Sodium methanethiolate → HCID 178437943, compound

HRID 541409Notes

Reaction equation

HRID 541409 reaction equation
[CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9](F)=[CH:10][C:11]([CH3:30])=[C:12]([C:14]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH:13]=2)=[N:6][N:7]=1)[CH3:2].[CH3:32][S-:33].[Na+]>CN(C)C=O>[CH2:1]([C:3]1[NH:4][C:5]([C:8]2[C:9]([S:33][CH3:32])=[CH:10][C:11]([CH3:30])=[C:12]([CH:13]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:6][N:7]=1)[CH3:2]

Participants

4

Reactant 2

HCID 4378561Sodium methanethiolateHCID 1784379414-(1-(5-(5-Ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile2×

Product 1

HCID 178437943HCID 178437943, compoundYield 19%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

To a round-bottom flask was added a solution of 4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 258.2, 20 mg, 0.050 mmol, 1.0 equiv) in N,N-dimethylformamide (3 mL). Sodium thiomethoxide (70 mg, 0.10 mmol, 2.0 equiv) was added to the reaction. The resulting mixture was stirred for 15 h at 110° C. in an oil bath, and then cooled to ambient temperature and quenched with 100 mL of ice water. The mixture was extracted with 50 mL of ethyl acetate and the combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product (50 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (37% CH3CN up to 49% in 7 min, up to 100% in 3 min, down to 37% in 2 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 4 mg (19%) of the title compound as a white solid. m/z (ES+) 446 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.69 (d, J=8.4 Hz, 2H), 7.61-7.43 (m, 3H), 7.35 (br s, 1H), ˜4.85 (1H partially obscured by water peak), 3.77-3.60 (m, 1H), ˜3.3 (1H partially obscured by methanol solvent peak), 3.08-2.94 (m, 2H), 2.91 (q, J=7.7 Hz, 2H), 2.51 (s, 3H), 2.47 & 2.37 (2 singlets, amide rotamers, Ar—CH3, 3H), 2.10-1.97 (m, 1H), 1.88-1.55 (m, 3H), 1.40 (t, 3H).

Workup

  1. temperaturecooled to ambient temperature
  2. customquenched with 100 mL of ice water
  3. extractionThe mixture was extracted with 50 mL of ethyl acetate
  4. washthe combined organic layers were washed with 2×50 mL of brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe product (50 mg) was further purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU))
  8. waitmobile phase, water with 0.05% TFA and CH3CN (37% CH3CN up to 49% in 7 min
  9. waitup to 100% in 3 min
  10. waitdown to 37% in 2 min)
  11. additionThe fractions containing pure compound

Sources & evidence

ORD record
ord-1d6364b0496c4cbe8b1c524caf5c662e
Source dataset
uspto-grants-2014_10
Patent number
US08871790B2

Reaction notes

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