Isopropylamine → 1-(1,1-Dimethylethyl) 4-methyl 4-[(4-chlorophenyl)methyl]-1,4-piperidinedicarboxylate

HRID 1470262Notes

Reaction equation

HRID 1470262 reaction equation
C(N)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[CH3:18][O:19][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].[Cl:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][CH:37]=1.[Cl-].[NH4+]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:18][O:19][C:20]([C:22]1([CH2:40][C:39]2[CH:42]=[CH:43][C:36]([Cl:35])=[CH:37][CH:38]=2)[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]1)=[O:21]

Participants

9

Reactant 6

HCID 6363IsopropylamineHCID 77231-Chloro-4-(chloromethyl)benzeneHCID 25517Ammonium ChlorideHCID 3928701-N-Boc-4-Piperidinecarboxylic acid methyl esterHCID 2724682Lithium diisopropylamideHCID 178418339Butyllithium

Product 1

HCID 598404671-(1,1-Dimethylethyl) 4-methyl 4-[(4-chlorophenyl)methyl]-1,4-piperidinedicarboxylateYield 34.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 12679HexamethylphosphoramideSolvent

Procedure

To a solution of isopropylamine (3.71 ml, 26.45 mmol) in THF (110 ml) at 0° C. was added n-butyllithium (10.1 ml of a 2.5M solution in hexanes, 25.25 mmol). The resulting LDA solution was added via cannula to a solution of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (5.85 g, 24.04 mmol) in THF (110 ml) and HMPA (20 ml) at −78° C. and stirring was continued for 1 hour. 4-Chlorobenzyl chloride (6.4 ml, 50.49 mmol) in THF (20 ml) was added and the solution was warmed to room temperature over 2 hours. After stirring for 18 hours, saturated aqueous ammonium chloride (500 ml) was added and the aqueous phase was extracted with diethyl ether (2×200 ml). The organic phases were combined, dried over magnesium sulphate and concentrated to dryness. Purification by silica column chromatography (0.5% methanol in DCM) gave the ester as an oil (3.03 g, 34%). LC-MS (LCT1) m/z 390 [M+Na+], Rt 8.02 min.

Workup

  1. stirringAfter stirring for 18 hours
  2. extractionthe aqueous phase was extracted with diethyl ether (2×200 ml)
  3. dry with materialdried over magnesium sulphate
  4. concentrationconcentrated to dryness
  5. customPurification by silica column chromatography (0.5% methanol in DCM)

Sources & evidence

ORD record
ord-1ab29bb43c37452faf64d2f973c48ec7
Source dataset
uspto-grants-2015_04
Patent number
US09006430B2

Reaction notes

Loading…