2-Bromothiazole → N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-thiazolyl)carbonyl-6-methylpyrimidinamine

HRID 1251500Notes

Reaction equation

HRID 1251500 reaction equation
C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Br:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[N:22]([C:25]1[N:30]=[C:29]([C:31](OC)=[O:32])[CH:28]=[C:27]([CH3:35])[N:26]=1)[CH2:23][CH3:24].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:16]=[CH:15][C:14]=1[N:22]([CH2:23][CH3:24])[C:25]1[N:30]=[C:29]([C:31]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[O:32])[CH:28]=[C:27]([CH3:35])[N:26]=1

Participants

7

Reactant 4

HCID 764302-BromothiazoleHCID 516892Sodium BicarbonateHCID 183237072-(N-(2-bromo-4-(2-propyl)phenyl)-N-ethylamino)-4-carbomethoxy-6-methyl-pyrimidineHCID 178418339Butyllithium

Product 1

HCID 18323732N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-thiazolyl)carbonyl-6-methylpyrimidinamineYield 85%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of n-butyl lithium in hexanes (2.4 M, 1.34 mL, 3.24 mmol) in anhydrous THF (5 mL) at −78° C. under a nitrogen atmosphere was added 2-bromothiazole (0.49 g, 0.27 mL, 3.0 mmol) dropwise. After the addition was complete, the reaction mixture was stirred at −78° C. for 30 min. A solution of methyl 2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate (Example 18) (1.0 g, 2.5 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was then warmed to −60° C. and stirred for 4 h. A saturated aqueous solution of NaHCO3 was added and the reaction mixture was warmed to ambient temperature. Three extractions with ethyl acetate, followed by two washings of the combined organic layers with water, drying over MgSO4, filtration and concentration in vacuo gave a dark brown oil. Column chromatography (ethyl acetate: hexanes::1:1) afforded the title product, a brown solid (950 mg, 85% yield, Rf 0.43): mp 97-98.5° C.; NMR (CDCl3, 300 MHz):8.0 (s, 1H), 7.60 (s, 1H), 7.4-7.2 (m, 4H, J=6), 3.05-2.9 (m, 1H), 2.8-2.7 (m, 1H), 2.6 (br s, 3H), 1.4-1.2 (m, 9H); CI-HRMS Calcd: 445.0698 (M+H), Found: 445.0699; Anal.(C20H21BrN4S): C, 54.05; H, 4.73; N, 12.61; Br, 18.02; S, 7.21; Found: C, 53.86; H, 4.66; N, 12.53; Br, 18.20; S, 7.46.

Workup

  1. additionAfter the addition
  2. temperatureThe reaction mixture was then warmed to −60° C.
  3. stirringstirred for 4 h
  4. temperaturethe reaction mixture was warmed to ambient temperature
  5. extractionThree extractions with ethyl acetate
  6. dry with materialdrying over MgSO4, filtration and concentration in vacuo
  7. customgave a dark brown oil

Sources & evidence

ORD record
ord-ab72c811e59e46d1968d5d9f01b67b44
Source dataset
uspto-grants-2002_01
Patent number
US06342503B1

Reaction notes

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