CN114276302B

CN114276302B - Method for preparing 2, 4-diaminoquinazoline derivative

Info

Publication number: CN114276302B
Application number: CN202210025051.4A
Authority: CN
Inventors: 郭立涛; 马绍辉; 崔宁宁
Original assignee: Shandong Baiqi Biomedical Co ltd
Current assignee: Shandong Baiqi Biomedical Co ltd
Priority date: 2022-01-11
Filing date: 2022-01-11
Publication date: 2023-07-25
Anticipated expiration: 2042-01-11
Also published as: CN114276302A

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for preparing a 2, 4-diaminoquinazoline derivative. The invention takes compound I and ammonia gas or primary amine as raw materials, and obtains 2, 4-diaminoquinazoline derivatives under the action of catalyst 1, 3-bis (diphenylphosphine) propane nickel dichloride. The invention can synthesize the diaminoquinazoline derivative mildly and efficiently, successfully solves the problems of high cost, high safety risk and high pollution existing in the synthesis of 2, 4-diaminoquinazoline and related derivatives, and has good industrialized prospect.

Description

Method for preparing 2, 4-diaminoquinazoline derivative

Technical Field

The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for preparing a 2, 4-diaminoquinazoline derivative.

Background

Quinazolines, also known as benzopyrimidines, are an important class of nitrogen-containing heterocyclic compounds, which are widely found in various alkaloids and organic molecules with biological pharmacological activities, including anti-tumor, anti-malaria, anti-inflammatory, antibacterial, anticonvulsant, anti-tuberculosis, antihypertensive and the like. In addition, the diaminoquinazoline derivative has a good application prospect in the aspect of improving the anti-tumor activity, and the structure can reduce the drug resistance of tumors to the targeted drugs and enhance the anti-tumor activity of related targeted drugs.

The existing method for synthesizing the diaminoquinazoline compounds mainly comprises the following steps of and has obvious disadvantages.

The method comprises the following steps: the raw materials react with ammonia gas at high temperature. For example:

(1) 2, 4-dichloro quinazoline and ammonia gas in an ethanol solution at 150 ℃ in an autoclave. Although the raw materials are inexpensive, high-temperature and high-pressure reaction is required without adding a catalyst, and operability and safety are poor.

(2) Starting from 2, 4-dimethyl thioquinazoline, reacting with ethanol solution of ammonia at 230 ℃ under high temperature and high pressure. Expensive raw materials, low safety, sulfur odor and difficult absorption of tail gas. The environmental friendliness and the economy are poor.

The second method is as follows: substituted benzonitriles are reacted with guanidine hydrochloride. For example:

starting from o-bromoxynil, the product reacts with guanidine hydrochloride, and 2, 4-diaminoquinazoline is synthesized at 80 ℃ under the action of cuprous iodide, and the yield is 66%. Raw material o-bromoxynil has high price, low yield and poor economy.

Disclosure of Invention

Aiming at the problems, the invention provides a method for preparing the 2, 4-diaminoquinazoline derivative, which can synthesize the diaminoquinazoline derivative mildly and efficiently, successfully solves the problems of high cost, high safety risk and high pollution existing in the synthesis of the 2, 4-diaminoquinazoline and related derivatives, and has good industrialized prospect.

The reaction route of the method for preparing the 2, 4-diaminoquinazoline derivative is as follows:

，

wherein:

r1 is selected from hydrogen or halogen or methoxy or amino or carboxyl or hydroxyl;

r2 is selected from hydrogen or halogen or methoxy or amino or carboxyl or hydroxyl or nitro;

r3 is selected from hydrogen or halogen or methoxy or amino or carboxyl or hydroxyl;

r4 is selected from hydrogen or halogen or methoxy or amino or carboxyl or hydroxyl;

r5 is selected from hydrogen or phenyl or methyl or cyclopropyl or isopropyl or benzyl

The catalyst is 1, 3-bis (diphenylphosphine) propane nickel dichloride.

The method comprises the following specific steps: adding an organic solvent containing ammonia gas and a catalyst into the compound I, stirring the mixture for reaction at 30-40 ℃, cooling the mixture after the reaction is finished, evaporating the solvent, adding hot water into the residue for pulping, filtering, leaching and drying the residue to obtain the compound II.

