CN105669566A - Preparation method of pharmaceutical intermediate N-arylquinazolinyl-amine compounds - Google Patents

Abstract

The invention discloses a preparation method of an N-arylquinazolin-2-amine compound, belonging to the field of drug synthesis. The method uses 3-bromobenzaldehyde as a starting material, and obtains N-arylquinazolin-2-amine compounds through five steps of nitration, reduction, ring closure with cyanamide, coupling and substitution. Compared with the existing route, the preparation method of the present invention has the characteristics of easy availability of raw materials, higher yield of the whole reaction route, mild reaction conditions, simple operation and lower production cost, and is very suitable for industrial production.

Description

A kind of preparation method of pharmaceutical intermediate N-aryl quinazoline-2-amine compound

technical field

The invention belongs to the field of medicinal chemistry and organic chemistry, and relates to a preparation method of a pharmaceutical intermediate compound, in particular to a preparation method of an N-arylquinazolin-2-amine compound as a pharmaceutical intermediate.

Background technique

Hepatocellular carcinoma (HCC) is a complex and diverse malignant tumor accompanied by a variety of genetic and epigenetic changes. About 1.25 million people die of liver cancer every year in the world, and about 45% of them occur in our country. my country is a high incidence area of liver cancer in the world, and the trend of high incidence is very serious. The mortality rate of liver cancer in my country has increased by 41.7% in the past 20 years. Fibroblast growth factor receptor 4 (Fibroblast growth factor receptor FGFR4) can initiate the growth of liver cancer tumors, especially when its high expression or gene changes lead to stable and constitutive activation, eventually causing the proliferation and growth of tumor cells. Compared with the FGFR family and other kinases, BLU9931 shows highly selective inhibition of FGFR4, and is a new type of irreversible kinase inhibitor targeting FGFR4. BLU9931 exhibits superior antitumor activity in mice xenogeneically suppressed with hepatocellular carcinoma.

In the field of organic chemistry and medicinal chemistry, N-arylquinazolin-2-amine compounds have an important role and status, which usually have certain pharmaceutical activity, and are often used to synthesize a variety of pharmaceutically active compounds, such as Anti-tumor FGFR-4 kinase inhibitor drugs, PDK1 kinase inhibitor drugs, etc.

It is precisely because of the important role of N-arylquinazolin-2-amine compounds in the fields of organic synthesis, medicinal chemistry, etc. that people have carried out a lot of research on their synthesis, and have obtained many novel synthetic routes and methods. Synthetic pathways for these compounds.

WO2014/011900 discloses that 2-amino-5-bromobenzoic acid is used as a raw material, and an important intermediate aryl-substituted quinazoline amine compound is obtained through six steps of reduction, oxidation, ring formation, substitution, coupling, and coupling. This route has great potential safety hazards in the process (requires low-temperature borane reduction, high-temperature reflux of phosphorus oxychloride), harsh experimental conditions and cannot be scaled up (the coupling reaction requires microwave conditions), and low yield (the yield of the coupling reaction is only 38% ) and other shortcomings. In addition, this route involves a two-step coupling reaction, which increases the cost of raw materials and the difficulty of post-processing, which does not conform to the concept of green chemistry. Therefore, it is necessary to explore more optimized preparation methods.

Contents of the invention

The object of the present invention is to provide a kind of preparation method of N-arylquinazolin-2-amine compound aiming at the above-mentioned deficiencies in the prior art.

The method uses 3-bromobenzaldehyde as a starting material, and prepares the compound through five-step reactions. The structure of this compound is as follows:

The object of the present invention is achieved in the following manner: a kind of preparation method of N-aryl quinazoline-2-amine compound, its characteristic is to be starting raw material with 3-bromobenzaldehyde, by nitration, reduction, and cyanide The five steps of ring closure, coupling and substitution of amines give important intermediate N-arylquinazolin-2-amine compounds. The reaction process is as follows:

