Acetyl chloride → 4-Acetylamino-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester

HRID 575111Notes

Reaction equation

HRID 575111 reaction equation
[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([N:20]=[N+]=[N-])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:20][C:42](=[O:44])[CH3:43])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=[O:4]

Participants

5

Reactant 3

HCID 6367Acetyl chlorideHCID 11776TriphenylphosphineHCID 866931404-Azido-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester

Product 1

HCID 866931414-Acetylamino-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl esterYield 54.8%

Reagents, catalysts & solvents 1

HCID 21881883Oxolane--water (1/1)Solvent

Conditions

Temperature
65 °C

Procedure

To a solution of 4-Azido-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (280 mg, 0.735 mmol) in THF/water (15 mL/3 mL) was added PPh3 (192.5 mg, 0.735 mmol). The reaction mixture was heated to 65° C. overnight. The mixture was cooled to −5° C., and TEA (222 mg, 2.200 mmol) was added followed by acetyl chloride (86.5 mg, 1.101 mmol). Then the mixture was stirred at room temperature for 1 h. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude product which was triturated with EtOAc and hexane (1:1) and then filtered to afford 4-Acetylamino-9-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (160 mg, 51%). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, J=2.5 Hz, 1H), 8.48 (s, 1H), 7.53 (dd, J1=8.7 Hz, J2=2.6 MHz, 1H), 7.13 (d, J=8.6 Hz, 2H), 5.51 (m, 1H), 4.41 (m, 1H), 4.23 (m, 1H), 3.96 (s, 3H), 1.90 (s, 3H); LC-MS (ESI & APCI): 399.1 (M+2).

Workup

  1. temperatureThe mixture was cooled to −5° C.
  2. customThe mixture was partitioned between EtOAc and H2O
  3. extractionthe aqueous layer was extracted with EtOAc (2×20 mL)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto afford crude product which
  9. customwas triturated with EtOAc and hexane (1:1)
  10. filtrationfiltered

Sources & evidence

ORD record
ord-65ac3f1e41854c67877ca9fcff45cbd6
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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