Nitromethane → 4-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide

HRID 589639Notes

Reaction equation

HRID 589639 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4](/[C:9](/[C:28]([F:31])([F:30])[F:29])=[CH:10]\[C:11]([C:13]2[CH:26]=[CH:25][C:16]([C:17]([NH:19][C:20]3([CH3:24])[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:27])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C1C=C(NC(N[C@H]([C@@H]2C[C@@H]3CCN2C[C@@H]3CC)C2C3C(=CC=C(OC)C=3)N=CC=2)=S)C=C(C(F)(F)F)C=1.[Cl-].[NH4+].[N+:75]([CH3:78])([O-:77])=[O:76]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]([CH2:78][N+:75]([O-:77])=[O:76])([C:28]([F:31])([F:30])[F:29])[CH2:10][C:11]([C:13]2[CH:26]=[CH:25][C:16]([C:17]([NH:19][C:20]3([CH3:24])[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:27])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1

Participants

5

Reactant 4

HCID 6375NitromethaneHCID 25517Ammonium ChlorideHCID 111693261-[3,5-Bis(trifluoromethyl)phenyl)-3-{(S)[(2S,4S,5R)-5-ethyl-1-aza-bicyclo[2.2.2]oct-2-yl]-(6-methoxy-4-quinolinyl)methyl}thioureaHCID 866959984-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide

Product 1

HCID 866959974-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamideYield 19%

Conditions

Temperature
60 °C

Procedure

4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide (0.100 g, 0.205 mmol) and 1-[3,5-bis(trifluoromethyl)phenyl)-3-{(S)[(2S,4S,5R)-5-ethyl-1-aza-bicyclo[2.2.2]oct-2-yl]-(6-methoxy-4-quinolinyl)methyl}thiourea (0.0305 g, 0.020 mmol) were dissolved in nitromethane (2.0 ml) and the resulting solution was stirred at 60° C. for 3 days. The reaction mixture was cooled to room temperature and aqueous saturated ammonium chloride was added. The resulting mixture was extracted with dichloromethane (3×) and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-N-(3-methyl-thietan-3-yl)-benzamide (0.021 g, 19%) as a light yellow solid. Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol=70:30, 1 ml/min, retention time 5.71 minutes (major enantiomer), 8.13 minutes (minor enantiomer)) indicated that the reaction proceeded with 79% enantioselectivity. 1H NMR (400 MHz, CDCl3) δ 7.82-7.78 (m, 2H), 7.47 (d, 1H), 7.43-7.41 (m, 1H), 7.19 (s, 2H), 5.90 (s, 1H), 5.60 (d, 1H), 5.45 (d, 1H), 4.13 (d, 1H), 3.97 (d, 1H), 3.88 (d, 2H), 3.09 (d, 2H), 2.53 (s, 3H), 1.87 (s, 3H).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. extractionThe resulting mixture was extracted with dichloromethane (3×)
  3. dry with materialthe combined organic fractions were dried over sodium sulfate
  4. customThe crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane)

Sources & evidence

ORD record
ord-94b85e6beae943de987842fb21b3ec5d
Source dataset
uspto-grants-2016_01
Patent number
US09233920B2

Reaction notes

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