Citric Acid → 4'-((R)-2-(tert-butoxycarbonylamino)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)biphenyl-4-carboxylic acid

HRID 1096648Notes

Reaction equation

HRID 1096648 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]2[N:40]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:39]3[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=3[N:37]=2)[CH2:31]1)=[O:29])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CC#N.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:27][C:28]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]2[N:40]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:39]3[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=3[N:37]=2)[CH2:31]1)=[O:29])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 4

HCID 311Citric AcidHCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 66784669methyl 4'-((R)-2-(tert-butoxycarbonylamino)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)biphenyl-4-carboxylate

Product 1

HCID 667848804'-((R)-2-(tert-butoxycarbonylamino)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)biphenyl-4-carboxylic acid

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent

Procedure

Methyl 4′-((R)-2-(tert-butoxycarbonylamino)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)biphenyl-4-carboxylate (53A) (prepared by the procedure for Example 53, Step A) (0.815 mmoles, 0.545 g) was added to a 25 mL round-bottomed flask equipped for stirring under nitrogen. Tetrahydrofuran (2 mL), methanol (1 mL), and LiOH (2.0 mmoles, 1.0 mL of 2N in H2O) were then added and the resultant solution was allowed to stir at room temperature for 16 hrs. Citric acid (2.09 mmoles, 0.403 g) in H2O (1 mL) was then added and the resultant solution was concentrated in-vacuo, filtered, and then purified by preparative LC/MS. The resultant fractions were collected and the solvent was removed in-vacuo affording a brown colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford 4′-((R)-2-(tert-butoxycarbonylamino)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutyl)biphenyl-4-carboxylic acid (86A) as a tan flocculent solid (0.637 mmoles, 0.417 g, 78% yield). ESI-MS: m/z 655.5 (M+H)+.

Workup

  1. additionwas added to a 25 mL round-bottomed flask
  2. customequipped
  3. stirringto stir at room temperature for 16 hrs
  4. concentrationthe resultant solution was concentrated in-vacuo
  5. filtrationfiltered
  6. custompurified by preparative LC/MS
  7. customThe resultant fractions were collected
  8. customthe solvent was removed in-vacuo
  9. customaffording a brown colored oil

Sources & evidence

ORD record
ord-ced6cff55ee64b72ac84af6ebeebd04c
Source dataset
uspto-grants-2012_03
Patent number
US08138168B1

Reaction notes

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