تفاعل #1836687

معادلة التفاعل

4-chloro-2-(methylthio)pyrimidine-5-carbonitrile

3-amino-1-methylcyclohexanol

DIEA

→

4-(((1S,3R)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile

المردود 33.0%

4-(((1R,3S)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile

المردود 34.0%

المذيبات

isopropanol

ظروف التفاعل

المعالجة

1. 1
   أخرىThe organic solvents were removed under reduced pressure
2. 2
   workup.ADDITIONThe residue was treated with water
3. 3
   استخلاصextracted with ethyl acetate
4. 4
   غسيلThe combined organic layers were washed with brine
5. 5
   تجفيفdried over sodium sulfate
6. 6
   تركيزconcentrated
7. 7
   أخرىto give the crude product, which
8. 8
   أخرىwas purified by silica gel column chromatography (20% ethyl acetate in petroleum)
9. 9
   أخرىto afford the cis-isomer (0.90 g, 3.24 mmol, 17% yield over 3 steps) and trans-isomer (1.80 g, 6.47 mmol, 34% yield over 3 steps)
10. 10
    أخرىThe cis-isomer (0.90 g, 3.24 mmol) was separated by chiral SFC (Column IF; method: 70-30-CO2-MeOH; CO2 Flow Rate: 2.1; Col. Temp.=40° C.)

الإجراء التجريبي

A mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (3.71 g, 20 mmol)), 3-amino-1-methylcyclohexanol (3.0 g, crude), DIEA (3.23 g, 25 mmol) in isopropanol (30 mL) was heated at 100° C. for 3 h. The organic solvents were removed under reduced pressure. The residue was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum) to afford the cis-isomer (0.90 g, 3.24 mmol, 17% yield over 3 steps) and trans-isomer (1.80 g, 6.47 mmol, 34% yield over 3 steps). The cis-isomer (0.90 g, 3.24 mmol) was separated by chiral SFC (Column IF; method: 70-30-CO2-MeOH; CO2 Flow Rate: 2.1; Col. Temp.=40° C.) to give 4-(((1S,3R)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (peak 1: 300 mg, 1.08 mmol, 33% yield, 100% e.e.) and 4-(((1R,3S)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (peak 2: 310 mg, 1.12 mmol, 34% yield, 100% e.e.), MS (ESI) m/z 279.1 [M+H]+.

المصدر