CN114276302A

CN114276302A - Method for preparing 2, 4-diamino quinazoline derivative

Info

Publication number: CN114276302A
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: 2022-04-05
Anticipated expiration: 2042-01-11
Also published as: CN114276302B

Abstract

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

Description

Method for preparing 2, 4-diamino quinazoline derivative

Technical Field

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

Background

Quinazoline, also known as benzopyrimidine, is an important nitrogen-containing heterocyclic compound which is widely present in various alkaloids and organic molecules with biological and pharmacological activities, and the activities comprise antitumor, antimalarial, anti-inflammatory, antibacterial, anticonvulsant, antitubercular, antihypertensive and the like. In addition, the diamino quinazoline derivative has a better application prospect in the aspect of improving the anti-tumor activity, and the structure can reduce the drug resistance of the tumor to the targeted drugs and enhance the anti-tumor activity of the related targeted drugs.

The prior method for synthesizing the diamino quinazoline compound mainly comprises the following steps, and the disadvantages are obvious.

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

(1) 2, 4-quinclorac and ammonia in ethanol at 150 ℃ in an autoclave. Although the raw materials are cheap, the reaction needs high temperature and high pressure without adding a catalyst, and the operability and the safety are poor.

(2) 2, 4-dimethylthioquinazoline and ethanol solution of ammonia gas react at 230 ℃ under high temperature and high pressure. Expensive raw materials, low safety, generation of sulfur odor, and difficult absorption of tail gas. It is poor in environmental friendliness and economical efficiency.

The second method comprises the following steps: the substituted benzonitrile is reacted with guanidine hydrochloride. For example:

starting from o-bromoxynil, reacting with guanidine hydrochloride, and synthesizing 2, 4-diaminoquinazolin at 80 ℃ under the action of cuprous iodide with the yield of 66%. The price of the raw material o-bromoxynil is high, the yield is low, and the economical efficiency is poor.

Disclosure of Invention

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

The method for preparing the 2, 4-diamino quinazoline derivative has the reaction route as follows:

，

wherein:

r1 is selected from hydrogen or halogen or methoxy or amino or carboxy or hydroxy;

r2 is selected from hydrogen or halogen or methoxy or amino or carboxy or hydroxy or nitro;

r3 is selected from hydrogen or halogen or methoxy or amino or carboxy or hydroxy;

r4 is selected from hydrogen or halogen or methoxy or amino or carboxy or hydroxy;

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

The catalyst is 1, 3-bis (diphenylphosphino) 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 and reacting at 30-40 ℃, cooling after the reaction is finished, evaporating the solvent, adding hot water into residues, pulping, filtering, leaching, and drying to obtain a compound II.

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

In the organic solvent containing ammonia gas or primary amine, the organic solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or a mixture thereof.

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

In terms of mole ratios, catalyst: 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) 1, 3-bis (diphenylphosphino) propane nickel dichloride is used as a catalyst, so that the reaction temperature is greatly reduced, the reaction does not need high temperature, the 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 requirements of the reaction on equipment are further reduced, the safety is greatly enhanced, and the safety and environmental protection concept is better met.

(2) The invention has 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-dimethoxyquinazoline, 350ml of 10% ammonia methanol solution and 0.4g of 1, 3-bis (diphenylphosphino) propane nickel dichloride are mixed in a 500ml three-port reaction bottle, stirred by magnetic force, heated to 30 ℃ in oil bath for reaction for 5 hours, and then naturally cooled to room temperature. Removing methanol by rotary evaporation, adding 50ml of hot water at 70 ℃ and pulping twice, performing suction filtration, rinsing with hot water, and performing forced air drying at 70 ℃ to constant weight to obtain 17.9g of similar white solid, wherein the yield is as follows: 90.5 percent.

Example 2

200g of raw material 2, 4-dichloro-6, 7-dimethoxyquinazoline, 3500ml of 10 percent ammonia methanol solution and 5g of 1, 3-bis (diphenylphosphino) propane nickel dichloride are mixed in a 5000ml three-port reaction bottle, stirred, electrically heated in an oil bath to the internal temperature of 40 ℃ for reaction for 5 hours, and then naturally cooled to the room temperature. Discharging after opening the kettle, removing methanol by rotary evaporation, adding 500ml of 2 hot water at 75 ℃ for pulping twice, performing suction filtration, rinsing with hot water, and drying by air blowing at 70 ℃ until the weight is constant to obtain 175g of white-like solids, wherein the yield is as follows: 88 percent.

