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With water; iron;hydrogenchloride; In ethanol; at 85℃;Industry scale;
6-ChJoropyrimidine-4,5-diamine[00162] Iron dust (1000 g, 17.9 mol) was added to a solution of the crude 6-chloro-5- nitropyrimidin-4-amine (500 g, 2.87 mol) in ethanol (5000 mL) and water (1000 mL). A catalytic amount of concentrated hydrochloric acid (10 mL) was slowly added to the reaction mixture over a period of 20 minutes. During the course of the addition the reaction temperature was observed to increase to 85 C without external heating and the reaction mixture's color changed from yellow-brown to dark red. After the reaction mixture had cooled down to a temperature of 50 C, the slurry was filtered through a Celite pad, which was then washed with ethanol (3 x 250 mL). The resulting filtrate was concentrated under reduced pressure to give a yellow solid. This solid was then washed with hexane and dried under reduced pressure to give the title compound as a brown solid. (253 g, overall yield over two steps: 37.1% yield). NMR (400 MHz, DMSO-d6): 6 7.61 (s, 1H), 6.71 (broad s, 2H), 4.94 (broad s, 2H). MS (EI) for C4H5C1N4: 145 (MU+).
Step 2: A solution of 6-chloropyrimidine-4,5 -diamine (432 mg, 3.0 mmol) in acetic anhydride (5 mL) was heated to 120 C for overnight. The reaction mixture was concentrated and water was added, and then extracted with EtOAc. The organic layer was separated and washed with water and brine, dried over Na2S04 and concentrated. The residue was suspended in POCI3 (10 mL) and heated to 120 C for overnight. The reaction was concentrated and diluted with EtOAc and sat. NaHC03 solution. The organic layer was separated and washed with water and brine, dried over Na2S04 and concentrated. Purified by a flash column chromatography (0-30% EtOAc in petroleum ether) to give the desired product 6-chloro-8-methyl-9H-purine (263 mg, 52% yield). LC-MS: m/z 169 (M+H)+.
5-(6-chloro-9H-purin-8-yl)-2-methylthiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trichlorophosphate; at 160℃; for 0.5h;Microwave irradiation;
6-chloropyrimidine-4,5-diamine (200mgs, 1.3mmol) and <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> (218 mgs, 1 .5 mmol) were dissolved in phosphoryl chloride (4 mL) in a 10 mL microwave vial. The reaction mixture was stirred at 160°C for 30 min in a microwave reactor. After cooling down to room temperature reaction mixture was diluted with diethyl-ether and solids filtered out. Solids were re-dissolved in dichloromethane and extracted with aqueous saturated solution of sodium bicarbonate. Organic layer was dried over Mg2SO4 and evaporated under reduced pressure. Solids were suspended in ACN and stirred over 1 hr. Solids were filtered out to yield 5-(6-chloro-9H-purin-8-yl)-2- methylthiazole.
General procedure: 6-Chloro-4,5-diaminopyrimidine (5 g, 35 mmol), ethyl orthopropionate49 mL and triethylamine 48 mL were dissolved in50 mL acetonitrile and stirred at 120 C overnight. The mixturewas concentrated in vacuum to yield the crude product 61 (5 g).
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