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n-[3-Chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methylsulfinyl)ethyl]amino]methyl]-2-furyl] -4-quinazolinamine polymorph and preparation method thereof

A fluorobenzyloxy, sulfinyl technology, applied in N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methylsulfinyl ) ethyl]amino]methyl]-2-furyl]-4-quinazolineamine polymorph and the field of preparation thereof, can solve the problems such as affecting the efficacy of active substances, unfavorable drug preparation and preservation, etc.

Active Publication Date: 2019-05-28
QILU PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] CN102030742A also discloses the process of obtaining compound I, but the yellow solid obtained after column chromatography in this application is not in the form of crystals, but a yellow viscous solid, which is not conducive to the preparation and preservation of drugs
If the active substance has different polymorphic forms, it must be ensured that the crystal form of the active substance does not change during the preparation of the pharmaceutical preparation, otherwise it may affect the efficacy of the active substance

Method used

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  • n-[3-Chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methylsulfinyl)ethyl]amino]methyl]-2-furyl] -4-quinazolinamine polymorph and preparation method thereof
  • n-[3-Chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methylsulfinyl)ethyl]amino]methyl]-2-furyl] -4-quinazolinamine polymorph and preparation method thereof
  • n-[3-Chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methylsulfinyl)ethyl]amino]methyl]-2-furyl] -4-quinazolinamine polymorph and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0091] Example 1: N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methylsulfinyl)ethyl]amino]methyl Base]-2-furyl]-4-quinazolinamine (compound I) preparation:

[0092] Preparation of 2-mercaptoethylamine protected by a.Boc:

[0093]

[0094] Add 25 g of di-tert-butyl dicarbonate, 14.4 g of 2-mercaptoethylamine hydrochloride and 140 ml of dichloromethane into the reaction flask, add 18 ml of triethylamine in batches under ice-bath conditions, stir and react overnight at room temperature, add excess 0.5M After washing with hydrochloric acid solution, the organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 5.7 g of Boc-protected 2-mercaptoethylamine (oily liquid), with a yield of 87%.

[0095] Preparation of b.Boc-protected 2-methylthioethylamine:

[0096]

[0097] Under the conditions of ice bath and nitrogen protection, add 1.2 g of NaH in batches to the solution of 7 g of B...

Embodiment 2

[0107] Example 2: N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methylsulfinyl)ethyl]amino]methyl Preparation of yl]-2-furyl]-4-quinazoline amino acid addition salt

[0108] For example: the preparation of compound I xylene sulfonate (compound II)

[0109]

[0110] Add 5 g (8.88 mmol) of compound I obtained in Example 1 into 25 ml of ethanol, stir to dissolve, add 4.58 g (26.5 mmol) of p-toluenesulfonic acid, and precipitate a yellow solid, filter it with suction, and dry it in the air to obtain 7.75 g of N-[ 3-Chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methylsulfinyl)ethyl]amino]methyl]-2-furyl]-4- Quinazolinamine xylene sulfonate (yellow viscous solid), yield 93.5%, purity 95.3%.

[0111] MS (m / z): [M-H] 907.1713.

[0112] Other acid addition salts such as hydrochloride, sulfate, nitrate, methanesulfonate, benzenesulfonate, oxalate, formate, acetate, benzoate, maleate, fumarate Salt, malate, tartrate, dibenzoyl tartrate, citrate, etc. can be prepared by a m...

Embodiment 3

[0113] Example 3: N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methylsulfinyl)ethyl]amino]methyl Base]-2-furyl]-4-quinazolinamine dihydrate crystal form A (crystal form A of formula III compound) preparation

[0114] Add 2 g of compound II prepared in Example 2 into a mixed system of 20 ml of dichloromethane and 10 ml of 3mol / L sodium hydroxide aqueous solution, stir to dissolve, leave to stand for liquid separation, stir and crystallize the organic layer, filter with suction, and dry in the air. 1.2 g of light yellow solid was obtained with a yield of 90% and a purity of 99.1%. The product obtained is subjected to X-ray powder diffraction, and the result shows that the product is the crystal form A of compound III, and the XRPD spectrum is shown in figure 1 shown.

[0115] The above product uses differential scanning thermal analysis, and its DSC-TGA spectrum is as follows figure 2 As shown, its melting point is 93~103 ℃, and the obtained product is determined to...

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Abstract

The invention relates to a polymorphic substance of N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methanesulfinyl)ethyl]amino]methyl]-2-furyl]-4-quinazolineamine and a preparation method thereof, in particular to a crystal form A or B of N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methanesulfinyl)ethyl]amino]methyl]-2-furyl]-4-quinazolineamine as a tyrosine kinase inhibitor. The invention further relates to the preparation method of the polymorphic substance, a pharmaceutical composition of the polymorphic substance and pharmaceutical application of the polymorphic substance and the pharmaceutical composition.

Description

[0001] The present invention is the application number 201210464607.6, the invention name is "N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methylsulfinyl)ethyl ]Amino]methyl]-2-furyl]-4-quinazolinamine polymorphs and preparation methods thereof", a divisional application of an invention patent application with a filing date of November 19, 2012. technical field [0002] The invention belongs to the field of medicine and chemical industry, and in particular relates to a new N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-[5-[[2-(methanol) with antitumor activity Sulfinyl) ethyl] amino] methyl] -2-furyl] -4-quinazolinamine (compound I) hydrate, the crystal form of the hydrate, its preparation method, and the hydrate as The pharmaceutical application for treating or adjuvantly treating tumors mediated by receptor tyrosine kinases or proliferation and migration of tumor cells driven by receptor tyrosine kinases in mammals (including humans). Background technique [0003] The C...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/04A61K31/506A61P35/00A61P35/02
CPCC07B2200/13C07D405/04
Inventor 范传文林栋张进
Owner QILU PHARMA HAINAN
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