4-Methylmorpholine → HCID 178454216, compound

HRID 1424187Notes

Reaction equation

HRID 1424187 reaction equation
[NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:26](O)=O)[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:51][C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][C:62]([C:65]#[N:66])=[C:61]([F:67])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[NH2:58]>C(#N)C>[C:65]([C:62]1[CH:63]=[CH:64][C:59]([C:54]2[CH:55]=[CH:56][C:57]3[NH:58][C:26]([C@@H:2]([NH:1][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[N:51][C:52]=3[CH:53]=2)=[CH:60][C:61]=1[F:67])#[N:66]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 11385960Boc-Asn(Trt)-OHHCID 866991143',4'-Diamino-3-fluoro-[1,1'-biphenyl]-4-carbonitrile

Product 1

HCID 178454216HCID 178454216, compoundYield 60%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a solution of Boc-Asn(Trt)-OH (100.4 mg, 0.2116 mmol) in acetonitrile (2.0 mL) cooled in an ice water bath was added 4-methylmorpholine (0.059 mL, 0.53 mmol) and isobutyl chloroformate (0.027 mL, 0.21 mmol). After stirring for 60 minutes, 3′,4′-diamino-3-fluoro-[1,1-biphenyl]-4-carbonitrile (Preparation 81, 42.7 mg, 0.188 mmol) was added and the mixture allowed to warm to room temperature. After stirring for 18 hours the reaction mixture was concentrated in vacuo and redissolved in acetic acid. After stirring at room temperature for 6.5 hours, the mixture was concentrated in vacuo, redissolved in ethyl acetate, washed with water, 0.5M HCl, and brine. The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (75 mg, 60%).

Workup

  1. stirringAfter stirring for 18 hours the reaction mixture
  2. concentrationwas concentrated in vacuo
  3. dissolutionredissolved in acetic acid
  4. stirringAfter stirring at room temperature for 6.5 hours
  5. concentrationthe mixture was concentrated in vacuo
  6. dissolutionredissolved in ethyl acetate
  7. washwashed with water, 0.5M HCl, and brine
  8. dry with materialThe organic layer was dried over anhydrous magnesium sulphate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified
  12. washeluting with a 0-100% ethyl acetate/hexanes gradient

Sources & evidence

ORD record
ord-501c3abc46dc40baa80d7dba3adde223
Source dataset
uspto-grants-2015_01
Patent number
US08927587B2

Reaction notes

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