Pyrimidine heterocyclic compounds, pyrimidine heterocyclic compound salts, and preparation method and application thereof
A technology of heterocyclic compounds and pyrimidines, which is applied in the field of medicinal chemistry, can solve the problems of drug resistance and curative effect reduction, and achieve the effects of low toxicity, high activity and high stability
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[0077] The present invention also provides a method for preparing the pyrimidine heterocyclic compound of the present invention, comprising: reacting the compound of formula (II) with Rq-H to obtain the pyrimidine heterocyclic compound;
[0078]
[0079] Among them, R 1 Selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, amino, acetamido or C3-C6 cycloalkyl;
[0080] R 2 Alkyl group selected from C1~C8, alkoxyl group of C1~C8, cycloalkyl group of C3~C6, amino group, amido group, cyano group, fluorine, chlorine or bromine;
[0081] The Rq is formula (Rq-1) or formula (Rq-2),
[0082]
[0083] R 3 Selected from C1~C5 alkyl, C1~C8 alkoxy or halogen; or two R 3 with R 3 A ring composed of carbon atoms where the ring is a four-membered ring, a five-membered ring or a six-membered ring
[0084] Said n is 1, 2 or 3;
[0085] R 4 selected from hydrogen or fluorine;
[0086] R 5 is selected from hydrogen, fluorine or chlorine, and R 4 and R 5 At least one is selected fr...
Embodiment 1
[0122] Intermediate 1: Synthesis of 4-((4-chloropyrimidin-2-yl)amino)benzonitrile (5)
[0123]
[0124] Step 1: Preparation of 2-chloro-4-methoxypyrimidine (2)
[0125] Dissolve 2,4-dichloropyrimidine (30g, 0.201mol) in methanol (300mL), add potassium methoxide (13g, 0.24mol) in batches at 0°C with stirring, and the reaction solution rises to room temperature, stirring overnight . Add an appropriate amount of water, extract 3 times with dichloromethane, combine the organic phases, wash with saturated brine, dry the organic phase, distill off the dichloromethane under reduced pressure to obtain a crude product, add n-hexane, stir at 0°C for 1 hour, and crystallize to obtain 16.5 g Compound 2, the yield was 57%.
[0126] The structure identification of the obtained compound is carried out, and the results are as follows: 1 H NMR (400MHz, CDCl 3 ): δ8.28(m, 1H), 6.67(m, 1H), 4.01(d, J=0.8Hz, 3H); LCMS(M+H) + : 145.0.
[0127] Step 2: Preparation of 4-((4-methoxypyrimidin...
Embodiment 2
[0146] The reaction process is as follows:
[0147]
[0148] Step 1: Preparation of ethyl 5-nitrobenzofuran-2-carboxylate (10)
[0149] Add 5-nitrosalicylaldehyde (20g, 0.119mol) and potassium carbonate (33g, 0.238mol) into a reaction flask of DMF (400mL), stir at room temperature for 1 hour, then slowly add ethyl bromoacetate (20g, 0.119mol), the temperature of the reaction solution was raised to 85°C, and the reaction was carried out for 6-7 hours, and the reaction was detected by spotting the plate until the reaction was complete. Cool to room temperature, add water and stir, a large amount of solids precipitated, suction filtered, washed with water, and dried to obtain 15g of yellow-gray solid 10, 89%.
[0150] The structure identification of the obtained compound is carried out, and the results are as follows: 1 H NMR (300MHz, CDCl 3 ): δ8.12(s, 1H), 7.87(s, 1H), 7.32(m, 2H), 4.35(q, J=7.5Hz and 14.4Hz, 2H), 1.33(m, 3H); LCMS(M +H) + : 236.1.
[0151] Step 2: Pre...
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