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Pharmaceutical salt of AZD9291 and preparation method thereof

A technology of AZD9291, medicinal salt, applied in the field of medicine, can solve the problems of high hygroscopicity of mesylate, easy deliquescence at high humidity, etc., to meet the requirements of bioavailability and efficacy, overcome the problem of easy deliquescence and low hygroscopicity. Effect

Active Publication Date: 2018-04-17
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, methanesulfonate has the problems of high hygroscopicity and high humidity and easy deliquescence.

Method used

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  • Pharmaceutical salt of AZD9291 and preparation method thereof
  • Pharmaceutical salt of AZD9291 and preparation method thereof
  • Pharmaceutical salt of AZD9291 and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: AZD9291 maleate salt

[0023] At room temperature, AZD9291 (5.0 g, 10 mmol) was added to the reaction flask, 50 ml of acetone was added and stirred to dissolve, and an aqueous solution (20 mL) of maleic acid (1.39 g, 12 mmol) was added dropwise with stirring, a yellow solid was precipitated, and stirred for about half of the solution. hours, suction filtration, the filter cake is rinsed with a small amount of acetone, and dried to obtain a yellow granular solid 4.97g (8.1mmol), yield: 81%. Purity: 99.4%. 1 HNMR (400 MHz, CD 3 OD): 8.75 (1H, s), 8.35 (1H, d, J = 8.2 Hz), 8.30 (1H, d, J = 5.5Hz), 8.20 (1H, s), 7.49 (1H, d, J = 8.2 Hz), 7.29-7.19 (3H, m), 7.01 (1H, s), 6.60-6.45 (2H, m), 6.29 (2H, s), 5.90-5.87(1H, dd, J =8.8, 2.0 Hz), 4.02 (3H, s), 3.91 (3H, s), 3.46 (2H, t, J =5.5 Hz), 3.27 (2H, t, J = 5.5 Hz), 2.87(6H,s), 2.75(3H,s); ESI-MS(m / z): 500.4 [M+1] + .

Embodiment 2

[0024] Example 2: AZD9291 Fumarate

[0025] At room temperature, AZD9291 (5.0 g, 10 mmol) was added to the reaction flask, 50 ml of acetone was added and stirred to dissolve, and an aqueous solution (20 mL) of fumaric acid (1.39 g, 12 mmol) was added dropwise with stirring, and a yellow solid was precipitated, and stirred for about half of the solution. hours, suction filtration, the filter cake is rinsed with a small amount of acetone, and dried to obtain a yellow granular solid 5.0g (8.2mmol), yield: 84%, purity: 99.4%, pale yellow solid. 1 HNMR (400 MHz, CD 3 OD): 1 HNMR (400 MHz, CD 3 OD): (400 MHz, CD 3 OD): 8.74 (1H,s), 8.33 (1H,d, J = 8.0 Hz), 8.31 (1H, d, J = 5.6 Hz), 8.21(1H, s), 7.50(1H, d, J = 8.0 Hz), 7.28-7.19 (3H, m), 7.00 (1H, s), 6.61-6.46 (2H, m), 6.30(2H, s), 5.91-5.88(1H, dd, J = 8.6, 2.0 Hz), 4.00 (3H, s), 3.90 (3H, s), 3.45(2H, t, J =5.5 Hz), 3.27 (2H, t, J = 5.5 Hz), 2.88(6H, s), 2.74(3H, s); ESI-MS(m / z): 500.3 [M+1] + .

Embodiment 3

[0026] Example 3: AZD9291 Gluconate

[0027] At room temperature, AZD9291 (5.0 g, 10 mmol) was added to the reaction flask, 50 ml of acetone was added and stirred to dissolve, and the aqueous solution of gluconic acid (2.35 g, 12 mmol) was added dropwise with stirring to precipitate a yellow solid, stirred for about half an hour, and suction filtered. , the filter cake was rinsed with a small amount of acetone, and dried to obtain a yellow granular solid 5.34g (7.7mmol), yield: 77%. Purity: 99.1%. Pale yellow solid. 1 HNMR (400 MHz, DMSO- d6 ): 8.75 (1H, s), 8.32 (1H, d, J = 8.1 Hz), 8.30 (1H,d, J = 5.5 Hz), 8.20 (1H, s), 7.52 (1H, d, J = 8.0 Hz), 7.30-7.20 (3H, m), 7.03 (1H, s), 6.60-6.47 (2H, m), 6.31 (2H, s), 5.90-5.87(1H, dd, J = 8.5, 2.0Hz), 4.2 (1H, d, J = 1.5 Hz), 4.17 (1H, d, J = Hz), 4.01 (3H, s), 3.92 (3H, s), 3.90 (1H, dd, J = 9.5, 1.5 Hz), 3.88 (1H, dd, J = 9.5, 1.5 Hz), 3.56 (1H,dd, J = 9.6, 1.5 Hz), 3.62(2H, d, J = 6.4 Hz), 3.46 (2H, t, J ...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical salt of AZD9291 and a preparation method thereof. The novel pharmaceutical salt of AZD9291 disclosed by the invention is maleate, fumarate, gluconate, malonate, succinate or lactate. AZD9291 reacts with maleic acid, fumaric acid, gluconic acid, malonic acid or succinic acid in a ketone or alcohol solvent, and by crystallization, the pharmaceutical salt is obtained. Compared with AZD9291 mesylate, the pharmaceutical salt of AZD9291 provided by the invention has lower hygroscopicity, overcoming the problem that the conventional AZD9291 mesylate can easily deliquesce, and therefore is more suitable for medicine development.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a medicinal salt of AZD9291 and a preparation method thereof. Background technique [0002] EGFR mutation is the most common gene mutation (50%-60%) in East Asian patients including Chinese lung adenocarcinoma, and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can benefit about 70% of patients with mutation. However, 50%-60% of patients with EGFR-TKIs with mutated EGFR-TKIs failed due to T790M mutation. AZD9291 (osimertinib) developed by AstraZeneca is a third-generation oral, irreversible and selective EGFR mutation inhibitor. AZD9291 targets the EGFR T790M mutation through the C797 amino acid covalent bond, thereby inhibiting the regulation of different cellular processes several downstream pathways. [0003] The AZD9291 salt used clinically is methanesulfonic acid, which has high biological toxicity and is not suitable for use in finished medicines...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61P35/00A61P11/00
CPCC07D403/04Y02A50/30
Inventor 戴惠芳
Owner FUDAN UNIV
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