Cesium carbonate → (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

HRID 575268Notes

Reaction equation

HRID 575268 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:16]Cl)=[C:13](I)[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:19][C:20]1[NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=1.[C:29]([O-:32])([O-])=O.[Cs+].[Cs+].BrC1C=CC2OCC[N:42]3C(CN4C5C=CC=CC=5N=C4C)=C(I)N=C3C=2C=1.C[Si](N[Si](C)(C)C)(C)C.[CH3:71][C:72]1[O:76][N:75]=[C:74]([C@:77]([OH:81])([C:79]#[CH:80])[CH3:78])[CH:73]=1>CN(C)C=O.O.CS(C)=O.BrC1C=CC2OCCN3C(CN4C5C=CC=CC=5N=C4C)=C(C(N)=O)N=C3C=2C=1.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].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:81][C@:77]([C:74]1[CH:73]=[C:72]([CH3:71])[O:76][N:75]=1)([CH3:78])[C:79]#[C:80][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:16][N:21]4[C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=[C:20]4[CH3:19])=[C:13]([C:29]([NH2:42])=[O:32])[N:14]=[C:7]3[C:6]=2[CH:18]=1

Participants

13

Reactant 6

HCID 10796Cesium carbonateHCID 119842-MethylbenzimidazoleHCID 13838HexamethyldisilazaneHCID 58221468(R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-olHCID 8669329310-Bromo-3-(chloromethyl)-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineHCID 8669329410-bromo-2-iodo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Product 1

HCID 86693292(R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamideYield 31%

Reagents, catalysts & solvents 6

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent2×HCID 8669328810-bromo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamideSolvent

Procedure

A mixture of 10-bromo-3-(chloromethyl)-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (200 mg, 0.46 mmol, 1.00 equiv), 2-methyl-1H-1,3-benzodiazole (304 mg, 2.30 mmol, 5.00 equiv), Cs2CO3 (450 mg, 1.38 mmol, 3.00 equiv) in N,N-dimethylformamide (2 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 140 mg (57%) of 10-bromo-2-iodo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine as a colorless solid. Similar to Example 10 (carbonylative amidation) a 20-mL sealed tube purged and maintained with an inert atmosphere of CO(g), was placed a solution of 10-bromo-2-iodo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (140 mg, 0.26 mmol, 1.00 equiv), HMDS (105 mg, 0.65 mmol, 2.50 equiv), Pd(dppf)Cl2 (21 mg, 0.10 equiv), and N,N-dimethylformamide (2 mL). The resulting solution was heated to 70° C. for 4 h and diluted with water. Then the resulting solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 90 mg (76%) of 10-bromo-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide as a yellow solid. Similar to as described in General Procedure E with the exceptions of using Pd(PPh3)4 in DMSO, 10-bromo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give the titled compound as a yellow solid (29 mg, 31%).

Workup

  1. extractionextracted with ethyl acetate
  2. dry with materialdried over anhydrous sodium sulfate
  3. concentrationconcentrated under vacuum
  4. customThis resulted in 140 mg (57%) of 10-bromo-2-iodo-3((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine as a colorless solid
  5. customSimilar to Example 10 (carbonylative amidation) a 20-mL sealed tube
  6. custompurged
  7. temperaturemaintained with an inert atmosphere of CO(g)
  8. temperatureThe resulting solution was heated to 70° C. for 4 h
  9. extractionThen the resulting solution was extracted with ethyl acetate
  10. dry with materialdried over anhydrous sodium sulfate
  11. concentrationconcentrated under vacuum
  12. customThis resulted in 90 mg (76%) of 10-bromo-3-((2-methyl-1H-benzo[d]imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide as a yellow solid

Sources & evidence

ORD record
ord-67a671aa80da4c0496788da7072b1988
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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