Hexachloroethane → 3,3-Difluoro-4-[8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester

HRID 451579Notes

Reaction equation

HRID 451579 reaction equation
[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:12]([N:16]=[C:17]([NH2:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C(N(CC)CC)C.CP(C)C.[F:39][C:40]1([F:55])[C:45](O)(O)[CH2:44][CH2:43][N:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:41]1.[B][B][B][B][B][B][B][B][B][B].C([O-])(O)=O.[Na+]>C1COCC1.CO>[C:51]([O:50][C:48]([N:42]1[CH2:43][CH2:44][CH:45]([NH:19][C:17]2[N:18]=[C:11]3[C:10]([C:3]4[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=4[F:1])=[CH:15][CH:14]=[CH:13][N:12]3[N:16]=2)[C:40]([F:55])([F:39])[CH2:41]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]

Participants

10

Reactant 7

HCID 6214HexachloroethaneHCID 8471TriethylamineHCID 68983TrimethylphosphineHCID 516892Sodium Bicarbonate2×HCID 57415845tert-Butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylateHCID 67341554HCID 67341554, compoundHCID 178419135HCID 178419135, compound3×

Product 1

HCID 673428633,3-Difluoro-4-[8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl esterYield 82%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent3×HCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of 8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (prepared in analogy to example 66a-c, 200 mg, 757 μmol) and hexachloroethane (215 mg, 908 mmol) under argon in dry THF (10 mL) was added triethylamine (230 mg, 317 μL, 2.27 mmol) followed by trimethylphosphine (1 M in THF, 908 μl, 908 μmol). The reaction mixture was stirred at room temperature for 0.5 hous, then tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (see example 247e, 230 mg, 908 μmol) was added and the mixture was heated to 150° C. in the microwave for 30 minutes. A solution of decaborane (92.5 mg, 98.4 μL, 757 μmol) in MeOH (1 mL) was added to the reaction mixture, then stirred at room temperature for 12 hours. Again a solution of decaborane (92.5 mg, 98.4 μL, 757 μmol) in MeOH (5 mL) was added and heated to 70° C. for 18 hours. Aqueous NaHCO3 solution was added to the reaction mixture, the aqueous phase was extracted with CH2Cl2, the organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane), whereby 85 mg of intermediate imine, 3,3-difluoro-4-[(E)-8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylimino]-piperidine-1-carboxylic acid tert-butyl ester, was isolated, which was again dissolved in dry MeOH (3 mL). Decaborane (21.6 mg, 23.0 μL, 177 μmol) was added and heated to 70° C. for 30 minutes. Aqueous NaHCO3 solution was added to the reaction mixture, the aqueous phase was extracted with CH2Cl2, the organic layers were combined, dried over Na2SO4, filtered and the solvents evaporated. The residue was purified (together with impure product fractions from first chromatography) by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane) to yield title compound as white foam (300 mg, 82%). MS ISP (m/e): 484.3/428.1/384.2 (13/100/41) [(M+H)+/(M−tBu)+/(M−Boc)+].

Workup

  1. temperaturethe mixture was heated to 150° C. in the microwave for 30 minutes
  2. stirringstirred at room temperature for 12 hours
  3. temperatureheated to 70° C. for 18 hours
  4. extractionthe aqueous phase was extracted with CH2Cl2
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. customthe solvents evaporated
  8. customThe residue was purified by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane), whereby 85 mg of intermediate imine, 3,3-difluoro-4-[(E)-8-(2,3,4-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylimino]-piperidine-1-carboxylic acid tert-butyl ester
  9. customwas isolated
  10. temperatureheated to 70° C. for 30 minutes
  11. extractionthe aqueous phase was extracted with CH2Cl2
  12. dry with materialdried over Na2SO4
  13. filtrationfiltered
  14. customthe solvents evaporated
  15. customThe residue was purified (together with impure product fractions from first chromatography) by flash chromatography (silica gel, 50 g, 0% to 15% MeOH/NH4OH (9:1) in dichloromethane)

Sources & evidence

ORD record
ord-052cb7d06f3847808d02c66e73a95177
Source dataset
uspto-grants-2013_07
Patent number
US08486967B2

Reaction notes

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