Nitrogen → 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-methylbenzamide

HRID 1748750Notes

Reaction equation

HRID 1748750 reaction equation
CC1(C)C2[C:23](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:22]C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:49]=[CH:48][C:47]([CH:50]2[S:56][CH2:55][CH:54]([CH3:57])[NH:53][C:52]3[N:58]([CH2:67][CH3:68])[N:59]=[C:60]([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=4)[C:51]2=3)=[C:46]([CH3:69])[CH:45]=1.C(O)(=O)C(O)=O.C([NH:78]N)C.BrC1C=CC(C=O)=C(C)C=1.SCC(=O)C.N#N>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:67]([N:58]1[C:52]2[NH:53][CH:54]([CH3:57])[CH2:55][S:56][CH:50]([C:47]3[CH:48]=[CH:49][C:44]([C:23]([NH2:78])=[O:22])=[CH:45][C:46]=3[CH3:69])[C:51]=2[C:60]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=2)=[N:59]1)[CH3:68]

Participants

9

Reactant 6

HCID 947NitrogenHCID 96181Hydrazine, ethyl-, ethanedioate (1:1)HCID 5201441-Mercapto-2-propanoneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 135551504-Bromo-2-methylbenzaldehydeHCID 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 1366400744-(1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylbenzamideYield 85%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A Barney reactor was charged with Pd(OAc)2 (0.337 mg, 1.50 μmol), Xantphos (0.913 mg, 1.58 μmol) and 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 (33.3 mg, 0.075 mmol, prepared using B from Example #2 step A with ethylhydrazine oxalate, J with 4-bromo-2-methyl-benzaldehyde (AstaTech) and 1-sulfanylpropan-2-one [Enamine] then K with Na(AcO)3BH). The solids were slurried in 1,4-dioxane (0.15 ml) and then sealed in the reactor. The atmosphere was inerted to N2 (5×15 psig) then flushed with NH3 (3×). The reactor was charged with NH3 (80 psig) (˜0.2 g) then with CO (33 psig) for a total pressure of ˜113 psig. The reactor was sealed and heated to about 90° C. with stirring at 750 rpm with a pressure of ˜150 psig. After about 16 h, the reactor was cooled to rt and purged with N2. The crude material was purified by flash chromatography (25 g silica gel; heptane/EtOAc 4:1 to 0:1) to give 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-methylbenzamide (0.156 g, 85%) as a mixture of stereoisomers: LC-MS (Table 1, Method g) Rt=2.00 and 2.02 min.; MS m/z: 408.1 and 408.1 (M+H)+.

Workup

  1. customprepared
  2. customsealed in the reactor
  3. customthen flushed with NH3 (3×)
  4. additionThe reactor was charged with NH3 (80 psig) (˜0.2 g)
  5. customThe reactor was sealed
  6. temperaturethe reactor was cooled to rt
  7. custompurged with N2
  8. customThe crude material was purified by flash chromatography (25 g silica gel; heptane/EtOAc 4:1 to 0:1)

Sources & evidence

ORD record
ord-1194032d938041b490d449325a6bfbda
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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