Sodium borohydride → [4-[6-Amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]methanol

HRID 908396Notes

Reaction equation

HRID 908396 reaction equation
[BH4-].[Na+].[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:11]([CH:28]=[O:29])=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:30]1[O:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1>CO.ClCCl>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:11]([CH2:28][OH:29])=[N:12][N:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:14]=2)=[CH:6][C:5]=1[C:30]1[O:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1

Participants

5

Reactant 2

HCID 4311764Sodium borohydride2×HCID 86630148Tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate

Product 1

HCID 67388492[4-[6-Amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]methanolYield 100.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

Sodium tetrahydroborate (42.6 mg) and tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate (550 mg) in methanol (10 ml) were stirred at room temperature for 1 hour. The reaction was incomplete and further sodium tetrahydroborate (42.6 mg) was added at room temperature and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100 ml) and washed with water (2×20 ml), dried over magnesium sulfate and concentrated to dryness. The residue was dissolved in dichloromethane (2 ml) and the solution was cooled to 0° C. and treated with trifluoroacetic acid (3 ml). The resulting solution was allowed to stir at room temperature for 1 hour and then concentrated to dryness. The residue was re-dissolved in methanolic ammonia (7N, 5 ml) and absorbed onto silica and purified by flash chromatography on silica gel eluting with 0 to 15% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford [4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-1-(4-piperidyl)pyrazol-3-yl]methanol (440 mg) as a solid. The tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-formyl-pyrazol-1-yl]piperidine-1-carboxylate used as starting material was prepared as follows: 4-bromo-2H-pyrazole-3-carbaldehyde (3 g), potassium carbonate (3.32 g) and tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (6.23 g) in acetonitrile (150 ml) were stirred at reflux overnight. The resulting precipitate was removed by filtration and the filtrate was concentrated and purified by flash chromatography on silica gel eluting with 0 to 20% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to yield tert-butyl 4-(4-bromo-3-formyl-pyrazol-1-yl)piperidine-1-carboxylate (4.10 g) as a clear colourless oil which crystallised on standing. NMR Spectrum: (CDCl3) 1.48 (s, 9H), 1.92 (dd, 1H), 1.96 (dd, 1H), 2.10-2.18 (m, 2H), 2.81-2.97 (m, 2H), 4.27 (bs, 2H), 4.28-4.38 (m, 1H), 7.543 (s, 1H), 9.96 (s, 1H); Mass spectrum: M+H+ 360.

Workup

  1. washwashed with water (2×20 ml)
  2. dry with materialdried over magnesium sulfate
  3. concentrationconcentrated to dryness
  4. dissolutionThe residue was dissolved in dichloromethane (2 ml)
  5. temperaturethe solution was cooled to 0° C.
  6. additiontreated with trifluoroacetic acid (3 ml)
  7. stirringto stir at room temperature for 1 hour
  8. concentrationconcentrated to dryness
  9. dissolutionThe residue was re-dissolved in methanolic ammonia (7N, 5 ml)
  10. customabsorbed onto silica
  11. custompurified by flash chromatography on silica gel eluting with 0 to 15% methanolic ammonia (7 N) in dichloromethane
  12. customThe solvent was evaporated to dryness

Sources & evidence

ORD record
ord-64713b4898624547a639a7afed5480e5
Source dataset
uspto-grants-2011_09
Patent number
US08017611B2

Reaction notes

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