Benzamide derivatives with anti-proliferative activity, pharmaceutical preparations thereof
A proliferative, medicinal carrier technology, applied in the direction of medical preparations containing active ingredients, organic active ingredients, antineoplastic drugs, etc., can solve the problems of low curative effect, high cost, and large side effects
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Embodiment 1
[0204] Example 1. Synthesis of N-(2-amino-5-fluorophenyl)-4((4-(pyridin-3-yl)pyrimidin-2-amino)methyl)benzamide (Compound 1)
[0205] Step 1. Synthesis of 3,3-Dimethylamino-1-pyridin-3-yl-propenone
[0206] Dissolve 2g of 3-acetylpyridine in 5ml of anhydrous N,N-dimethylformamide, then add 5ml of N,N-dimethylformamide diacetal to the solution, after the addition, heat to 110°C for reaction 3 hours, thin layer chromatography showed that the reaction was over, N,N-dimethylformamide was recovered under reduced pressure, the residue was placed in a refrigerator overnight, a yellow solid was precipitated, suction filtered, washed with ethyl acetate / petroleum ether 1:1 to obtain Yellow solid 2.05g.
[0207] Product melting point m.p.82-83℃;
[0208] Step 2. Synthesis of 4-guanidinomethyl-benzoic acid
[0209] 2g of methyl isothiourea sulfate was dissolved in 10ml of 1mol / L sodium hydroxide aqueous solution, 2.15g of 4-aminomethylbenzoic acid was slowly added dropwise under ice ba...
Embodiment 2
[0274] Example 2. Synthesis of N-(2-amino-5-fluorophenyl)-4-((4-methoxyphenylamino)methyl)benzamide (Compound 5)
[0275] Step 1. Synthesis of methyl p-aldehyde benzoate
[0276] Dissolve 2.0 g of p-aldehyde benzoic acid in 20 ml of methanol, slowly add 1.81 ml of thionyl chloride dropwise under an ice bath, and after the addition is completed, after heating and refluxing for 3 hours, thin layer chromatography shows that the reaction is complete, and the solvent is recovered under reduced pressure. It was cooled and filtered to obtain 2.13 g of a pale yellow solid.
[0277] Product melting point m.p.59-61℃;
[0278] Step 2. Synthesis of methyl 4-((4-methoxyphenylamino)methyl)benzoate hydrochloride
[0279] Dissolve 1.59g of p-aminoanisole and 2.13g of step 1 product in 15ml of methanol, and add 3.07g of NaBH in batches under ice bath 4, and added dropwise glacial acetic acid to keep the pH of the reaction solution at 5 to 6, thin layer chromatography showed that the reactio...
Embodiment 3
[0318] Example 3. Synthesis of 4-(((phenethyl)(2-hydroxyethyl)amino)methyl)-N-(2-amino-5-fluorophenyl)benzamide (Compound 8)
[0319] Step 1. Synthesis of methyl 4-((phenethylamino)methyl)benzoate hydrochloride
[0320] 1.43ml of phenethylamine and 1.46g of methyl p-formylbenzoate were dissolved in 10ml of methanol, 2.5g of sodium borohydride was added in batches under an ice bath, and glacial acetic acid was added dropwise to keep the pH of the reaction solution at 5 to 6. Chromatography indicated that the reaction was completed, the solvent was removed under reduced pressure, the residue was distributed in ethyl acetate / water, adjusted to be acidic with 2N hydrochloric acid, and a large amount of white solid was precipitated, which was filtered and dried to obtain 2.06 g of white solid.
[0321] Step 2. Synthesis of methyl 4-(((2-(tert-butyldimethylsiloxy)ethyl)(phenethyl)amino)methyl)benzoate
[0322] Take a 100ml dry three-neck flask, under the protection of dry nitrogen,...
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