Preparation method of Venoclara impurity

Abstract

The invention provides a chemical compound as shown in a formula (I) of a vonaka impurity reference substance and a synthetic route thereof. According to the invention, a brand-new impurity possibly generated in a Vickers synthesis process is obtained based on reaction conditions and reaction products of a condensation reaction through research on a synthesis route of Vickers, an impurity spectrum of Vickers is enriched and perfected, comprehensive control on the quality of Vickers is facilitated, and the quality of Vickers is improved. The yield of the vonakula is improved, and the method has important significance for optimizing the production process of the vonakula.

Description

Technical Field

[0001] The invention relates to the technical field of chemical drug analysis and drug synthesis, and in particular to a method for preparing venetoclax impurity. Background Art

[0002] Venetoclax (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, its structural formula is:

[0003]

[0004] Venetoclax is a first-in-class synthetic peptide developed by AbbVie and is a Bcl-2 selective inhibitor (Bcl-2 protein is an important regulatory component of cell apoptosis and is widely present and highly expressed in tumor cells). Venetoclax is currently the only apoptosis drug approved for marketing in the world that is developed based on the mechanism of cell apoptosis.

[0005] On December 2, 2020, Venetoclax was approved by the China National Medical Products Administration (NMPA) and is marketed by AbbVie under the trade name Currently, no company in China has registered APIs or applied for tablets.

[0006] The global sales of Venetoclax has been rising steadily, reaching RMB 14 billion in 2022. In China, the price of each 0.1g Venetoclax tablet ranges from RMB 117.5 to RMB 4,860. Based on the sales of RMB 14 billion in 2022, it is estimated that the global usage of Venetoclax API in 2022 will be about 300 to 11,900 kg, and the global annual demand is estimated to be more than 1,000 kg.

[0007] Looking at the main synthetic process of venetoclax, its preparation is basically to obtain aldehyde products by a one-pot reaction of 3,3-dimethylcyclohexanone, and then obtain the main side chain fragment 1-(4-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine hydrochloride through reductive amination; then the essential coupling is carried out with the benzene ring connected to the main fragment 5-hydroxy-7-azaindole, and the obtained product is condensed with the main fragment benzenesulfonamide and hydrolyzed to obtain the finished product of venetoclax. Its synthetic route is as follows:

[0008]

[0009] Although some venetoclax impurities have been reported in existing literature and data, further research on other impurities that may be produced in the venetoclax synthesis process or subsequent preparation and storage processes can not only enrich and improve the impurity spectrum of venetoclax, but also has great significance for the comprehensive control of venetoclax quality. Summary of the invention

[0010] The technical problem to be solved by the present invention is to overcome the defects of the prior art. The present invention proposes a method for preparing venetoclax impurities, improves the impurity spectrum of venetoclax, and applies the method to the quality control of venetoclax.

[0011] In order to solve the above technical problems, the technical solution adopted by the present invention is: a method for preparing venetoclax impurity, characterized in that the venetoclax impurity has a structure as shown in formula (I):

[0012]

[0013] The specific synthetic route of the venetoclax impurity is as follows:

[0014]

[0015] Furthermore, the compound of formula (II) reacts with the compound of formula (III) in the presence of a solvent and a condensing agent to obtain a compound of formula (I), and the molar ratio of the compound of formula (II), the compound of formula (III) and the condensing agent is 1:1-3:1.1-3.

[0016] Furthermore, the reaction temperature of the condensation reaction is 10-50°C, and the reaction time is 6-24h.

[0017] Furthermore, the condensing agent is any one of N,N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0018] Furthermore, the solvent is any one of dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide or tetrahydrofuran, or a mixture of several of them.

[0019] Furthermore, an activator is included, and the molar ratio between the compound of formula (II) and the activator is 1:1.2-3, and the activator includes any one of 4-dimethylaminopyridine, 1-hydroxybenzotriazole, N-hydroxysuccinimide, and pentafluorophenol.

