Hydrochloric Acid → HCID 131730503, compound

HRID 1963653Notes

Reaction equation

HRID 1963653 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]([CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[CH2:8][CH:9]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:41]([O:43][C:44](=[O:49])[CH2:45][C:46]([O-:48])=O)[CH3:42].[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.O.CC(OC)(C)C>[C:25]([C:23]1[CH:22]=[C:7]([CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:24]=1)[CH2:8][C@H:9]1[CH2:14][C@H:13]([C:15](=[O:17])[CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:49])[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19])([CH3:28])([CH3:26])[CH3:27].[C:1]([C:5]1[CH:6]=[C:7]([CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[CH2:8][C@H:9]1[CH2:14][C@@H:13]([C:46](=[O:48])[CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:49])[CH2:12][CH2:11][N:10]1[C:18]([O:20][CH3:21])=[O:19])([CH3:3])([CH3:4])[CH3:2]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66731923HCID 66731923, compound2×

Product 2

HCID 131730502HCID 131730502, compoundYield 17%HCID 131730503HCID 131730503, compoundYield 46%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 15413tert-Butyl methyl etherSolventHCID 178479889HCID 178479889, compoundSolvent2×

Procedure

2-(3,5-Di-tert-butylbenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.723 g, 9.56 mmol) (reference compound 61) was dissolved in methyl THF (70 mL) and di(1H-imidazol-1-yl)methanone (2.325 g, 14.34 mmol) added. The suspension was stirred at room temperature under nitrogen overnight (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (2.93 g, 17.20 mmol) was suspended in methyl THF (70.0 mL) and magnesium chloride (1.638 g, 17.20 mmol) added. The suspension was stirred at 50° C. under nitrogen overnight using an oversized stirring bar (flask 2). The yellow suspension in flask 1 was now added to the white suspension in flask 2. The resulting white suspension was stirred under nitrogen at room temperature for 2 days. The mixture was acidified to pH 1 with 3.8 M HCl and MTBE and water added. The phases were separated and the organic phase washed with water, satd NaHCO3 and water. Evaporated the solvents to yield a yellow oil. The diastereomers were separated in 2 runs on Biotage (0%=>40% EtOAc in heptane, 8 CV; Biotage® KP-SIL 340 g column). Trans-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.734 g, 17%) and cis-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.027 g, 46%) were isolated as colorless oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.19-1.35 (m, 21H), 1.63-1.99 (m, 4H), 2.62-3.05 (m, 4H), 3.46 (s, 2H), 3.57-3.64 (m, 3H), 3.88-3.97 (m, 1H), 4.07-4.26 (m, 3H), 6.97-7.01 (m, 2H), 7.24-7.28 (m, 1H). MS m/z 460 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.11-1.39 (m, 21H), 1.40-2.02 (m, 4H), 2.52-3.14 (m, 4H), 3.33-3.55 (m, 3H), 3.64 (s, br., 2H), 3.98-4.35 (m, 3H), 4.37-4.80 (m, 1H), 6.91-7.12 (m, 2H), 7.24-7.30 (m, 1H). MS m/z 460 (M+H)+

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen overnight
  2. additionThe yellow suspension in flask 1 was now added to the white suspension in flask 2
  3. stirringThe resulting white suspension was stirred under nitrogen at room temperature for 2 days
  4. additionadded
  5. customThe phases were separated
  6. washthe organic phase washed with water
  7. customEvaporated the solvents
  8. customto yield a yellow oil
  9. customThe diastereomers were separated in 2

Sources & evidence

ORD record
ord-d0dc778674734b2bb2fb6c1b7223b557
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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