1-Hydroxybenzotriazole → 5-(5-chloro-thiophen-2-yl)-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide

HRID 1093750Notes

Reaction equation

HRID 1093750 reaction equation
CCN(C(C)C)C(C)C.[Cl:10][C:11]1[S:15][C:14]([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)=[CH:13][CH:12]=1.C(C1SC(Cl)=CC=1)(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:60][C:61]1[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:62]=1[O:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CN(C=O)C.O>[F:60][C:61]1[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:62]=1[O:63][CH:64]1[CH2:65][CH2:66][N:67]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:14]3[S:15][C:11]([Cl:10])=[CH:12][CH:13]=3)[NH:20][N:19]=2)=[O:22])[CH2:68][CH2:69]1

Participants

9

Reactant 6

HCID 757711-HydroxybenzotriazoleHCID 805722-Acetyl-5-chlorothiopheneHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 66591553HCID 66591553, compoundHCID 66591784{[5-(5-chloro-thiophen-2-yl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid

Product 1

HCID 442352755-(5-chloro-thiophen-2-yl)-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amideYield 65.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

DIPEA (120 mg, 0.98 mmol) was added to a stirred solution of {[5-(5-chloro-thiophen-2-yl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (80 mg, 0.28 mmol) (prepared by the method used for the synthesis of Intermediate 30, starting from 2-acetyl-5-chlorothiophene) in DMF (2 mL) followed by HOBt (40 mg, 0.29 mmol) and EDCI.HCl (56 mg, 0.29 mmol). After 5 minutes 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride (70 mg, 0.28 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from 10% EtOAc in hexane afforded 84 mg (65.1% Yield) of 5-(5-chloro-thiophen-2-yl)-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 481, 90.38%. 1H NMR (300 MHz, DMSO-d6): δ 13.6 (s, 1H), 8.6 (m, 1H), 7.18 (m, 4H), 7.1 (m, 1H), 6.8 (m, 1H), 4.7 (m, 1H), 4.2 (d, 2H), 3.8 (m, 1H), 3.7 (m, 1H), 1.9 (m, 2H), 1.6 (m, 2H).

Workup

  1. customprepared by the method
  2. additionwas added to the reaction mixture
  3. extractionextracted with ethyl acetate
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customPurification
  7. customby recrystallisation from 10% EtOAc in hexane

Sources & evidence

ORD record
ord-a1f663c07503484591c51c041d4230c5
Source dataset
uspto-grants-2012_03
Patent number
US08129376B2

Reaction notes

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