[0020] Compared with the prior art, the beneficial effects of the present invention include: through the study of the synthesis route of venetoclax, based on the reaction conditions and reaction products of the condensation reaction, a new impurity that may be produced in the venetoclax synthesis process is obtained, which enriches and improves the impurity spectrum of venetoclax, helps to comprehensively control the quality of venetoclax, improves the yield of venetoclax, and is of great significance for optimizing the production process of venetoclax. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The disclosure of the present invention is described with reference to the accompanying drawings. It should be understood that the drawings are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. In the accompanying drawings, the same reference numerals are used to refer to the same components. Among them:

[0022] Figure 1 Schematic diagram of the synthetic route of the compound of formula (I);

[0023] Figure 2 is the HPLC spectrum of the compound of formula (I);

[0024] Figure 3 is the MS spectrum of the compound of formula (I);

[0025] Figure 4 The compound of formula (I) 13 C NMR spectrum;

[0026] Figure 5 A method for synthesizing a venetola intermediate 1 HNMR spectrum;

[0027] Figure 6 The HPLC spectrum of the product obtained by the nucleophilic reaction according to the synthetic route of Venetoclax;

[0028] Figure 7 The HPLC spectrum of the obtained crude product of Venetoclax is shown in FIG. DETAILED DESCRIPTION

[0029] It is easy to understand that according to the technical solution of the present invention, without changing the essential spirit of the present invention, a person skilled in the art can propose a variety of interchangeable structural modes and implementation modes. Therefore, the following specific implementation modes and drawings are only exemplary descriptions of the technical solution of the present invention, and should not be regarded as the whole of the present invention or as a limitation or restriction to the technical solution of the present invention.

[0030] A venetoclax impurity, the synthesis route of which is as follows Figure 1 As shown, having a structure as shown in formula (I):

[0031]

[0032] The specific preparation method is: the compound of formula (II) reacts with the compound of formula (III) in the presence of a suitable solvent, an activating agent and a condensing agent to obtain the compound of formula (I).

[0033] Embodiment 1:

[0034] Add the compound of formula (II) (10.0 g, 36.7 mmol, 1.0 eq) to a three-necked reaction flask, dissolve it in 200 mL of dichloromethane (DCM), and add the compound of formula (III) (11.6 g, 36.7 mmol, 1.0 eq), 4-dimethylaminopyridine (DMAP) (5.38 g, 44.0 mmol, 1.2 eq), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl) (7.7 g, 40.4 mmol, 1.1 eq) in sequence at room temperature. Control the temperature at 20-30°C and stir the reaction for 20 hours. After the reaction is completed, the temperature is lowered, 100 mL of 5% acetic acid aqueous solution is added for washing once, and then 100 mL of 5.0% sodium bicarbonate solution is used for washing once, the organic phase is dried over 20 g of anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude compound of formula (I), and the crude compound of formula (I) is crystallized from a dichloromethane / methanol system to obtain 6.98 g of a solid compound of formula (I) with a purity of 95.4% and a yield of 33.4%.

[0035] Final material testing:

[0036] The HPLC spectrum of the white solid is as follows Figure 2 As shown;

[0037] The MS spectrum of the white solid is as follows Figure 3 As shown;

[0038] White solid 13 C NMR spectrum Figure 4 As shown;

[0039] White solid 1 HNMR spectrum Figure 5 shown.

[0040] Embodiment 2:

[0041] Add the compound of formula (II) (10.0 g, 36.7 mmol, 1.0 eq) to a three-necked reaction flask, dissolve it with 300 mL of dichloromethane (DCM), and add the compound of formula (III) (23.15 g, 73.4 mmol, 2.0 eq), 4-dimethylaminopyridine (DMAP) (6.72 g, 55.1 mmol, 1.5 eq), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl) (10.55 g, 55.1 mmol, 1.5 eq) in sequence at room temperature. Control the temperature at 30-40°C and stir the reaction for 12 hours. After the reaction is completed, the temperature is lowered, 100 mL of 5% acetic acid aqueous solution is added for washing once, and then 100 mL of 5.0% sodium bicarbonate solution is used for washing once, the organic phase is dried over 20 g of anhydrous sodium sulfate, filtered, and spin-dried to obtain a crude compound of formula (I), and the crude compound of formula (I) is crystallized from a dichloromethane / methanol system to obtain 6.00 g of a solid compound of formula (I) with a purity of 96.2% and a yield of 28.5%.

[0042] The formation of the venetoclax impurity in the synthesis process of venetoclax will be described below.

