Quinazoline compound as well as preparation method and application thereof in preparing tyrosine kinase inhibitor

A technology of quinazolines and compounds, which is applied in the field of pharmaceutical preparation, can solve the problems of low conversion rate, low yield, unsuitability for industrial production of quinazoline crotyl compounds, etc., and achieve the effect of easy mass production

Inactive Publication Date: 2014-11-19
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the reduction reaction from compound 2 to compound 1 can obtain a yield of 97.8%, this is only a 10-gram scale process that can be completely reproduced and cannot be scaled up; the reaction from compound 1 to compound Ia is an anhydrous reaction. The conversion rate is lower than 50%, and the purity of the crude product is lower than 70%; and the compound 1 cannot be completely conver

Method used

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  • Quinazoline compound as well as preparation method and application thereof in preparing tyrosine kinase inhibitor
  • Quinazoline compound as well as preparation method and application thereof in preparing tyrosine kinase inhibitor
  • Quinazoline compound as well as preparation method and application thereof in preparing tyrosine kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 Preparation of Compound IIIa by Catalytic Hydrogenation

[0048] 1. The reaction equation is as follows:

[0049]

[0050] 2. The feeding ratio is as follows:

[0051] Material name

molecular weight

Actual feeding amount

The molar ratio of

weight ratio

Compound IIa

384.70

600.0g

1

1

THF(1)

72.11

4.0kg

6.7

Methanol

32.04

0.7kg

1.2

Raney Nickel

85.67

120.0g

0.9

0.2

ammonium chloride

53.49

60.0g

0.7

0.1

Saturated Salt Water (1)

/

4.2kg

7

Saturated Salt Water (2)

/

3.2kg

5.3

THF(2)

72.11

1000mL

0.75

[0052] 3. Process operation steps

[0053] Compound IIa was added to a 10L double-jacketed glass reactor, then THF (1) and methanol were added to the reactor, and the compound II was stirred to dissolve. Then add Raney nickel and ammoniu...

Embodiment 2

[0054] The preparation of embodiment 2 compound IVa

[0055] 1. The reaction equation is as follows:

[0056]

[0057] 2. The feeding ratio is as follows:

[0058] Material name

molecular weight

Actual feeding amount

The molar ratio of

weight ratio

Compound IIIa

354.71

516.5g

1

1

diethylphosphonoacetic acid

196.14

599.9g

2.1

1.2

N,N'-Carbonyldiimidazole (CDI)

162.15

495.9g

2.1

1.0

THF(1)

72.11

1.81kg

3.5

THF(2)

72.11

729.3g

1.4

THF(3)

72.11

2.29kg

4.4

Methyl tert-butyl ether (MTBE)

88.15

12.91kg

25

MTBE: THF mixture (1)

/

2804.8g

5.4

purified water

18

1452.7g

2.8

MTBE: THF mixture (2)

/

1874.9g

3.6

[0059] 3. Process operation steps

[0060] Add CDI into a 10L reaction kettle, then add THF (1), st...

Embodiment 3-7

[0068] Examples 3-7 respectively provide methods for preparing corresponding compound (IV) from different compounds (III), the steps are basically the same as in Example 2, and the conditions refer to Table 1 (for the preparation method of compound (III), refer to Example 1 of CN10283550A).

[0069] Table 1

[0070]

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PUM

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Abstract

The invention relates to a novel quinazoline compound and a method for preparing a quinazoline crotyl compound for treating or preventing various adaptation diseases related to EGFR and HER2 kinase functions from the quinazoline compound. The method comprises the following steps: firstly, reacting a raw material with amino with diethylphosphonoacetic acid and N,N'-carbonyl dimidazole in a solvent at 25 DEG C to 50 DEG C, so as to transform the amino in the raw material into diethyl phosphorus acetamido to obtain an intermediate, and subsequently reacting the intermediate with N,N'-di-substituted acetaldehyde in a solvent in the presence of an alkali substance at minus 30 DEG C to minus 20 DEG C, thereby generating the target compound. By adopting the procedures, by virtue of simple aftertreatment, the target product of which the purity is greater than 98% is obtained, the total yield of the target product is as high as 74%, and in addition, by adopting the method, preparation of kilo-rate target products is successfully achieved, and batch production is easy to achieve.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to quinazoline compounds, their preparation method and their application in the preparation of tyrosine kinase inhibitors. Background technique [0002] CN102838550A discloses the quinazoline crotyl compound with general formula (I), [0003] [0004] where: R 1 for CH 2 F, CHF 2 , C 2 ~C 12 Fluorocarbonyl, C 2 ~C 12 Chlorinated hydrocarbon group; R 2 , R 3 independently hydrogen, C 1 ~C 12 Hydrocarbyl. [0005] The above-mentioned quinazoline crotyl compounds have been proved to be ideal high-efficiency dual irreversible tyrosine kinase inhibitors, which can inhibit the activity and phosphorylation of kinases by acting on the intracellular part of EGFR and competitively binding with ATP, and block EGFR tyrosine kinase. ATP-binding site of amino acid kinase to achieve the purpose of specific inhibition of EGFR. Such compounds can be used for the preparat...

Claims

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Application Information

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IPC IPC(8): C07F9/6512C07D239/94
CPCC07D239/94
Inventor 殷建明吕裕斌李邦良
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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