Ethyl diazoacetate → ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate

HRID 2199851Notes

Reaction equation

HRID 2199851 reaction equation
[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[C:10]([CH3:16])[N:11]=[C:12]([C@@H:14]3[CH2:15][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)[N:3]=1

Participants

4

Reactant 2

HCID 12192Ethyl diazoacetateHCID 86732066HCID 86732066, compound

Product 1

HCID 86732076ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (1-3) (1.00 g, 4.65 mmol, 1.0 eq.) in degassed toluene (20 mL) was added ethyl diazoacetate (0.98 mL, 9.30 mmol, 2.0 eq.) and the reaction was heated to 120° C. The reaction was monitored by LC-MS and after 2 h the mixture was cooled to room temperature and the toluene was removed by roto-evaporation. The resulting residue was purified by silica gel column chromatography (10-40% EtOAc/hexanes) to afford racemic ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate as a white solid. Further purification by chiral SFC provided the active isomer (1-4) as the second eluting peak that was used in subsequent reactions. Analytical separation conditions are as follows: Chiralcel OJ-H, 4.6 mm×25 cm, 90/10 CO2/MeOH+0.1% diethylamine, flow rate=2.4 mL/min; peak 1=2.0 min, peak 2=2.6 min. 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 4.17 (q, 2H, J=7.1 Hz), 2.88 (s, 3H), 2.64-2.55 (m, 1H), 2.62 (s, 3H), 2.41 (s, 3H), 2.36 (ddd, 1H, J=8.6, 5.7, 3.8 Hz), 1.74-1.61 (m, 2H), 1.28 (t, 3H, J=7.1 Hz). MS: m/z=302 (M+H).

Workup

  1. temperaturethe mixture was cooled to room temperature
  2. customthe toluene was removed by roto-evaporation
  3. customThe resulting residue was purified by silica gel column chromatography (10-40% EtOAc/hexanes)

Sources & evidence

ORD record
ord-2401eef54c0c4174b4aefe5acc462868
Source dataset
uspto-grants-2016_06
Patent number
US09359348B2

Reaction notes

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