Preparation and application of 3-cyano-6-methyl-2(1H)-pyridone_Industrial additives

Preparation and application background and overview of 3-cyano-6-methyl-2(1H)-pyridone

3-Cyano-6-methyl-2(1H)-pyridone is an intermediate of Milirinone. Milrinone is the common name of 1,6-dihydro-2-methyl-6-oxo-[3,4’dipyridine]-5-carbonitrile. Milrinone is a phosphodiesterase III (PDEIII) inhibitor. It is a second-generation bipyridine cardiotonic drug launched in the United States in 1987. It is a homologue of amrinone and has the same mechanism of action. The cardiotonic activity is 10-30 times that of amrinone, with fewer side effects and effective both oral and intravenous injection.

Preparation and application of 3-cyano-6-methyl-2(1H)-pyridone

Add 950 ml of tetrahydrofuran (THF) solution of 46.5g sodium methoxide into the reaction vessel, cool it to the internal temperature of 0~5°C in an ice bath, add dropwise a solution of 46.5g acetone and 59.6g ethyl formate within 1 hour, and add dropwise After completion, remove the ice bath, slowly warm to room temperature within 1 hour, and concentrate under reduced pressure (not exceeding 50°C). Transfer the concentrate to the reaction vessel, add 67g of cyanoacetamide in ml aqueous solution and piperidine acetic acid (condensation reaction catalyst), reflux for 2 hours, cool to room temperature, adjust the pH to about 5 with acetic acid, let it stand at room temperature overnight, and cool in an ice bath. 45 min, suction filtration, washing with ice water three times, and vacuum drying at 80°C overnight to obtain 65.5 g of yellow solid 3-cyano-6-methyl-2(1H)-pyridone (yield 61.0%). ¹HNMR(DMSO-d6)δ12.50(brs,1H),8.03(d,1H),6.21(d,1H),2.29(s,3H).

Preparation and application of 3-cyano-6-methyl-2(1H)-pyridone

The method for synthesizing milrinone from 3-cyano-6-methyl-2(1H)-pyridone is as follows:

Preparation and application step 1 of 3-cyano-6-methyl-2(1H)-pyridone,

Add 26.2g 3-cyano-6-methyl-2(1H)-pyridone and 36.5g NBS in 250ml dichloroethane solution into the reaction vessel fluorophenylboronic acid, heat to reflux for 18h, cool to room temperature, and filter. The solid was slurried in dimethyl sulfoxide with 500 ml of water for 2 hours, filtered, washed with water, and dried under vacuum to obtain 38.4 g of compound 3 as a white solid (yield 92.3%). ¹HNMR(DMSO-d6)δ12.92(brs,1H),8.30(s,1H),2.35(s,3H).

Preparation and application step 2 of 3-cyano-6-methyl-2(1H)-pyridone,

Add 21.3g of compound 3, 12.9g of 4-pyridineboronic acid, 50ml of toluene, 50ml of 2M sodium hydroxide aqueous solution, and 2.3g of tetrakis(triphenylphosphine)palladium into the reaction vessel, reflux for 18h under nitrogen atmosphere, and cool to room temperature. Add 10 ml of 50% sodium hydroxide aqueous solution, stir for 15 minutes, separate the aqueous layer, adjust the pH of the aqueous layer to about 6 with acetic acid, and precipitate the solid. The yield is 15.3 g of milrinone as a white solid (yield: 72.5%). ¹HNMR(DMSO-d6)δ12.86(brs,1H),8.62(d,2H),8.20(s,1H)7.40(d,2H),2.31(d,3H).

References

[1][China invention, China invention authorization] CN201510383580.1 A new method of synthesizing milrinone [Public]/A method of synthesizing milrinone [Authorized]