Acetic Acid → (S)-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol

HRID 1486766Notes

Reaction equation

HRID 1486766 reaction equation
[NH:1]([C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]2[CH2:13][CH:12]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)[CH2:11]2)[CH:4]=1)[NH2:2].[CH3:24][C:25]([OH:27])=O>CC(N(C)C)=O.CC(N(C)C)=O>[CH3:4][C:5]1[N:6]=[C:7]([C@@H:25]([OH:27])[CH3:24])[N:1]([C:3]2[CH:4]=[C:5]([N:10]3[CH2:11][CH:12]([C:14]4[N:18]([CH3:19])[C:17]5[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=5[N:15]=4)[CH2:13]3)[N:6]=[C:7]([CH3:9])[N:8]=2)[N:2]=1

Participants

4

Reactant 2

HCID 176Acetic AcidHCID 894937102-(1-(6-hydrazinyl-2-methylpyrimidin-4-yl)azetidin-3-yl)-1-methyl-1H-benzo[d]imidazole

Product 1

HCID 74767261(S)-1-(3-methyl-1-(2-methyl-6-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)azetidin-1-yl)pyrimidin-4-yl)-1H-1,2,4-triazol-5-yl)ethanol

Reagents, catalysts & solvents 1

HCID 19097097DMA dimethylacetamideSolvent

Procedure

A solution of Intermediate 2 (11.0 g, 35.6 mmol) in AcOH (100 mL) was added to crude Intermediate 13 (24.2 g, 89 mmol, prepared by heating the corresponding primary amide in neat DMA-DMA at 50° C. overnight followed by removal of excess DMA-DMA by rotary evaporation). The reaction mixture was allowed to stir for 10 min at room temperature and then heated at 80° C. for 1 h. Sampling of the reaction by LCMS suggested cyclization to the silyl-protected hydroxy triazole had occurred. The reaction was allowed to stir at 80° C. for an additional 16 h at which point complete de-silylation of the hydroxy group had occurred. The reaction was cooled to room temperature, poured carefully over saturated aqueous sodium bicarbonate solution (200 mL), and the aqueous layer was made basic to pH˜8 by the addition of solid sodium bicarbonate. The solution was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-10% 2-propanol/DCM) to give Example 1 as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.76-7.74 (m, 1H), 7.35-7.28 (m, 3H), 6.96 (m, 1H), 6.62 (s, 1H), 5.12-5.07 (m, 1H), 4.71-4.58 (br s, 4H), 4.34-4.24 (m, 1H), 3.75 (s, 3H), 2.54 (s, 3H), 2.43 (s, 3H) 1.71 (d, J=6.6 Hz, 3H); MS: m/z=405.5 (M+H).

Workup

  1. customprepared
  2. customfollowed by removal of excess DMA-DMA by rotary evaporation)
  3. temperatureheated at 80° C. for 1 h
  4. aliquotSampling of the reaction by LCMS
  5. stirringto stir at 80° C. for an additional 16 h at which point complete de-silylation of the hydroxy group
  6. temperatureThe reaction was cooled to room temperature
  7. additionpoured carefully over saturated aqueous sodium bicarbonate solution (200 mL)
  8. additionthe aqueous layer was made basic to pH˜8 by the addition of solid sodium bicarbonate
  9. extractionThe solution was extracted with ethyl acetate
  10. dry with materialthe organic layer was dried over sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe crude product was purified by silica gel chromatography (0-10% 2-propanol/DCM)

Sources & evidence

ORD record
ord-49bd604850f641338d8c5056901c658c
Source dataset
uspto-grants-2016_08
Patent number
US09428492B2

Reaction notes

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