Sodium Carbonate → 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

HRID 1096645Notes

Reaction equation

HRID 1096645 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]3[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]4[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44].O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:36]([O:35][C:34]([NH:33][C@@H:9]([CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]3[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=3[N:20]=2)[CH2:14]1)=[O:12])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:48]2[CH:49]=[CH:50][C:45]([C:43]([O:42][CH3:41])=[O:44])=[CH:46][CH:47]=2)=[CH:3][CH:4]=1)=[O:40])([CH3:39])([CH3:38])[CH3:37]

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 27343694-Methoxycarbonylphenylboronic acidHCID 66791560tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate

Product 1

HCID 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-carboxylateYield 70%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent

Conditions

Temperature
120 °C

Procedure

tert-Butyl (R)-1-(4-bromophenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (6A) (as prepared in Example 6, Step A) (0.114 mmol, 0.070 g) and 4-(methoxycarbonyl)phenylboronic acid (0.148 mmol, 0.027 g) were added to a 5 mL microwave vessel equipped with a magnetic stir bar. Dioxane (2 mL) and Na2CO3 (1 mL of a 2 M aq. soln.) were then added and the reaction vessel was flushed with nitrogen gas. PdCl2(dppf) (0.006 mmol, 0.004 g) was added, the reaction vessel was sealed and placed in a microwave reactor and heated to 120° C. for 15 minutes. The reaction solution was then poured into water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo. This crude material was directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording 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) as a clear oil. (0.08 mmol, 0.054 g, 70% yield). ESI-MS: m/z 669.4 (M+H)+.

Workup

  1. customequipped with a magnetic stir bar
  2. addition) were then added
  3. customthe reaction vessel was flushed with nitrogen gas
  4. customthe reaction vessel was sealed
  5. customplaced in a microwave reactor
  6. extractionextracted with ethyl acetate
  7. washwashed once with saturated aqueous sodium chloride
  8. customThe organic layer was collected
  9. dry with materialsubsequently dried with anhydrous Na2SO4
  10. filtrationfiltered
  11. customThis filtrate was collected
  12. concentrationconcentrated
  13. customdried in-vacuo
  14. customThis crude material was directly purified by preparative LC/MS (25-85% CH3CN in H2O)
  15. customThe resultant fractions were collected
  16. customthe solvent was removed in-vacuo

Sources & evidence

ORD record
ord-c3320fe5f9a849be8a28ecd8fea0f6e3
Source dataset
uspto-grants-2012_03
Patent number
US08138168B1

Reaction notes

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