Hydrochloric Acid → Methyl 2-(3-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate

HRID 1963388Notes

Reaction equation

HRID 1963388 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17]([OH:19])=O)[CH2:14][CH2:13][N:12]2[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:36]([O:38][C:39](=[O:44])[CH2:40]C([O-])=O)[CH3:37].[K+].[Cl-].[Mg+2].[Cl-].Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.CC(OC)(C)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17](=[O:19])[CH2:40][C:39]([O:38][CH2:36][CH3:37])=[O:44])[CH2:14][CH2:13][N:12]2[C:20]([O:22][CH3:23])=[O:21])[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667322282-(3-tert-Butylphenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×

Product 1

HCID 66731921Methyl 2-(3-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylateYield 95%

Reagents, catalysts & solvents 2

HCID 15413tert-Butyl methyl etherSolventHCID 178479889HCID 178479889, compoundSolvent2×

Procedure

2-(3-tert-Butylphenyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.73 g, 8.55 mmol) (reference compound 14) was dissolved in methyl THF (40 mL) and di(1H-imidazol-1-yl)methanone (2.079 g, 12.82 mmol) added. The suspension was stirred at room temperature under nitrogen for 2 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (2.62 g, 15.39 mmol) was suspended in methyl THF (60 mL) and magnesium chloride (1.465 g, 15.39 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3 h using an oversized stirring bar (flask 2). The beige suspension in flask 1 was now added to the white suspension in flask 2. The resulting beige suspension was stirred under nitrogen at room temperature for 23 h. The mixture was acidified to pH 1 with 0.5 M HCl (100 mL) and MTBE (200 mL) was added. The phases were separated and the organic phase extracted with water (30 mL), satd NaHCO3 (30 mL) and water (30 mL), dried over anhydrous Na2SO4, and evaporated to yield crude methyl 2-(3-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (3.14 g, 95%) as a brown oil.

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen for 3 h
  2. additionThe beige suspension in flask 1 was now added to the white suspension in flask 2
  3. stirringThe resulting beige suspension was stirred under nitrogen at room temperature for 23 h
  4. additionwas added
  5. customThe phases were separated
  6. extractionthe organic phase extracted with water (30 mL), satd NaHCO3 (30 mL) and water (30 mL)
  7. dry with materialdried over anhydrous Na2SO4
  8. customevaporated

Sources & evidence

ORD record
ord-8b09289796be42dcaf100006e8039c5a
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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