Veratrole → N-Boc-(2,3-dimethoxyphenyl)-4-piperidinylmethanone

HRID 2055875Notes

Reaction equation

HRID 2055875 reaction equation
[C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].C([Li])CCC.COCN[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]>O1CCCC1>[CH3:4][O:3][C:2]1[C:1]([O:9][CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:21]

Participants

5

Reactant 3

HCID 7043Veratrole2×HCID 442032024-(Methoxymethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl esterHCID 178418339Butyllithium

Product 1

HCID 46780868N-Boc-(2,3-dimethoxyphenyl)-4-piperidinylmethanone

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A suitable reactor maintained under nitrogen is charged with veratrole (12.5 kg, 90.0 mol) and about 87 kg of tetrahydrofuran. The solution is cooled and maintained below −10° C. while adding n-butyl lithium (22.9 kg, 83.3 mol, 23.3% solution in hexane). The mixture is warmed to about 0° C. for 1 hour, then to about 25° C. for at least 2 hours. In a separate reactor maintained under nitrogen is charged with 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) as a heptanes wet cake (15.6 kg, 57.3 mol, dry weight basis) and about 66 kg of tetrahydrofuran. The mixture is cooled below −10° C.1 and the lithiated veratrole solution is added at such a rate to maintain the temperature below −10° C. The mixture is warmed to about 25° C. for at least 6 hours.2 When complete, the title compound may be utilized in Scheme H, step a, Example 108 as the reaction solution. 1The solution is sampled and analyzed by GC to determine the amount of 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) present.2The solution is sampled and analyzed by GC to confirm the complete formation of 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7). The reaction is complete if less than 3 area % of 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) is detected.

Workup

  1. temperatureA suitable reactor maintained under nitrogen
  2. temperatureThe solution is cooled
  3. temperaturemaintained below −10° C.
  4. waitto about 25° C. for at least 2 hours
  5. temperatureIn a separate reactor maintained under nitrogen
  6. temperatureThe mixture is cooled below −10° C
  7. temperatureto maintain the temperature below −10° C
  8. temperatureThe mixture is warmed to about 25° C. for at least 6 hours

Sources & evidence

ORD record
ord-6e44ce0f43ba4aa5958060fdc32a8893
Source dataset
uspto-grants-2008_02
Patent number
US07332607B2

Reaction notes

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