Azotinib impurity 01A and control method thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly discloses an azatinib impurity 01A and a control method thereof, in the process of preparing an intermediate AL-1 through a coupling reaction, the impurity 01A without iodine is generated, the impurity is possibly derived into an impurity F and an impurity A subsequently, and the quality stability of azatinib API is influenced; the impurity control method provided by the invention comprises the following steps: when SM1 and SM2 are used as raw materials to carry out a coupling reaction to prepare AL-1, pretreating the reaction raw materials and a solvent by using a molecular sieve, and reacting at 5-15 DEG C by using Pd (OAc) 2 as a catalyst and 2-dicyclohexylphosphine-2 ', 6'-dimethoxy-biphenyl as a ligand. The proportion of the impurity 01A in the obtained intermediate is reduced to 4.25%, the purity of the intermediate AL-01 is improved to 90% or above, a cheap Pd (OAc) 2 catalyst is used for replacing a precious NHC-Pd (II) catalyst, and the production cost is reduced while the stable quality is guaranteed.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, relates to the synthesis research of alectinib, and particularly relates to an alectinib impurity 01A and a control method thereof. Background Art

[0002] Alectinib, chemical name: 9-ethyl-6,11-dihydro-6,6-dimethyl-8-[4-(4-morpholinyl)-1-piperidinyl]-11-oxo-5H-benzo[b]carbazole-3-carbonitrile, and the raw material drug is the hydrochloride salt of alectinib, and the structure is as follows:

[0003]

[0004] Alectinib is a second-generation ALK inhibitor developed by Chugai Pharmaceutical Co., Ltd. It was first launched in Japan in July 2014, approved by the US FDA in December 2015, and approved by the CFDA for listing in China in August 2018. The domestic trade name is: Ansensa. Compared with the first-generation ALK inhibitor crizotinib, alectinib has significant clinical advantages. It has inhibitory effects on mutations such as L1196M, F1174L, R1275Q, and C1156Y that are resistant to crizotinib. At the same time, it can effectively inhibit the central nervous system metastasis of tumors and has fewer adverse reactions.

[0005] Since the advent of alectinib, due to its good efficacy and high safety, scientific research personnel and pharmaceutical companies have conducted extensive exploration and research on its synthesis methods. Currently, the most mature and reliable synthesis route is as follows:

[0006]

[0007] In the existing literature, there are few reports on alectinib impurities. The research on the generation of impurities in the alectinib synthesis process is a dynamic development and continuous promotion process, which is crucial for improving the quality standard of alectinib raw material drug and promoting the quality control of alectinib raw material drug. Summary of the Invention

[0008] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide an alectinib impurity 01A, which is an iodine-eliminating impurity generated in the coupling process; another purpose of the present invention is to provide a control method for this impurity, which realizes the control of the impurity content while reducing the production cost of key intermediates.

[0009] The present invention is achieved through the following technical solutions:

[0010] An alectinib impurity 01A, and its structural formula is as follows:

[0011]

[0012] In the original research synthesis route, during the iodination reaction process, there may be impurities with incomplete halogenation, which are derived into impurity 01A as the process progresses. Impurity 01A with iodine loss is also generated during the preparation of intermediate AL-1.

[0013] This impurity may be subsequently derived into impurity F and impurity A:

[0014]

[0015] Based on this, a further improvement scheme of this application is:

[0016] A method for controlling alectinib impurity 01A. Specifically, when preparing AL-1 by coupling reaction with SM1 and SM2 as raw materials, after pretreating the reaction raw materials and solvent with molecular sieve, using Pd(OAc) 2 (palladium acetate) as a catalyst, 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl as a ligand, and the reaction temperature is 5-15 °C.

[0017] Further, the process of molecular sieve pretreatment is: at room temperature and under nitrogen protection, mix SM1, SM2 and the solvent, stir evenly and then add the activated molecular sieve, continue to stir and stand. After treatment, the water content of the system is less than 0.05%.

[0018] Further, the mass ratio of SM1 to the molecular sieve is 1:0.5-3

[0019] Further, the solvent is one or more mixtures of DME (ethylene glycol dimethyl ether), MTBE (methyl tert-butyl ether), Et 2 O (diethyl ether).

[0020] Further, the SM 1 、SM 2 、Pd(OAc) 2 and the molar ratio of 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl is 1:1-1.5:0.01-0.03:0.04-0.08.

[0021] Further, the control method also includes a post-treatment process.

