Water → HCID 67191222, compound

HRID 546245Notes

Reaction equation

HRID 546245 reaction equation
C[Si](C)(C)N[Si](C)(C)C.[OH:10][C@H:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:12]([N:14]([CH3:26])[C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=1)[CH3:13].C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:55][CH:56]3[CH2:60][CH2:59][CH2:58][CH2:57]3)=N2)C=1)(C)(C)C.O>O1CCCC1>[CH:56]1([CH2:55][C@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23][CH3:24])[CH:18]=2)[C:15]([N:14]([C@H:12]([CH3:13])[C@H:11]([OH:10])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])=[O:25])[CH2:60][CH2:59][CH2:58][CH2:57]1

Participants

6

Reactant 4

HCID 962WaterHCID 13838HexamethyldisilazaneHCID 67188009HCID 67188009, compoundHCID 67190452HCID 67190452, compound

Product 1

HCID 67191222HCID 67191222, compoundYield 58%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

To a solution of 1,1,1,3,3,3-Hexamethyldisilazane (1.81 g, 11.19 mmol) in tetrahydrofuran (15 mL) cooled to −20° C. under nitrogen was added n-butylithium (6.4 mL of a 1.6 M solution, 10.21 mmol) slowly keeping the temperature at −20° C. for 30 min. N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methylsulfanyl-phenyl)-acetamide (1.60 g, 4.86 mmol) in tetrahydrofuran (15 mL) was added slowly to the reaction maintaining the temperature at −20° C. After the addition was complete the reaction was warmed to 0° C. and stirred for 30 min. A solution of 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.31 g, 10.21 mmol) and iodomethylcyclopentane (prepared in PCT WO2004/052869 A1 Example 1, 1.23 g, 5.84 mmol) were added to the reaction at 0° C. and stirring continued for 3 h. The reaction was poured into water (60 mL) and extracted with ethyl acetate. The ethyl acetate fractions were washed with water, 2 N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride solution and then dried over magnesium sulfate. Filtration and concentration afforded the crude product which was purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) to yield (R)-3-cyclopentyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methylsulfanyl-phenyl)-propionamide (1.16 g, 58%) as a clear sticky solid.

Workup

  1. customat −20° C.
  2. customfor 30 min
  3. additionAfter the addition
  4. temperaturewas warmed to 0° C.
  5. stirringstirring
  6. waitcontinued for 3 h
  7. extractionextracted with ethyl acetate
  8. washThe ethyl acetate fractions were washed with water, 2 N aqueous hydrochloric acid solution, saturated sodium bicarbonate and saturated sodium chloride solution
  9. dry with materialdried over magnesium sulfate
  10. filtrationFiltration and concentration
  11. customafforded the crude product which
  12. customwas purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-c7716e87da824991bcf4a81db98a7cd5
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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