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

HRID 626901Notes

Reaction equation

HRID 626901 reaction equation
[NH2:1][C@:2]1([CH2:9][C:10]#[C:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[CH:21]=[CH:20][C:19]=3[F:27])[CH:15]=[C:14]([CH3:28])[N:13]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]>CC#N.CCOC(C)=O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:25]([O:24][C:22]1[CH:21]=[CH:20][C:19]([F:27])=[C:18]([C:16]2[CH:15]=[C:14]([CH3:28])[N:13]=[C:12]([C:11]3[CH2:10][CH2:9][C@:2]4([CH2:6][CH2:5][N:4]([CH3:7])[C:3]4=[O:8])[N:1]=3)[N:17]=2)[CH:23]=1)[CH3:26]

Participants

5

Reactant 1

HCID 90015517(3R)-3-Amino-3-[3-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]prop-2-ynyl]-1-methyl-pyrrolidin-2-one

Product 1

HCID 90015243(5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-oneYield 74.9%

Reagents, catalysts & solvents 3

HCID 76223Silver(I) trifluoromethanesulfonateCatalyst2×HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
40 °C

Procedure

Silver trifluoromethanesulphonate (60.06 mg, 0.23 mmol) was added to a solution of (3R)-3-amino-3-[3-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]prop-2-ynyl]-1-methyl-pyrrolidin-2-one (which may be prepared as described in Description 19) (447 mg, 1.17 mmol) in MeCN (20 mL) at 20° C. and the reaction was stirred for 66 hrs. An additional 10 mol % AgOTf was added, stirring was continued for an additional 3 days then the mixture was heated to 40° C. until no starting material remained. The solvent was evaporated and the residue was partitioned between water and EtOAc. The organic layer was dried (Na2SO4) and the solvent was evaporated to afford a brown oil. This was purified using a Biotage Isolera with a 25 g SNAP cartridge, eluting with a 0 to 50% mixture (9% MeOH; 89% EtOAc and 2% 880 NH3) in EtOAc affording the (5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (D20) (335 mg, 0.876 mmol, 74.9% yield) as a light brown solid.

Workup

  1. stirringstirring
  2. waitwas continued for an additional 3 days
  3. customThe solvent was evaporated
  4. customthe residue was partitioned between water and EtOAc
  5. dry with materialThe organic layer was dried (Na2SO4)
  6. customthe solvent was evaporated
  7. customto afford a brown oil
  8. customThis was purified

Sources & evidence

ORD record
ord-0535d3f5adc94c0ba6deac88f607b6aa
Source dataset
uspto-grants-2016_04
Patent number
US09309254B2

Reaction notes

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