(3R)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one → (5R)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one

HRID 626894Notes

Reaction equation

HRID 626894 reaction equation
[NH2:1][C@:2]1([CH2:9][C:10]#[C:11][C:12]2[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:13]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]>CC#N.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:7][N:4]1[CH2:5][CH2:6][C@@:2]2([N:1]=[C:11]([C:12]3[N:17]=[C:16]([CH3:18])[CH:15]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)[N:13]=3)[CH2:10][CH2:9]2)[C:3]1=[O:8]

Participants

4

Reactant 1

HCID 90016090(3R)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one

Product 1

HCID 90015778(5R)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-oneYield 105%

Reagents, catalysts & solvents 2

HCID 76223Silver(I) trifluoromethanesulfonateCatalyst2×HCID 6342AcetonitrileSolvent

Conditions

Temperature
40 °C

Procedure

Silver trifluoromethanesulphonate (22.69 mg, 0.09 mmol) was added to a solution of (3R)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (which may be prepared as described in Description 14) (343 mg, 0.88 mmol) in MeCN (20 mL) at 20° C. and the reaction was stirred for 18 hrs. The reaction was heated to 40° C. and stirring was continued for 3 days. Additional AgOTf (10 mol %) was added and stirring was continued at 40° C. for 18 hrs. The solvent was evaporated and the residue was purified using a Biotage Isolera with a 25 g SNAP cartridge, eluting with 0 to 100% (mixture of 1% of 2M NH3 in MeOH; 9% MeOH; 90% EtOAc)/EtOAc affording (5R)-7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one (D15) (359 mg, 0.924 mmol) as a light brown solid with a few % of impurities present. 300 MHz NMR δH (CDCl3) 1.89-2.00 (1H, m), 2.16-2.25 (1H, m), 2.59-2.72 (2H, m), 2.72 (3H, s), 2.92 (3H, s), 3.30-3.45 (2H, m), 3.55-3.78 (2H, m), 7.64 (1H, s), 7.79 (2H, d), 8.26 (2H, d).

Workup

  1. stirringstirring
  2. waitwas continued for 3 days
  3. stirringstirring
  4. waitwas continued at 40° C. for 18 hrs
  5. customThe solvent was evaporated
  6. customthe residue was purified
  7. washeluting with 0 to 100% (mixture of 1% of 2M NH3 in MeOH; 9% MeOH; 90% EtOAc)/EtOAc

Sources & evidence

ORD record
ord-711869fb48004582848d2cdac4601f31
Source dataset
uspto-grants-2016_04
Patent number
US09309254B2

Reaction notes

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