N-Methyl-o-phenylenediamine → trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole

HRID 1498779Notes

Reaction equation

HRID 1498779 reaction equation
[CH3:1][NH:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C[Al](C)C.C(O[C:17]([C@@H:19]1[CH2:21][C@H:20]1[C:22]1[CH:27]=[C:26]([N:28]2[C:32]([CH3:33])=[N:31][C:30]([CH3:34])=[N:29]2)[N:25]=[C:24]([S:35][CH3:36])[N:23]=1)=O)C>C1(C)C=CC=CC=1>[CH3:34][C:30]1[N:31]=[C:32]([CH3:33])[N:28]([C:26]2[N:25]=[C:24]([S:35][CH3:36])[N:23]=[C:22]([C@@H:20]3[CH2:21][C@H:19]3[C:17]3[N:2]([CH3:1])[C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:9]=3)[CH:27]=2)[N:29]=1

Participants

5

Reactant 3

HCID 78498N-Methyl-o-phenylenediamineHCID 16682925TrimethylaluminumHCID 86732038ethyl-trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropanecarboxylate

Product 1

HCID 71547705trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
130 °C

Procedure

To N1-methylbenzene-1,2-diamine (2.01 g, 16.5 mmol, 1.1 eq.) dissolved in toluene (20 mL) was added trimethylaluminium solution (2.0 M in toluene, 22.5 mL, 44.98 mmol, 3.0 eq.) under nitrogen at 0° C. dropwise. The reaction was stirred at a temperature between 10° C. to 20° C. for 30 minutes followed by the addition of ethyl-trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropanecarboxylate (1-4) (5.00 g, 14.99 mmol, 1.0 eq.) in toluene (80 mL) and the reaction was heated to 130° C. for 12 hours. The reaction was cooled to room temperature and quenched with saturated sodium bicarbonate (100 mL) then extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrate to dryness. The crude product was purified by silica gel column chromatography (0-30% acetone in dichloromethane) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-5) as a pale pink solid. 1H NMR (400 MHz, CDCl3) δ 7.72-7.67 (m, 1H), 7.56 (s, 1H), 7.31-7.22 (m, 3H), 3.81 (s, 3H), 2.90 (s, 3H), 2.86-2.76 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.06-1.97 (m, 2H). LRMS m/z (M+H) 392 found, 392 required. m.p. 157-159° C.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. customquenched with saturated sodium bicarbonate (100 mL)
  3. extractionthen extracted with ethyl acetate (3×200 mL)
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrate to dryness
  7. customThe crude product was purified by silica gel column chromatography (0-30% acetone in dichloromethane)

Sources & evidence

ORD record
ord-adb604f325884fa0a8f9287fe26d1732
Source dataset
uspto-grants-2015_12
Patent number
US09200001B2

Reaction notes

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