Hydrochloric Acid → cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate

HRID 1963538Notes

Reaction equation

HRID 1963538 reaction equation
[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([OH:15])=O)[CH2:10][CH2:9][N:8]2[C:16]([O:18][CH3:19])=[O:17])=[CH:4][CH:3]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:34]([O:36][C:37](=[O:42])[CH2:38][C:39]([O-:41])=O)[CH3:35].[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>[CH2:34]([O:36][C:37](=[O:42])[CH2:38][C:13]([C@@H:11]1[CH2:10][CH2:9][N:8]([C:16]([O:18][CH3:19])=[O:17])[C@@H:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=2)[CH2:12]1)=[O:15])[CH3:35].[CH2:34]([O:36][C:37](=[O:42])[CH2:38][C:39]([C@H:11]1[CH2:10][CH2:9][N:8]([C:16]([O:18][CH3:19])=[O:17])[C@@H:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=2)[CH2:12]1)=[O:41])[CH3:35]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 667316402-(4-Fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×

Product 2

HCID 131730457trans-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylateYield 10.36%HCID 131730458cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylateYield 57.3%

Reagents, catalysts & solvents 2

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

Procedure

2-(4-Fluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.428 g, 14.99 mmol) (reference compound 43) was dissolved in methyl THF (100 mL) and di(1H-imidazol-1-yl)methanone (3.65 g, 22.49 mmol) added. The suspension was stirred at room temperature overnight under nitrogen (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (4.59 g, 26.99 mmol) was suspended in methyl THF (100 mL) and magnesium chloride (2.57 g, 26.99 mmol) added. The suspension was stirred at 50° C. under nitrogen for 3 h (flask 2). The slightly 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 overnight. The mixture was acidified to pH 1 with 3.8 M HCl and MTBE added. The phases were separated and the organic phase extracted with water, sat NaHCO3 and water. Evaporated the solvents to yield a yellow oil. The diastereoisomers were separated on Biotage (0%=>70% EtOAc in heptane, 7 CV; Biotage® KP-SIL 340 g column). Mixed fractions were repurified on Biotage (30%=>65% EtOAc in heptane, 10 CV; Biotage® KP-SIL 50 g column). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (0.458 g, 10.36%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (2.531 g, 57.3%) were isolated. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.20-1.25 (m, 3H), 1.61-1.68 (m, 1H), 1.77-1.91 (m, 3H), 2.64-2.73 (m, 2H), 2.82-2.87 (m, 1H), 2.94-3.00 (m, 1H), 3.43 (s, 2H), 3.60 (s, 3H), 3.90 (dd, 1H), 4.11-4.17 (m, 3H), 6.91-6.96 (m, 2H), 7.08-7.13 (m, 2H). MS m/z 366 (M+H)+. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.15-1.26 (m, 3H), 1.39-1.94 (m, 4H), 2.59-3.00 (m, 4H), 3.32-3.66 (m, 5H), 3.96-4.28 (m, 3H), 4.50 (d, br., 1H), 6.88-6.95 (m, 2H), 6.99-7.18 (m, 2H). MS m/z 366 (M+H)+

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen for 3 h (flask 2)
  2. additionThe slightly 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 overnight
  4. additionadded
  5. customThe phases were separated
  6. extractionthe organic phase extracted with water
  7. customEvaporated the solvents
  8. customto yield a yellow oil
  9. customThe diastereoisomers were separated on Biotage (0%=>70% EtOAc in heptane, 7 CV; Biotage® KP-SIL 340 g column)
  10. customMixed fractions were repurified on Biotage (30%=>65% EtOAc in heptane, 10 CV; Biotage® KP-SIL 50 g column)

Sources & evidence

ORD record
ord-320817069a1f4ad699bf4871f1746fc4
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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