In the organic solvent containing ammonia gas or primary amine, the mass fraction of the ammonia gas or primary amine is 8-11%.

Among the organic solvents containing ammonia gas or primary amine, the organic solvents are selected from methanol or ethanol or isopropanol or tetrahydrofuran or dioxane or a mixture thereof.

The mass volume ratio of the compound I to the organic solvent containing ammonia or primary amine is 1g:15-20mL.

The catalyst comprises the following components in mole ratio: compound i=1-5:100.

Ammonia gas or primary amine: compound i=1:1-1.5.

The temperature of the beating hot water is 60-80 ℃.

The primary amine includes but is not limited to methylamine or isopropylamine or cyclopropylamine or aniline or benzylamine.

The invention has the following beneficial effects:

(1) The 1, 3-bis (diphenylphosphine) propane nickel dichloride is used as a catalyst, so that the reaction temperature is greatly reduced, the reaction does not need to be carried out at high temperature, excessive volatilization of ammonia gas or primary amine steam is avoided, and the normal pressure reaction is realized. Because the reaction is carried out under mild conditions, the requirement of the reaction on equipment is further reduced, the safety is greatly enhanced, and the method is more in line with the safety and environmental protection concept.

(2) The invention has the advantages of cheap and easily obtained raw materials, short synthetic route, greatly reduced production cost and simple post-treatment; the reaction solvent can be recycled, the cost is further reduced, and the three wastes are greatly reduced.

Detailed Description

Example 1

20g of raw material 2, 4-dichloro-6, 7-dimethoxy quinazoline, 350ml of 10% ammonia methanol solution and 0.4g of 1, 3-bis (diphenylphosphine) propane nickel dichloride are mixed in a 500ml three-port reaction bottle, magnetically stirred, heated to 30 ℃ in an oil bath for reaction for 5 hours, and then naturally cooled to room temperature. Removing methanol by rotary evaporation, adding 50ml of hot water of which the temperature is 70 ℃ for pulping twice, carrying out suction filtration, leaching by hot water, and carrying out forced air drying at 70 ℃ until the weight is constant to obtain 17.9g of white solid, wherein the yield is: 90.5%.

Example 2

200g of raw material 2, 4-dichloro-6, 7-dimethoxy quinazoline and 3500ml of 10% ammonia methanol solution, 5g of 1, 3-bis (diphenylphosphine) propane nickel dichloride are mixed in a 5000ml three-port reaction bottle, stirring is started, oil bath is electrically heated to an internal temperature of 40 ℃ for reaction for 5 hours, and then natural cooling to room temperature is carried out. Discharging the kettle, removing methanol by rotary evaporation, pulping twice by adding 500ml of hot water at 75 ℃ of 2, filtering, leaching by hot water, and drying by blowing at 70 ℃ to constant weight to obtain 175g of white solid, wherein the yield: 88%.

Example 3

20g of raw material (2, 4-dichloro-6-nitroquinazoline), 350ml of 10% ammonia methanol solution and 0.35g of 1, 3-bis (diphenylphosphine) propane nickel dichloride are mixed in a 500ml three-port reaction bottle, magnetically stirred, heated to 35 ℃ in an oil bath for reaction for 5 hours, and then naturally cooled to room temperature. Removing methanol by rotary evaporation, adding 50ml of hot water of which the temperature is 80 ℃ for pulping twice, carrying out suction filtration, leaching by hot water, and carrying out forced air drying at 70 ℃ until the constant weight is obtained, thus obtaining 15.0g of white solid, and obtaining the yield: 89.2%.

Example 4

10g of the raw material (2, 4-dichloro-6-methoxyquinazoline), 150ml of 10% methylamine methanol solution and 0.2g of 1, 3-bis (diphenylphosphine) propane nickel dichloride are mixed in a three-port reaction flask of 250ml, magnetically stirred, heated to 30 ℃ in an oil bath for reaction for 5 hours, and then naturally cooled to room temperature. Removing methanol by rotary evaporation, adding 15ml of hot water with the temperature of 2 to pulp twice at 70 ℃, carrying out suction filtration, leaching by hot water, and carrying out forced air drying at 70 ℃ to constant weight to obtain 8.9g of white solid, wherein the yield: 93.6%.

