Lithium Hexamethyldisilazide → HCID 57513783, compound

HRID 2368442Notes

Reaction equation

HRID 2368442 reaction equation
CO[C:3](=[O:21])[C:4]([CH3:20])([NH:6][C:7]([N:9]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1)=[O:8])[CH3:5].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:32]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[N:42][C:41]([NH2:51])=[N:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[CH2:32]([N:39]1[C:43]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)=[N:42][C:41]([NH:51][C:3]([C:4]([NH:6][C:7]([N:9]2[CH2:13][CH2:12][C@H:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10]2)=[O:8])([CH3:5])[CH3:20])=[O:21])=[N:40]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1

Participants

5

Reactant 3

HCID 2733832Lithium Hexamethyldisilazide2×HCID 57435373HCID 57435373, compoundHCID 57513844HCID 57513844, compound

Product 1

HCID 57513783HCID 57513783, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Procedure

THF (3 mL) was added to a flask containing 2-methyl-2-[((R)-3-phenyl-pyrrolidine-1-carbonyl)-amino]-propionic acid methyl ester (100 mg, 0.344 mmol) at 0° C. under N2. In a dropwise fashion 1 M LiHMDS in THF (344 uL, 0.344 mmol) was added to the flask. Upon complete addition the reaction was allowed to warm to room temp. After 2.5 hr 1-benzyl-5-(4-fluorophenyl)-1H-1,2,4-triazol-3-amine (92 mg, 0.344 mmol) in THF (1 mL) was added to the reaction. The reaction was allowed to stir overnight. The next day more 1 M LiHMDS in THF (172 uL, 0.172 mmol) was added. The reaction was stirred an additional 5.5 hr before being quenched with sat. NH4Cl (10 mL). The reaction was diluted with EtOAc (60 mL) and extracted with water (5 mL). The organic phase was dried over Na2SO4 and the solvent evaporated. The residue was purified by silica gel chromatography (60-100 EtOAc/HEP) followed by HPLC (C18, 50-100% MeOH/H2O+5 mM NH4OH) to afford the title compound as a white solid: 1H NMR (400 MHz, DICHLOROMETHANE-d2) 1.58 (d, J=3.92 Hz, 6H) 2.01-2.15 (m, 1H) 2.25-2.36 (m, 1H) 3.36 (t, J=9.22 Hz, 1H) 3.40-3.53 (m, 2H) 3.62-3.70 (m, 1H) 3.87 (t, J=8.21 Hz, 1H) 4.74 (br. s., 1H) 5.44 (s, 2H) 7.19-7.36 (m, 9H) 7.36-7.44 (m, 3H) 7.62-7.70 (m, 2H) 10.76 (br. s., 1H); Rt (method A)=1.61 min (M+H)+=527.2.

Workup

  1. additionUpon complete addition the reaction
  2. stirringThe reaction was stirred an additional 5.5 hr
  3. custombefore being quenched with sat. NH4Cl (10 mL)
  4. additionThe reaction was diluted with EtOAc (60 mL)
  5. extractionextracted with water (5 mL)
  6. dry with materialThe organic phase was dried over Na2SO4
  7. customthe solvent evaporated
  8. customThe residue was purified by silica gel chromatography (60-100 EtOAc/HEP)

Sources & evidence

ORD record
ord-4e720b8288764c35adaf5704540280e0
Source dataset
uspto-grants-2014_04
Patent number
US08703761B2

Reaction notes

Loading…