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Example 38; 3-Chloro-N-(2-cyclobutyl-pyrimidin-4-yl)-2-methyl-benzenesulfonamide; Step A]: 2-Cyclobutyl-pyrimidin-4-ylamine; This intermediate was made according to example 2, step A] method from cyclobutanecarboxamidine hydrochloride (0.3 g, obtained from <strong>[4426-11-3]cyclobutanecarbonitrile</strong> in analogy to Synth. Commun. 12 (13), 1982, 989-993 and Tetrahedron Lett. 31 (14), 1990, 1969-1972) and 3-ethoxy-acrylonitrile (0.3 g). 2-Cyclobutyl-pyrimidin-4-ylamine was obtained as a light brown solid (0.26 g): 1H NMR (delta, DMSO-d6): 7.98 (d, 1H), 6.66 (br s, 2H), 6.21 (s, 1H), 3.35-3-37 (m, 1H), 2.33-2.23 (m, 2H), 2.19-2.12 (m, 2H), 1.99-1.88 (m, 1H), 1.82-1.74 (m, 1H).
Step 2: Cyclobutanecarboximidamide hydrochloride Hydrogen chloride gas was bubbled through a solution of <strong>[4426-11-3]cyclobutanecarbonitrile</strong> (2.0 g, 24.65 mmol) in methanol (10 mL) and diethyl ether (12 mL) for 2 h at 0C. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol and cooled to 0C. Methanolic ammonia was added and the reaction mixture was stirred for 1 h at room temperature. The solvent was removed under reduced pressure to afford cyclobutanecarboximidamide hydrochloride (3.0 g, 92%). The material was used for the next step without further purification.
2-cyclobutyl-4-(dimethoxymethyl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
300 mg
With triethylamine; In ethanol; at 20℃; for 16h;Inert atmosphere; Reflux;
Step 3: 2-Cyclobutyl-4-(dimethoxymethyl)pyrimidine To a solution of 4-(dimethylamino)-1 , 1-dimethoxybut-3-en-2-one (2.0 g, 1 1 .5 mmol) in ethanol was added <strong>[71690-89-6]cyclobutanecarboximidamide hydrochloride</strong> (3.0 g, 22.3 mmol) and triethylamine (2.33 g, 23.0 mmol) under nitrogen at room temperature. The reaction mixture was refluxed for 16 h. The solvent was removed under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via column chromatography to afford 2- cyclobutyl-4-(dimethoxymethyl)pyrimidine as a colorless liquid (300 mg, 12%). MS (ES+APCI) (M+H) 209.2; LCMS retention time: 3.257 minutes (Method J).
Ethanol (100 ml) is carefully added to NaH (95% purity, 1 .01 g, 40.1 mmol, 2.70 eq) and kept in a flask at -70 C under nitrogen. The resulting mixture is slowly warmed to ambient temperature and the <strong>[71690-89-6]cyclobutanecarboxamidine hydrochlorid</strong> (5.00 g, 37.2 mmol, 2.50 eq.) was added in portions. The mixture is warmed to 50 C and maintained at this temperature for 1 h followed by the portion wise addition of mucobromic acid (3.83 g, 14.9 mmol, 1 .00 eq.) while keeping the temperature around 50 C. The mixture is cooled to ambient temperature and allowed to stir for additional 16 h. All volatile components are removed under reduced pressure and the resulting residue is titrated with aq. HCI (2 mol/L). The solids are collected by filtration, washed with water and dried yielding the title compound (2.24 g, yield 59 %) as a colorless solid. MS (ESI) m/z 257.3 [M + H+]
19%
