CN115108980A - Preparation method of 4-bit acylated derivative of 2-methylquinoline compound - Google Patents

Abstract

The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of a 4-position acylated derivative of a 2-methylquinoline compound. The method is realized by the following steps: adding a 2-methylquinoline compound Mixed with aldehyde, Selectfluor acts as an oxidant, reacts under the catalysis of silver nitrate, and obtains the acylated derivative of 2-methylquinoline compound at position 4 after column chromatography. The method provided by the invention uses Selectfluor as an oxidant, and is carried out in an aqueous solution under the catalysis of silver nitrate, the substrate has good solubility, wide applicability, high reaction yield and strong controllability. The method provided by the invention is environmentally friendly, has few side reaction products, and is green and efficient.

Description

A kind of preparation method of 4-position acylated derivatives of 2-methylquinoline compounds

technical field

The invention belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of a 4-position acylated derivative of a 2-methylquinoline compound.

Background technique

The acylated derivatives at position 4 of 2-methylquinoline compounds belong to the class of quinoline compounds. Quinoline and its derivatives are ubiquitous in natural products and medicines, and have a wide range of biological activities. Quinoline and its derivatives are very important nitrogen-containing heterocyclic compounds, which can be widely used in the fields of drugs, fungicides, herbicides, corrosion inhibitors and functional materials. It has been reported that quinoline and its derivatives have a wide range of biological activities, such as anticancer, antibacterial, anti-inflammatory, and anti-HIV. In addition, quinoline heterocycles are often introduced into drug molecules as the parent structure of medicines or pesticides. Therefore, the synthesis of acylated derivatives at position 4 of 2-methylquinoline compounds has very important pharmaceutical value and economic value.

Minisci reaction is an efficient way to synthesize quinoline derivatives. Minisci reaction can be carried out at high temperature, but it is often accompanied by the formation of a large number of by-products, and also brings the residue of harmful substances. For greener and more efficient synthesis of quinoline derivatives, various catalysts and new technologies are used. Sutherland et al. developed a method for the preparation of acylated derivatives at position 4 of 2-methylquinoline compounds synthesized by using triethyl chloroformate combined with TBHP as an acetyl radical source via an iron catalyst. . However, the experimental temperature is higher and the yield is lower (Eur. J. Org. Chem. 2019, 8, 1815-1819). Wenlong Li et al. developed a method for synthesizing quinoline compounds. This method can obtain the acylated derivatives of 2-methylquinoline compounds at position 4, but the reaction route is complicated and requires more reactants. (J. Med. Chem. 2018, 62, 993-1013). Therefore, the development of a simple synthesis method and a process with good selectivity has become an urgent problem to be solved.

SUMMARY OF THE INVENTION

In view of the problems existing in the prior art, the present invention discloses a preparation method of the acylated derivatives at position 4 of 2-methylquinoline compounds. Strong sex.

In order to achieve the above purpose, the technical solutions are as follows:

The invention provides a preparation method of a 4-position acylated derivative of a 2-methylquinoline compound,

Include the following steps:

(1) Mix 2-methylquinoline compounds and aldehydes, and use Selectfluor as an oxidant to react in a solvent under the catalysis of silver nitrate;

(2) 4-position acylated derivatives of 2-methylquinoline compounds are obtained after column chromatography;

Wherein, the structural formula of the acylated derivative at position 4 of the 2-methylquinoline compound is:

；

;

In the formula, the R ₁ is halogen, nitro, trifluoromethyl, methyl or hydrogen, and R ₂ is an alkyl group or a phenyl group.

Further, the molar ratio of the 2-methylquinoline compound to the aldehyde is 1:1.0-5.0; the preferred molar ratio is 1:3.0.

Further, the general formula of the 2-methylquinoline compound is:

；

;

The R is halogen, nitro, trifluoromethyl, methyl or hydrogen.

The aldehyde is n-butyraldehyde, isobutyraldehyde or benzaldehyde.

Further, the molar ratio of the 2-methylquinoline compound and silver nitrate is 1:0.2-1.0; the preferred molar ratio is 1:0.25.

Further, the molar ratio of the 2-methylquinoline compound and Selectfluor is 1:3-6; the preferred molar ratio is 1:4.

Further, the solvent is water; the solvent and silver nitrate material-to-liquid ratio is 1 mL: 0.025 mmol.

Further, the reaction temperature is 30-50 °C; the preferred reaction temperature is 30 °C; the reaction time is 20-24 h.

Further, the eluent of the column chromatography is ethyl acetate and n-hexane in a volume ratio of 1:15.

In the present invention, the reaction equation is as follows:

。

.

