust the pH to 6 - 7, precipitate solids, control the temperature at 0 - 10 °C and stir for 3 hours, filter by suction, wash the filter cake with 20 ml of water, and dry the filter cake in a blast dryer at 60 °C to obtain 17.4 g of a pale yellow solid with a purity of 99.45% and a yield of 96%.

[0031] The above embodiments and the descriptions in the specification only illustrate the principle of the present invention. Without departing from the spirit and scope of the present invention, the present invention needs to be continuously changed and improved, and these changes and improvements all fall within the scope of the present invention claimed. The scope of protection claimed by the present invention is defined by the appended claims and their equivalents.

Claims

1. A preparation method of venetoclax intermediate, characterized in that It includes the following steps: (1) The compound of formula (Ⅰ) undergoes a nucleophilic substitution reaction with methanol under the catalysis of a copper reagent to obtain the compound of formula (Ⅱ): (2) The methyl group of the compound of formula (Ⅱ) is reduced under the action of a Lewis acid to obtain the compound of formula (Ⅲ): The reaction temperature of step (1) is 90 °C, the reaction time is 2 hours, and the molar ratio of cuprous bromide to the compound of formula (Ⅰ) is 1.05:1 - 1.20:

1. Preferably, ethylene glycol dimethyl ether is used as the solvent in this step; the reaction temperature of step (2) is 40 °C, the reaction time is 2 hours, the molar ratio of anhydrous aluminum trichloride to the compound of formula (Ⅱ) is 1.5:1 - 2.5:1, and the molar ratio of trimethylamine hydrochloride to the compound of formula (Ⅱ) is 3.00:1 - 4.00:

1. Preferably, dichloromethane is used as the solvent in this step.

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