Cesium carbonate → 1-{3-[3-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-3-(4-fluoro-phenoxy)-propan-2-ol

HRID 410373Notes

Reaction equation

HRID 410373 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][CH:16]([OH:26])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:7]1=[NH:27].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:77]1([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[CH2:83][N:84]1[CH2:89][CH2:88][NH:87][CH2:86][CH2:85]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:77]1([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[CH2:83][N:84]1[CH2:85][CH2:86][N:87]([C:2]2[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=2)[CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]([CH2:15][CH:16]([OH:26])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:7]2=[NH:27])[CH2:88][CH2:89]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 183819371-Biphenyl-2-ylmethyl-piperazineHCID 462412121-[3-(3-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-3-(4-fluoro-phenoxy)-propan-2-ol

Product 1

HCID 585649711-{3-[3-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-3-(4-fluoro-phenoxy)-propan-2-olYield 7.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent2×

Conditions

Temperature
95 °C

Procedure

To a degassed solution of 1-[3-(3-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-3-(4-fluoro-phenoxy)-propan-2-ol (0.100 g, 0.21 mmol) in toluene (3 ml) at rt under nitrogen was added Pd(OAc)2 (1 mg, 4.45 μmop and BINAP (5 mg, 8.03 μmol). Nitrogen was bubbled through the mixture for 10 min before a degassed solution of 1-biphenyl-2-ylmethyl-piperazine (64 mg, 0.25 mmol) in toluene (1 ml) was introduced. After 5 min Cs2CO3 (1.39 g, 4.27 mmol) was added. During all additions nitrogen was continuously bubbled through the reaction. Once the additions were completed the reaction vessel was sealed and then heated to 95° C. where it was maintained for 1d. After this time, the reaction was cooled to rt and additional Pd(OAc)2 (1 mg, 4.45 □mol) and BINAP (5 mg, 8.03 □mol) were added. The reaction was then returned to 95° C. where it was maintained for 3 d. The suspension was then cooled to rt, filtered through Celite® and the collected solids were washed with dichloromethane. The combined filtrate and washings were concentrated under reduced pressure and the crude product was purified by preparative HPLC twice. The purified product was partitioned between a saturated solution of NaHCO3 and dichloromethane and the organic phase was separated. The aqueous layer was extracted with additional dichloromethane and then the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-{3-[3-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-3-(4-fluoro-phenoxy)-propan-2-ol (10 mg, 7%). HPLC-MS 642 [M+1]+, 322.

Workup

  1. additionwas introduced
  2. customDuring all additions nitrogen was continuously bubbled through the reaction
  3. customwas sealed
  4. temperaturewas maintained for 1d
  5. temperatureAfter this time, the reaction was cooled to rt
  6. additionadditional Pd(OAc)2 (1 mg, 4.45 □mol) and BINAP (5 mg, 8.03 □mol) were added
  7. customwas then returned to 95° C.
  8. temperaturewas maintained for 3 d
  9. temperatureThe suspension was then cooled to rt
  10. filtrationfiltered through Celite®
  11. washthe collected solids were washed with dichloromethane
  12. concentrationThe combined filtrate and washings were concentrated under reduced pressure
  13. customthe crude product was purified by preparative HPLC twice
  14. customThe purified product was partitioned between a saturated solution of NaHCO3 and dichloromethane
  15. customthe organic phase was separated
  16. extractionThe aqueous layer was extracted with additional dichloromethane
  17. washthe combined organic fractions were washed with brine
  18. dry with materialdried (Na2SO4)
  19. filtrationfiltered
  20. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-389964cd22d9448eaabdd076fc2064a6
Source dataset
uspto-grants-2014_06
Patent number
US08759520B2

Reaction notes

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