Phenol → HCID 86723994, compound

HRID 1475379Notes

Reaction equation

HRID 1475379 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[CH:27]=[C:26](Cl)[N:25]=[CH:24][C:23]=3[C:22]([CH3:31])([CH3:30])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1([OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][O:15][CH3:16])[N:11]([CH2:17][C:18]([N:20]2[C:28]3[CH:27]=[C:26]([O:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:25]=[CH:24][C:23]=3[C:22]([CH3:31])([CH3:30])[CH2:21]2)=[O:19])[CH2:10][C@H:9]1[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 996PhenolHCID 62657Potassium Phosphate, TribasicHCID 11618717Di-tert-butyl(2',4',6'-tris(propan-2-yl)-(1,1'-biphenyl)-2-yl)phosphaneHCID 86723995HCID 86723995, compound

Product 1

HCID 86723994HCID 86723994, compoundYield 17%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

(2R,5R)-4-[2-(6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl)-2-oxo-ethyl]-5-methoxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.21 mol), phenol (24 mg, 0.206 mol), K3PO4 (96 mg, 0.43 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (3 mg, 0.01 mmol), Pd(OAc)2 were combined and slurried in toluene (0.714 mL). The reaction was degassed with nitrogen and heated to 100° C. After 18 h the reaction was cooled to RT. MeOH was added and the solution passed through a Phenomenex NH2 column, eluting with MeOH and then 2.0 M ammonia in MeOH to release the amine. The residue was purified by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), to give (75 mg). Further purification by preparative HPLC (basic method), gave the title compound (19 mg, 17%) as a colourless oil. 1H NMR (Me-d3-OD): 7.91 (1H, s), 7.51 (1H, s), 7.42 (2H, t), 7.22 (1H, t), 7.10 (2H, d), 4.22-4.12 (1H, m), 4.05 (2H, q), 3.95 (1H, d), 3.70 (1H, d), 3.60 (1H, dd), 3.52 (1H, d), 3.00 (1H, s), 2.85 (1H, dd), 2.64 (1H, dd), 1.48 (9H, s), 1.43 (6H, s), 1.22 (3H, d).

Workup

  1. customThe reaction was degassed with nitrogen
  2. temperatureAfter 18 h the reaction was cooled to RT
  3. additionMeOH was added
  4. washeluting with MeOH
  5. customThe residue was purified by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol)
  6. customto give (75 mg)
  7. customFurther purification by preparative HPLC (basic method)

Sources & evidence

ORD record
ord-7f87998052064adcbe289894cf0b9702
Source dataset
uspto-grants-2015_04
Patent number
US09018214B2

Reaction notes

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