4-Methylmorpholine → HCID 66640695, compound

HRID 1094745Notes

Reaction equation

HRID 1094745 reaction equation
CO[C:3]([C:5]1[S:6][C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[N:19]([CH:24]([CH3:26])[CH3:25])[C:20]([CH3:23])=[N:21][CH:22]=3)[CH:15]=[CH:14][N:13]=2)=[C:8]([CH3:10])[CH:9]=1)=[O:4].[OH-].[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:53]([O:57][C:58](=[O:74])[NH:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)=[CH:62][C:61]=1[NH2:73])([CH3:56])([CH3:55])[CH3:54].CN1CCOCC1>CO.C1COCC1.CN(C=O)C.O.C(#N)C>[C:53]([O:57][C:58](=[O:74])[NH:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:67]=[CH:68][C:69]([F:72])=[CH:70][CH:71]=2)=[CH:62][C:61]=1[NH:73][C:3]([C:5]1[S:6][C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[N:19]([CH:24]([CH3:26])[CH3:25])[C:20]([CH3:23])=[N:21][CH:22]=3)[CH:15]=[CH:14][N:13]=2)=[C:8]([CH3:10])[CH:9]=1)=[O:4])([CH3:56])([CH3:54])[CH3:55]

Participants

10

Reactant 5

HCID 79724-MethylmorpholineHCID 14798Sodium HydroxideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59737201Tert-butyl (3-amino-4'-fluoro-[1,1'-biphenyl]-4-YL)carbamateHCID 66639925HCID 66639925, compound

Product 1

HCID 66640695HCID 66640695, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 21899815MeOH tetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To the above ester in MeOH/THF (10:5) (15 mL) was added 3N NaOH (5.0 mL) and stirred at 60° C. After 14 hours. The reaction mixture was concentrated, diluted with water and washed with ether (30 mL). The aqueous phase was then neutralized with 6 N HCl (1.5 mL), extracted with ethyl acetate, and then dried (MgSO4). Filtration and concentration gave the acid which was used further without purification. MS found for C17H19N5O2S as (M+H)+ 358.24. To the above acid (70 mg, 0.2 mmol) in DMF (2 mL), was added HATU (114 mg, 0.3 mmol), (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester (118 mg, 0.4 mmol) and NMM (0.1 mL, 0.78 mmol) and stirred at 50° C. for 16 hours. The reaction mixture was diluted with water and acetonitrile. The resulting solid was filtered, washed with water, and dried to give [4′-fluoro-3-({5-[4-(3-isopropyl-2-methyl-3H-imidazol-4-yl)-pyrimidin-2-ylamino]-4-methyl-thiophene-2-carbonyl}-amino)-biphenyl-4-yl]-carbamic acid tert-butyl ester. MS found for C34H36FN7O3S as (M+H)+ 642.02.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. additiondiluted with water
  3. washwashed with ether (30 mL)
  4. extractionextracted with ethyl acetate
  5. dry with materialdried (MgSO4)
  6. filtrationFiltration and concentration
  7. customgave the acid which
  8. customwas used further without purification
  9. stirringstirred at 50° C. for 16 hours
  10. filtrationThe resulting solid was filtered
  11. washwashed with water
  12. customdried

Sources & evidence

ORD record
ord-487168fdb9354bb19a5881958a48710d
Source dataset
uspto-grants-2012_03
Patent number
US08134000B2

Reaction notes

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