Cyclobutylamine → 9-Bromo-4-cyclobutylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester

HRID 575107Notes

Reaction equation

HRID 575107 reaction equation
[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8](Br)[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].[CH:21]1([NH2:25])[CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:25][CH:21]3[CH2:24][CH2:23][CH2:22]3)[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 75645CyclobutylamineHCID 81531DiisopropylethylamineHCID 866930844,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester

Product 1

HCID 866931389-Bromo-4-cyclobutylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl esterYield 28.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 4,9-Dibromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (400 mg, 0.95 mmol) in DMF (9 mL) were added cyclobutanamine (81.5 mg, 1.15 mmol), DIPEA (370 mg, 2.86 mmol). The reaction mixture was stirred in autoclave at 90° C. overnight. Then the mixture was cooled to room temperature and 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, concentrated in vacuo and purified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%) to afford 9-Bromo-4-cyclobutylamino-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (110 mg, 28%). NMR (400 MHz, DMSO-d6): δ 8.44 (d, J=2.5 Hz, 1H), 7.47 (dd, J1=8.6 Hz, J2=2.5 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 4.42 (m, 2H), 3.96 (m, 1H), 3.14 (m, 1H), 2.15 (m, 1H), 1.74 (m, 2H), 1.55 (m, 2H).

Workup

  1. temperatureThen the mixture was cooled to room temperature
  2. custompartitioned 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 in vacuo
  8. custompurified by flash column chromatography (silica gel, EtOAc in hexane from 10% to 20%)

Sources & evidence

ORD record
ord-7edcdee87078427d816cb01632002175
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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