Novel cyano-substituted dihydropyrimidine compounds and their use to treat diseases
A compound, cyano technology, applied in the field of new compounds
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Embodiment 15
[0132] Example 15-cyano-3,6-dihydro-4-methyl-6-(3-nitrophenyl)-2-thio-1-(2H)-pyrimidinecarboxylic acid ethyl ester
[0133] A. Step 1
[0134] A mixture of 6.42 g of acetoacetamide, 8.0 g of 3-nitrobenzaldehyde, 0.61 ml of acetic acid and 0.21 ml of piperidine in 30 ml of toluene was heated to reflux. Azeotropic water was removed using a Dean Stark trap. After reflux for 2 h, the reaction mixture was cooled to room temperature and a large amount of solid appeared, which was treated with a solution of 300 ml EtOAc and 25 ml MeOH, then the solid was filtered off and rinsed twice with 15 ml EtOAc to obtain 3.1 g of the desired product in 25% yield.
[0135] B. Step 2
[0136] A mixture of 200 mg of the product of step 1 of Example 1, 198 mg of 2-(4-methoxybenzyl)-2-thiopseudourea hydrochloride, and 84 mg of sodium acetate in 3.6 ml of DMF was heated at 85° C. for 15 h, and then Cool to room temperature. The resulting reaction mixture was purified by...
Embodiment 1
[0140] Add 17 μL of ethyl chloroformate to a solution of the compound (60 mg) and pyridine (0.1 ml) in Step 3 of Example 1 in 0.6 ml of dichloromethane, stir for 2.5 h, then add 22 μL of ethyl chloroformate, and stir the reaction mixture for 2 h, Then 0.3ml of trifluoroacetic acid was added, and the resulting mixture was stirred for another 1 h, concentrated in vacuo, diluted with DMF, methanol and a small amount of dichloromethane, filtered, and then purified by preparative HPLC (column: YMC S5 ODS 20×100mm) to obtain 22.5 mg product, yield 42.7%. MS(M-H) +=345. HPLC RT=2.85min (YMC S5 ODS column 4.6×50mm, 10-90% methanol aqueous solution containing 0.2% phosphoric acid, 4min, 4ml / min, monitored at 220nm)
Embodiment 25
[0141] Example 25-cyano-3,6-dihydro-4-methyl-6-(3-nitrophenyl)-2-oxo-1-(2H)-pyrimidinecarboxylic acid ethyl ester
[0142] A. Step 1
[0143] 10.92 g of sodium bicarbonate was added dropwise to a DMF (100 ml) solution of 7.83 g of the compound in Step 1 of Example 1 and 7.48 g of O-methylisourea hydrogensulfate, generating gas. The reaction mixture was stirred for 2 h, then heated at 65 °C overnight, cooled to room temperature, diluted with 800 ml EtOAc, washed with water (2 x 100 ml) and brine (1 x 100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was triturated with ethyl acetate-dichloromethane-hexane to obtain 5.48 g of the desired solid product (56%).
[0144] B. Step 2
[0145] A mixture of Example 2 Step 1 compound (209mg) and Burgess reagent (274.5mg) in dichloromethane (5ml) and THF (10ml) was stirred overnight. The reaction mixture was concentrated in vacuo, diluted wit...
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