Water → 2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(3,4'-difluoro-[1,1'-biphenyl]-4-yl)acetamide

HRID 1525898Notes

Reaction equation

HRID 1525898 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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].C(Cl)Cl.C(#N)C>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:32]5[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=5)=[CH:3][C:4]=4[F:27])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1

Participants

8

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 2856454-Fluorophenylboronic acidHCID 71271075HCID 71271075, compound

Product 1

HCID 712758162-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(3,4'-difluoro-[1,1'-biphenyl]-4-yl)acetamideYield 64.4%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 6342AcetonitrileSolventHCID 312751,4-DioxaneSolvent

Procedure

A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.341 mmol) in dry 1,4-dioxane (1.5 mL) was treated with (4-fluorophenyl)boronic acid (0.375 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.017 mmol) and 2M aq potassium carbonate (1.022 mmol). The solution was degassed with a stream of nitrogen for three minutes, at which point the reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min. The resulting black mixture was diluted with water (50 mL) and extracted three times with ethyl acetate. The combined organic layers were treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH) and by reverse phase HPLC (10-50% acetonitrile with 0.1% TFA/water with 0.1% TFA). Fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜10 with 30% w/v aq ammonium hydroxide. This mixture was concentrated to a minimal volume in vacuo and was then extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Lyophilization of the product from water (w/25% acetonitrile) afforded the title compound as a white solid (100 mg, 61% yield). MS(ES)+m/e 456.1 [M+H]+.

Workup

  1. customThe solution was degassed with a stream of nitrogen for three minutes, at which
  2. customwas purged with nitrogen
  3. customsealed
  4. customthe mixture irradiated in a Biotage Initiator Microwave at 120° C. for 15 min
  5. additionThe resulting black mixture was diluted with water (50 mL)
  6. extractionextracted three times with ethyl acetate
  7. additionThe combined organic layers were treated with Silicycle Si-thiol (20 mg)
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe crude material was purified by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH) and by reverse phase HPLC (10-50% acetonitrile with 0.1% TFA/water with 0.1% TFA)
  12. additionFractions containing the desired product
  13. concentrationThis mixture was concentrated to a minimal volume in vacuo
  14. extractionwas then extracted with dichloromethane three times
  15. dry with materialThe combined organic layers were dried over sodium sulfate
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-b34dd14012f14d0f80d8f10359f1bc3c
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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