Dihydropyrimidine-spiro derivatives, preparation method and application thereof
A technology of dihydropyrimidine and derivatives, applied in the field of medicine, can solve the problems of strong liver toxicity, poor water solubility, poor metabolic stability and the like
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Embodiment 1
[0058] Example 1. Preparation of Compound 2
[0059] Dissolve 2-thiazolecarboxamidine hydrochloride (0.50g, 3.05mmol), 2-bromo-4-fluorobenzaldehyde (0.93g, 4.60mmol), sodium acetate (0.50g, 6.13mmol) in 50mL of absolute ethanol In the solution, ethyl acetoacetate (600 μL, 4.60 mmol) was added at room temperature, and the reaction was refluxed at 80° C. for 8 h; after the reaction, filtered to remove salts. The mother liquor was cooled to room temperature, and yellow crystals (2) were precipitated. The remaining mother liquor was decompressed to remove absolute ethanol, water (60 mL) was added, extracted with ethyl acetate (25 mL×3), the organic phases were collected and combined, extracted once with saturated sodium chloride (25 mL), and the organic phase was extracted with anhydrous magnesium sulfate dry. Filtration, dry loading, separation by flash column chromatography, and recrystallization from dichloromethane-n-hexane system to obtain a yellow powder, which was combine...
Embodiment 2
[0061] Example 2. Preparation of Compound 3
[0062] Intermediate 2 (0.50 g, 1.17 mmol) was dissolved in 50 mL of dichloromethane, N-bromosuccinimide (0.22 g, 1.24 mmol) was slowly added, and the reaction was carried out under reflux at 40 °C for 1.5 h; after the reaction was completed, cooled After reaching room temperature, the solvent was removed by rotary evaporation, water (50 mL) was added, extracted three times with ethyl acetate (20 mL×3), the organic phases were combined, extracted once with saturated sodium chloride solution (25 mL), and dried over anhydrous sodium sulfate; The sample was loaded, separated on a silica gel column by rapid preparative chromatography, and recrystallized from a dichloromethane-n-hexane mixed solvent to obtain 0.35 g of a yellow solid with a yield of 59%; the melting point was 123-128°C.
[0063] 1 H NMR (400MHz, CDCl 3 )δ7.84(d,J=3.1Hz,1H),7.52(s,2H),7.44-7.35(m,1H),7.32(dd,J=8.1,2.6Hz,1H),7.02(t,J =8.0Hz,1H),6.09(s,1H),4.94(d,J=8.9Hz...
Embodiment 3
[0064] Example 3. Preparation of compounds 4(a-c)
[0065] Different substituted spiro rings (0.442 mmol) and NaH (54 mg, 1.33 mmol) were dissolved in dry tetrahydrofuran solution and stirred at room temperature for 0.5-1 h until the substituted spiro rings were dissolved. A solution of Intermediate 3 (220 mg, 0.440 mmol) in tetrahydrofuran was added dropwise. Stir at room temperature for 0.5 h. After the reaction was completed, tetrahydrofuran was removed under reduced pressure, water (25 mL) was added, extracted with ethyl acetate (20 mL×3), the organic phases were collected and combined, extracted once with saturated sodium chloride (25 mL), and the organic phase was dried over anhydrous magnesium sulfate . Filtration and flash column chromatography. The target compound 4(a-c) was obtained by recrystallization from dichloromethane-n-hexane system.
[0066] The substituted spiro ring used was tert-butyl 7-oxo-2,6-diazaspiro[3,4]octane-2-carboxylate. The product 4a is a ...
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