Pyridine → HCID 136348456, compound

HRID 1748813Notes

Reaction equation

HRID 1748813 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([C:15]([NH2:17])=O)[NH:11][C:10]3[N:18]([CH3:27])[N:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:9]2=3)=[C:4]([CH3:28])[CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)Cl>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH:12]([C:15]#[N:17])[NH:11][C:10]3[N:18]([CH3:27])[N:19]=[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:9]2=3)=[C:4]([CH3:28])[CH:3]=1

Participants

5

Reactant 3

HCID 1049PyridineHCID 24813Phosphorus oxychlorideHCID 136348454HCID 136348454, compound

Product 1

HCID 136348456HCID 136348456, compoundYield 52%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a solution of rac-(4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine-7-carboxamide (0.050 g, 0.055 mmol, Example #10) in DCE (0.5 ml)/pyridine (0.2 ml) at 0° C. was added POCl3 (0.051 ml, 0.545 mmol) dropwise. The icebath was removed about 5 min after the complete addition. The reaction was stirred at rt for about 16 h. The reaction was quenched by adding it dropwise to stirring H2O (20 mL). A saturated solution of NaHCO3 was added slowly until gas evolution had stopped. The reaction was extracted with DCM (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-50% EtOAc/heptane) to give rac-(4R,7S)-4-(4-bromo-2-methylphenyl)-1-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine-7-carbonitrile (0.026 g, 0.028 mmol, 52%) as a white solid: LC-MS (Table 1, Method g): LC-MS (Table 1, Method g) Rt=2.52 min, m/z 440/442 (M+H)+; 1H-NMR (DMSO-d6, Bruker 400 MHz) δ 8.50-8.47 (m, 1H), 7.85-7.82 (m, 1H), 7.79-7.71 (m, 1H), 7.39 (d, J=2.1 Hz, 1H), 7.26-7.19 (m, 2H), 7.08 (d, J=8.3 Hz, 1H), 6.82 (s, 1H), 6.62 (d, J=5.5 Hz, 1H), 5.02-4.98 (m, 1H), 3.79 (s, 3H), 3.04 (dd, J=15.3, 4.9 Hz, 1H), 2.80 (dd, J=15.4, 2.2 Hz, 1H), 2.51 (s, 3H).

Workup

  1. customThe icebath was removed about 5 min
  2. additionafter the complete addition
  3. customThe reaction was quenched
  4. additionby adding it dropwise
  5. stirringto stirring H2O (20 mL)
  6. additionA saturated solution of NaHCO3 was added slowly until gas evolution
  7. extractionThe reaction was extracted with DCM (50 mL)
  8. washThe organic layer was washed with brine (50 mL)
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationwas concentrated in vacuo
  12. customThe residue was purified by column chromatography (SiO2, 0-50% EtOAc/heptane)

Sources & evidence

ORD record
ord-9dc0ec2969274d7ea508b469e1e9eb21
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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