Methanol → Ly-2940094

HRID 1517626Notes

Reaction equation

HRID 1517626 reaction equation
[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:32])([F:31])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH:25]=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3.[BH4-].[Na+].CO>ClCCl>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:32])([F:31])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH2:25][OH:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3

Participants

5

Reactant 3

HCID 887MethanolHCID 4311764Sodium borohydrideHCID 582685962-[4-[(2-Chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehyde

Product 1

HCID 52914971Ly-2940094Yield 92.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of 2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehyde (180 g, 377 mmol) in anhydrous dichloromethane (1.5 L) at 0° C. is sequentially added sodium borohydride (7.2 g, 188.5 mmol) and anhydrous methanol (0.5 L) and the contents are allowed to reach room temperature while stirring 30 min. LC/MS analysis of the reaction mixture reveals completion. Volatiles are removed under reduced pressure and the residue obtained is partitioned between dichloromethane (2 L) and water (300 mL). The layers are separated and the organic layer is sequentially washed with 1 N aqueous solution of sodium hydroxide (300 mL), water (3×300 mL), brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue is purified on silica gel using 50-55% ethyl acetate in hexane containing 1% triethylamine to afford [2-[4-[(2-Chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol as a solid (167 g, 92% yield). MS (m/z): 481 (M+1).

Workup

  1. customat 0° C.
  2. customto reach room temperature
  3. customVolatiles are removed under reduced pressure
  4. customthe residue obtained
  5. customis partitioned between dichloromethane (2 L) and water (300 mL)
  6. customThe layers are separated
  7. washthe organic layer is sequentially washed with 1 N aqueous solution of sodium hydroxide (300 mL), water (3×300 mL), brine
  8. dry with materialdried (sodium sulfate)
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue is purified on silica gel using 50-55% ethyl acetate in hexane containing 1% triethylamine

Sources & evidence

ORD record
ord-82b6d5645aa44ee6b27505bf5b94dd34
Source dataset
uspto-grants-2012_07
Patent number
US08232289B2

Reaction notes

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