Thioglycolic Acid → rac-4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-methyl-3-(pyridin-2-yl)-6,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7(4H)-one

HRID 1748820Notes

Reaction equation

HRID 1748820 reaction equation
[CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:3]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:31]=O)=[C:27]([CH3:30])[CH:28]=3)[CH:23]=[N:22]2)=[CH:17][CH:16]=1.[SH:33][CH2:34][C:35](O)=[O:36]>O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([CH:31]4[S:33][CH2:34][C:35](=[O:36])[NH:7][C:6]5[N:2]([CH3:1])[N:3]=[C:4]([C:8]6[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=6)[C:5]4=5)=[C:27]([CH3:30])[CH:28]=3)[CH:23]=[N:22]2)=[CH:19][CH:20]=1

Participants

5

Reactant 3

HCID 1133Thioglycolic Acid2×HCID 133248371-Methyl-3-Pyridin-2-Yl-1H-Pyrazol-5-AmineHCID 867241441-(4-fluorophenyl)-6-methyl-1H-indazole-5-carbaldehyde

Product 1

HCID 136639940rac-4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-methyl-3-(pyridin-2-yl)-6,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7(4H)-oneYield 30.8%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

A reaction vial was charged with 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (0.07 g, 0.39 mmol, Example #2, step B), 1-(4-fluorophenyl)-6-methyl-1H-indazole-5-carbaldehyde (0.10 g, 0.39 mmol) and water (0.4 mL). The mixture was stirred for about 1 min then 2-mercaptoacetic acid (0.03 mL, 0.39 mmol) was added and the vial was sealed and warmed in a preheated bath to about 110° C. After stirring for 30 min, 2-mercaptoacetic acid (0.014 mL, 0.20 mmol) was added and continued heating for about 90 min. The vial was cooled to ambient temperature and the water was decanted. The solid was sonicated in Et2O (30 mL) and collected by vacuum filtration. The solid was then rinsed with heptane (30 mL) then dissolve in DCM and purified by column chromatography (EtOAc/heptane 100:0 to 0:100) to afford rac-4-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-1-methyl-3-(pyridin-2-yl)-6,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7(4H)-one (0.06 g, 0.12 mmol, 29%). LC-MS (Table 1, Method g) Rt=2.32 min, m/z 485 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ 10.11 (s, 1H), 8.36-8.30 (m, 1H), 8.10 (s, 1H), 7.79-7.69 (m, 3H), 7.64-7.60 (m, 1H), 7.54 (s, 1H), 7.40-7.36 (m, 2H), 7.27 (s, 1H), 7.12-7.04 (m, 1H), 6.74 (s, 1H), 3.90 (s, 3H), 3.42-3.38 (m, 1H), 3.18-3.14 (m, 1H), 2.70 (s, 3H).

Workup

  1. customA reaction
  2. customthe vial was sealed
  3. stirringAfter stirring for 30 min
  4. temperaturecontinued heating for about 90 min
  5. temperatureThe vial was cooled to ambient temperature
  6. customthe water was decanted
  7. customThe solid was sonicated in Et2O (30 mL)
  8. filtrationcollected by vacuum filtration
  9. washThe solid was then rinsed with heptane (30 mL)
  10. dissolutionthen dissolve in DCM
  11. custompurified by column chromatography (EtOAc/heptane 100:0 to 0:100)

Sources & evidence

ORD record
ord-98eacf46e2744f65855550502acbe3aa
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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