Sodium hydride → 3,5-Bis(trifluoromethyl)benzyl 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)piperidine-1-carboxylate

HRID 2093596Notes

Reaction equation

HRID 2093596 reaction equation
[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH2:13][OH:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[C:19]([C:21]1[CH:22]=[C:23]([CH:59]([CH3:61])[CH3:60])[C:24]2[O:28][C:27]([C:29]3[CH:57]=[CH:56][C:32]([C:33]([NH:35][CH2:36][CH:37]4[CH2:42][CH2:41][N:40]([C:43](OCC5C=CC([N+]([O-])=O)=CC=5)=[O:44])[CH2:39][CH2:38]4)=[O:34])=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:58]=1)#[N:20]>O1CCCC1>[C:19]([C:21]1[CH:22]=[C:23]([CH:59]([CH3:61])[CH3:60])[C:24]2[O:28][C:27]([C:29]3[CH:30]=[CH:31][C:32]([C:33]([NH:35][CH2:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:14][CH2:13][C:5]5[CH:4]=[C:3]([C:2]([F:15])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=5)=[O:44])[CH2:41][CH2:42]4)=[O:34])=[CH:56][CH:57]=3)=[N:26][C:25]=2[CH:58]=1)#[N:20]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1229333,5-Bis(trifluoromethyl)benzyl alcoholHCID 687421394-Nitrobenzyl 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)piperidine-1-carboxylate

Product 1

HCID 251712393,5-Bis(trifluoromethyl)benzyl 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)piperidine-1-carboxylateYield 21.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of [3,5-bis(trifluoromethyl)phenyl]methanol (17 mg) in tetrahydrofuran (5 ml) was added sodium hydride (5 mg, 60% dispersion in mineral oil). The mixture was allowed to stir for 5 min, and then 4-nitrobenzyl 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]amino}methyl)piperidine-1-carboxylate (20 mg) was added. The reaction mixture was stirred overnight at room temperature, and then was concentrated. The residue was purified by reverse-phase HPLC on a Biotage Parallex Flex, Kromasil C18 21×100 mm column, eluting at 15 mL/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (5 mg, 21%). Mass spectrum (ESI) 673.1 (M+1). NMR signals are doubled and broadened because of restricted rotation about the amide C—N bond. 1H NMR (500 MHz, CDCl3): δ 8.34 (d, J=8 Hz, 2H), 7.95 (m, 2H), 7.93 (s, 1H), 7.83 (s, 1H), 7.80 (s, 2H), 7.52 (s, 1H), 6.316 (app t, 1H), 5.23 (s, 2H), 4.23 (m, 2H), 2.82-2.90 (m, 2H), 1.89-1.93 (m, 1H), 1.83 (m, 3H), 1.73 (m, 3H), 1.46 (d, J=7 Hz, 6H), 1.21-1.31 (m, 4H).

Workup

  1. stirringThe reaction mixture was stirred overnight at room temperature
  2. concentrationwas concentrated
  3. customThe residue was purified by reverse-phase HPLC on a Biotage Parallex Flex, Kromasil C18 21×100 mm column
  4. washeluting at 15 mL/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min
  5. waithold for 2 min
  6. waitback to 90% water over 0.5 min
  7. waithold for 0.5 min

Sources & evidence

ORD record
ord-4fad2cff21e34ad1b07f0762eeff5d57
Source dataset
uspto-grants-2013_05
Patent number
US08445480B2

Reaction notes

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