4-Methylmorpholine → HCID 22050071, compound

HRID 1831956Notes

Reaction equation

HRID 1831956 reaction equation
[CH3:1][O:2][CH2:3][C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.N=C=N.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:52]=[CH:53][CH:54]=1)[CH2:32][N:33]1[C:38]([CH3:39])=[CH:37][C:36]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=2[F:49])=[C:35]([Br:50])[C:34]1=[O:51].CN=C=O>CN(C)C=O.O1CCCC1>[Br:50][C:35]1[C:34](=[O:51])[N:33]([CH2:32][C:31]2[CH:30]=[C:29]([CH:54]=[CH:53][CH:52]=2)[CH2:28][NH:27][C:4](=[O:6])[CH2:3][O:2][CH3:1])[C:38]([CH3:39])=[CH:37][C:36]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[F:49]

Participants

9

Reactant 6

HCID 79724-MethylmorpholineHCID 12228Methyl IsocyanateHCID 12251Methoxyacetic AcidHCID 757711-HydroxybenzotriazoleHCID 160435CarbodiimideHCID 11155124HCID 11155124, compound

Product 1

HCID 22050071HCID 22050071, compoundYield 92.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent3×HCID 8028TetrahydrofuranSolvent

Procedure

To a reaction vessel (borosilicate culture tube) was added methoxyacetic acid (0.09 g, 1.00 mmol) A stock solution of 1-hydroxybenzotriazole (3 mL, 0.16 M) and N-methylmorpholine (3 mL, 0.43 M) in N,N-dimethylformamide were added to the reaction vessel followed by approximately 0.97 g of the polymer bound carbodiimide resin (1.38 mmol/g). Additional N,N-dimethylformamide (3 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 4 hours. 1-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (EXAMPLE 161) (0.30 g, 0.668 mmol) was then added to the reaction vessel followed by additional N,N-dimethylformamide (5.0 mL) and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (20 mL) and treated with approximately 2.06 g of polyamine resin (2.63 mmol/g) and approximately 2.67 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with tetrahydrofuran (2×10 mL). The filtrate was evaporated by blowing N2 over the vial while heating (60° C.) in a reaction block (KEM-Lab Parallel Reactor) afforded a tan solid (0.321 g, 89.4%). 1H NMR (400 MHz, DMF-d6) δ 8.33 (br s, 1H), 7.81 (app q, J=7.85 Hz, 1H), 7.40-7.23 (m, 5H), 7.09 (d, J=7.25 Hz, 1H), 6.68 (s, 1H), 5.46 (s, 2H), 5.42 (s, 2H), 4.45 (d, J=6.24 Hz, 2H), 3.93 (s, 2H), 3.39 (s, 3H), 2.44 (s, 3H). ES-HRMS m/z 521.0891 (M+H C24H23BrF2N2O4 requires 521.0882).

Workup

  1. additionwere added to the reaction vessel
  2. stirringthe reaction apparatus was orbitally shaken at room temperature overnight
  3. stirringthe orbital shaking
  4. waitwas continued at 200 RPM at room temperature for 4 hours
  5. customthe solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial
  6. customAfter partial evaporation the insoluble byproducts
  7. washwere rinsed with tetrahydrofuran (2×10 mL)
  8. customThe filtrate was evaporated
  9. temperatureheating (60° C.) in a reaction block (KEM-Lab Parallel Reactor)

Sources & evidence

ORD record
ord-466cd39349c44b488afc51940a692277
Source dataset
uspto-grants-2006_06
Patent number
US07067540B2

Reaction notes

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