4-Methylmorpholine → HCID 25107210, compound

HRID 1397488Notes

Reaction equation

HRID 1397488 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]3([O:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:23]1([C:31](O)=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24]1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:25]12[CH2:24][CH:23]([C:31]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[S:12][C:11]([C:13]5([O:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:16][CH2:15][CH2:14]5)=[N:10][CH:9]=4)=[CH:4][CH:3]=3)=[O:32])[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 3023241-Benzocyclobutenecarboxylic acidHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 68720623HCID 68720623, compound

Product 1

HCID 25107210HCID 25107210, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of Example 24B (0.150 g, 0.470 mmol), 1,2-dihydrocyclobutabenzene-1-carboxylic acid (0.070 g, 0.470 mmol), N-methylmorpholine (0.103 mL, 0.940 mmol), and 1-hydroxybenzotriazole hydrate (0.080 g, 0.940 mmol) in N,N-dimethylformamide-(2 mL) was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.115 g, 0.589 mmol). The solution was heated to 50° C. for 3 h, cooled to room temperature, and partitioned between H2O (2 mL) and ethyl acetate (2 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×2 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol (5 mL) and 2 N NaOH (0.50 mL) was added. After 5 h, the methanol was removed under reduced pressure. The aqueous was acidified with 10% HCl to pH 1. The solid was filtered and air-dried. Purification of the residue by RP-HPLC (preparative reversed-phase high pressure liquid chromatography) using a Zorbax SB-C18 7M 21.2×250 mm column with UV detection analyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min) provided the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.67-1.94 (m, 2 H), 2.39-2.47 (m, 4 H), 3.31-3.40 (m, 2 H), 3.93 (s, 2 H) 4.44 (dd, J=4.9 and 2.9 Hz, 1 H), 7.09-7.31 (m, 4 H), 7.56-7.68 (m, 2 H), 7.67-7.78 (m, 2 H), 8.07 (s, 1 H), 10.37 (s, 1 H); MS (ESI) m/z 435 [M+H]+.

Workup

  1. temperaturecooled to room temperature
  2. custompartitioned between H2O (2 mL) and ethyl acetate (2 mL)
  3. customThe layers were separated
  4. extractionthe aqueous was extracted with additional ethyl acetate (2×2 mL)
  5. dry with materialThe combined organics were dried with anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. dissolutionThe residue was dissolved in methanol (5 mL)
  9. addition2 N NaOH (0.50 mL) was added
  10. customthe methanol was removed under reduced pressure
  11. filtrationThe solid was filtered
  12. customair-dried
  13. customPurification of the residue by RP-HPLC (preparative reversed-phase high pressure liquid chromatography)
  14. customanalyzed at 220 and 254 nM (preparative method: water with 0.1% trifluoroacetic acid and CH3CN with 0.1% trifluoroacetic acid gradient 5-95% CH3CN over 30 minutes at 15 mL/min)

Sources & evidence

ORD record
ord-7ba535a4ea534215b8e55edfeafc5553
Source dataset
uspto-grants-2014_12
Patent number
US08901152B2

Reaction notes

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