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Axitinib fumarate, crystal form thereof and preparation methods for Axitinib fumarate and crystal form thereof

A technology of nifumarate and axitinib, applied in the field of medicinal chemistry, can solve the problems of high heavy metal palladium residue, high organic impurity content, poor appearance and the like in axitinib, and achieve good photostability and palladium residue. reduced, good effect

Active Publication Date: 2017-03-01
ZHEJIANG JIUZHOU PHARM CO LTD
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  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In order to solve the problems of high residual heavy metal palladium, poor appearance and high organic impurity content of axitinib prepared by two palladium-catalyzed coupling methods in the existing literature, the present invention adopts the following technical scheme:

Method used

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  • Axitinib fumarate, crystal form thereof and preparation methods for Axitinib fumarate and crystal form thereof
  • Axitinib fumarate, crystal form thereof and preparation methods for Axitinib fumarate and crystal form thereof
  • Axitinib fumarate, crystal form thereof and preparation methods for Axitinib fumarate and crystal form thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061]Embodiment 1: Preparation of axitinib fumarate

[0062] Add 150ml of ethanol and axitinib crude product at normal temperature (according to Organic Process Research & Development 2014, 18, 266-274, HPLC purity 87.7%, HPLC detection data are as follows Table 1 or see figure 1 , palladium residue 131ppm) (10g, 0.0259mol) into the reaction flask, under stirring, drop into fumaric acid (3.3g, 0.0284mol); warm up to 65~75°C and stir for 1 hour; then cool to room temperature, and carry out suction filtration After the suction filtration, the wet product was put into 50-60°C for vacuum drying to obtain 10.8g of axitinib fumarate, with a yield of 83%, HPLC 96.1%, and residual palladium of 11.5ppm. The HPLC detection data are shown in Table 2 or See figure 2 .

[0063] Table 1

[0064] keep time high width area %area 2.358 1738.32 22.000 12205.41 0.0827 8.875 7276.51 37.600 73246.94 0.4965 10.429 1521.78 26.800 14088.90 0.0955 13....

Embodiment 2

[0070] Embodiment 2: the preparation of axitinib fumarate

[0071] At normal temperature, 150ml of isopropanol and axitinib (according to Organic Process Research & Development 2014, 18, 266-274, HPLC purity 97.7%, HPLC detection data are as follows in Table 3 or see image 3 , palladium residue 65.2ppm) (10g, 0.0259mol) into the reaction flask, under stirring, drop into fumaric acid (3.3g, 0.0284mol); heat up to 65~75°C and stir for 1 hour; then cool to 0°C, and carry out After suction filtration, the wet product was placed at 50-60°C for vacuum drying to obtain 12.8 g of axitinib fumarate, with a yield of 98.4%, HPLC of 99.9%, and residual palladium of 5.7 ppm. HPLC detection data is as follows table 4 or see Figure 4 .

[0072] table 3

[0073] keep time high width area %area 2.340 1960.44 23.600 14980.44 0.1019 8.648 3934.0535.2 00 44757.95 0.3044 13.225 5017.56 40.800 57950.38 0.3941 13.929 2679.38 35.200 31555.30 0.21...

Embodiment 3

[0078] Embodiment 3: Preparation of axitinib fumarate in crystalline form (using ethanol and NNP as solvent)

[0079] Add 150ml of ethanol, 10ml of N-methylpyrrolidone and crude axitinib at room temperature (according to Organic Process Research & Development 2014, 18, 266-274, HPLC detection data are as follows in Table 5 or see Figure 5 , HPLC purity 97.7%, palladium residual 69.6ppm) (10g, 0.0259mol) into the reaction flask, under stirring, drop into fumaric acid (3.3g, 0.0284mol); be heated to 65~75 ℃ and stir for 1 hour; then cool to room temperature ℃, carry out suction filtration on it, after the suction filtration, put the wet product into vacuum drying at 50℃~60℃ and 80℃~100℃ respectively, and see Figure 8 It is the ethanolate of axitinib fumarate in vacuum (drying temperature is 50 ℃ ~ 60 ℃), see Figure 9 It is Form A of axitinib fumarate (vacuum drying temperature is 80°C to 100°C). A total of 13.0 g of axitinib fumarate was obtained, with a yield of 99.9%, HPL...

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Abstract

The invention relates to the technical field of medical chemistry and particularly relates to Axitinib fumarate, a crystal form thereof and preparation methods for the Axitinib fumarate and the crystal form thereof. The prepared Axitinib fumarate and the crystal form thereof are high in Axitinib fumarate yield and high in purity. In addition, the Axitinib fumarate provided by the invention can further be used for preparing Axitinib after the Axitinib fumarate is dissociated. According to the preparation method for the Axitinib fumarate, disclosed by the invention, the Axitinib fumarate is prepared through subjecting the Axitinib and fumaric acid to a salt forming reaction. The Axitinib may be a direct crude product prepared by disclosures in the existing documents, or may also be pure Axitinib which is obtained through carrying out certain-aftertreatment impurity removal. Even if crude Axitinib and fumaric acid are subjected to salt forming, the Axitinib fumarate with high purity can be prepared through the salt forming reaction.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to axitinib fumarate and its crystal form. Background technique [0002] Axitinib (Axitinib) was approved by the FDA on January 27, 2012, for advanced renal cell carcinoma (Renal Cell Carcinoma, RCC) that has failed other systemic treatments. Axitinib was developed by Pfizer Company, trade name Inlyta. . [0003] [0004] The synthesis of axitinib is accomplished by two palladium-catalyzed couplings centered on indazole. As in the following route disclosed by Organic Process Research & Development 2014, 18, 266-274, Step 1 is the first palladium-catalyzed coupling, [0005] [0006] In the disclosed following route, Step 4 is the second palladium-catalyzed Heck coupling, [0007] [0008] The above-mentioned Organic Process Research & Development 2014, 18, 266-274 also further provides some methods for removing impurities and reducing palladium residues, but...

Claims

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Application Information

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IPC IPC(8): C07D401/06
CPCC07D401/06C07B2200/13
Inventor 徐建康叶美其吴昊应远国叶恺诸林冰丁嘉民朱勇辉
Owner ZHEJIANG JIUZHOU PHARM CO LTD
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