[0043] In the present invention, the preparation of venetoclax is to obtain aldehyde products from 3,3-dimethylcyclohexanone through a one-pot reaction, and then obtain the main side chain fragment 1-(4-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl)piperazine hydrochloride through reductive amination; then the main fragment 5-hydroxy-7-azaindole is connected to the benzene ring for essential coupling, and the obtained product is condensed with the main fragment benzenesulfonamide and hydrolyzed to obtain the venetoclax finished product, and the aforementioned venetoclax impurities are generated in the venetoclax crude product during this preparation process.

[0044] In the preparation process of venetoclax, the synthesis of its key intermediate I is to form compound A by Grignard transformation of 2,4-difluoro-1-iodobenzene, and then to obtain compound A and compound B by high temperature reaction under alkaline conditions, as follows:

[0045]

[0046] In this reaction process, the impurity of formula II is generated mainly in two ways, as follows:

[0047] 1. Under alkaline conditions, the tert-butyloxycarbonyl group in the structure of intermediate I will degrade to form carboxylic acid, that is, to form an impurity of formula II. The synthetic route is as follows:

[0048]

[0049] 2. During the formation of compound 1, the tert-butyloxycarbonyl group in the structure is first hydrolyzed and then combined with compound 2 to form an impurity of formula II. The synthetic route is as follows:

[0050]

[0051] Therefore, in the intermediate I, there are more impurities of formula II, and its liquid phase spectrum is as follows Figure 6 shown.

[0052] A method for preparing venetoclax is disclosed in the invention patent with publication number CN118271318A and titled "A method for preparing venetoclax". The method discloses a process for synthesizing venetoclax by condensation reaction using intermediate 3. A condensation agent and a solvent are also used to obtain a crude venetoclax product at a similar molar ratio and reaction temperature. Therefore, under the same condensation agent and reaction temperature environment, the compound of formula (II) and the compound of formula (III) have sufficient conditions to synthesize the venetoclax impurity shown in the structure of formula (I) of the present invention, which is present in the obtained crude venetoclax product. Its liquid phase spectrum is as follows: Figure 7 shown.

[0053] In the subsequent steps of Vinecola, the impurity of formula II does not participate in the reaction during the formation of intermediates II and intermediate III due to its poor solubility, and will still remain in intermediate III, and be derived into the finished product to form impurity of formula I, which is difficult to remove. Generally, it takes three crystallizations to remove it completely (<0.1%). Due to multiple crystallizations, the yield loss is large, and the yield is only 27.1%. Therefore, in order to avoid multiple crystallizations and improve the yield, after many experiments, we found that the removal of impurity of formula I is best carried out in the front-end process, mainly in the front process, that is, in the intermediate I through ethyl acetate / n-heptane crystallization to remove impurity of formula II, so as to reduce the formation of impurity of formula I in the finished product of Vinecola. In this way, only one crystallization is required, and the finished product is qualified if it is impurity I, and the yield is also increased from the previous 27.1% to 32.6%.

[0054] The technical scope of the present invention is not limited to the contents in the above description. Those skilled in the art can make various deformations and modifications to the above embodiments without departing from the technical idea of ​​the present invention, and these deformations and modifications should all fall within the protection scope of the present invention.

Claims

1. A method for preparing venetoclax impurity, characterized in that: The structure of the venetoclax impurity is shown in formula (I): The specific synthetic route of the venetoclax impurity is as follows:

2. The method for preparing the venetoclax impurity according to claim 1, characterized in that: The compound of formula (II) reacts with the compound of formula (III) in the presence of a solvent and a condensing agent to obtain a compound of formula (I), wherein the molar ratio of the compound of formula (II), the compound of formula (III) and the condensing agent is 1:1-3:1.1-3.

3. The method for preparing the venetoclax impurity according to claim 2, characterized in that: The reaction temperature of the condensation reaction is 10-50°C, and the reaction time is 6-24h.

4. The method for preparing the venetoclax impurity according to claim 3, characterized in that: The condensing agent is any one of N,N'-dicyclohexylcarbodiimide, diisopropylcarbodiimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

5. The method for preparing the venetoclax impurity according to claim 3, characterized in that: The solvent is any one of dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide or tetrahydrofuran, or a mixture of the two or more thereof.

6. The method for preparing venetoclax impurity according to claim 1, characterized in that: The invention also comprises an activator, wherein the molar ratio between the compound of formula (II) and the activator is 1:1.2-3, and the activator comprises any one of 4-dimethylaminopyridine, 1-hydroxybenzotriazole, N-hydroxysuccinimide and pentafluorophenol.

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