Example 3

20g of raw material (2, 4-dichloro-6-nitroquinazoline), 350ml of 10% ammonia methanol solution and 0.35g of 1, 3-bis (diphenylphosphino) propane nickel dichloride are mixed in a 500ml three-port reaction bottle, stirred by magnetic force, heated to 35 ℃ in oil bath for reaction for 5 hours, and then naturally cooled to room temperature. Removing methanol by rotary evaporation, adding 50ml of hot water at 80 ℃ and pulping twice, performing suction filtration, rinsing with hot water, and performing forced air drying at 70 ℃ to constant weight to obtain 15.0g of similar white solid, wherein the yield is as follows: 89.2 percent.

Example 4

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

Example 5

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

Example 6

5g of raw material (2, 4-dichloroquinazoline), 100ml of 10% isopropylamine methanol solution and 0.1g of 1, 3-bis (diphenylphosphino) propane nickel dichloride are mixed in a 250ml three-mouth reaction bottle, stirred by magnetic force, heated in oil bath to 40 ℃ for reaction for 5 hours, and then naturally cooled to room temperature. Removing methanol by rotary evaporation, adding 10ml of 2 hot water at 66 ℃ for pulping twice, performing suction filtration, rinsing with hot water, and performing forced air drying at 70 ℃ to constant weight to obtain 5.8g of similar white solid, wherein the yield is as follows: 95.1 percent.

Example 7

10g of raw material (2, 4-dichloroquinazoline), 150ml of 10% benzylamine methanol solution and 0.1g of 1, 3-bis (diphenylphosphino) propane nickel dichloride are mixed in a 250ml three-mouth reaction bottle, stirred by magnetic force, heated in oil bath to 40 ℃ for reaction for 5 hours, and then naturally cooled to room temperature. Removing methanol by rotary evaporation, adding 15ml of 2 hot water at 72 ℃ for pulping twice, performing suction filtration, rinsing with hot water, and performing forced air drying at 70 ℃ until the weight is constant to obtain 13.1g of similar white solid with the yield of 79%.

Claims

1. A method for preparing 2, 4-diamino quinazoline derivatives is characterized in that the reaction route is as follows:

，

wherein:

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

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

2. A process for the preparation of a 2, 4-diaminoquinazoline derivative according to claim 1, characterised by the specific steps of: adding an organic solvent containing ammonia gas or primary amine and a catalyst into the compound I, stirring and reacting at 30-40 ℃, cooling after the reaction is finished, evaporating the solvent, adding hot water into residues, pulping, filtering, leaching, drying and obtaining a compound II.

3. A process for preparing a 2, 4-diaminoquinazoline derivative according to claim 2, characterized in that the mass fraction of ammonia or a primary amine in the organic solvent containing ammonia or a primary amine is 8-11%.

4. A process for the preparation of a 2, 4-diaminoquinazoline derivative according to claim 2, characterised in that 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 a 2, 4-diaminoquinazoline derivative according to claim 2, characterized in that the mass to volume ratio of compound I to the organic solvent containing ammonia gas or a primary amine is 1g:15-20 mL.

6. A process for the preparation of a 2, 4-diaminoquinazoline derivative according to claim 2, characterised in that, in terms of mole ratios, the catalyst: compound I =1-5: 100.

7. A process for the preparation of a 2, 4-diaminoquinazoline derivative according to claim 2, characterized in that, in terms of mass ratio, ammonia gas or a primary amine: compound I =1: 1-1.5.

8. A process for the preparation of a 2, 4-diaminoquinazoline derivative according to claim 2, characterized in that the temperature of the heated beating water is 60-80 ℃.

9. A process for the preparation of a 2, 4-diaminoquinazoline derivative according to claim 2, characterised in that the primary amine includes but is not limited to methylamine or isopropylamine or cyclopropylamine or aniline or benzylamine.