Acetic Acid → (2S)-1-(1,3-benzoxazol-2-yl)-N2-2-[(cis)-2,4,6-trimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide

HRID 2119373Notes

Reaction equation

HRID 2119373 reaction equation
[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][CH2:19][CH2:20][N:21]1[C@H:26]([CH3:27])[CH2:25][NH:24][CH2:23][C@@H:22]1[CH3:28])=[O:17].C=O.[C:31]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C.C(OCC)C>[NH3:3].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][CH2:19][CH2:20][N:21]1[C@H:26]([CH3:27])[CH2:25][N:24]([CH3:31])[CH2:23][C@@H:22]1[CH3:28])=[O:17]

Participants

8

Reactant 4

HCID 176Acetic Acid2×HCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 9821522(2S)-1-(1,3-benzoxazol-2-yl)-N2-2-[(cis)-2,6-dimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide

Product 2

HCID 222AmmoniaHCID 9952780(2S)-1-(1,3-benzoxazol-2-yl)-N2-2-[(cis)-2,4,6-trimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamideYield 94.9%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6342AcetonitrileSolvent

Procedure

A solution of (2S)-1-(1,3-benzoxazol-2-yl)-N2-2-[(cis)-2,6-dimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide (108 mg) [see Example 8] and 37% aqueous formaldehyde (0.21 ml) in acetonitrile (3 ml) was added to sodium cyanoborohydride (86.5 mg), followed by glacial acetic acid (0.1 ml). The reaction mixture was stirred at room temperature for 1.5 hours, after which time glacial acetic acid (0.1 ml) was added, and the mixture was stirred for a further 30 minutes. Diethyl ether was added to the mixture and the organic layer was washed several times with 2N aqueous sodium hydroxide solution. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 97:3.5:0.5 changing to 97:3:1, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution, to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-2-[(cis)-2,4,6-trimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide (53.1 mg) as a white solid.

Workup

  1. stirringthe mixture was stirred for a further 30 minutes
  2. washthe organic layer was washed several times with 2N aqueous sodium hydroxide solution
  3. customThe organic layer was separated
  4. dry with materialdried over magnesium sulphate
  5. customthe solvent removed under reduced pressure
  6. customThe crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 97:3.5:0.5 changing to 97:3:1, by volume, dichloromethane

Sources & evidence

ORD record
ord-808cbbad62ae423cbca0d70947dc0ddb
Source dataset
uspto-grants-2004_02
Patent number
US06686357B1

Reaction notes

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