Example 5

30g of raw material (2, 4-dichloro-6-methoxyquinazoline), 450ml of 10% methylamine methanol solution and 0.5g of 1, 3-bis (diphenylphosphine) propane nickel dichloride are mixed in a three-port reaction bottle of 1000ml, magnetically stirred, heated to 40 ℃ in an oil bath for reaction for 5 hours, and then naturally cooled to room temperature. Removing methanol by rotary evaporation, adding 50ml of hot water of 66 ℃ for pulping twice, carrying out suction filtration and hot water leaching, and carrying out forced air drying at 70 ℃ until the constant weight is obtained to obtain 23.2g of white solid, wherein the yield is: 91.3%.

Example 6

5g of raw material (2, 4-dichloro quinazoline), 100ml of 10% isopropyl amine methanol solution and 0.1g of 1, 3-bis (diphenylphosphine) propane nickel dichloride are mixed in a three-port reaction bottle of 250ml, magnetically stirred, heated to 40 ℃ in an oil bath for reaction for 5 hours, and then naturally cooled to room temperature. Removing methanol by rotary evaporation, adding 10ml of hot water of which the temperature is 66 ℃ for pulping twice, carrying out suction filtration, leaching by hot water, and carrying out forced air drying at 70 ℃ until the constant weight is obtained, thus obtaining 5.8g of white solid, and the yield: 95.1%.

Example 7

10g of the raw material (2, 4-dichloroquinazoline), 150ml of 10% benzyl amine methanol solution and 0.1g of 1, 3-bis (diphenylphosphine) propane nickel dichloride are mixed in a three-port reaction bottle of 250ml, magnetically stirred, heated to 40 ℃ in an oil bath for reaction for 5 hours, and then naturally cooled to room temperature. The methanol is removed by rotary evaporation, 15ml of hot water at 72 ℃ is added for pulping twice, suction filtration and hot water leaching are carried out, and blast drying is carried out at 70 ℃ until the constant weight is obtained to obtain 13.1g of white solid with the yield of 79 percent.

Claims

1. A process for the preparation of a 2, 4-diaminoquinazoline derivative, which comprises the following steps:

wherein:

r5 is selected from hydrogen or phenyl or methyl or cyclopropyl or isopropyl or benzyl;

the catalyst is 1, 3-bis (diphenylphosphine) propane nickel dichloride.

2. A process for the preparation of 2, 4-diaminoquinazoline derivatives according to claim 1, characterized in that it comprises the following specific steps: adding an organic solvent containing ammonia gas or primary amine and a catalyst into the compound I, stirring the mixture at 30-40 ℃ for reaction, cooling the mixture after the reaction is finished, evaporating the solvent, adding hot water into the residue for pulping, filtering, leaching and drying the residue to obtain the compound II.

3. A process for the preparation of 2, 4-diaminoquinazoline derivatives according to claim 2, wherein the mass fraction of ammonia or primary amine in the organic solvent containing ammonia or primary amine is from 8 to 11%.

4. A process for the preparation of 2, 4-diaminoquinazoline derivatives according to claim 2 wherein the organic solvent containing ammonia or a primary amine is selected from methanol or ethanol or isopropanol or tetrahydrofuran or dioxane or mixtures thereof.

5. A process for the preparation of 2, 4-diaminoquinazoline derivatives according to claim 2, wherein the mass to volume ratio of compound I to the organic solvent containing ammonia or primary amine is from 1g:15 to 20mL.

6. A process for the preparation of 2, 4-diaminoquinazoline derivatives according to claim 2, wherein the catalyst, in terms of molar ratio: compound i=1-5:100.

7. A process for the preparation of 2, 4-diaminoquinazoline derivatives according to claim 2, wherein the ammonia or primary amine is present in a mass ratio: compound i=1:1-1.5.

8. A process for the preparation of 2, 4-diaminoquinazoline derivatives according to claim 2, wherein the beating hot water temperature is 60-80 ℃.

9. A process for the preparation of 2, 4-diaminoquinazoline derivatives according to claim 2, wherein the primary amine is methylamine or isopropylamine or cyclopropylamine or aniline or benzylamine.