Hydrochloric Acid → 9-[1-(2-Hydroxy-ethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide

HRID 708022Notes

Reaction equation

HRID 708022 reaction equation
[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C([O-])(=O)C.[K+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:37]4[CH:36]=[N:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 517044Potassium AcetateHCID 582040029-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amideHCID 593418191-[2-(oxan-2-yloxy)ethyl]-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Product 1

HCID 582041499-[1-(2-Hydroxy-ethyl)-1H-pyrazol-4-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amideYield 6.2%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (57 mg, 0.138 mmol), 1-(2-(tetrahydro-2H-pyran-2yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (67 mg, 0.208 mmol), Tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.0138 mmol), 1.5 mL 1 M potassium acetate in water, and 1.5 mL acetonitrile were combined in a microwave vial and placed on the CEM microwave for 20 minutes at 140° C. Complete reaction by LCMS. Diluted reaction with 2 M HCl and extracted product with ethyl acetate. Some of the THP group fell off during work-up. The final Intermediate was in the ethyl acetate layer, which was dried over magnesium sulfate and concentrated in vacuo. Flash purified 0 to 10% MeOH in dichloromethane and again concentrated in vacuo. The THP intermediate was deprotected with 1 M HCl in dioxane (5 mL0 over 72 hours). Complete deprotection by LCMS. Concentrated in vacuo and purified by HPLC to give 277 (3.8 mg, 6% yield, M+1 443.1)

Workup

  1. customreaction by LCMS
  2. additionDiluted
  3. extractionextracted product with ethyl acetate
  4. dry with materialwas dried over magnesium sulfate
  5. concentrationconcentrated in vacuo
  6. customFlash purified 0 to 10% MeOH in dichloromethane
  7. concentrationagain concentrated in vacuo
  8. customwas deprotected with 1 M HCl in dioxane (5 mL0 over 72 hours)
  9. concentrationConcentrated in vacuo
  10. custompurified by HPLC

Sources & evidence

ORD record
ord-f3fbe649d55242e18b29be36a5a0b5ce
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

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