Dimethylformamide → HCID 71667529, compound

HRID 1481862Notes

Reaction equation

HRID 1481862 reaction equation
[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[C:9]2=[O:12])=[CH:4][C:3]=1[N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:24][CH2:23]1.CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:73]1([C:76]2[O:77][CH:78]=[C:79]([C:81](O)=[O:82])[N:80]=2)[CH2:75][CH2:74]1>O.C(OCC)(=O)C>[O:12]=[C:9]1[C:10]2[C:5](=[CH:4][C:3]([N:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])[CH2:26][CH2:27]3)=[C:2]([NH:1][C:81]([C:79]3[N:80]=[C:76]([CH:73]4[CH2:75][CH2:74]4)[O:77][CH:78]=3)=[O:82])[CH:11]=2)[CH2:6][CH2:7][N:8]1[CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21]

Participants

8

Reactant 5

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 252192732-Cyclopropyl-1,3-oxazole-4-carboxylic acidHCID 89692879HCID 89692879, compound

Product 1

HCID 71667529HCID 71667529, compoundYield 10%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a 40 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 7-amino-2-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-6-(4-o-tolyl-piperazin-1-yl)-3,4-dihydro-2H-isoquinolin-1-one 10d (48.10 mg, 0.10 mmol) was taken up in clean, dry N,N-dimethylformamide (2.00 ml, 25.83 mmol) and the mixture was stirred at room temperature and under an inert nitrogen atmosphere until all solids were in solution. To this was added the HATU (47.50 mg, 0.12 mmol) followed by the N,N-diisopropylethylamine (0.04 ml, 0.23 mmol) and the mixture was stirred until all solids were in solution. The reaction mixture was allowed to stir for 15 min and then the 2-cyclopropyl-oxazole-4-carboxylic acid 1h (20.70 mg, 0.14 mmol) was added in one portion. The reaction was then allowed to stir overnight at room temperature. The reaction was diluted with 10 ml of water and 10 ml of ethyl acetate. The layers were separated and the product was extracted from the aqueous with ethyl acetate (3×15 ml). The organic phases were combined, washed with brine (1×25 ml) and then with saturated lithium chloride aqueous solution (2×15 ml). The organic solution was then dried over Na2SO4; the solution was then decanted and the solvent was removed under reduced pressure. The product was purified using silica gel column chromatography, eluting with a gradient of 100% dichloromethane to 7.5% MeOH in dichloromethane. A secondary purification was undertaken using reverse-phase prep HPLC, eluting a gradient of 30% MeOH in water to 100% MeOH over a five minute period. The product, 2-cyclopropyl-oxazole-4-carboxylic acid [1-oxo-2-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-6-(4-o-tolyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide 10e (6.10 mg, 0.01 mmol), was isolated as a slightly off-white solid.

Workup

  1. customIn a 40 ml scintillation vial equipped with a magnetic stir bar
  2. customfitted with a nitrogen inlet
  3. stirringthe mixture was stirred until all solids
  4. stirringto stir for 15 min
  5. stirringto stir overnight at room temperature
  6. customThe layers were separated
  7. extractionthe product was extracted from the aqueous with ethyl acetate (3×15 ml)
  8. washwashed with brine (1×25 ml)
  9. dry with materialThe organic solution was then dried over Na2SO4
  10. customthe solution was then decanted
  11. customthe solvent was removed under reduced pressure
  12. customThe product was purified
  13. washeluting with a gradient of 100% dichloromethane to 7.5% MeOH in dichloromethane
  14. customA secondary purification
  15. washeluting a gradient of 30% MeOH in water to 100% MeOH over a five minute period

Sources & evidence

ORD record
ord-236834f2d980448e9ff43abd81a57748
Source dataset
uspto-grants-2016_08
Patent number
US09409897B2

Reaction notes

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