Sodium Carbonate → tert-butyl (R)-1-(biphenyl-4-yl)-4-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate

HRID 1096609Notes

Reaction equation

HRID 1096609 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[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[C:29]([Cl:33])=[CH:30][CH:31]=[CH:32][C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[C:42]1(B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.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:2]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[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[C:29]([Cl:33])=[CH:30][CH:31]=[CH:32][C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 66827Phenylboronic AcidHCID 66791528tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate

Product 1

HCID 66791486tert-butyl (R)-1-(biphenyl-4-yl)-4-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate

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-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (31A) (0.111 mmol max, crude oil) and phenylboronic acid (0.144 mmol, 0.018 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 in aqueous solution) 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 (gradient 25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(biphenyl-4-yl)-4-((R)-3-(7-chloro-1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (31B) as a clear oil. ESI-MS: m/z 645.5 (M+H)+.

Workup

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

Sources & evidence

ORD record
ord-398c071e3319498986b39ad0ad08f898
Source dataset
uspto-grants-2012_03
Patent number
US08138168B1

Reaction notes

Loading…