Sodium Hydroxide → [5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamic acid benzyl ester

HRID 707833

Reaction equation

HRID 707833 reaction equation
[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14](O)=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1[N:44]=[N:43][C:38]2[CH:39]=CC=N[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:52]([O:59][C:60]([NH:62][C:63](=[NH:66])SC)=[O:61])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(=O)(O)[O-].[Na+].Cl.C(NN)(C)C.[OH-].[Na+].[O-]Cl.[Na+]>C1COCC1>[CH2:52]([O:59][C:60](=[O:61])[NH:62][C:63]1[N:66]=[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=4[C:6]=3[N:7]=2)[N:43]([CH:38]([CH3:37])[CH3:39])[N:44]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1

Participants

10

Reactant 8

HCID 14798Sodium HydroxideHCID 81531Diisopropylethylamine2×HCID 855731-Isopropylhydrazine hydrochlorideHCID 516892Sodium BicarbonateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 23665760Sodium HypochloriteHCID 579001668-Bromo-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylic acidHCID 140362141Benzyl [amino(methylsulfanyl)methylene]carbamate

Product 1

HCID 58204121[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamic acid benzyl esterYield 57%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
95 °C

Procedure

To a suspension of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (1.86 g, 5.70 mmol) in anhydrous THF (75 mL) was added diisopropylethylamine (2 mL, 11.4 mmol), HATU (2.39 g, 6.27 mmol) and 1-benzyloxycarbonyl-2-methyl-isothiourea (1.47 g, 6.56 mmol) at RT. After stirring for 24 hours an aqueous saturated sodium bicarbonate solution was added and the mixture extracted with 1:1 EtOAc/THF solution (×2). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting solid was added to DMF (50 mL) and treated with diisopropylethylamine (4 mL, 22.8 mmol) and isopropylhydrazine hydrochloride (941 mg, 8.55 mmol). The mixture was heated to 95° C. and scrubbed with 1N NaOH solution and NaOCl solution. After 2 hours the mixture was allowed to cool to RT, extracted with EtOAc and washed with water. The organic layer was dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0-50% EtOAc in cyclohexane) to afford [5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamic acid benzyl ester (1.75 g, 57%). LCMS: RT=5.11 min, [M+H]+=540/542

Workup

  1. additionwas added
  2. extractionthe mixture extracted with 1:1 EtOAc/THF solution (×2)
  3. washwashed with brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. additionThe resulting solid was added to DMF (50 mL)
  7. temperatureto cool to RT
  8. extractionextracted with EtOAc
  9. washwashed with water
  10. dry with materialThe organic layer was dried (Na2SO4)
  11. concentrationconcentrated in vacuo
  12. customThe resultant residue was purified by flash chromatography (SiO2, gradient 0-50% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-6e0357c0239247ff868129bd225bbaa9
Source dataset
uspto-grants-2015_11
Patent number
US09175009B2

Linked notes

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