Hydrochloric Acid → 7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one
Reaction equation
[CH3:1][N:2]1[C:27](=[O:28])[C@:5]2([CH2:9][CH2:8][C:7]([C:10]3[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[N:11]=3)=[N:6]2)[CH2:4][CH2:3]1.C(N)(C)(C)C.B.Cl.CC(C)=O.C(=O)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([NH:6][CH:7]([C:10]3[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)[N:11]=3)[CH2:8][CH2:9]2)[C:27]1=[O:28]Participants
Reactant 4
Product 1
Reagents, catalysts & solvents 1
Conditions
- Temperature
- -70 °C
Procedure
(5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 15a) (78.34 g, 201.7 mmol) was added to a 5 L three necked round bottomed flask containing an overhead stirrer, 500 ml pressure-equalising dropping funnel with a nitrogen inlet and thermometer. To this was added DCM (1000 mL) and the stirred mixture cooled to approx. −70° C. The dropping funnel was charged with a pre-sonicated solution of borane tert-butylamine (19.3 g, 221.87 mmol) in DCM (200 mL). The borane complex was added slowly maintaining the temperature below −70° C. over approx. 30 minutes. After addition the reaction was stirred at below −70° C. for 90 minutes. The dropping funnel was charged with 6M HCl (400 ml) and this was added dropwise over approx. 15 minutes. The reaction temperature warmed to −50° C. during the addition. After addition was complete the acetone/dry-ice bath was removed and the reaction mixture warmed to room temperature then stirred for a further 30 minutes. In a separate 10 L flask was added sodium carbonate (200 g) and water (1 L). To this flask was added an overhead stirrer. The reaction mixture was carefully added (note: gas evolution) to the sodium carbonate solution and stirring was maintained until gas evolution ceased. The mixture was transferred to a 6 L separating funnel and the phases were separated. The aqueous layer was washed with DCM (2×200 ml) and the combined organics were dried (MgSO4). The solvent was evaporated to afford 7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one as an amber oil (77.8 g), a 96:4 ratio of (2R,5S) and (2S,5S) isomers.
Workup
- additioncontaining an overhead stirrer
- additionThe borane complex was added slowly
- temperaturemaintaining the temperature below −70° C. over approx. 30 minutes
- additionAfter addition the reaction
- additionthis was added dropwise over approx. 15 minutes
- temperatureThe reaction temperature warmed to −50° C. during the addition
- additionAfter addition
- customwas removed
- temperaturethe reaction mixture warmed to room temperature
- stirringthen stirred for a further 30 minutes
- additionIn a separate 10 L flask was added sodium carbonate (200 g) and water (1 L)
- additionTo this flask was added an overhead stirrer
- additionThe reaction mixture was carefully added (note: gas evolution) to the sodium carbonate solution
- stirringstirring
- temperaturewas maintained until gas evolution
- customseparating funnel
- customthe phases were separated
- washThe aqueous layer was washed with DCM (2×200 ml)
- dry with materialthe combined organics were dried (MgSO4)
- customThe solvent was evaporated
Sources & evidence
- ORD record
- ord-ef7f0cb3d4474d2ebc5fe8e58b1255c7
- Source dataset
- uspto-grants-2016_04
- Patent number
- US09309254B2
Reaction notes
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