Diisopropylethylamine → HCID 118162118, compound

HRID 1749477Notes

Reaction equation

HRID 1749477 reaction equation
Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:3]=1.[NH2:20][CH:21]1[CH2:24][CH:23]([NH:25]C(=O)OC(C)(C)C)[C:22]1([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:20][C@H:21]1[CH2:24][C@H:23]([NH:25][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[N:3]=2)[C:22]1([CH3:34])[CH3:33]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 1127028651392803-57-4HCID 118162107HCID 118162107, compound

Product 1

HCID 118162118HCID 118162118, compoundYield 63.7%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
125 °C

Procedure

To a mixture of 4-chloro-2-((3-chlorophenethyl)amino)pyrimidine-5-carbonitrile (600 mg, 2.04 mmol) and tert-butyl (3-amino-2,2-dimethylcyclobutyl)carbamate (490 mg, 2.29 mmol) in dioxane (20 mL) was added DIEA (738 mg, 5.73 mmol). The resulting mixture was stirred at 125° C. under microwave irradiation for 5 h. After removal of the organic solvent under reduced pressure, the residue was diluted with ethyl acetate and the organic layer ws washed with aqueous solution of ammonia chloride. The organic layer was separated and dried over sodium sulfate and concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (10% to 33% ethyl acetate in petroleum) to afford the title compound (610 mg, 1.30 mmol, 63% yield) as a pale yellow solid. The racemic product (500 mg, 1.06 mmol) was separated by chiral preparative supercritical fluid chromatography (chiral column: OJ, Column size: 0.46 cm I.D.×25 cm L, 5 um; Mobile phase: CO2:MeOH:DEA=60:40:0.1, Flow: 2.5 mL/min, 220 nm T=35° C.) to give four isomers: tert-butyl ((1S,3S)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 1, 100 mg, 0.21 mmol, 20% yield, RT=7.88 min, d.e.=100%, e.e. =100%), tert-butyl ((1R,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 3, 102 mg, 0.22 mmol, 20% yield, RT=9.37 min, d.e.=100%, e.e. =100%), tert-butyl ((1R,3S)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 2, 85 mg, 0.18 mmol, 17% yield, RT=8.29 min, d.e.=100%, e.e. =100%) and tert-butyl ((1S,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (peak 4, 82 mg, 0.17 mmol, 17% yield, RT=10.96 min, d.e.=100%, e.e. =100%). MS (ESI) m/z 471.2 [M+H]+

Workup

  1. customAfter removal of the organic solvent under reduced pressure
  2. additionthe residue was diluted with ethyl acetate
  3. washthe organic layer ws washed with aqueous solution of ammonia chloride
  4. customThe organic layer was separated
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated under vacuum
  7. customto give the crude product, which
  8. customwas purified by silica gel chromatography (10% to 33% ethyl acetate in petroleum)

Sources & evidence

ORD record
ord-ae91e02c84a94f81b7fff15765a037b6
Source dataset
uspto-grants-2015_10
Patent number
US09156798B2

Reaction notes

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