Water → HCID 86684919, compound

HRID 2402915Notes

Reaction equation

HRID 2402915 reaction equation
[F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1.[C:18]([C:20]1([NH:23][C:24]([C@H:26]2[N:30]([C:31]([C:33]3([CH3:36])[CH2:35][CH2:34]3)=[O:32])[CH2:29][C@@H:28](OS(C3C=CC=CC=3)(=O)=O)[CH2:27]2)=[O:25])[CH2:22][CH2:21]1)#[N:19].CC(C)([O-])C.[Li+].O>C1COCC1.C1(C)C=CC=CC=1>[C:18]([C:20]1([NH:23][C:24]([C@@H:26]2[CH2:27][C@@H:28]([S:11][C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:16])[F:17])=[CH:6][C:7]=3[C:12]([F:13])([F:14])[F:15])[CH2:29][N:30]2[C:31]([C:33]2([CH3:36])[CH2:35][CH2:34]2)=[O:32])=[O:25])[CH2:21][CH2:22]1)#[N:19]

Participants

7

Reactant 4

HCID 962WaterHCID 236647642-Propanol, 2-methyl-, lithium salt (1:1)HCID 86684908HCID 86684908, compoundHCID 86684918HCID 86684918, compound

Product 1

HCID 86684919HCID 86684919, compoundYield 95.7%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred suspension of 4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenethiol (30.4 g, 110 mmol) and benzenesulfonate (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-methyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (41.7 g, 100 mmol) in THF (50 mL) was added at room temperature 20% lithium tert-butoxide in THF (44.0 g≅49.5 mL, 110 mmol) over 40 min. After stirring at room temperature for 18 h, the reaction mixture was hydrolyzed with deionized water (400 mL) and extracted twice with ethyl acetate (400 mL & 200 mL). Both organic layers were washed with 10% brine (200 mL), combined, dried over Na2SO4, and filtered. Evaporation of the solvent and careful drying (45° C./≧10 mbar) gave 56.3 g crude product as voluminous, off-white foam, which was dissolved in 250 mL toluene at 50° C. The crystallization, which started during cooling, was completed after stirring at room temperature for 1 h by the dropwise addition of 200 mL heptane (note 11), followed by stirring at room temperature for 20 h. Filtration and drying (50° C./10 mbar/3 days for removal of toluene to ˜1%) yielded 51.2 g (95.7%) title product as an off-white crystalline powder, mp. 66-76° C. [α]D20=−67.5 (c 1.0; CHCl3). 1H NMR (CDCl3, 400 MHz) δ0.55-0.70 (m, 2H), 0.87-0.95 (m, 1H), 1.02-1.10 (m, 1H), 1.13-1.23 (m, 2H), 1.31 (s, 3H), 1.42-1.55 (m, 2H), 1.85-1.97 (m, 1H), 2.74-2.85 (m, 1H), 3.80-4.00 (m, 3H), 4.40 (q, J=7.8 Hz, 2H), 4.60 (dd, J1=8.1 Hz, J2=4.6 Hz, 1H), 7.11 (dd, J1=8.6 Hz, J2=2.7 Hz, 1H), 7.30 (d, J=3.0 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 8.05 (s, 1H).

Workup

  1. extractionextracted twice with ethyl acetate (400 mL & 200 mL)
  2. washBoth organic layers were washed with 10% brine (200 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. customEvaporation of the solvent
  6. customcareful drying (45° C./≧10 mbar)
  7. customgave 56.3 g crude product as voluminous, off-white foam, which
  8. customThe crystallization, which
  9. temperatureduring cooling
  10. stirringafter stirring at room temperature for 1 h by the dropwise addition of 200 mL heptane (note 11)
  11. stirringby stirring at room temperature for 20 h
  12. filtrationFiltration
  13. customdrying
  14. custom(50° C./10 mbar/3 days for removal of toluene to ˜1%)

Sources & evidence

ORD record
ord-c47cb555ba4348059473f0776ad42956
Source dataset
uspto-grants-2014_08
Patent number
US08796471B2

Reaction notes

Loading…