Water → HCID 54674830, compound

HRID 2095673Notes

Reaction equation

HRID 2095673 reaction equation
Br[C:2]1[C:3]([CH2:8]O)=[N:4][N:5]([CH3:7])[CH:6]=1.C1C=CC(OP(OC2C=CC=CC=2)([N:19]=[N+]=[N-])=O)=CC=1.N12CCCN=C1CCCCC2.C(Cl)Cl.[Cl:43][C:44]1[C:49]([F:50])=[CH:48][CH:47]=[C:46]([O:51][CH3:52])[C:45]=1[C@H:53]([C:55]1[C:63]2[C:58](=[N:59][CH:60]=[C:61](B3OC(C)(C)C(C)(C)O3)[CH:62]=2)[NH:57][CH:56]=1)[CH3:54].C([O-])([O-])=O.[K+].[K+].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N-]=[N+]=[N-]>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.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:43][C:44]1[C:49]([F:50])=[CH:48][CH:47]=[C:46]([O:51][CH3:52])[C:45]=1[C@H:53]([C:55]1[C:63]2[C:58](=[N:59][CH:60]=[C:61]([C:2]3[C:3]([CH2:8][NH2:19])=[N:4][N:5]([CH3:7])[CH:6]=3)[CH:62]=2)[NH:57][CH:56]=1)[CH3:54]

Participants

13

Reactant 9

HCID 962WaterHCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 11776TriphenylphosphineHCID 33558AzideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 123414Diphenylphosphoryl azideHCID 24229713(4-Bromo-1-methyl-1H-pyrazol-3-yl)methanolHCID 670040713-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

Product 1

HCID 54674830HCID 54674830, compound

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Procedure

A mixture of (4-bromo-1-methyl-1H-pyrazol-3-yl)methanol (100.0 mg, 0.5235 mmol), diphenylphosphonic azide (0.141 mL, 0.654 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.106 mL, 0.707 mmol) and DCM (5 mL, 80 mmol) was stirred at rt overnight. The solution was dried in vacuo, and 3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (15.0 mg, 0.0348 mmol), Pd(PPh3)4 (2 mg, 0.002 mmol), (1,1′bis-(diphenylphosphino)-ferrocene) palladium dichloride (2 mg, 0.003 mmol), K2CO3 (15.0 mg, 0.108 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) were added to the flask. The mixture was heated to 95° C. for 1 h. The reaction was cooled to 60° C., and PPh3 (30.0 mg, 0.114 mmol) was added. The solution was heated at 65° C. until all azide was reduced to the primary amine. The organic solvent was removed in vacuo, and the material was extracted with DCM and water at pH=2. The organic layer was removed, and the aq. layer was brought to pH=9 with sat. K2CO3. The material was extracted with DCM, and the organic layer concentrated in vacuo, redissolved in MeOH (1 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.83 (d, J=7.3 Hz, 3H), 3.69 (s, 3H), 3.96 (s, 3H), 4.09 (q, J=14.5 Hz, 2H), 5.09-5.17 (m, 1H), 6.92 (dd, J=9.1, 4.3 Hz, 1H), 7.12 (t, J=8.8 Hz, 1H), 7.40 (d, J=1.0 Hz, 1H), 7.47 (s, 1H), 7.74 (s, 1H), 8.13 (d, J=2.0 Hz, 1H). MS (ES+): m/z=414.02/416.01 (100/50) [MH+]. HPLC: tR=2.77 min (polar—5 min, ZQ3).

Workup

  1. temperatureThe mixture was heated to 95° C. for 1 h
  2. temperatureThe reaction was cooled to 60° C.
  3. customThe organic solvent was removed in vacuo
  4. extractionthe material was extracted with DCM and water at pH=2
  5. customThe organic layer was removed
  6. extractionThe material was extracted with DCM
  7. concentrationthe organic layer concentrated in vacuo
  8. dissolutionredissolved in MeOH (1 mL)
  9. custompurified via HPLC
  10. additionThe fractions containing the pure product
  11. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-bc0eaa10719542a3871df3447d9d55b9
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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