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

HRID 1749505Notes

Reaction equation

HRID 1749505 reaction equation
Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][C:15]([CH3:20])([OH:19])[CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:19][C@:15]1([CH3:20])[CH2:16][CH2:17][CH2:18][C@H:13]([NH:12][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:14]1.[OH:19][C@@:15]1([CH3:20])[CH2:16][CH2:17][CH2:18][C@@H:13]([NH:12][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:14]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 131141834-Chloro-2-(methylsulfanyl)pyrimidine-5-carbonitrileHCID 134950983-Amino-1-methylcyclohexan-1-ol

Product 2

HCID 1181620774-(((1S,3R)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrileYield 33%HCID 1181622264-(((1R,3S)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrileYield 34%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
100 °C

Procedure

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]+.

Workup

  1. customThe organic solvents were removed under reduced pressure
  2. additionThe residue was treated with water
  3. extractionextracted with ethyl acetate
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated
  7. customto give the crude product, which
  8. customwas purified by silica gel column chromatography (20% ethyl acetate in petroleum)
  9. customto 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. customThe 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.)

Sources & evidence

ORD record
ord-7bac73e6d320436ba0d8d585dcae9dcd
Source dataset
uspto-grants-2015_10
Patent number
US09156798B2

Reaction notes

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