The beneficial effects of the present invention are:

(1) The method provided by the present invention uses Selectfluor as an oxidant and is catalyzed by silver nitrate, and is carried out in an aqueous solution. The substrate has good solubility and wide applicability; the reaction yield is high and the controllability is strong.

(2) The method provided by the present invention is environmentally friendly, has few side reaction products, is green and efficient.

Detailed ways

The following examples further illustrate the technical solutions of the present invention, but are not intended to limit the protection scope of the present invention.

Example 1

2-Methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magneton were added to the aqueous solution (10 ml) and reacted at 30 °C for 24 h. 20 ml of water and 20 ml of ethyl acetate were added with sodium bicarbonate and stirred rapidly until no bubbles were formed, extracted with ethyl acetate (3*20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 194.1 mg of the product 1-(2-methyl-4-quinolinyl)-1-butanone with a yield of 91%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (dd, J = 8.5, 0.8 Hz, 1H), 8.04 (d, J =8.1 Hz, 1H), 7.70 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.52 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.38 (s, 1H), 2.96 (t, J = 7.2 Hz, 2H), 2.77 (s, 3H), 1.79 (h, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 204.37 , 158.31 , 148.58 , 144.27 , 129.81 , 129.05 , 127.04 , 124,19.0 , 12 44.42 , 25.29 , 17.48 , 13.68 .

Example 2

2-Methylquinoline (1 mmol), isobutyraldehyde (3.0 mmol), silver nitrate (0.5 mmol), Selectfluor (4 mmol) and magneton were added to the aqueous solution (10 ml) and reacted at 30 °C for 24 h. 20 ml of water and 20 ml of ethyl acetate were added with sodium bicarbonate and stirred rapidly until no bubbles were formed, extracted with ethyl acetate (3*20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave the product 2-methyl-1-(2-methylquinolin-4-yl)propan-1-one 181.3 mg, yield is 85%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.73–7.67 (m, 1H), 7.51 (dd, J = 11.3, 3.9 Hz, 1H), 7.32 (s, 1H), 3.37 (dt, J = 13.8, 6.9 Hz, 1H), 2.77 (s, 3H), 1.21 (d, J = 6.9 Hz, 6H). ¹³ CNMR (151 MHz, CDCl ₃ ) δ 208.20 , 158.25 , 148.41 , 145.06 , 129.87 , 129.03 , 126.92 , 124.92 , 122.55 , 118.83 , 40.14 , 25.32 , 18.04 .

Example 3

2-Methylquinoline (1 mmol), benzaldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magneton were added to the aqueous solution (10 ml) and reacted at 30 °C for 24 h. ml water and 20 ml ethyl acetate, add sodium bicarbonate and stir rapidly until no bubbles are generated, extract with ethyl acetate (3*20 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter and concentrate. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 162.9 mg of the product 4-isopropyl-2-methylquinoline with a yield of 88%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, J = 8.5 Hz, 1H), 7.86–7.81 (m, 2H), 7.76 (d, J = 8.3 Hz, 1H), 7.73–7.67 (m, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.45 (dd, J = 15.8, 8.2 Hz, 3H), 7.28 (s, 1H), 2.78 (s, 3H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 158.71 , 154.16 , 147.98 , 129.38 , 128.69 , 125.22 , 125.04 , 122.79 , 117.63 , 28.09 , 25.41 , 22.80 .

Example 4

6-Fluoro-2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnon were added to an aqueous solution (10 ml) and heated at 30 °C React for 24 h, add 20 ml of water and 20 ml of ethyl acetate, add sodium bicarbonate and stir rapidly until no bubbles are generated, extract with ethyl acetate (3*20 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter and concentrate. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 217.4 mg of the product 1-(6-fluoro-2-methylquinolin-4-yl)butanone with a yield of 94%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03–8.00 (m, 1H), 7.99 (dd, J = 7.0, 3.8Hz, 1H), 7.48 (s, 1H), 7.47–7.42 (m, 1H), 2.97 (t, J = 7.2 Hz, 2H), 2.75 (s, 3H), 1.78 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 203.42 , 161.05 (d, J = 247.7 Hz), 157.58 (d, J = 2.8 Hz), 145.92 , 142.43 (d, J = 5.8 Hz), 131.33 (d, J = 9.3 Hz), 122.79 ( d, J = 10.7 Hz), 121.04 , 119.87 (d, J = 25.8 Hz), 109.09 (d, J = 24.3 Hz), 43.77 , 25.11 , 17.50 , 13.66 .

