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Crystal form a of aminopyrimidine mesylate and its preparation method and application

A technology of aminopyrimidine and mesylate, applied in the field of drug synthesis, to achieve high bioavailability, good solubility and high purity

Active Publication Date: 2021-02-19
BETA PHARMA (SHANGHAI) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] But so far, the third-generation EGFR inhibitors in the world, except for AstraZeneca's osimertinib (Tagrisso ) has been successfully developed, and no effective drug against T790M drug-resistant mutation patients has been approved for clinical use, and several candidate drugs for T790M mutation are in the clinical development stage

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  • Crystal form a of aminopyrimidine mesylate and its preparation method and application
  • Crystal form a of aminopyrimidine mesylate and its preparation method and application
  • Crystal form a of aminopyrimidine mesylate and its preparation method and application

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preparation example Construction

[0041] Step 1 - Preparation of Intermediate J:

[0042]

[0043] Preparation: Add 6L of anhydrous tetrahydrofuran solvent to a 10L reaction flask, protect with nitrogen, and cool to 0°C. While stirring, 101 g of sodium hydrogen (101 g, 2.52 mol) was slowly added, and the internal temperature did not exceed 10° C., and 234 g of dimethylaminoethanol (234 g, 2.62 mol) was added. After the addition, the temperature was adjusted to room temperature to prepare a sodium alkoxide solution.

[0044] In the 30L reaction flask, add N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)-2-pyrimidinamine ( Starting material B) (430g, 1.10mol), then add 9L of tetrahydrofuran, start stirring, dissolve clear, control the temperature at 10±10°C, and slowly add the prepared sodium alkoxide solution dropwise. Control the temperature at 10±10°C and keep it warm for 5.0h. When the raw material content is ≤0.5%, the reaction ends. Control the temperature at 10±10°C, slowly add 3% hy...

Embodiment 1

[0055]

[0056] The compound of formula I (3 g, 6.1 mmol) was dissolved in 24 ml of dimethyl sulfoxide DMSO solvent, heated to 65 degrees, and stirred to dissolve. An equivalent of methanesulfonic acid (0.59 g, 6.1 mmol) was added to the system. Cool down to 50°C, and slowly add 12ml of isopropyl acetate IPAc. Stir at 50°C for 1 hour, then cool down to 15°C. 21 ml IPAc was added at 4 hours. The solution was stirred and crystallized at 15°C, filtered under reduced pressure, the filter cake was washed with isopropyl acetate, and washed with acetone to reduce the residual DMSO solvent. Air blow drying at 50°C (or vacuum drying at 50°C under reduced pressure) yielded 3.16 g of a light yellow solid (crystalline form A). HPLC purity 100%, yield 88%, DMSO:<100ppm; IPAc:<100ppm. MS m / z: 487.2 [M+1-MsOH]. Melting point: 242-244°C.

[0057] NMR data (attached figure 2 ): 1 HNMR (d6-DMSO): δppm: 9.57 (brs, 1H), 9.40 (s, 1H), 8.71 (s, 1H), 8.48 (s, 1H), 8.32 (d, 1H, J=7.9), 8....

Embodiment 2

[0060]

[0061] The compound of formula I (28.25 g, 58.1 mmol) was dissolved in 224 ml of dimethyl sulfoxide DMSO solvent, heated to 15-35 degrees, and stirred to dissolve. 0.97 equiv of methanesulfonic acid (5.4 g, 0.97 mmol) was added portionwise to the system. 448 ml methyl isobutyl ketone (MIBK) was added slowly. Stir for 1 hour, then cool down to 10-15 degrees. The solution forms a salt reaction at 10-15 degrees, takes a sample, and detects the residual compound of formula I in the mother liquor by HPLC (≤0.4%). After the reaction was completed, suction filtration under reduced pressure gave 32 g of the crude product of the compound mesylate of formula I.

[0062] Add 3 g of the crude mesylate salt of the compound of formula I into 24 ml of dimethyl sulfoxide DMSO solvent, stir to dissolve at 65 degrees, cool down, slowly add 48 ml of methyl isobutyl ketone (MIBK), and stir for crystallization 6-8 hours, suction filtration under reduced pressure, air blow drying at ...

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Abstract

The present invention provides the crystal form A of the mesylate of aminopyrimidine compound. The X-ray powder diffraction in 2θ angle is 11.06±0.2°, 12.57±0.2°, 13.74±0.2°, 14.65±0.2°, 15.48± 0.2°, 16.58±0.2°, 17.83±0.2°, 19.20±0.2°, 19.79±0.2°, 20.88±0.2°, 22.05±0.2°, 23.06±0.2°, 24.23±0.2°, 25.10±0.2°, 25.71± There are diffraction peaks near 0.2°, 26.15±0.2°, 27.37±0.2°, and 27.42±0.2° (see Figure 3). The preparation method of the crystal form A is also provided. The crystal form A of the aminopyrimidine compound mesylate of the present invention has good solubility and high bioavailability in animals. It can be used in the treatment or prevention of mammals, especially humans, diseases or medical conditions mediated by epidermal growth factor (EGFR) mutations (activated or drug-resistant), especially in drug combinations for cancer.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to the crystal form A of aminopyrimidine compound methanesulfonate and its preparation method and application. Background technique [0002] Epidermal growth factor receptor (EGFR) is a type of transmembrane receptor tyrosine kinase in the human body. The activation (ie, phosphorylation) of this region has important effects on the proliferation, angiogenesis, tumor invasion, metastasis and apoptosis of tumor cells. Inhibition is important. EGFR kinases are implicated in the disease progression of most cancers, and these receptors are overexpressed in many major human tumors. Overexpression, mutation, or high expression of ligands combined with these family members will lead to some tumor diseases, such as non-small cell lung cancer, colorectal cancer, breast cancer, head and neck cancer, cervical cancer, bladder cancer, thyroid cancer cancer, stomach cancer and kidney can...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/04A61K31/506A61P35/00
CPCC07D403/04A61P35/00C07B2200/13
Inventor 汤春M·N·格雷科M·J·科斯坦佐张晓霞J·彭D·张Y·卢
Owner BETA PHARMA (SHANGHAI) CO LTD
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