To a stirred suspension of <strong>[71690-89-6]cyclobutanecarboximidamide hydrochloride</strong> (1 : 1) (2 g, 14.9 mmol) in ethanol (16 mL) was added 2 M sodium ethoxide in ethanol (15 mL, 29.7 mmol) at r.t. The suspension was heated at 50 C for 5 minutes before the drop wise addition of a solution of mucobromic acid (2.68 g, 10.4 mmol) in ethanol (8 mL) at 50 C. The reaction mixture was stirred at 50 C for 30 minutes, further 2 M sodium ethoxide in ethanol (7.5 mL, 14.9 mmol) was added and the reaction stirred for a further 15 minutes at 50 C. The cooled reaction mixture was concentrated in vacuo, the resulting residue dissolved in 2 N hydrochloric acid (40 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2S04) and reduced in vacuo. The residue was partitioned between EtOAc (100 mL) and 2 N sodium hydroxide solution (50 mL), the aqueous phase was separated and washed with EtOAc (100 mL). The combined aqueous extracts were acidified to pH 4 using 2 M hydrochloric acid, and re-extracted into dichloromethane (3 x 100 mL). The combined organic extracts were dried (Na2S04) and reduced in vacuo to afford the title compound as a pale orange solid (830 mg, 19%).lU NMR (250 MHz, MeOD) delta ppm 8.97 (s, 1H), 3.81 (p, J 8.1 Hz, 1H), 2.55 - 2.35 (m, 4H), 2.18 - 2.05 (m, 1H), 2.01 - 1.86 (m, 1H).
ethyl 2-(3,4-dichlorophenoxy)-4,4,4-trifluoro-3-oxobutanoate[ No CAS ]
[ 71690-89-6 ]
2-cyclobutyl-5-(3,4-dichlorophenoxy)-6-(trifluoromethyl)pyrimidin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In 1,4-dioxane; at 20 - 110℃; for 18h;Reflux;
A mixture of 20.15 g (146 mmol) of potassium carbonate, 10.5 g (109 mmol) of guanidine hydrochloride and 20 g (36.5 mmol, purity 69%) of ethyl 2-[4-chloro-3-(trifluoromethyl)phenoxy]-4,4,4-trifluoro-3-oxobutanoate (Example 9A) in 150 ml of dioxane was heated under reflux for 1 h. The reaction mixture was then added to 1.8 litres of water and neutralized with 1 N hydrochloric acid. The precipitated solid was filtered off with suction, washed with water and taken up in a little ethyl acetate, and the resulting solution was added dropwise with stirring to 1 litre of petroleum ether. The resulting precipitate was filtered off with suction, taken up in 100 ml of 0.5 N sulphuric acid and 100 ml of acetonitrile, stirred for 30 min and then added to 1 litre of water. After 15 min of stirring, the mixture was once more filtered off with suction and the precipitate was washed with water. The product was taken up in ethyl acetate and, together with silica gel, reconcentrated under reduced pressure. This material was chromatographed on silica gel using a mixture of cyclohexane and ethyl acetate (1:1). The product-containing fractions were concentrated and the residue was dried under reduced pressure. This gave 10.5 g (77% of theory) of the title compound in a purity of 99% (HPLC). LC-MS (Method 1): Rt=1.02 min; MS (ESpos): m/z=374.0 (M+H)+ 1H NMR (400 MHz, DMSO-d6): delta=7.07 (br. s, 2H), 7.31 (dd, 1H), 7.42 (d, 1H), 7.62 (d, 1H), 11.86 (br. s, 1H).
methyl (±)-(3R,3aR,8bR)-8b-hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-3-phenyl-1-(tosyloxy)-3a,8b-dihydro-3H-cyclopenta[b]benzofuran-2-carboxylate[ No CAS ]
[ 71690-89-6 ]
methyl (±)-(3aR,4R,5S,5aR,10bR)-2-cyclobutyl-3a-hydroxy-8,10-dimethoxy-5a-(4-methoxyphenyl)-5-phenyl-3a,4,5,5a-tetrahydro-1H-benzofuro[3',2':1,5]cyclopenta[1,2-d]imidazole-4-carboxylate[ No CAS ]
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