Cesium carbonate → 3-{3-[2-[Tert-butoxycarbonylimino]-3-(3-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-2,3-dihydro-benzoimidazol-1-yl]-propoxy)-benzoic acid

HRID 410370Notes

Reaction equation

HRID 410370 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[C:7]1=[N:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].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:85][C:86]1[CH:91]=[CH:90][C:89]([C:92]2[CH2:97][CH2:96][C:95]([CH3:99])([CH3:98])[CH2:94][C:93]=2[CH2:100][N:101]2[CH2:106][CH2:105][NH:104][CH2:103][CH2:102]2)=[CH:88][CH:87]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:32]([O:31][C:29]([N:28]=[C:7]1[N:8]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]1[CH2:5][C:4]1[CH:36]=[CH:37][CH:38]=[C:2]([N:104]2[CH2:103][CH2:102][N:101]([CH2:100][C:93]3[CH2:94][C:95]([CH3:99])([CH3:98])[CH2:96][CH2:97][C:92]=3[C:89]3[CH:90]=[CH:91][C:86]([Cl:85])=[CH:87][CH:88]=3)[CH2:106][CH2:105]2)[CH:3]=1)=[O:30])([CH3:34])([CH3:35])[CH3:33]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-2×HCID 585649441-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazineHCID 674283863-(3-{3-(3-Bromo-benzyl)-2-[tert-butoxycarbonylimino]-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid

Product 1

HCID 674299233-{3-[2-[Tert-butoxycarbonylimino]-3-(3-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-2,3-dihydro-benzoimidazol-1-yl]-propoxy)-benzoic acid

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst2×HCID 1140TolueneSolvent2×

Conditions

Temperature
95 °C

Procedure

To a degassed solution of 3-(3-{3-(3-bromo-benzyl)-2-[tert-butoxycarbonylimino]-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid (0.15 g, 0.25 mmol) in toluene (2 ml) at rt under nitrogen was added Pd(OAc)2 (5 mg, 0.12 mmol) and BINAP (30 mg, 0.048 mmol). Nitrogen was bubbled through the mixture for 10 min before a degassed solution of 1-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazine (90 mg, 0.28 mmol) in toluene (1 ml) was introduced. After 5 min Cs2CO3 (0.84 g, 2.58 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 3 h. After this time, the reaction was cooled to rt and additional Pd(OAc)2 (5 mg, 0.12 mmol) and BINAP (30 mg, 0.048 mmol) were introduced. The reaction was then heated to 95° C. where it was maintained for a further 2 h. After this time, the reaction was cooled to rt and filtered through Celite®. The collected solids were washed with dichloromethane and the combined filtrate and washings were concentrated under reduced pressure. The crude product 3-{3-[2-[tert-butoxycarbonylimino]-3-(3-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid (290 mg) was used in the next step without further purification. HPLC-MS 818, 820 [M+1]+.

Workup

  1. additionwas introduced
  2. customDuring all additions nitrogen was continuously bubbled through the reaction
  3. customwas sealed
  4. temperaturewas maintained for 3 h
  5. temperatureAfter this time, the reaction was cooled to rt
  6. temperatureThe reaction was then heated to 95° C. where it
  7. temperaturewas maintained for a further 2 h
  8. temperatureAfter this time, the reaction was cooled to rt
  9. filtrationfiltered through Celite®
  10. washThe collected solids were washed with dichloromethane
  11. concentrationthe combined filtrate and washings were concentrated under reduced pressure
  12. customThe crude product 3-{3-[2-[tert-butoxycarbonylimino]-3-(3-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid (290 mg) was used in the next step without further purification

Sources & evidence

ORD record
ord-55239517c1a5441c99293ed54479d831
Source dataset
uspto-grants-2014_06
Patent number
US08759520B2

Reaction notes

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