4-Methylmorpholine → HCID 57856422, compound

HRID 2365469Notes

Reaction equation

HRID 2365469 reaction equation
Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:12][C:13]2[C:14]3[N:15]([CH:28]=[CH:29][N:30]=3)[CH:16]=[C:17]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)C(O)=O)[N:18]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][C:33]=1[CH3:42].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CC[O:74][CH2:73]C1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:12][C:13]2[C:14]3[N:15]([CH:28]=[CH:29][N:30]=3)[CH:16]=[C:17]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:73]([NH:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][C:33]=3[CH3:42])=[O:74])[N:18]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 2724699PyBOPHCID 2736799Methyl 4-amino-3-methylbenzoate2×HCID 69000368HCID 69000368, compound

Product 1

HCID 57856422HCID 57856422, compoundYield 36%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzoic acid hydrochloride salt (80 mg, 0.187 mmol), methyl 4-amino-3-methylbenzoate (46 mg, 0.281 mmol), benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (124 mg, 0.281 mmol) and 4-methylmorpholine (95 mg, 0.937 mmol) in DMF (1.5 mL) was stirred at ambient temperature for 18 h. The mixture was then stirred at 45° C. for 6 h before additional methyl 4-amino-3-methylbenzoate (46 mg, 0.281 mmol) was added and the resulting mixture was stirred at ambient temperature for 18 h. To the reaction mixture was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (97 mg, 0.187 mmol) and the resulting mixture was stirred at 45° C. for 18 h and then at ambient temperature for 6 d. After this time, the reaction was diluted with ethyl acetate (50 mL) and washed with water (30 mL) then 5% aqueous lithium chloride solution (30 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 39:1 methylene chloride/methanol) to afford methyl 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)-3-methylbenzoate (36 mg, 36%): ESI MS m/z 538 [M+H]+.

Workup

  1. additionwas added
  2. stirringthe resulting mixture was stirred at ambient temperature for 18 h
  3. stirringthe resulting mixture was stirred at 45° C. for 18 h
  4. waitat ambient temperature for 6 d
  5. washwashed with water (30 mL)
  6. dry with materialThe organic layer was dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. customThe residue obtained
  10. customwas purified by chromatography (silica, methylene chloride to 39:1 methylene chloride/methanol)

Sources & evidence

ORD record
ord-302e5b86b6bd49a387aafd07c4bf2597
Source dataset
uspto-grants-2014_04
Patent number
US08697699B2

Reaction notes

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