Benzyl Alcohol → (2R,4R)-4-[(3-Acetoxymethoxy-3H-benzotriazole-5-carbonyl)amino]-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic Acid

HRID 516450Notes

Reaction equation

HRID 516450 reaction equation
Cl.O1CCOCC1.[Cl:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([NH:29][C:30]([C:32]3[CH:41]=[CH:40][C:35]4[N:36]=[N:37][N:38]([OH:39])[C:34]=4[CH:33]=3)=[O:31])[CH2:23][C@@H:24]([OH:28])[C:25]([OH:27])=[O:26])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O)C1C=CC=CC=1.[C:50]([O:53][CH2:54]Br)(=[O:52])[CH3:51].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.CO>[Pd]>[C:50]([O:53][CH2:54][O:39][N:38]1[C:34]2[CH:33]=[C:32]([C:30]([NH:29][C@H:22]([CH2:21][C:18]3[CH:17]=[CH:16][C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=4)=[CH:20][CH:19]=3)[CH2:23][C@@H:24]([OH:28])[C:25]([OH:27])=[O:26])=[O:31])[CH:41]=[CH:40][C:35]=2[N:36]=[N:37]1)(=[O:52])[CH3:51]

Participants

10

Reactant 8

HCID 244Benzyl AlcoholHCID 313Hydrochloric AcidHCID 887MethanolHCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 68536Bromomethyl acetateHCID 67970017(2R,4R)-5-(3'-Chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl)amino]pentanoic Acid

Product 1

HCID 72203605(2R,4R)-4-[(3-Acetoxymethoxy-3H-benzotriazole-5-carbonyl)amino]-5-(3'-chlorobiphenyl-4-yl)-2-hydroxypentanoic AcidYield 9.4%

Reagents, catalysts & solvents 1

HCID 23938PalladiumCatalyst

Conditions

Temperature
60 °C

Procedure

4.0 M HCl in 1,4-dioxane (270 mL, 1.1 mmol) was added to a solution of (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl)amino]pentanoic acid (130 mg, 270 μmol) in benzyl alcohol (559 μL, 5.4 mmol), and stirred at 60° C. for 1.5 hours. The mixture was then purified (C18 column chromatography, 55 g column, using 30-90% MeCN in water with 0.05% TFA) to yield an off-white solid. Bromomethyl acetate (45.5 mg, 297 μmol) was added to a solution of this off-white solid and K2CO3 (82.2 mg, 595 μmol) in DMF (3.1 mL, 40.0 mmol) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then purified (column chromatography, small column, using 40-90% MeCN in water with 0.05% TFA) to yield a clear colorless viscous liquid. 10% Pd/C, 50% wet (0.45 mmol/g loading; 30.0 mg, 13.5 μmol) was added to a solution of this clear colorless viscous liquid in MeOH (4.1 mL, 102 mmol) and the resulting mixture was stirred under hydrogen for 30 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to yield a clear colorless liquid. The crude liquid was purified (C18 column chromatography, 55 g column, using 30-85% MeCN in water with 0.05% TFA) to yield the title compound (14.0 mg) as a white solid. MS m/z [M+H]+ calc'd for C27H25ClN4O7, 553.14. found 553.1.

Workup

  1. customThe mixture was then purified (C18 column chromatography, 55 g column, using 30-90% MeCN in water with 0.05% TFA)
  2. customto yield an off-white solid
  3. stirringthe resulting mixture was stirred at room temperature for 1 hour
  4. customThe mixture was then purified (column chromatography, small column, using 40-90% MeCN in water with 0.05% TFA)
  5. customto yield a clear colorless viscous liquid
  6. stirringthe resulting mixture was stirred under hydrogen for 30 minutes
  7. filtrationThe mixture was filtered
  8. concentrationthe filtrate was concentrated in vacuo
  9. customto yield a clear colorless liquid
  10. customThe crude liquid was purified (C18 column chromatography, 55 g column, using 30-85% MeCN in water with 0.05% TFA)

Sources & evidence

ORD record
ord-06fb4f23f1b042aba12f4f05e0a7ec0b
Source dataset
uspto-grants-2015_08
Patent number
US09108934B2

Reaction notes

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