Example 5

6-Chloro-2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnon were added to aqueous solution (10 ml) and heated at 30 °C React for 24 h, add 20 ml of water and 20 ml of ethyl acetate, add sodium bicarbonate and stir rapidly until no bubbles are generated, extract with ethyl acetate (3*20 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter and concentrate. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 208.1 mg of the product 1-(6-chloro-2-methylquinolin-4-yl)butanone with a yield of 84%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.60 (dd, J = 9.0, 2.2 Hz, 1H), 7.44 (s, 1H), 2.95 (t, J = 7.2 Hz, 2H), 2.74 (s, 3H), 1.77 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 203.37 , 158.64 , 147.03 , 142.41 , 133.22 , 130.69 , 130.46 , 124.22 , 122,.65 , 120.93 , 43.92 , 25.22 , .17.

Example 6

6-Bromo-2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.5 mmol), Selectfluor (4 mmol) and magnon were added to aqueous solution (10 ml) and heated at 30 °C React for 24 h, add 20 ml of water and 20 ml of ethyl acetate, add sodium bicarbonate and quickly stir until no bubbles are generated, extract with ethyl acetate (3*20 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate . Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 245.4 mg of the product 1-(6-bromo-2-methylquinolin-4-yl)butanone with a yield of 84%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.60 (dd, J = 9.0, 2.2 Hz, 1H), 7.44 (s, 1H), 2.95 (t, J = 7.2 Hz, 2H), 2.74 (s, 3H), 1.77 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). ¹³ C NMR (151 MHz, CDCl ₃ ) δ 203.37 , 158.64 , 147.03 , 142.41 , 133.22 , 130.69 , 130.46 , 124.22 , 122,.65 , 120.93 , 43.92 , 25.22 , .17.

Example 7

8-Fluoro-2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnon were added to an aqueous solution (10 ml) and heated at 30 °C React for 24 h, add 20 ml of water and 20 ml of ethyl acetate, add sodium bicarbonate and stir rapidly until no bubbles are generated, extract with ethyl acetate (3*20 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter and concentrate. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 212.7 mg of the product 1-(8-fluoro-2-methylquinolin-4-yl)butanone with a yield of 92%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95 (d, J = 8.3 Hz, 1H), 7.48–7.36 (m, 3H), 2.97 (t, J = 7.2 Hz, 2H), 2.82 (s, 3H) , 1.78 (h, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 203.85 , 158.96 (d, J = 1.5 Hz), 157.53 ( d, J = 255.9 Hz), 144.03 (d, J = 2.5 Hz), 138.85 (d, J = 11.1 Hz), 126.70 (d, J = 8.1 Hz), 123.69 (d, J = 1.5 Hz), 120.76 ( d, J = 4.9 Hz), 120.66 , 113.95 (d, J = 19.0 Hz), 44.34 , 25.48 , 17.43 , 13.65 .

Example 8

2-Methyl-6-(trifluoromethyl)quinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnon were added to aqueous solution (10 ml) and react at 30 °C for 24 h, add 20 ml of water and 20 ml of ethyl acetate, add sodium bicarbonate, stir rapidly until no bubbles are formed, extract with ethyl acetate (3*20 mL), combine the organic layers, and dry over anhydrous sodium sulfate , filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 244.7 mg of the product 2,4-dimethyl-6-(trifluoromethyl)quinoline with a yield of 87%.

¹ H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 8.8, 1.6 Hz, 1H), 7.52 (s, 1H), 2.99 (t, J = 7.2 Hz, 2H), 2.79(s, 3H), 1.84–1.74 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). ¹³ C NMR (151 MHz, CDCl3)δ 203.26 , 160.98 , 149.53 , 143.98 , 130.16 , 128.91 (q, J = 32.5 Hz), 126.65 , 125.60 (d, J = 2.9 Hz), 123.95 (d, J = 272.5 Hz), 123.42 (q, J = 42.5 Hz) ), 121.27 , 44.01 , 25.45 , 17.40 , 13.65 .

Comparative Example 1

2-Methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), Selectfluor (4 mmol) and magneton were added to an aqueous solution (10 ml) and reacted at 30 °C for 24 h, 20 ml of water and 20 ml of Add ethyl acetate, add sodium bicarbonate and stir rapidly until no bubbles appear, extract with ethyl acetate (3*20 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter and concentrate. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) did not obtain the target product 1-(2-methyl-4-quinolinyl)-1-butanone with a yield of 0%.

Comparative Example 2

2-Methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.1 mmol), Selectfluor (4 mmol) and magneton were added to an aqueous solution (10 ml) and reacted at 30 °C for 24 h. 20 ml of water and 20 ml of ethyl acetate were added with sodium bicarbonate and stirred rapidly until no bubbles were formed, extracted with ethyl acetate (3*20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 132.2 mg of the product 1-(2-methyl-4-quinolinyl)-1-butanone with a yield of 62%.

