p-Toluenesulfonic acid → ethyl 2-(4-(4-chloro-2-methylphenyl)-1,3,7-trimethyl-4,6-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-6-yl)acetate

HRID 1748809Notes

Reaction equation

HRID 1748809 reaction equation
[CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[C:12]([CH3:18])[CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[SH:30][CH:31]([C:38](=O)[CH3:39])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C([O-])(O)=O.[Na+]>C(#N)C.C(Cl)Cl>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]2[S:30][CH:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:38]([CH3:39])=[N:7][C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:8])[C:5]2=3)=[C:12]([CH3:18])[CH:11]=1

Participants

8

Reactant 5

HCID 6101p-Toluenesulfonic acidHCID 516892Sodium BicarbonateHCID 5207211,3-Dimethyl-1H-pyrazol-5-amineHCID 27576584-Chloro-2-methylbenzaldehydeHCID 86724137Ethyl 3-mercapto-4-oxopentanoate

Product 1

HCID 86724138ethyl 2-(4-(4-chloro-2-methylphenyl)-1,3,7-trimethyl-4,6-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-6-yl)acetateYield 37.7%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 1,3-dimethyl-1H-pyrazol-5-amine (0.58 g, 5.22 mmol, Oakwood Chemicals), 4-chloro-2-methylbenzaldehyde (0.81 g, 5.22 mmol, Ark Pharm) and p-TSA (0.10 g, 0.52 mmol) in acetonitrile (10.5 mL) was added ethyl 3-mercapto-4-oxopentanoate (1.74 g, 9.87 mmol) and stirred at about 90° C. for about 18 h. The reaction mixture was cooled to ambient temperature and saturated NaHCO3 (15 mL) and DCM (20 mL) were added. The organic layer was separated and the aqueous layer was back extracted using DCM (20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:50) to afford ethyl 2-(4-(4-chloro-2-methylphenyl)-1,3,7-trimethyl-4,6-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-6-yl)acetate (0.85 g, 1.97 mmol, 37%). LC-MS (Table 1, Method g) Rt=2.66, 2.63 min, m/z 406 (M+H)+.

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. customThe organic layer was separated
  3. extractionthe aqueous layer was back extracted
  4. dry with materialThe combined organic layers were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe crude material was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:50)

Sources & evidence

ORD record
ord-76e3b585e3414ca78b15c37c993a7ce5
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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