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Triethylamine → 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-(4,5-dihydro-3,5-dimethyl-1H-pyrazol-1-yl]ethanone

HRID 1916447
Notes
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Reaction equation

HRID 1916447 reaction equation
[CH3:1][C:2]1[CH2:6][CH:5]([CH3:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH:20]1[O:24][N:23]=[C:22]([C:25]2[N:26]=[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH2:21]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH:20]1[O:24][N:23]=[C:22]([C:25]2[N:26]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:9](=[O:11])[CH2:8][N:4]4[CH:5]([CH3:7])[CH2:6][C:2]([CH3:1])=[N:3]4)[CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH2:21]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 8471Triethylamine2×HCID 757711-HydroxybenzotriazoleHCID 666185904-[4-[5-(2,6-Difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]piperidineHCID 67379411HCID 67379411, compound2×

Product 1

HCID 673793771-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]-1-piperidinyl]-2-(4,5-dihydro-3,5-dimethyl-1H-pyrazol-1-yl]ethanone

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A mixture of 4,5-dihydro-3,5-dimethyl-1H-pyrazole-1-acetic acid (i.e. the product of Step B) (0.10 g, 0.64 mmol), 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]piperidine (i.e. the product of Example 1, Step D) (175 mg, 0.5 mmol), N3-(ethylcarbodimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride (191 mg, 1.0 mmol), 1-hydroxybenzotriazole (5 mg, 0.037 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dichloromethane (4 mL) was stirred at room temperature. After 6 h, more N3-(ethylcarbodimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride (191 mg, 1.0 mmol) and triethylamine (0.14 mL, 1.0 mmol) were added to the reaction mixture. After 3 days, the reaction mixture was diluted with dichloromethane, washed with saturated aqueous ammonium chloride solution and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography on silica gel (0 to 100% gradient of ethyl acetate in hexanes, and then 20% methanol in ethyl acetate as eluant) to provide the title compound, a compound of the present invention, as a tan solid (124 mg).

Workup

  1. waitAfter 3 days
  2. washwashed with saturated aqueous ammonium chloride solution
  3. concentrationconcentrated under reduced pressure
  4. customThe resulting residue was purified by medium pressure liquid chromatography on silica gel (0 to 100% gradient of ethyl acetate in hexanes

Sources & evidence

ORD record
ord-5efce5baf7f1430ca253fe4b055124b6
Source dataset
uspto-grants-2013_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08618137B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes