Triphenylphosphine → HCID 86683482, compound

HRID 515820Notes

Reaction equation

HRID 515820 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[S:16])[N:14]([C:17]3[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[C:13](=[O:29])[C:9]32[CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]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>[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:15](=[S:16])[N:14]([C:17]4[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=4)[C:13](=[O:29])[C:9]43[CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=2)[CH2:33][CH2:32]1

Participants

6

Reactant 4

HCID 11776Triphenylphosphine2×HCID 660484-Piperidinol, 1-methyl-2×HCID 75555Diisopropyl diazene-1,2-dicarboxylate2×HCID 86683483HCID 86683483, compound2×

Product 1

HCID 86683482HCID 86683482, compoundYield 24.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 63, 150 mg, 0.36 mmol), 1-methylpiperidin-4-ol (50 μL, 0.39 mmol), and triphenylphosphine (125 mg, 0.47 mmol) in anhydrous THF (2 mL) was added diisopropyl azodicarboxylate (0.1 mL, 0.47 mmol) and the reaction mixture was stirred at room temperature overnight. Additional 1-methylpiperidin-4-ol (50 μL, 0.39 mmol), triphenylphosphine (125 mg, 0.47 mmol) and diisopropyl azodicarboxylate (0.1 mL, 0.47 mmol) was added and the reaction was allowed to stir an additional 16 h. The mixture was partitioned between EtOAc and water and the aqueous layer was extracted with EtOAc (2×). The combined organics were washed with water and brine, then dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (0 to 80% EtOAc/hexanes, then 0 to 5% MeOH/dichloromethane) gave impure product which was further purified by preparative HPLC (40 to 75% acetonitrile/water, 0.1% TFA) to afford 45 mg of 5-(5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.22 (d, 1H), 8.76 (d, 1H), 7.30 (d, 2H), 7.15 (d, 2H), 4.52-4.39 (m, 1H), 2.72-2.56 (m, 4H), 2.49-2.38 (m, 2H), 2.25-2.14 (m, 5H), 2.03-1.90 (m, 3H), 1.77-1.49 (m, 3H). LCMS [M+1]+ 516.0.

Workup

  1. stirringto stir an additional 16 h
  2. customThe mixture was partitioned between EtOAc and water
  3. extractionthe aqueous layer was extracted with EtOAc (2×)
  4. washThe combined organics were washed with water and brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated in vacuo
  7. customPurification by silica gel chromatography (0 to 80% EtOAc/hexanes
  8. custom0 to 5% MeOH/dichloromethane) gave impure product which
  9. customwas further purified by preparative HPLC (40 to 75% acetonitrile/water, 0.1% TFA)

Sources & evidence

ORD record
ord-f90df654d29442a6ab2700f0e2fe8436
Source dataset
uspto-grants-2015_08
Patent number
US09108944B2

Reaction notes

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