Diisopropylamine → 3-Amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one

HRID 626893Notes

Reaction equation

HRID 626893 reaction equation
[NH2:1][C:2]1([CH2:9][C:10]#[CH:11])[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8].I[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:14]=1.C(NC(C)C)(C)C>COC(C)(C)C.[Cu](I)I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1([CH2:9][C:10]#[C:11][C:13]2[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)[N:14]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]

Participants

7

Reactant 3

HCID 7912DiisopropylamineHCID 896492053-Amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-oneHCID 90014635HCID 90014635, compound

Product 1

HCID 1180360983-Amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-oneYield 80.3%

Reagents, catalysts & solvents 3

HCID 83717Copper iodideCatalystHCID 178419050HCID 178419050, compoundCatalystHCID 15413tert-Butyl methyl etherSolvent

Procedure

To a stirred solution of 3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (which may be prepared as described in Description 3) (2.3 g, 15.11 mmol) in tert-butyl methyl ether (50 mL) was added 2-iodo-4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidine (which may be prepared as described in Description 12) (6.05 g, 16.62 mmol). diisopropylamine (6.35 mL, 45.34 mmol) was then added, followed by copper iodide (57.56 mg, 0.300 mmol) and bis(triphenylphosphine)palladium (II) dichloride (106.07 mg, 0.1500 mmol). The reaction was then stirred at room temperature for 5 days. The reaction mixture was transferred to a separating funnel and the flask washed with an additional quantity of tert-butyl methyl ether (15 ml). The organic solution was washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over magnesium sulphate, filtered, and then the magnesium sulphate washed with dichloromethane (30 ml). The filtrate was concentrated at reduced pressure to give a yellow foam. The product was purified by silica gel chromatography eluting with ethyl acetate followed by an increasing percentage of a solution of 10% 0.880 ammonia in methanol, to give the title compound (D14b) as a yellow foam (4.71 g). This racemate was consistent by NMR and mass spectroscopy with the R isomer prepared in Description 14.

Workup

  1. customThe reaction mixture was transferred to a separating funnel
  2. washthe flask washed with an additional quantity of tert-butyl methyl ether (15 ml)
  3. washThe organic solution was washed with water (2×50 mL) and brine (50 mL)
  4. dry with materialThe organic phase was dried over magnesium sulphate
  5. filtrationfiltered
  6. washthe magnesium sulphate washed with dichloromethane (30 ml)
  7. concentrationThe filtrate was concentrated at reduced pressure
  8. customto give a yellow foam
  9. customThe product was purified by silica gel chromatography
  10. washeluting with ethyl acetate

Sources & evidence

ORD record
ord-6fdcbbace1ee4c3f81a02084ad51b9b2
Source dataset
uspto-grants-2016_04
Patent number
US09309254B2

Reaction notes

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