Sodium hydride → 2-(4-((2'-Chloro-4',4'-difluoro-4,5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-pyridine

HRID 1517619Notes

Reaction equation

HRID 1517619 reaction equation
[C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].CO[C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:17]1[CH:21]=[C:20]([CH2:22][N:23]2[CH2:39][CH2:38][C:26]3([C:31]4[S:32][C:33]([Cl:35])=[CH:34][C:30]=4[C:29]([F:37])([F:36])[CH2:28][O:27]3)[CH2:25][CH2:24]2)[C:19]([CH3:40])=[N:18]1>O1CCCC1>[Cl:35][C:33]1[S:32][C:31]2[C:26]3([CH2:25][CH2:24][N:23]([CH2:22][C:20]4[C:19]([CH3:40])=[N:18][N:17]([C:12]5[C:11]([C:10]6[O:5][N:4]=[C:1]([CH3:2])[N:3]=6)=[CH:16][CH:15]=[CH:14][N:13]=5)[CH:21]=4)[CH2:39][CH2:38]3)[O:27][CH2:28][C:29]([F:36])([F:37])[C:30]=2[CH:34]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 30926N-HydroxyacetamidineHCID 671682472-(4-((2'-chloro-4',4'-difluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-nicotinic acid methyl ester

Product 1

HCID 582686012-(4-((2'-Chloro-4',4'-difluoro-4,5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-pyridineYield 22.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of acetamide oxime (154 mg, 2.1 mmol) in 7 mL tetrahydrofuran, are added under argon 139 mg of grinded 4A molecular sieves and sodium hydride (2.1 mmol; 84 mg as 60% in mineral oil). The mixture is allowed to stir for 30 min at 50° C. After cooling to room temperature, 2-(4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-nicotinic acid methyl ester (309 mg, 0.6 mmol) is added and then the mixture is heated at 50° C. for 40 min. Quenched after cooling with water and extracted with dichloromethane. After drying the organic phase with magnesium sulfate and evaporation of the solvent, the residue is diluted in methanol and purified using a 5 g SCX cartridge. The resulting residue is further purified by semipreparative reverse phase HPLC_MS using a XBridge column (Sum, 19×100 mm) and a gradient between 60 and 80% of B in A in 5 min at flow 25 mL/min (basic conditions A: ammonium bicarbonate 20 mM pH9 and B: acetonitrile) to give 71 mg of the title compound. MS (m/z): 533 (M+1).

Workup

  1. temperatureAfter cooling to room temperature
  2. temperaturethe mixture is heated at 50° C. for 40 min
  3. customQuenched
  4. temperatureafter cooling with water
  5. extractionextracted with dichloromethane
  6. customAfter drying the organic phase
  7. customwith magnesium sulfate and evaporation of the solvent
  8. additionthe residue is diluted in methanol
  9. custompurified
  10. customThe resulting residue is further purified by semipreparative reverse phase HPLC_MS
  11. waita gradient between 60 and 80% of B in A in 5 min at flow 25 mL/min (basic conditions A: ammonium bicarbonate 20 mM pH9 and B

Sources & evidence

ORD record
ord-adceefae5e2d4ff6894ee205a1ff03b9
Source dataset
uspto-grants-2012_07
Patent number
US08232289B2

Reaction notes

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