Specifically, the above method includes the following steps:

a, with 3-bromobenzaldehyde (compound II) as starting material, obtain 5-bromo-2-nitrobenzaldehyde (compound III) through nitration;

b, 5-bromo-2-nitrobenzaldehyde (compound III) is reduced to obtain 2-amino-5-bromobenzaldehyde (compound IV);

c, 2-amino-5-bromobenzaldehyde (compound IV) and cyanamide ring closure to obtain 6-bromoquinazolin-2-amine (compound V);

d, 6-bromoquinazolin-2-amine (compound V) and 3,5-dimethoxyphenylboronic acid are coupled under palladium catalyst to obtain 6-(3,5-dimethoxyphenyl)quinone Azolin-2-amine (compound VI);

e, 6-(3,5-dimethoxyphenyl) quinazoline-2-amine (compound VI) is substituted by o-fluoronitrobenzene and its multi-substituted derivatives to obtain N-aryl quinazoline-2 - Amines (Compound I).

The step a is specifically: Compound II reacts with nitric acid or sodium nitrate in sulfuric acid as a solvent at 0-40° C. Compound III is obtained after 1-12 hours, and the molar ratio of compound II to nitric acid or sodium nitrate is 1:1.0 -1.5; sulfuric acid concentration is 70-98%;

The step b specifically includes: reducing compound III with iron powder/hydrochloric acid, ferric hydroxide/hydrazine hydrate or stannous chloride in ethanol solvent, reacting at 40-80°C for 2-12h to obtain compound IV, compound III and reduction The molar ratio of the agent is 1:0.1-0.5;

The step c is specifically: compound IV and cyanamide in the solvent N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or N-methylpyrrolidone, at 60-200°C The compound V was obtained by reacting for 2-12 hours, and the molar ratio of compound IV to cyanamide was 1:1.2-3.0;

The step d is specifically: compound V and 3,5-dimethoxyphenylboronic acid in solvent ethylene glycol dimethyl ether, 1,4-dioxane, isopropanol or ethanol, adding catalyst palladium carbon, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or tetrakis(triphenylphosphine)palladium, add inorganic base potassium carbonate, sodium carbonate or cesium carbonate, react at 60-100℃ , 18-24h to obtain compound VI, the molar ratio of compound V to 3,5-dimethoxyphenylboronic acid is 1:1.1-1.5, the molar ratio of compound V to palladium catalyst is 1:0.05-0.5, compound V and inorganic The molar ratio of alkali is 1:1.5-2.5;

The step e is specifically: react compound VI with o-fluoronitrobenzene and its multi-substituted derivatives in a solvent N,N-dimethylformamide or tetrahydrofuran, add NaH as a base, and react at 0°C-room temperature for 18 -24h to obtain compound I, the molar ratio of compound VI to o-fluoronitrobenzene and its multi-substituted derivatives is 1:1.1-1.5, and the molar ratio of compound VI to NaH is 1:1.1-1.5.

Compared with the prior art, the preparation method of the present invention has easy-to-obtain raw materials, high yield of the whole reaction route, mild reaction conditions, simple operation and low production cost, and is very suitable for industrial production.

detailed description

The preparation method of the N-arylquinazolin-2-amine compound of the present invention is described in detail below with specific examples.

Example 1

1.1 Synthesis of compound III

Under ice-water bath conditions, add 289ml of sulfuric acid (5.4mol) with a mass fraction of 98% in a 1L three-necked round-bottomed flask, then slowly add 64ml of compound II (0.54mol) dropwise while stirring and adjusting the price, after the addition, the temperature of the system drops to 10 After ℃, slowly add 27ml of nitric acid (0.59mol) with a mass fraction of 65% to the system dropwise, after the addition is monitored by TLC, after 4 hours of reaction, the substrate reaction is complete, and the reaction system is slowly poured into 2L of ice water, suction filtered, and the filter cake is watered. Wash until the filtrate is free of acidity, and the solid is recrystallized from n-hexane and ethyl acetate to obtain 91 g of compound III as a white solid, with a yield of 73.1%.

¹ HNMR (400MHz, CDCl3) δ10.41 (s, 1H), 8.06 (d, J = 2.1Hz, 1H), 8.03 (d, J = 8.6Hz, 1H), 7.88 (dd, J = 8.6, 2.1Hz ,1H).

¹³ CNMR (101MHz, CDCl3) δ186.74, 136.51, 132.65, 129.57, 126.13.

