HCID 67960627, compound → HCID 86698461, compound

HRID 527675Notes

Reaction equation

HRID 527675 reaction equation
[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=2)[O:5][CH2:4][CH2:3]1.[CH3:20][C:21]([O:24][C:25]([NH:27][C@:28]([CH3:40])([CH2:38][CH3:39])[C:29](=[O:37])SC1C=CC=CN=1)=[O:26])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:40][C@:28]([NH:27][C:25](=[O:26])[O:24][C:21]([CH3:23])([CH3:22])[CH3:20])([C:29]([NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[CH:2]([CH3:1])[CH2:3][CH2:4][O:5]3)=[N:14][CH:15]=1)=[O:37])[CH2:38][CH3:39]

Participants

4

Reactant 2

HCID 67960627HCID 67960627, compound2×HCID 86698462HCID 86698462, compound10×

Product 1

HCID 86698461HCID 86698461, compoundYield 78.2%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
140 °C

Procedure

2-[(4-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-5-pyrimidinamine (Intermediate 217, 144 mg, 0.56 mmol) was dissolved in toluene (8.0 mL) and S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 86 mg, 0.28 mmol) was added. The reaction mixture was stirred at 140° C. for 20 minutes. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 134 mg, 0.43 mmol) was added and the mixture was stirred at 140° C. for 15 minutes. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 100 mg, 0.32 mmol) was added and the reaction mixture was stirred at 50° C. overnight and at 80° C. and for 4 hours. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 100 mg, 0.32 mmol) was added and the reaction mixture was stirred at 80° C. for 20 hours. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 50 mg, 0.16 mmol) was added and the reaction mixture was stirred for additional 30 hours at 80° C. After cooling volatiles were removed and the residue was purified by flash chromatography (Biotage SP1) on silica gel using a 10 g SNAP silica cartridge as column and cyclohexane/ethyl acetate from 10:0 to 1:1 as eluents affording the title compound (100 mg).

Workup

  1. stirringthe mixture was stirred at 140° C. for 15 minutes
  2. stirringthe reaction mixture was stirred at 50° C. overnight and at 80° C. and for 4 hours
  3. stirringthe reaction mixture was stirred at 80° C. for 20 hours
  4. stirringthe reaction mixture was stirred for additional 30 hours at 80° C
  5. temperatureAfter cooling volatiles
  6. customwere removed
  7. customthe residue was purified by flash chromatography (Biotage SP1) on silica gel using a 10 g SNAP silica cartridge as column and cyclohexane/ethyl acetate from 10:0 to 1:1 as eluents

Sources & evidence

ORD record
ord-d89e14b585e148c9bf785ebe8936d260
Source dataset
uspto-grants-2016_05
Patent number
US09346790B2

Reaction notes

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