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Synthesis of 1-tert-butyl-1H-pyrazol-5-amine To 600 ml of ethanol were successively added 59.94 g of tert-butylhydrazine hydrochloride, 79.3 g of sodium acetate and 50 ml of 2-chloroacrylonitrile at room temperature, followed by stirring the reaction mixture at 80 C. for 12 hours. After removing the solvent in vacuo, water was added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The obtained ethyl acetate solution was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=2/1-1/2) to give the title compound as a pale yellow oil.
With potassium phosphate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃;
(1) Synthesis of N-(1-tert-butyl-1H-pyrazol-5-yl)-6-chloropyrazin-2-amineA mixture of 60.6 g of 2,6-dichloropyrazine, 62.2 g of <strong>[442850-71-7]1-tert-butyl-1H-pyrazol-5-amine</strong> as obtained in Reference 3, 23.5 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 21.0 g of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 172.6 g of potassium phosphate and 1.17 l of 1,4-dioxane was stirred at 100 C. overnight, followed by cooling down to room temperature. An insoluble matter was filtered off using Celite and washed with ethyl acetate. The resulting ethyl acetate solution was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=4/1-2/1) to give the title compound as a yellow solid.
With potassium phosphate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 4.0h;
A mixture of 1.33 g of 1-tert-butyl 4-ethyl 4-((6-bromopyridin-2-yl)methyl)piperidine- 1,4-dicarboxylate, 650 mg of 1-tert-butyl- lH-pyrazol-5-amine (WO2007/126126, page72, Reference 1), 360 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 322 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 1.98 g of potassium phosphate and 30 ml of 1 ,4-dioxane was stirred at 1000C for 4 hours, followed by cooling down to room temperature. An insoluble matter was filtered off using Celite and washed with ethyl acetate. The resulting ethyl acetate solution was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 20/1 - 3/2) to give the title compound as a pale brown oil.
N-(1-tert-butyl-1H-pyrazol-5-yl)-2-chloro-6-methylpyrimidine-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; In 1,4-dioxane; at 100℃; for 12.0h;
(1) Synthesis ofN-(1-tert-butyl-1H-pyrazol-5-yl)-2-chloro-6-methylpyrimidine-4-amine A mixture of 9.70 g of 2,4-dichloro-6-methyl-pyrimidine, 4.50 g of 1-tert-butyl -1H-pyrazol-5-amine obtained in Reference Example 1, 1.79 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 1.60 g of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 13.27 g of potassium phosphate, and 100 ml of 1,4-dioxane was stirred at 100C for 12 hours, cooled to room temperature, and then diluted with ethyl acetate. An insoluble matter was filtered off using Celite and the resulting ethyl acetate solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 9/1 to 1/1) to give the title compound.
With sodium acetate; In ethanol; at 80℃; for 18.0h;
tert-Butylhydrazinehydrochloride (5.99 g, 48.1 mmol) was added to EtOH (60 mL) to form a slurry. To this was added NaOAc (7.93 g, 96.7 mmol) and 2-chloroacrylonitrile (5 mL,62.6 mmol). The solution was heated to 80 C for 18 h, cooled, and the solvent removed in vacuo. The residue was slowly diluted with distilled H2O (35 mL) and partitioned between sat. aq NaHCO3 (40 mL) and EtOAc (40 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine (20 mL), dried (MgSO4), and the solvent removed in vacuo to afford a red oil; yield: 7.95 g (91%); bp 93-94C/0.9 Torr (yellow liquid). The product was a 5:1 mixture of the title compound 6c and its 1-tert-butyl-3-amino isomer. The crude product was used to prepare the Meldrum?s acid derivative 3c, which was purified by recrystallization (see below).
4-(4-chloro-6-methoxy-2-methyl-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole[ No CAS ]
[ 76-05-1 ]
[ 442850-71-7 ]
N-(1-(tert-butyl)-1H-pyrazol-5-yl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-2-methyl-9H-pyrimido[4,5-b]indol-4-amine trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20 mg
Example 132 Synthesis of N-(1-(tert-butyl)-1H-pyrazol-5-yl)-7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-2-methyl-9H-pyrimido[4,5-b]indol-4-amine (Cpd. No. 183) Pd2(dba)3 (18 mg) and BINAP (26 mg) were mixed in anhydrous toluene. And the mixture was heated at reflux for 3-4 minutes. This mixture was transferred into a round-bottom flask containing S13 (60 mg), <strong>[442850-71-7]1-(tert-butyl)-1H-pyrazol-5-amine</strong> (84 mg), K3PO4 (130 mg), and toluene (2 mL). The mixture was heated at reflux for overnight before quenching with methanol. The reaction mixture was filtered and the mixture was purified by HPLC to yield Cpd. No. 183 as a CF3CO2H salt in 20 mg. ESI-MS calculated for C24H28N7O2 [M+H]+=446.23; Observed: 446.65.
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