2-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid → 1-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]tetrahydro-1(2H)-pyridazinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone

HRID 75174

Reaction equation

HRID 75174 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][NH:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.[CH3:25][C:26]1[N:30]([CH2:31][C:32](O)=[O:33])[N:29]=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1>ClCCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:32](=[O:33])[CH2:31][N:30]4[C:26]([CH3:25])=[CH:27][C:28]([C:35]([F:38])([F:37])[F:36])=[N:29]4)[NH:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1

Participants

4

Reactant 2

HCID 5961182-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acidHCID 673224374-[4-[5-(2,6-Difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]hexahydropyridazine2×

Product 1

HCID 866744671-[4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]tetrahydro-1(2H)-pyridazinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A mixture of 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]hexahydropyridazine (i.e. the product of Step H) (0.29 g, 0.83 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (0.19 g, 0.91 mmol) and N,N-dicyclohexylcarbodiimide (0.19 g, 0.91 mmol) in dichloromethane (5 mL) was stirred at room temperature for 48 h. More dichloromethane was added to the reaction mixture, the mixture was filtered, washing thoroughly with dichloromethane. The filtrate was concentrated under reduced pressure and loaded onto a chromatotron plate (4 mm). The plate was eluted with dichloromethane, followed by a gradient of 0.5% to 2% methanol in dichloromethane. Fractions containing product material were further purified by HPLC using an Alltima C18 column (250×22 mm), monitored at wavelength 225 nm and eluted with 60% methanol and 0.1% 2,2,2-trifluoroacetic acid in water to provide the title compound (69 mg), a compound of the present invention.

Workup

  1. filtrationthe mixture was filtered
  2. washwashing thoroughly with dichloromethane
  3. concentrationThe filtrate was concentrated under reduced pressure
  4. washThe plate was eluted with dichloromethane
  5. additionFractions containing product material
  6. customwere further purified by HPLC
  7. washeluted with 60% methanol and 0.1% 2,2,2-trifluoroacetic acid in water

Sources & evidence

ORD record
ord-0c4c8040853043be8315d94e4fb8bec8
Source dataset
uspto-grants-2014_09
Patent number
US08835427B2

Linked notes

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