[0022] The beneficial effects of this application are:

[0023] Comparing with the data in Table 1, it can be seen that in the present invention, molecular sieve is used for pretreatment to reduce the moisture in the raw materials, and Pd(OAc)2 is used as the catalyst. The reaction is carried out at 5-15 °C. The proportion of impurity 01A in the obtained intermediate drops to 4.25%, while the purity of intermediate AL-01 is increased to over 90%, and the yield is increased by about 10% compared with the original research process. While ensuring the stable quality, the production cost is reduced. At the same time, a relatively cheap Pd(OAc) 2 catalyst is used to replace the precious NHC-Pd(II) catalyst, so that the material cost is reduced from 40,000 yuan / kg to 34,000 yuan / kg, and the competitiveness of the project is improved. Description of the Drawings

[0024] Figure 1 is the MS spectrum of impurity 01A

[0025] Figure 2 is the 1H NMR spectrum of impurity 01A;

[0026] Figure 3 is the HPLC chromatogram of intermediate AL-1 prepared by the method of the present invention, i.e., Example 8;

[0027] Figure 4 is the HPLC chromatogram of intermediate AL-1 prepared by Example 1;

[0028] Figure 5 is the HPLC chromatogram of intermediate AL-1 prepared by Example 3;

[0029] Figure 6 is the HPLC chromatogram of the reaction solution of Example 4;

[0030] Figure 7 is the HPLC chromatogram of intermediate AL-1 prepared by Example 9;

[0031] Figure 8 is the HPLC chromatogram of the reaction solution of Example 10;

[0032] Figure 9 is the HPLC chromatogram of the reaction solution of Example 11;

[0033] Figure 10 is the HPLC chromatogram of the reaction solution of Example 12. Detailed Embodiments

[0034] The present invention will be introduced in detail below with specific examples.

[0035]

[0036] Example 1: Original research process (US9126931B2)

[0037] Under nitrogen atmosphere, 150 g of SM1, 60 g of SM2 and 300 mL of DME were added to a 2 L three-necked flask, and 2.54 g of NHC-Pd(II) (allyl chloride [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl]palladium) was added. The temperature of the system was cooled to -5 to 5 °C. A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran was added dropwise to the reaction flask while controlling the dropping temperature at -5 to 5 °C. After the addition, the mixture was stirred at 35 - 45 °C for 4 h. After the reaction was completed, post-treatment was carried out to obtain the product AL-1.

[0038] The post-treatment process was as follows: 750 mL of isopropyl acetate and 300 mL of 20% ammonium chloride solution were added to the system, and the mixture was allowed to stand and separated. The organic phase was retained. 600 mL of 10% aqueous sodium chloride solution was added to the organic phase, and the mixture was allowed to stand and separated. The organic phase was retained. The organic phase was concentrated under reduced pressure to 400 mL, and then concentrated under reduced pressure with 700 mL of DME. 30 mL of purified water and 4.8 g of N-acetylcysteine were added to the system, and the temperature was controlled at 40 - 45 °C. The mixture was stirred for 1 h while maintaining the temperature. The temperature was lowered to 20 - 30 °C, and the mixture was filtered to remove insoluble substances. The filter cake was washed with 400 mL of DME. The filtrate was concentrated under reduced pressure to 400 mL, 2.3 L of acetone was added, and the temperature was raised to 50 - 60 °C and stirred for 1 h. 37 g of pyridine hydrochloride, a mixture of 30 mL of ethanol and 80 mL of acetone were added to the system, and the mixture was stirred, cooled, and maintained at a temperature of 10 - 20 °C and stirred for 1 h. The mixture was filtered under reduced pressure, and the filter cake was washed with acetone. The filter cake was transferred to a forced-air dryer and dried under vacuum at 50 - 60 °C for 8 h to obtain the intermediate AL-01.

[0039] The obtained intermediate AL-01 was detected by high performance liquid chromatography. Among them, the content of AL-01 was 82.70%, and the maximum single impurity content was 7.78%.

[0040] Example 2: Confirmation of Impurity 01A

[0041] The maximum single impurity in the intermediate AL-01 prepared in Example 1 was separated and purified by medium-pressure chromatography preparation method and its structure was confirmed. The results were as follows:

[0042] LC-MS: M+1 = 389.22

[0043] 1 H NMR (500 MHz, DMSO-d 6 ) δ11.97(1H, s), 8.00(1H, d), 7.91(1H, s), 7.46(1H, d), 7.04(4H, m), 2.55(2H, m), 1.81(6H, s), 1.22(9H, s), 1.12(3H, m).

[0044] The chemical structure of impurity 01A was obtained as follows:

[0045]

[0046] Example 3

[0047] This example attempts to control the content of the maximum single impurity, that is, impurity 01A, by reducing the reaction temperature of the original process. The specific process is as follows: After the addition of materials is completed, the reaction temperature is controlled at 5 - 15 °C, and the reaction is stirred for 10 h until the reaction is complete. Other operations are substantially the same as those in Example 1. The obtained intermediate AL-01 was subjected to content analysis, and the results are shown in Table 1. It can be seen from Table 1 that when the reaction temperature is reduced to 5 - 15 °C, the reaction rate drops significantly. If the reaction is to be complete, the reaction time needs to be extended. However, when the reaction is complete, the proportion of impurity 01A in the reaction solution does not decrease.

[0048] Example 4

[0049] This example uses Pd(OAc) 2 as a catalyst, and other operations are the same as those in Example 1. As the reaction proceeds, the content of the product in the reaction solution is very low, and it is regarded as no reaction occurring.

[0050] Example 5

[0051] This example uses Pd(dppf)Cl 2 (dichloropalladium [1,1'-bis(diphenylphosphino)ferrocene]) as a catalyst, and other operations are the same as those in Example 1. As the reaction proceeds, the content of the product in the reaction solution is very low, and it is regarded as no reaction occurring.

[0052] Example 6

[0053] This example uses Pd 2 (dba) 3 (dibenzylideneacetone palladium(II)) as a catalyst, and other operations are the same as those in Example 1. As the reaction proceeds, the content of the product in the reaction solution is very low, and it is regarded as no reaction occurring.

[0054] Example 7

[0055] This example uses Pd(PPh 3 ) 4 (tetrakis(triphenylphosphine)palladium) as a catalyst, and other operations are the same as those in Example 1. As the reaction proceeds, the content of the product in the reaction solution is very low, and it is regarded as no reaction occurring.

[0056] Example 8

[0057] Pretreatment: Under room temperature and nitrogen protection, 150 g of SM1, 60 g of SM2, and 300 mL of DME were added to a 2 L three-necked flask, mechanically stirred for 0.5 h, 300 g of activated molecular sieve was added, and stirring was continued for 1 h. After standing for 8 h, the KF moisture determination showed that the moisture in the system was less than 0.05%.

[0058] Reaction: Under nitrogen atmosphere, transfer the DME solution of SM1 and SM2 into a 2 L reaction flask, add 1.45 g of Pd(OAc) 2 and 7.18 g of 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl. Cool the system to -5 to 5 °C; add dropwise the sodium bis(trimethylsilyl)amide solution in tetrahydrofuran to the reaction flask while controlling the addition temperature at -5 to 5 °C; after the addition, stir the reaction at 5 to 15 °C for 4 h until the reaction is complete.

[0059] Work-up: The same as in Example 1.

[0060] Perform content analysis on the obtained intermediate AL-01. Among them, the content of AL-01 is 91.18%, the content of impurity 01A is 4.25%. Compared with the original research process, the single impurity content in this example is significantly reduced.

[0061] Example 9

[0062] In this example, control the reaction temperature at 35 - 45 °C and stir the reaction for 4 h. Other operations are the same as in Example 8. Perform content analysis on the obtained intermediate AL-01, and the results are shown in Table 1.

[0063] Example 10

[0064] In this example, use Pd(dppf)Cl 2 as the catalyst. Other operations are the same as in Example 8. As the reaction proceeds, the product content in the reaction solution is relatively low.

[0065] Example 11

[0066] In this example, use Pd 2 (dba) 3 as the catalyst. Other operations are the same as in Example 8. As the reaction proceeds, the product content in the reaction solution is relatively low.

[0067] Example 12

[0068] In this example, use Pd(PPh 3 ) 4 as the catalyst. Other operations are the same as in Example 8. As the reaction proceeds, the product content in the reaction solution is relatively low.

[0069] Table 1 Comparison of process conditions, quality and yield

[0070]

[0071]

[0072] Comparing with the data in Table 1, it can be seen that in the present invention, molecular sieve is used for pretreatment to reduce the moisture in the raw materials, Pd(OAc)2 is used as the catalyst, and the reaction is carried out at 5-15°C. The proportion of impurity 01A in the obtained intermediate drops to 4.25%, while the purity of intermediate AL-01 is increased to over 90%, and the yield is increased by about 10% compared with the original research process. While ensuring the stable quality, the production cost is reduced. At the same time, the relatively cheap Pd(OAc)2 catalyst is used to replace the expensive NHC-Pd(II) catalyst, and the material cost is reduced from 40,000 yuan / kg to 34,000 yuan / kg, improving the competitiveness of the project.

[0073] The above embodiments are only for illustrating the technical concept and features of the present invention, and the purpose is to enable those who are familiar with this technology to understand the content of the present invention and implement it accordingly, and it cannot be used to limit the protection scope of the present invention. All equivalent transformations or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. An alectinib impurity 01A, characterized in that The structure is shown below:

2. A method for controlling the impurity 01A of Alectinib as claimed in claim 1, characterized in that: When SM1 and SM2 are used as raw materials for coupling reaction to prepare AL-1, the reaction raw materials and solvent are pretreated with molecular sieves, Pd(OAc)2 is used as a catalyst, 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl is used as a ligand, and the reaction temperature is 5 to 15°C; 3. The method for controlling the alectinib impurity 01A according to claim 2, characterized in that: The process of molecular sieve pretreatment is as follows: at room temperature and under nitrogen protection, SM1, SM2 and solvent are mixed, stirred evenly, activated molecular sieves are added, stirring is continued, and standing is continued. After treatment, the water content of the system is less than 0.05%.

4. The method for controlling the alectinib impurity 01A according to claim 2 or 3, characterized in that: The solvent is one of DME, MTBE, and Et2O, or a mixture of two or more thereof.

5. The method for controlling the alectinib impurity 01A according to claim 2, characterized in that: The mass ratio of SM1 to molecular sieve is 1:0.5-3.

6. The method for controlling the alectinib impurity 01A according to claim 2, characterized in that: The molar ratio of SM1, SM2, Pd(OAc)2 and 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl is 1:1-1.5:0.01-0.03:0.04-0.

08.

7. The method for controlling the alectinib impurity 01A according to claim 2, characterized in that: The control method also includes a post-processing process.

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