Neurologically-active compounds
A compound, heteroaryl fusion technology, applied in the treatment of neurological diseases, neurodegenerative diseases such as Alzheimer's disease, can solve the problems of limited oral bioavailability, limited effect, poor water solubility, etc.
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Embodiment 1
[0270] Example 1 -Preparation of compound 2-7A2-2-7R2 by alkylation of 5,7-dichloro-8-methoxy-3H-quinazolin-4-one (2-5) and then deprotection
[0271]
[0272] To a stirring solution of 2-5 (1.5 g, 6.1 mmol) and chloride (7.3 mmol) in anhydrous DMF (30 mL) was added K 2 CO 3 (9.3 mmol) and the resulting mixture was heated at 95°C for 16 hours, cooled and concentrated. The residue was extracted with ethyl acetate or dichloromethane (3x), the extracts were combined and washed sequentially with water and brine, and dried. followed by trituration with a suitable solvent, recrystallization or SiO 2 - Silica gel chromatography to give the corresponding 3-substituted-8-methoxy-3H-quinazolin-4-ones (2-6).
[0273] Examples of chlorides used: 1-(2-chloroethyl)pyrrolidine gives 2-6A, 2-(chloromethyl)cyclopropane gives 2-6B, 2-(2-chloroethyl)-1-methane Pyrrolidine gives 2-6C, 2-(chloromethyl)pyridine gives 2-6D, 4-(2-chloroethyl)morpholine gives 2-6E, 2-chloromethyl-4-methylthia...
Embodiment 2
[0303] Example 2 -PCl 3 -mediated condensation of 4,6-dichloro-2-carboxamido-3-hydroxybenzoic acid with amines (2-8)
[0304]
[0305] To stirring 4,6-dichloro-2-carboxamido-3-hydroxybenzoic acid (2-8) (200 mg, 0.80 mmol), amine (0.88 mmol) and toluene (5 mL) over 2 minutes ) was added dropwise to the mixture of PCl 3 (0.12 mL, 1.38 mmol) in toluene (1 mL). The resulting suspension was heated at reflux for 4-16 hours and cooled. Add saturated NaHCO 3 Make pH 9. The pH of the mixture was then readjusted to 7 (5N HCl) and extracted with dichloromethane (3x), and the extracts were combined and dried (Na 2 SO 4 ). Removal of volatiles gave 5,7-dichloro-8-hydroxy-3-(substituted)-3H-quinazolin-4-ones (2-7). In some cases, by cleaning with a suitable solvent or SiO 2 - Silica gel column chromatography or recrystallization to purify the crude product, the suitable solvent is generally diethyl ether or 5% methanol in diethyl ether; the characteristic data of compounds 2-7...
Embodiment 3
[0322] Example 3: Preparation of 2,3-disubstituted-3H-quinazolin-4-one (4-9)
[0323]
[0324] Step 1: To a solution of acid 1-8 (1.00 g, 4.50 mmol) in anhydrous benzene (8.3 mL) was added thionyl chloride (2.09 g, 17.6 mmol) dropwise under argon atmosphere. The mixture was heated at reflux for 5 hours, after which excess thionyl chloride and benzene were removed by evaporation. The residue was dissolved in anhydrous dichloromethane (8.3 mL), cooled to 0°C, and treated with n-propylamine (798 mg, 13.5 mmol). The mixture was stirred at 0 °C for 15 minutes, then allowed to warm to room temperature and stirred for a further 16 hours. Evaporation and purification of the crude residue by column chromatography (ethyl acetate / petroleum ether, 3:7-1:1) afforded benzamide, 2-amino-4,6-dichloro-3-hydroxy-N -(n-propyl)benzamide (4-14, R 1 = n-propyl) (550 mg, 46%).
[0325] 2-Amino-4,6-dichloro-3-hydroxy-N-propylbenzamide: 1 H NMR (DMSO-d 6 ): δ8.39(t, J=5.6, 1H), 6.67(s, 1H,), ...
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