Cesium carbonate → 3-[3-(3-{4-[4-(4'-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester

HRID 410367Notes

Reaction equation

HRID 410367 reaction equation
Br.[CH2:2]([O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=3)[C:17]2=[NH:33])[CH:7]=1)[CH3:3].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.[Cl:81][C:82]1[CH:87]=[CH:86][C:85]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][C:89]=2[CH2:94][N:95]2[CH2:100][CH2:99][NH:98][CH2:97][CH2:96]2)=[CH:84][CH:83]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:2]([O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N:98]4[CH2:97][CH2:96][N:95]([CH2:94][C:89]5[CH:90]=[CH:91][CH:92]=[CH:93][C:88]=5[C:85]5[CH:86]=[CH:87][C:82]([Cl:81])=[CH:83][CH:84]=5)[CH2:100][CH2:99]4)=[CH:28][CH:27]=3)[C:17]2=[NH:33])[CH:7]=1)[CH3:3]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 178344231-((4'-Chlorobiphenyl-2-yl)methyl)piperazineHCID 1317316403-{3-[3-(4-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid ethyl ester, hydrobromide salt

Product 1

HCID 462412113-[3-(3-{4-[4-(4'-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl esterYield 61%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent2×

Conditions

Temperature
95 °C

Procedure

To a degassed solution of 3-{3-[3-(4-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid ethyl ester, hydrobromide salt (0.2 g, 0.34 mmol) in anhydrous toluene (3 ml) was added Pd(OAc)2 (33 mg, 0.077 mmol). Nitrogen was bubbled through the suspension for 10 min before BINAP (49 mg, 0.079 mmol) was added. After a further 2 min 1-(4′-chloro-biphenyl-2-ylmethyl)-piperazine (112 mg, 0.39 mmol) in degassed toluene (3 ml) was introduced and then after an additional 2 min Cs2CO3 (2.5 g, 7.69 mmol) was added and the reaction was stirred for 2 min. Throughout all of the additions nitrogen was continuously bubbled through the reaction mixture. The reaction was then sealed and heated to 95° C. where it was maintained for 5 h. After this time, the reaction was cooled to rt and filtered through Celite®. The collected solids were washed with additional dichloromethane and then the combined filtrate and washings were concentrated under reduced pressure to give the crude product. Purification by chromatography on silica eluting with 5% MeOH/dichloromethane provided 3-[3-(3-{4-[4-(4′-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzyl}-2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester (147 mg, 61%). HPLC-MS 715 [M+1]+, 358.

Workup

  1. additionwas added
  2. customThroughout all of the additions nitrogen was continuously bubbled through the reaction mixture
  3. customThe reaction was then sealed
  4. temperaturewas maintained for 5 h
  5. temperatureAfter this time, the reaction was cooled to rt
  6. filtrationfiltered through Celite®
  7. washThe collected solids were washed with additional dichloromethane
  8. concentrationthe combined filtrate and washings were concentrated under reduced pressure
  9. customto give the crude product
  10. customPurification by chromatography on silica eluting with 5% MeOH/dichloromethane

Sources & evidence

ORD record
ord-2e06831ac45a492a9881d87ebe8543ea
Source dataset
uspto-grants-2014_06
Patent number
US08759520B2

Reaction notes

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