1,4-Dioxane hydrochloride → (1-Amino-cyclopropyl)-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-methanone

HRID 708162Notes

Reaction equation

HRID 708162 reaction equation
C(OC(=O)[NH:7][C:8]1([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH2:14]2)=[O:12])[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][C:8]1([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH2:14]2)=[O:12])[CH2:9][CH2:10]1

Participants

4

Reactant 2

HCID 204431481,4-Dioxane hydrochlorideHCID 67050572(1-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carbonyl}-cyclopropyl)-carbamic acid tert-butyl ester

Product 1

HCID 58203965(1-Amino-cyclopropyl)-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-methanoneYield 59%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a suspension of (1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carbonyl}-cyclopropyl)-carbamic acid tert-butyl ester (225 mg, 0.41 mmol) in MeOH (3.1 mL) was added 4N HCl/dioxan (1.0 mL, 4.1 mmol) and the reaction mixture was stirred for 18 hours. The resulting solid was filtered off and washed with diethyl ether before being partitioned between DCM and an aqueous saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with DCM (×2). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-8% 2N NH3/MeOH in DCM). The resulting solid was suspended in ether and collected by filtration to give 425 as a white solid (108 mg, 59%). LCMS: RT=7.96 min, [M+H]+=451. 1H NMR δ (ppm) (DMSO-d6): 8.35 (1H, d, J=8.20 Hz), 8.02 (1H, s), 7.20 (1H, dd, J=8.22, 1.81 Hz), 7.05 (1H, s), 5.86-5.78 (1H, m), 4.59 (2H, t, J=9.01 Hz), 4.40 (2H, t, J=5.07 Hz), 4.20 (2H, d, J=7.67 Hz), 3.85 (1H, t, J=7.50 Hz), 3.44 (2H, t, J=5.08 Hz), 2.18 (2H, s), 1.58 (6H, d, J=6.59 Hz), 1.09-1.06 (2H, m), 0.70 (2H, q, J=3.28 Hz)

Workup

  1. filtrationThe resulting solid was filtered off
  2. washwashed with diethyl ether
  3. custombefore being partitioned between DCM
  4. customThe phases were separated
  5. extractionthe aqueous phase was extracted with DCM (×2)
  6. washThe combined organic extracts were washed with brine
  7. dry with materialdried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customThe resultant residue was purified by flash chromatography (SiO2, 0-8% 2N NH3/MeOH in DCM)
  10. filtrationcollected by filtration

Sources & evidence

ORD record
ord-ae898e7be7e64049ab62d3c80dd14fcb
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Reaction notes

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