Tetrahydrofuran → 3-tert-butyl-4-chloro-N-(6-(2-chlorophenyl)-2-methoxy-3-nitropyridin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

HRID 570283Notes

Reaction equation

HRID 570283 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-:18])=[O:17])=[C:10]([NH2:19])[CH:9]=1.[H-].[Na+].[C:22]([C:26]1[C:30](C(Cl)=O)=[CH:29][N:28]([CH3:34])[N:27]=1)([CH3:25])([CH3:24])[CH3:23].[Cl-:35].[NH4+].[O:37]1[CH2:41]CCC1>>[C:22]([C:26]1[C:30]([Cl:35])=[C:29]([C:41]([NH:19][C:10]2[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:13]=[C:12]([O:14][CH3:15])[C:11]=2[N+:16]([O-:18])=[O:17])=[O:37])[N:28]([CH3:34])[N:27]=1)([CH3:23])([CH3:24])[CH3:25]

Participants

6

Reactant 5

HCID 8028Tetrahydrofuran2×HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 674116886-(2-Chlorophenyl)-2-methoxy-3-nitropyridin-4-amineHCID 867203403-tert-butyl-1-methyl-1H-pyrazole-4-carbonyl chloride

Product 1

HCID 674096383-tert-butyl-4-chloro-N-(6-(2-chlorophenyl)-2-methoxy-3-nitropyridin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide

Conditions

Temperature
1 °C

Procedure

A 5 L, four neck round bottom flask equipped with mechanical stirrer, nitrogen inlet, addition funnel with stopper, and thermocouple was charged 6-(2-chlorophenyl)-2-methoxy-3-nitropyridin-4-amine (111.40 g, 0.398 mol) and tetrahydrofuran (1.90 L). The resulting mixture was cooled to 3° C. in ice-water bath and then treated with sodium hydride (31.85 g, 0.796 mol) carefully in one portion with an exotherm to 7° C. observed, to yield a deep-red slurry. This slurry was chilled to 1° C. and a solution of 3-tert-butyl-1-methyl-1H-pyrazole-4-carbonyl chloride (113.05 g, 0.438 mol) in tetrahydrofuran (0.275 L) was added dropwise via addition funnel over 30 min, with an exotherm to 10° C. observed. The ice bath was drained and the resulting mixture reached 8° C. over 30 min. The resulting mixture was then poured into saturated ammonium chloride (2.5 L) and extracted with ethyl acetate (2 L, 2×1 L). The combined organics were washed with brine (1 L) and dried (MgSO4) overnight, protecting from light. The organic phases were concentrated to yield a the title compound as a residue. The residue was triturated with heptane (2.25 L) at 60° C. for 30 min, and the resulting mixture cooled to room temperature while protecting from light. The resulting solids were collected by filtration, washed with heptane (250 mL), and dried in a vacuum oven (50° C.) for 5 h to yield 3-tert-butyl-4-chloro-N-(6-(2-chlorophenyl)-2-methoxy-3-nitropyridin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 1.41 (s, 9H), 4.10 (s, 3H), 4.12 (s, 3H), 7.34-7.43 (m, 2H), 7.47-7.55 (m, 1H), 7.60-7.68 (m, 1H), 8.49 (s, 1H), 10.13 (br. s., 1H)

Workup

  1. customA 5 L, four neck round bottom flask equipped with mechanical stirrer, nitrogen inlet, addition funnel with stopper
  2. customto yield a deep-red slurry
  3. extractionextracted with ethyl acetate (2 L, 2×1 L)
  4. washThe combined organics were washed with brine (1 L)
  5. dry with materialdried (MgSO4) overnight
  6. concentrationThe organic phases were concentrated

Sources & evidence

ORD record
ord-64f3986516cd45dfbd6bcb7ef8b7d6df
Source dataset
uspto-grants-2015_05
Patent number
US09023846B2

Reaction notes

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