2-Methyl-3-butyn-2-ol → 4-(4-(1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylphenyl)-2-methylbut-3-yn-2-ol

HRID 1748772Notes

Reaction equation

HRID 1748772 reaction equation
C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[S:33][CH2:32][CH:31]([CH3:34])[NH:30][C:29]3[N:35]([CH2:44][CH3:45])[N:36]=[C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[C:28]2=3)=[C:23]([CH3:46])[CH:22]=1.[CH3:47][C:48]([OH:52])([C:50]#[CH:51])[CH3:49]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:44]([N:35]1[C:29]2[NH:30][CH:31]([CH3:34])[CH2:32][S:33][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([C:51]#[C:50][C:48]([CH3:49])([OH:52])[CH3:47])=[CH:22][C:23]=3[CH3:46])[C:28]=2[C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:36]1)[CH3:45]

Participants

7

Reactant 3

HCID 82582-Methyl-3-butyn-2-olHCID 11776TriphenylphosphineHCID 1363484404-(4-bromo-2-methylphenyl)-1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine

Product 1

HCID 1363484394-(4-(1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylphenyl)-2-methylbut-3-yn-2-olYield 59.4%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
150 °C

Procedure

To a microwave vial was added CuI (2.7 mg, 0.014 mmol), PdCl2(PPh3)2 (0.040 g, 0.056 mmol), PPh3 (0.059 g, 0.23 mmol), 4-(4-bromo-2-methylphenyl)-1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine (0.500 g, 1.13 mmol, prepared using B from Example #2, step A with ethyl hydrazine oxalate, J with 4-bromobenzaldehyde and 1-sulfanylpropan-2-one [Enamine] and K with Na(OAc)3BH) as a solution in DMF (3.76 ml), 2-methylbut-3-yn-2-ol (0.197 ml, 2.26 mmol) and TEA (2.36 ml, 16.9 mmol). The vial was sealed and the solution was sparged with N2 for about 15 min. The mixture was heated in a microwave (300 W, pressure limit 250 atm) at 150° C. for 6 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; heptane/EtOAc 1:0 to 0:1) to give 4-(4-(1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylphenyl)-2-methylbut-3-yn-2-ol (0.3 g, 59% yield); LC-MS (Table 1, Method g) Rt=2.52 and 2.55 min.; MS m/z: 447.17 and 447.17 (M+H)+.

Workup

  1. customThe vial was sealed
  2. customthe solution was sparged with N2 for about 15 min
  3. additionThe mixture was diluted with water (25 mL)
  4. extractionextracted with EtOAc (2×25 mL)
  5. washThe organic layer was washed with water (25 mL), brine (25 mL)
  6. dry with materialdried with MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude material was purified by flash chromatography (silica gel; heptane/EtOAc 1:0 to 0:1)

Sources & evidence

ORD record
ord-33a9b522c04a4117993ea5fac5c290d2
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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