Dimethylamine, hydrochloride → 4-Dimethylcarbamoylmethyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide

HRID 575127Notes

Reaction equation

HRID 575127 reaction equation
[C:1]([C:4]1[S:5][C:6]2[CH:7]([CH2:24][C:25]([OH:27])=O)[CH2:8][O:9][C:10]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:14][C:11]=3[C:12]=2[N:13]=1)(=[O:3])[NH2:2].Cl.[CH3:29][NH:30][CH3:31].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:29][N:30]([CH3:31])[C:25]([CH2:24][CH:7]1[C:6]2[S:5][C:4]([C:1]([NH2:2])=[O:3])=[N:13][C:12]=2[C:11]2[CH:14]=[C:15]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])[CH:16]=[CH:17][C:10]=2[O:9][CH2:8]1)=[O:27]

Participants

7

Reactant 5

HCID 10473Dimethylamine, hydrochlorideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 86693151[2-Carbamoyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-4-yl]-acetic acid

Product 1

HCID 866931524-Dimethylcarbamoylmethyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amideYield 46.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

To a mixture of [2-Carbamoyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-4-yl]-acetic acid (60 mg, 0.155 mmol) in DCM (20 mL) were added Dimethylamine Hydrochloride (31.7 mg, 0.388 mmol), HOBt (31.5 mg, 0.233 mmol), EDCI (44.7 mg, 0.233 mmol) and DIPEA (60.3 mg, 0.466 mmol). The mixture stirred in autoclave at 60° 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 and concentrated in vacuo. The residue was triturated with EtOAc and hexane (1:1) to afford 4-Dimethylcarbamoylmethyl-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (30 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 8.61 (d, J=1.8 Hz, 1H), 8.42 (s, 1H), 7.85 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 5.45 (s, 1H), 4.5 (m, 1H), 4.10 (m, 1H), 3.93 (m, 1H), 2.90 (d, J=16 Hz, 6H), 2.82 (m, 1H), 2.69 (m, 1H), 1.47 (s, 6H); LC-MS (ESI & APCI): 414.5 (M+1).

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. customThe residue was triturated with EtOAc and hexane (1:1)

Sources & evidence

ORD record
ord-237b531e8bc44448beb158bb5a9b858f
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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