Triphenylphosphine → 5-(5-(3-Fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

HRID 515817

Reaction equation

HRID 515817 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:13][CH2:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:31][N:32]1[C:36]([CH2:37][CH2:38]O)=[CH:35][CH:34]=[N:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[S:17])[N:15]([C:18]3[CH:19]=[C:20]([C:26]([F:29])([F:27])[F:28])[C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[C:14](=[O:30])[C:10]32[CH2:11][CH2:12][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH2:38][CH2:37][C:36]1[N:32]([CH3:31])[N:33]=[CH:34][CH:35]=1

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 218324192-(1-methyl-1H-pyrazol-5-yl)ethan-1-olHCID 533732145-(5-(3-Fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile2×

Product 1

HCID 866834795-(5-(3-Fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 5-(5-(3-fluoro-4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 1, 100 mg, 0.23 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (43.5 mg, 0.34 mmol), triphenylphosphine (89 mg, 0.34 mmol), and diisopropyl azodicarboxylate (0.07 mL, 0.34 mmol) in THF (5 mL) was stirred at room temperature for 18 h. The reaction mixture was absorbed on silica gel and purified by column chromatography on silica gel eluting with EtOAc/hexanes to afford impure desired product that was repurified by reverse phase HPLC (acetonitrile/water:TFA). The fractions containing the desired compound were combined, acetonitrile was removed in vacuo, and the remaining aqueous layer was treated with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with DCM (3×), the organics were combined, dried over sodium sulfate, and evaporated to dryness to afford 29 mg of 5-(5-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yflethoxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl) picolinonitrile as a beige solid. LCMS [M+1]+ 545.5.

Workup

  1. customThe reaction mixture was absorbed on silica gel
  2. custompurified by column chromatography on silica gel eluting with EtOAc/hexanes

Sources & evidence

ORD record
ord-c50c5067d46043409d443ee50f4b18ca
Source dataset
uspto-grants-2015_08
Patent number
US09108944B2

Linked notes

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