Comparative Example 3

2-Methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (1.5 mmol), Selectfluor (4 mmol) and magneton were added to the aqueous solution (10 ml) and reacted at 30 °C for 24 h, and 20 ml of water was added and 20 ml of ethyl acetate, add sodium bicarbonate and rapidly stir until no bubbles are generated, extract with ethyl acetate (3*20 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter and concentrate. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 177.0 mg of the product 1-(2-methyl-4-quinolinyl)-1-butanone with a yield of 83%.

Comparative Example 4

2-Methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (0.5 mmol) and magneton were added to the aqueous solution (10 ml) and reacted at 30 °C for 24 h, Add 20 ml of water and 20 ml of ethyl acetate, add sodium bicarbonate and stir rapidly until no bubbles are generated, extract with ethyl acetate (3*20 mL), combine the organic layers, dry over anhydrous sodium sulfate, filter and concentrate. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 25.6 mg of the product 1-(2-methyl-4-quinolinyl)-1-butanone with a yield of 12%.

Comparative Example 5

2-Methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (8 mmol) and magneton were added to the aqueous solution (10 ml) and reacted at 30 °C for 24 h. 20 ml of water and 20 ml of ethyl acetate were added with sodium bicarbonate and stirred rapidly until no bubbles were formed, extracted with ethyl acetate (3*20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 170.6 mg of the product 1-(2-methyl-4-quinolinyl)-1-butanone with a yield of 80%.

Comparative Example 6

2-Methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magneton were added to the aqueous solution (10 ml) and reacted at 20 °C for 24 h. 20 ml of water and 20 ml of ethyl acetate were added with sodium bicarbonate and stirred rapidly until no bubbles were formed, extracted with ethyl acetate (3*20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 142.9 mg of the product 1-(2-methyl-4-quinolinyl)-1-butanone with a yield of 67%.

Comparative Example 7

2-Methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magneton were added to the aqueous solution (10 ml) and reacted at 60 °C for 24 h. 20 ml of water and 20 ml of ethyl acetate were added with sodium bicarbonate and stirred rapidly until no bubbles were formed, extracted with ethyl acetate (3*20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 119.4 mg of the product 1-(2-methyl-4-quinolinyl)-1-butanone with a yield of 56%.

Comparative Example 8

2-Methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), copper sulfate (0.25 mmol), Selectfluor (4 mmol) and magneton were added to the aqueous solution (10 ml) and reacted at 30 °C for 24 h. 20 ml of water and 20 ml of ethyl acetate were added with sodium bicarbonate and stirred rapidly until no bubbles were formed, extracted with ethyl acetate (3*20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane=1:15) gave 172.7 mg of the product 1-(2-methyl-4-quinolinyl)-1-butanone with a yield of 65%.

Claims (8)

1. A preparation method of a 4-bit acylated derivative of a 2-methylquinoline compound is characterized in that,

the method comprises the following steps:

(1) mixing a 2-methylquinoline compound and aldehyde, taking Selectfluor as an oxidant, and reacting in a solvent under the catalysis of silver nitrate;

(2) obtaining a 4-bit acylated derivative of the 2-methylquinoline compound after column chromatography;

wherein, the structural formula of the 4-bit acylated derivative of the 2-methylquinoline compound is as follows:

in the formula, the R ₁ Is halogen, nitro, trifluoromethyl, methyl or hydrogen, R ₂ Alkyl and phenyl.

2. The method according to claim 1, wherein the molar ratio of the 2-methylquinoline compound to the aldehyde is 1: 1.0-5.0; the preferred molar ratio is 1: 3.0.

3. the method according to claim 1, wherein the 2-methylquinoline compound has a general formula:

；

r is halogen, nitro, trifluoromethyl, methyl or hydrogen;

the aldehyde is n-butyraldehyde, isobutyraldehyde or benzaldehyde.

4. The preparation method according to claim 1, wherein the molar ratio of the 2-methylquinoline compound to the silver nitrate is 1: 0.2-1.0; the preferred molar ratio is 1: 0.25.

5. the preparation method according to claim 1, wherein the molar ratio of the 2-methylquinoline compound to the Selectfluor is 1: 3-6; the preferred molar ratio is 1: 4.

6. the method according to claim 1, wherein the solvent is water; the ratio of water to silver nitrate is 1 mL: 0.025 mmol.

7. The method according to any one of claims 1 to 6, wherein the reaction temperature is 30 to 50 ℃; the preferred reaction temperature is 30 ℃.

8. The preparation method according to claim 1, wherein the eluent for the column chromatography is ethyl acetate and n-hexane in a volume ratio of 1: 15.