Example 2

1.2 Synthesis of Compound IV

Add 90g of compound III (0.39mmol) into a 1L round bottom flask, add 300ml of absolute ethanol to the system, add 32g of reduced iron powder (0.58mol) under stirring conditions, add 0.1M HCl 200ml to the system, heat the oil bath to 80°C, After 4 hours of reaction, the reaction of the substrate was complete, part of the ethanol was removed by rotary evaporation, the solid was precipitated, filtered with suction, and the solid was slurried with dichloromethane to obtain 71 g of compound III as a light yellow powder with a yield of 92%. HPLC analysis showed that the purity was 97%, and it was directly used in the next reaction without further separation and purification.

Example 3

1.3 Preparation of compound V

70g of compound IV (0.35mmol) was added to a 500ml beaker, 250ml of ether was added successively, 25ml of mass fraction was 37% hydrochloric acid and stirred for 5 minutes, suction filtered, the solid was added into a 500ml round bottom flask, and 29g of cyanamide (0.70mol ), add 60ml of N,N-dimethylformamide, heat the oil bath to 80°C, monitor by TLC, after 12 hours of reaction, the substrate reaction is complete, cool the reaction system, add 300ml of water, filter with suction, solid ethyl acetate and n-hexane The product was obtained by recrystallization, and 56g of compound V light yellow powder was obtained by suction filtration, with a yield of 72%. m.p.

¹ H NMR (400MHz, DMSO) δ: 9.09 (s, 1H), 8.05 (d, J = 2.1Hz, 1H), 7.77 (dd, J = 9.0, 2.3Hz, 1H), 7.36 (d, J = 9.0Hz ,1H),6.99(s,2H).

¹³ CNMR (101MHz, DMSO) δ: 161.64, 160.99, 150.60, 136.75, 129.81, 126.86, 120.51, 113.20.

Example 4

1.4 Preparation of compound VI

Put 2.00g (8.9mmol) of compound V, 2.44g (13.4mmol) of 3,5-dimethoxyphenylboronic acid, 475mg (0.45mmol) of 10% palladium/carbon and 2.47g (17.9mmol) of potassium carbonate in a 250mL round bottom In the flask, 60 mL of ethylene glycol dimethyl ether and 10 mL of water were used as solvents, and heated to 80° C. for 3 hours under nitrogen protection. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain a crude product. Then add as little hot ethyl acetate as possible to dissolve, then quickly add a large amount of cold ether and cool rapidly, a large amount of light yellow solid precipitates, and is filtered and washed to obtain 2.01 g of compound VI as a yellow solid, with a yield of 80.1%. m.p.210-212°C ;ESI-MSm/z:281.96,[M+H]+.

1H NMR (400MHz, DMSO) δ: 9.16(s, 1H), 8.12(d, J=2.0Hz, 1H), 8.03(dd, J=8.8, 2.0Hz, 1H), 7.48(d, J=8.8Hz, 1H), 6.89(s, 2H), 6.88(d, J=1.9Hz, 2H), 6.52(d, J=2.0Hz, 1H), 3.83(s, 6H).

13CNMR (101MHz, DMSO) δ: 162.68, 160.91, 151.42, 141.43, 133.34, 133.05, 125.42, 124.91, 119.48, 104.58, 99.19, 55.26.

Example 5

1.5 Preparation of compound VII

Take 570 mg (14.22 mmol) of NaH (60%) and add 20 mL of redistilled tetrahydrofuran (THF) under the protection of nitrogen, and cool in an ice bath for 15 minutes; take 2 g of compound VI and dissolve it in 50 mL of redistilled THF. It was added dropwise to the above system, and after the dropwise addition was completed, it was stirred at room temperature for 2 hours; THF was slowly added dropwise to the system. After the addition was complete, the ice bath was removed, the system was slowly raised to room temperature, and the reaction was continued overnight with stirring. 50 mL of water was added to quench the reaction, and the system was extracted with ethyl acetate (30 mL×3). The organic layers were combined, washed 3 times with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated. Recrystallization with ethyl acetate and petroleum ether gave Compound VII as a red solid 2.58g, yield 87.2%. m.p.125-127°C; ESI-MSm/z: 417.11, [M+H]+.

