4-Methylmorpholine → (S)-tert-butyl 1-(3-bromo-2-(5-fluoropyridin-3-ylamino)phenylamino)-1-oxopropan-2-ylcarbamate

HRID 2036665Notes

Reaction equation

HRID 2036665 reaction equation
[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[Br:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([NH2:44])[C:35]=1[NH:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([F:43])[CH:42]=1.[NH4+].[Cl-]>C(Cl)Cl>[Br:29][C:30]1[C:35]([NH:36][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([F:43])[CH:42]=2)=[C:34]([NH:44][C:4](=[O:6])[C@@H:2]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:3])[CH:33]=[CH:32][CH:31]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 25517Ammonium ChlorideHCID 62365Isobutyl chloroformateHCID 85082Tert-butoxycarbonylalanineHCID 584592496-bromo-N1-(5-fluoropyridin-3-yl)benzene-1,2-diamine

Product 1

HCID 58459349(S)-tert-butyl 1-(3-bromo-2-(5-fluoropyridin-3-ylamino)phenylamino)-1-oxopropan-2-ylcarbamate

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-10 °C

Procedure

To a −10° C. solution (NaCl-ice bath) of Boc-L-Ala-OH (6.36 g, 33.6 mmol) and N-methylmorpholine (3.88 mL, 35.3 mmol) in DCM (84 mL) was added isobutyl chloroformate (4.40 mL, 33.6 mmol). The resulting cloudy colorless mixture was stirred at −10° C. for 30 min. To the mixture was then added a solution of 6-bromo-N1-(5-fluoropyridin-3-yl)benzene-1,2-diamine (4.7437 g, 16.81 mmol) in DCM (84 mL). The resulting mixture was allowed to warm to rt with stirring. After 20 h, satd. NH4Cl (100 mL) was added to the mixture. The cloudy organic layer was separated. The aqueous mixture was extracted with DCM (1×100 mL) and the organic extracts concentrated in vacuo to provide a crude product. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (120 g), eluting with a gradient of 0% to 100% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide (S)-tert-butyl 1-(3-bromo-2-(5-fluoropyridin-3-ylamino)phenylamino)-1-oxopropan-2-ylcarbamate as orange solid: LC-MS (ESI) m/z 453.0 [M+H (79Br)]+ and 455.0 [M+H (81Br)]+.

Workup

  1. temperatureto warm to rt
  2. stirringwith stirring
  3. waitAfter 20 h
  4. customThe cloudy organic layer was separated
  5. extractionThe aqueous mixture was extracted with DCM (1×100 mL)
  6. concentrationthe organic extracts concentrated in vacuo
  7. customto provide a crude product
  8. customThe crude material was absorbed onto a plug of silica gel
  9. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (120 g)
  10. washeluting with a gradient of 0% to 100% DCM:MeOH:NH4OH (89:9:1) in DCM

Sources & evidence

ORD record
ord-b10979eb36814a0ab61c4a8fd30cca31
Source dataset
uspto-grants-2013_11
Patent number
US08575183B2

Reaction notes

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