Diisopropylethylamine → 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(4-(2,2,2-trifluoroethoxy)cyclohexyl-amino)pyrimidine-5-carboxamide

HRID 2280712Notes

Reaction equation

HRID 2280712 reaction equation
[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH2:3]1.Cl.Cl.Cl.[F:25][C:26]([F:37])([F:36])[CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C>CS(C)=O>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:35][CH:32]3[CH2:33][CH2:34][CH:29]([O:28][CH2:27][C:26]([F:25])([F:36])[F:37])[CH2:30][CH2:31]3)[N:10]=2)[CH2:3]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 709818234-((1R,3S)-3-Hydroxycyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamideHCID 1317335094-(2,2,2-Trifluoroethoxy)-cyclohexanamine trihydrochloride

Product 1

HCID 665758424-((1R,3S)-3-hydroxycyclohexylamino)-2-(4-(2,2,2-trifluoroethoxy)cyclohexyl-amino)pyrimidine-5-carboxamideYield 22.36%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
100 °C

Procedure

To a stirring solution of 4-((1R,3S)-3-hydroxycyclohexyl-amino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (440 mg, 1.400 mmol; synthesis described herein) and bis-4-(2,2,2-trifluoroethoxy)-cyclohexanamine trihydrochloride (529 mg, 2.099 mmol) in DMSO (6.964 mL) was added DIEA (0.978 mL, 5.60 mmol). The resulting mixture was allowed to stir overnight at 100° C. The crude reaction mixture was concentrated, purified by silica gel chromatography (0-10% methanol/dichloromethane), and then purified by reversed-phase silica gel chromatography (methanol/water with 0.1% formic acid modifier). The product containing fractions were neutralized and concentrated to afford 4-((1R,3S)-3-hydroxycyclohexylamino)-2-(4-(2,2,2-trifluoroethoxy)cyclohexyl-amino)pyrimidine-5-carboxamide (135 mg, 0.313 mmol, 22.36% yield) as a mixture of 2 stereoisomers. MS (ESI) m/z 432.2 [M+H]+. This mixture was separated using chiral super-fluid chromatography (AD-H column) to afford 87.8 mg (0.203 mmol) of a single, faster eluting, stereoisomer (PEAK 1) and 24.2 mg (0.056 mmol) of a second single, slower eluting, stereoisomer (PEAK 2).

Workup

  1. customsynthesis
  2. customThe crude reaction mixture
  3. concentrationwas concentrated
  4. custompurified by silica gel chromatography (0-10% methanol/dichloromethane)
  5. custompurified by reversed-phase silica gel chromatography (methanol/water with 0.1% formic acid modifier)
  6. additionThe product containing fractions
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-c4596e4f973e4acda8fe8869e7ac8dde
Source dataset
uspto-grants-2015_09
Patent number
US09139534B2

Reaction notes

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