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AZD 9291 pharmaceutical salt and crystal form and preparation method thereof

A technology of AZD9291, 1.AZD9291, applied in organic chemical methods, drug combinations, anti-tumor drugs, etc., can solve the problems of inconvenient preparation processing operations, high hygroscopicity of mesylate, and poor solvent solubility, and achieves overcoming The effect of high humidity and easy deliquescence, meeting the requirements of bioavailability and efficacy, and facilitating processing operations

Active Publication Date: 2017-02-22
BIORTUS BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, the methanesulfonate has the problems of high hygroscopicity and easy deliquescence under high humidity
[0007] WO2016 / 124137 discloses the phosphate salt of AZD9291, its crystal form and its preparation method. Although it has improved solubility and hygroscopicity compared with AZD9291, it is also easy to absorb water when placed in a normal place (RH80%, 25°C), and some solvents The solubility is not strong, and the crystals are formed into lumps, which need to be ground and processed, which is inconvenient for subsequent preparation processing operations

Method used

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  • AZD 9291 pharmaceutical salt and crystal form and preparation method thereof
  • AZD 9291 pharmaceutical salt and crystal form and preparation method thereof
  • AZD 9291 pharmaceutical salt and crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1: AZD9291 Sulfate

[0061] At room temperature, add AZD9291 (5g, 10mmol, 1.0eq) to the reaction flask, add 50mL of acetone and stir to dissolve, add dropwise an aqueous solution (20mL) of sulfuric acid (1.18g, 12mmol, 1.2eq) under stirring, a yellow solid is precipitated, stir about After half an hour, filter with suction, rinse the filter cake with a small amount of acetone, and dry to obtain 5 g (8.4 mmol) of a yellow granular solid, with a molar yield of 84%. After testing, the purity: 99.4%. Melting point: 255.2°C-257.3°C.

[0062] The AZD9291 sulfate product prepared by the above method, its 1 HNMR such as Figure 5 As shown, the identification data are as follows: 1 HNMR (400MH Z ,DMSO)δ:9.54(1H,s),9.25(1H,s),8.66(1H,s),8.62(1H,s),8.32~8.30(2H,d,J=5.6Hz),7.57~7.55 (1H, d, J=8Hz), 7.31~7.26(2H,m), 7.20~7.16(1H,t,J=7.4Hz), 7.05(1H,s), 6.75~6.68(1H,m), 6.38 ~6.31(1H,m),5.83~5.81(1H,d,J=10.4Hz),3.92~3.91(6H,d,J=5.2Hz),3.33~3.31(4H,m),2.84(6H,s ),2.66(...

Embodiment 2

[0067] Embodiment 2: AZD9291 p-toluenesulfonate

[0068] At room temperature, add AZD9291 (5g, 10mmol, 1.0eq) to the reaction flask, add 50mL of acetone and add TsOH·H 2 O (2.4g, 12mmol, 1.2eq) in aqueous solution (5ml), precipitated a yellow solid, stirred for half an hour, filtered with suction, rinsed the filter cake with a small amount of acetone, and dried to obtain 4.03g (6.0mmol) yellow granular solid, Molar yield 60%. After testing, the purity is 99.7%, and the melting point is 214.0℃~215.6℃.

[0069] The AZD9291 p-toluenesulfonate product prepared by the above method, its 1 HNMR such as Figure 9 As shown, the identification data are as follows: 1 HNMR (400MH Z,DMSO)δ:9.57(1H,s),9.19(1H,s),8.76(1H,s),8.55(1H,s),8.34~8.32(2H,m),8.00(1H,s),7.56 ~7.54(1H,d),7.50~7.48(2H,d),7.28~7.24(2H,m),7.19~7.11(3H,m),7.03(1H,s),6.71~6.64(1H,m) ,6.38~6.33(1H,dd),5.84~5.81(1H,m),3.92~3.91(6H,d),3.32~3.27(4H,m),2.84~2.83(6H,d),2.64(3H, s),2.30(3H,s);ESI-MSm / z:500.3[M+H] + ,250....

Embodiment 3

[0073] Embodiment 3: AZD9291 tartrate

[0074] At room temperature, add AZD9291 (5g, 10mmol, 1.0eq) to the reaction flask, add 50mL of acetone to dissolve, add tartaric acid (1.8g, 12mmol, 1.2eq) aqueous solution (5mL) under stirring, precipitate a light yellow solid, stir for half an hour , suction filtration, the filter cake was rinsed with a small amount of acetone, and dried to obtain 5 g (7.7 mmol) of light yellow granular solid with a molar yield of 77%. After testing: purity 99.9%; melting point: 169.6°C ~ 172.0°C.

[0075] The AZD9291 tartrate product prepared by the above method, its 1 HNMR such as Figure 13 As shown, the identification data are as follows: 1 HNMR (400MH Z ,MeOD)δ:8.75(1H,s),8.36~8.34(1H,d,J=8Hz),8.30~8.29(1H,d,J=5.28Hz),8.23(1H,s),7.49~7.47( 1H,d,J=8Hz),7.28~7.18(3H,m),7.00(1H,s),6.62~6.48(2H,m),5.90~5.87(1H,dd,J=9.6Hz,2Hz), 4.44(2H,s),4.03(3H,s),3.92(3H,s),3.50~3.47(2H,t,J=5.4Hz),3.29~3.26(2H,t,J=5.6Hz),2.88 (6H,s),2.75(3H,s);ESI-MS m / z:500....

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Abstract

The invention relates to novel AZD 9291 pharmaceutical salt. The chemical structural formula of AZD 9291 is shown in the specification. The pharmaceutical salt is sulfate or tosilate or tartrate or acetate or citrate. The AZD 9291 pharmaceutical salt has solubility equivalent to or higher than that of AZD 9291 mesylate, can meet bioavailability and efficacy requirements, is higher in bio-safety and lower in hygroscopicity, solves the problems that existing AZD 9291 mesylate is high in toxicity and prone to deliquescence, and is more suitable for drug development.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a medicinal salt of AZD9291, its crystal form and a preparation method. Background technique [0002] Targeted therapy for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations is the current standard of care for patients with advanced non-small cell lung cancer (NSCLC). However, the effects of these drugs are generally short-lived, with resistance developing within 9-11 months, which occurs because cancer cells are able to evade the therapeutic activity of EGFR or ALK inhibitors by mutating and changing their growth patterns . [0003] AZD9291, developed by AstraZeneca, is a third-generation oral, irreversible, selective EGFR mutation inhibitor that can be used for both activating and resistant mutant EGFR, that is, for patients with advanced non-small cell lung cancer, 50% Acquired resistance to anti-EGFR therapy is caused by the T790M mutation, and AZD9...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61P35/00
CPCC07B2200/13C07D471/04
Inventor 周平刘洋田会敏张海军吴家权孟五一
Owner BIORTUS BIOSCI
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