1H NMR (400MHz, DMSO) δ: 9.56(s, 1H), 9.29(s, 1H), 8.23(d, J=1.9Hz, 1H), 8.10(dd, J=8.8, 1.8Hz, 1H), 7.81( d, J=7.5Hz, 1H), 7.66(d, J=7.4Hz, 1H), 7.47(d, J=8.5Hz, 1H), 7.37(t, J=7.8Hz, 1H), 6.90(d, J＝2.1Hz, 2H), 6.53(t, J＝2.1Hz, 1H), 3.83(s, 6H), 2.38(s, 3H).

13CNMR (101MHz, DMSO) δ: 162.86, 160.95, 157.48, 146.14, 141.16, 137.12, 134.97, 134.82, 133.62, 130.91, 125.50, 125.46, 125.42, 122.45, 120.53, 1994.33, 1994.43.1

Claims (6)

1. a kind of preparation method of N-aryl quinazoline-2-amine compound, this compound has the structure shown in general formula I: In the formula, R is a single-substituted or multi-substituted aromatic ring structure, which is characterized in that the preparation of the compound is based on 3-bromobenzaldehyde as a starting material, through nitration, reduction, ring closure with cyanamide, coupling, substitution Five steps obtain intermediate N-aryl quinazoline-2-amine compound; Concrete steps are as follows: a. With 3-bromobenzaldehyde, namely compound II, as the starting material, 5-bromo-2-nitrobenzaldehyde, namely compound III, is obtained through nitration; b. Compound III is reduced to obtain 2-amino-5-bromobenzaldehyde, namely compound IV; c, ring closure of compound IV and cyanamide to obtain 6-bromoquinazolin-2-amine, namely compound V; d. Compound V is coupled with 3,5-dimethoxyphenylboronic acid under the action of a palladium catalyst to obtain 6-(3,5-dimethoxyphenyl)quinazolin-2-amine, namely compound VI; e. Compound VI is substituted by o-fluoronitrobenzene and its multi-substituted derivatives to obtain N-arylquinazolin-2-amine, namely compound I. 2. The preparation method according to claim 1, characterized in that said step a is specifically: compound II reacts with nitric acid or sodium nitrate in sulfuric acid as a solvent at 0-40°C, and obtains compound III after 1-12 hours , the molar ratio of compound II to nitric acid or sodium nitrate is 1:1.0-1.5, and the concentration of sulfuric acid is 70-98%. 3. The preparation method according to claim 1, characterized in that said step b is specifically: Compound III is reduced with iron powder/hydrochloric acid, ferric hydroxide/hydrazine hydrate or stannous chloride in solvent ethanol, 40- Compound IV was obtained by reacting at 80°C for 2-12 hours, and the molar ratio of compound III to reducing agent was 1:0.1-0.5. 4. The preparation method according to claim 1, characterized in that said step c is specifically: compound IV and cyanamide in solvent N,N-dimethylformamide, N,N-dimethylacetamide, In methyl sulfoxide or N-methylpyrrolidone, react at 60-200°C for 2-12 hours to obtain compound V, and the molar ratio of compound IV to cyanamide is 1:1.2-3.0. 5. The preparation method according to claim 1, characterized in that said step d is specifically: compound V and 3,5-dimethoxyphenylboronic acid in the solvent ethylene glycol dimethyl ether, 1,4-dioxo Hexacyclic, isopropanol or ethanol, add catalyst palladium carbon, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or tetrakis(triphenylphosphine)palladium, add inorganic base Potassium carbonate, sodium carbonate or cesium carbonate, react at 60-100°C, 18-24h to obtain compound VI, the molar ratio of compound V to 3,5-dimethoxyphenylboronic acid is 1:1.1-1.5, compound V and palladium The molar ratio of the catalyst is 1:0.05-0.5, and the molar ratio of the compound V to the inorganic base is 1:1.5-2.5. 6. The preparation method according to claim 1, characterized in that said step e is specifically: making compound VI derivatize with o-fluoronitrobenzene and its multiple substitutions in solvent N,N-dimethylformamide or tetrahydrofuran Add NaH as a base, react at 0°C-room temperature for 18-24h to obtain compound I, the molar ratio of compound VI to o-fluoronitrobenzene and its multi-substituted derivatives is 1:1.1-1.5, and the molar ratio of compound VI to NaH The molar ratio is 1:1.1-1.5.