Hydrochloric Acid → 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine

HRID 1773144Notes

Reaction equation

HRID 1773144 reaction equation
[I-].[K+].C(Br)C.[Cl:6][C:7]1[C:11](N(CC)C(=O)C)=[CH:10][N:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:8]=1.Cl[C:25]1[C:29](NC(=O)C)=CN(C2C=NC=CC=2)[N:26]=1.Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:6][C:7]1([NH:26][CH2:25][CH3:29])[CH:11]=[CH:10][N:9]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[NH:8]1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 4875Potassium IodideHCID 6332Ethyl BromideHCID 72194633N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamideHCID 118023019N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide

Product 1

HCID 1180221923-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 962WaterSolvent

Procedure

3-Chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazol-amine (1d) may be prepared through the reaction pathway sequence disclosed in Scheme 5. In step d1, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (1c) may be alkylated with ethyl bromide (EtBr) in the presence of a base, such as sodium hydride (NaH), sodium tert-butoxide (NaOt-Bu), potassium tert-butoxide (KOt-Bu), or potassium tert-amyloxide in a polar aprotic solvent, such as tetrahydrofuran, at temperatures from about 20° C. to about 40° C., over a period of time of about 60 hours to about 168 hours, to yield N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′). It has been discovered that use of an additive, such as potassium iodide (KI) or tetrabutylammonium iodide (TBAI) decreases the time necessary for the reaction to complete to about 24 hours. It was also discovered that heating the reaction at about 50° C. to about 70° C. in a sealed reactor (to prevent loss of ethyl bromide) decreases the reaction time to about 24 hours. In step d2, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′) may be treated with hydrochloric acid in water at temperatures from about 70° C. to about 90° C., to yield 3-chloro-N-ethyl-1-(pyridin-3-yl)-1H-pyrazolamine (1d). The reaction pathway sequence disclosed in Scheme 5 may also be performed without the isolation of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (1c′).

Workup

  1. customnecessary for the reaction
  2. temperaturethat heating
  3. customto about 24 hours

Sources & evidence

ORD record
ord-b118b9364c924023a351e85be801ff24
Source dataset
uspto-grants-2016_02
Patent number
US09255082B2

Reaction notes

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