Methanol → HCID 136348431, compound

HRID 1748751Notes

Reaction equation

HRID 1748751 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH2:24][CH3:25])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([CH3:26])[CH:3]=1.CN([CH:30]=[O:31])C.C(N(CC)CC)C.[CH3:39][OH:40]>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:24]([N:15]1[C:10]2[NH:11][CH2:12][CH2:13][S:14][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:39]([O:31][CH3:30])=[O:40])=[CH:3][C:4]=3[CH3:26])[C:9]=2[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:16]1)[CH3:25]

Participants

7

Reactant 4

HCID 887MethanolHCID 6228DimethylformamideHCID 8471TriethylamineHCID 136348432HCID 136348432, compound

Product 1

HCID 136348431HCID 136348431, compoundYield 55%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

Conditions

Temperature
85 °C

Procedure

A microwave vial was charged with 4-(4-bromo-2-methylphenyl)-1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine (0.70 g, 1.63 mmol, prepared using B from Example #2, Step A with ethyl hydrazine, C with 4-bromo-2-methylbenzaldehyde (Asta Tech) and 2-mercaptoacetic acid followed by D with borane-THF complex), Pd(OAc)2 (0.04 g, 0.16 mmol), dppf (0.18 g, 0.32 mmol) and DMF (13.5 mL). Nitrogen was bubbled through the reaction mixture for about 10 min. The mixture was evacuated and then back-filled with CO three times. Methanol (3.3 mL) and triethylamine (1.2 mL, 16.3 mmol) were added. The reaction mixture was heated, in a sealed microwave vessel, for about 3 h at about 85° C. After cooling to rt, the mixture was partially concentrated under reduced pressure. The crude product was partitioned between EtOAc (40 mL) and water (10 mL). The organic layer was washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:100) to afford methyl 4-(1-ethyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzoate (0.36 g, 55%): LC-MS (Table 1, Method g) Rt=2.38 min, m/z 409 (M+H)+.

Workup

  1. customNitrogen was bubbled through the reaction mixture for about 10 min
  2. customThe mixture was evacuated
  3. additionback-filled with CO three times
  4. temperatureAfter cooling to rt
  5. concentrationthe mixture was partially concentrated under reduced pressure
  6. customThe crude product was partitioned between EtOAc (40 mL) and water (10 mL)
  7. washThe organic layer was washed with brine (10 mL)
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe crude material was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:100)

Sources & evidence

ORD record
ord-830bec77584640f9815c70aa08a1f5e1
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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