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Methanol solvate of quinazoline intermediate and preparation method thereof

A methanol solvate and intermediate technology, applied in the field of methanol solvate of quinazoline intermediates and its preparation, can solve the problems of quinazoline intermediate refinement, purification, and storage difficulties, and achieve a simple and reliable preparation method , easy operation, high purity effect

Active Publication Date: 2013-09-11
HAINAN SIMCERE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by this invention is to overcome the existing formula I compound - a kind of quinazoline intermediate refinement, purification, the difficult defect of preservation, to provide a kind of methanol solvate of quinazoline intermediate, which is Crystalline compound, easy to store, easy to operate, good stability, high purity; and the preparation method is simple and reliable, suitable for industrial implementation

Method used

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  • Methanol solvate of quinazoline intermediate and preparation method thereof
  • Methanol solvate of quinazoline intermediate and preparation method thereof
  • Methanol solvate of quinazoline intermediate and preparation method thereof

Examples

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Effect test

Embodiment 1

[0021] A kind of preparation method of quinazoline intermediate I is synthesized in two steps, and its general reaction formula is as follows:

[0022] .

[0023] The first step: the preparation of (4-(6-benzyloxy-7-methoxyquinazolin-4-yl)oxy)-3-fluoroaniline (Ⅲ)

[0024] Add 6-benzyloxy-4-chloro-7-methoxyquinazoline (10.0 g, 1 eq), 4-amino-2-fluorophenol (4.65 g, 1.1 eq), tert-butanol to the reaction flask Potassium (4.5 g, 1.2 eq), DMF (500 mL), heated to 55 oC React for 3 hours, stop the reaction, remove the solvent under reduced pressure, and dry the column to obtain (4-(6-benzyloxy-7-methoxyquinazolin-4-yl)oxy)-3-fluoroaniline 7 g.

[0025] The second step: the preparation of 4-(4-amino-2-fluorophenoxy)-7-methoxyquinazolin-6-ol (I)

[0026] Add (4-(6-benzyloxy-7-methoxyquinazolin-4-yl)oxy)-3-fluoroaniline (3.0 g, 1 eq), methanol (150 mL), Pd-C (0.6 g), under the action of hydrogen at 0 oC After reacting for 6 hours, stop the reaction, remove the insoluble ma...

Embodiment 2~8

[0029] The conditions for preparing methanol solvates with different soluble solvents and methanol are listed in Table 1, and the specific operations are as follows: 0.1 g of the crude product of Compound I is dissolved in a soluble solvent at a certain temperature, and after the solution is dissolved, continuous Add a certain amount of methanol, gradually lower the temperature to a certain temperature under stirring, and precipitate methanol solvate. Example 8 is the recrystallization of the methanol solvate obtained in Example 7.

[0030] Table 1

[0031]

[0032] Note: The purity in the table is determined by high performance liquid chromatography, and the chromatographic conditions are as follows: phenomenonex C18ODS-H, mobile phase: acetonitrile: water = 50:50, detection wavelength: 254nM, column temperature 40°C.

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Abstract

The invention discloses a methanol solvate of a quinazoline intermediate shown in formula I in the specification and a preparation method thereof. The methanol solvate has high purity and good stability and is easy to operate and preserve. The preparation method is simple and reliable and is suitable to be implemented industrially.

Description

technical field [0001] The invention relates to a methanol solvate of a quinazoline intermediate and a preparation method thereof. Background technique [0002] The quinazoline skeleton is an important class of heterocyclic structures with a wide range of biological activities, especially in many small molecule antitumor drugs. Compound I is an important intermediate for the synthesis of a class of novel small molecule kinase inhibitors. In previous literature reports, there are many difficulties in the refinement, purification, storage and subsequent reaction of this compound to obtain high-purity compound II. It is well known that in chemical synthesis processes, especially in industrial manufacturing processes, it is preferable that the compounds produced by a certain method are of high purity or can be isolated and refined into a crystalline form which is easy to handle. [0003] Contents of the invention [0004] The technical problem to be solved by this inventi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/88
Inventor 黄伟
Owner HAINAN SIMCERE PHARMA CO LTD