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A kind of salt form, crystal form and preparation method of EGFR inhibitor

A technology of crystal form and solvent addition, which is applied in the application field of drugs for the treatment of non-small cell lung cancer, and can solve problems such as diarrhea and rash

Active Publication Date: 2021-09-14
GUANGDONG ZHONGSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] AstraZeneca AZD9291 is an oral small-molecule third epidermal growth factor tyrosine kinase inhibitor. AZD9291 has a strong specific binding ability for drug-resistant mutation T790M and sensitive mutation sites (19Del and L858R), so it is effective for Patients with drug-resistant non-small cell lung cancer after first-line TKI treatment have a good therapeutic effect, but because it also inhibits EGFR wild-type to a certain extent, clinically, side effects such as diarrhea and rash will occur

Method used

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  • A kind of salt form, crystal form and preparation method of EGFR inhibitor
  • A kind of salt form, crystal form and preparation method of EGFR inhibitor
  • A kind of salt form, crystal form and preparation method of EGFR inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Preparation of compounds of formula (I): Example 1

[0098]

[0099] step 1:

[0100] N 2 Protected, pyridine (1.74Kg, 22.01mol, 1.10 eq.) In dichloromethane (20L) was cooled to -20 deg.] C, was slowly added dropwise trifluoromethanesulfonic anhydride (5.87Kg, 20.81mol, 1.04 equiv) was added dropwise completion of the reaction system at -20 ℃ and stirred for 0.5 hours and was slowly added dropwise 2-bromoethanol (2.50Kg, 20.01mol, 1.0 eq), and stir the reaction temperature was maintained below 0 ℃ 1.0 h, TLC (petroleum ether: acetic acid ethyl ester = 5: 1) showed the reaction was complete. After the reaction was filtered directly into the reaction system, and the filtrate was concentrated and then petroleum ether (15L), the precipitated solid was filtered and the filtrate was concentrated to give compound b (4.80Kg, 93.33% yield) as a dark yellow oil. 1 HNMR (400MHz, CDCL 3 ): 4.77 (t, J = 6.40Hz, 2H), 3.63 (t, J = 6.40Hz, 2H).

[0101] Step 2:

[0102] Compound b (8.5Kg...

Embodiment 2

[0122] Compounds of formula (II): Example 2

[0123] 8L of acetone was added to the 50L reaction vessel at room temperature was added the formula (I) compound (1.10Kg, 1.97mol, 1.0 eq.) In the reactor, stirred to dissolution clarification, thiourea resin (220.44g, 20% mass ratio ) was added to the reaction solution, stirred overnight at 25 deg.] C, vacuum filtration, the filter cake was washed with acetone 3L. The combined acetone solution is transferred to a 50L reactor, heated to 65 ℃, pressure-equalizing dropping funnel was slowly added dropwise methanesulfonic acid (185.34g, 1.93mol, 0.98 eq.), Dropwise addition, the solution was clear. After 30min, the solution to precipitate an off-white solid. Incubated for 2 hours, cooled to 25 ℃. N 2 Protection under reduced pressure suction, the filter cake was vacuum oven dried to constant weight to give of formula (II) compound as a brown solid (965G, 73% yield). 1 H NMR (400MHz, CD 3 OD): δ, 8.37 (s, 1H), 8.34 (d, J = 3.07Hz, 1H), 7.8...

Embodiment 3

[0124] Preparation of Compound A crystalline form of formula (II): Example 3

[0125] The compounds of formula (I) to take 120mg, 0.5mL was added dissolved in tetrahydrofuran, then added slowly with stirring 0.14mL methanesulfonic acid - tetrahydrofuran solution (V / V, 1: 9). After stirring overnight centrifugation, the residual solid sample placed in a vacuum oven (30 ℃) was dried overnight at 25 ℃, of formula (II) A crystalline form of the compound.

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Abstract

The invention discloses a salt form and a crystal form of an EGFR inhibitor and a preparation method thereof, and also includes the application of the salt form and the crystal form in preparing a medicine for treating non-small cell lung cancer.

Description

Technical field [0001] The present invention relates to a salt type, crystal form, and a preparation method thereof of a T790M mutated EGFR inhibitor, further comprising the application of the saline and crystalline form in the treatment of non-small cell lung cancer drugs. Background technique [0002] Protein tyrosine kinases are enzymes that catalyze the phosphate groups from ATP or GTP to tyrosine residues from ATP or GTP. The receptor tyrosine kinase activates the secondary signal passage by causing phosphorylation from the extracellular to the intracellular transmission signal. A variety of cellular processes are regulated by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, and cell survival. In addition, many diseases or conditions are related to one or more kinase activity, abnormal or disorders. [0003] The epidermal growth factor receptor belongs to a transmembrane tyrosine kinase receptor ERBB family, incl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/04A61K31/5383A61P35/00
CPCC07B2200/13C07D498/04
Inventor 丁照中陈曙辉胡利红刘希乐张路李卫东郭慎慎
Owner GUANGDONG ZHONGSHENG PHARMA