Hydrochloric Acid → (1R,3S)-methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate
Reaction equation
C(O[C:6]([NH:8][CH:9]1[CH2:14][C:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[N:36]=C(Cl)[C:34]([F:38])=[CH:33][N:32]=1>CO>[Cl:30][C:31]1[N:36]=[C:6]([NH:8][C@H:9]2[CH2:10][CH2:11][CH2:12][C@@:13]([CH3:19])([C:15]([O:17][CH3:18])=[O:16])[CH2:14]2)[C:34]([F:38])=[CH:33][N:32]=1Participants
Reactant 4
Product 1
Reagents, catalysts & solvents 1
Procedure
A stirred solution of methyl 5-(tert-butoxycarbonylamino)-1-methylcyclohexanecarboxylate, 52g, (5.63 g, 20.75 mmol) in MeOH (20 mL) was treated with HCl gas for 10 minutes. The resulting solution was stirred at room temperature for 1 hour, then concentrated to dryness and redissolved in THF (50 mL). To the reaction mixture was added iPr2NEt (10.84 mL, 62.25 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (5.20 g, 31.12 mmol) sequentially. The reaction was stirred at reflux overnight, concentrated in vacuo and resulting residue was purified by silica gel chromatography (1:1 Hexane:EtOAc), yielding 2.2 g of the racemic product as a yellow oil. 300 mg of the racemic methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1-methylcyclohexanecarboxylate was submitted for SFC chiral separation, yielding 100 mg of the desired product, 52h, as a yellow oil.
Workup
- concentrationconcentrated to dryness
- dissolutionredissolved in THF (50 mL)
- stirringThe reaction was stirred
- temperatureat reflux overnight
- concentrationconcentrated in vacuo
- customresulting residue
- customwas purified by silica gel chromatography (1:1 Hexane:EtOAc)
Sources & evidence
- ORD record
- ord-0fe23e41c9504b78ae7bb5ee2aac91b1
- Source dataset
- uspto-grants-2016_05
- Patent number
- US09345708B2
Reaction notes
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