Hydrochloric Acid → HCID 131730494, compound

HRID 1963632Notes

Reaction equation

HRID 1963632 reaction equation
[Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([O-:11])=O)[CH3:5].[K+].[F:14][C:15]1[CH:16]=[C:17]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:18][CH:19]1[CH2:24][CH:23]([C:25](O)=[O:26])[CH2:22][CH2:21][N:20]1[C:28]([O:30][CH3:31])=[O:29].N1(C(N2C=CN=C2)=O)C=CN=C1.Cl>CN1C2C(N=C(N)NC=2NCC1CNC1C=CC(C(NC(C(O)=O)CCC(O)=O)=O)=CC=1)=O.CC(OC)(C)C>[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([C@@H:23]1[CH2:22][CH2:21][N:20]([C:28]([O:30][CH3:31])=[O:29])[C@@H:19]([CH2:18][C:17]2[CH:32]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:34]=[C:15]([F:14])[CH:16]=2)[CH2:24]1)=[O:11])[CH3:5].[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:25]([C@H:23]1[CH2:22][CH2:21][N:20]([C:28]([O:30][CH3:31])=[O:29])[C@@H:19]([CH2:18][C:17]2[CH:32]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:34]=[C:15]([F:14])[CH:16]=2)[CH2:24]1)=[O:26])[CH3:5]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66731960HCID 66731960, compound2×

Product 2

HCID 131730493HCID 131730493, compoundYield 14%HCID 131730494HCID 131730494, compoundYield 46%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
50 °C

Procedure

Magnesium chloride (2.3 g, 24.16 mmol) and potassium 3-ethoxy-3-oxopropanoate (4 g, 23.50 mmol) were suspended in methyl THF (70 mL) under nitrogen and the resulting suspension was stirred at 50° C. with an oversized stirring bar for 18 h, then cooled to room temperature (flask 1). To a suspension of 2-(3-fluoro-5-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.58 g, 12.61 mmol) (reference compound 58) in methyl THF (70.0 mL) was added di(1H-imidazol-1-yl)methanone (3.36 g, 20.72 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 2 h (flask 2). The contents of flask 2 is transferred into flask 1 by transfer needle. Wash with methyl THF (30 mL). Resulting suspension stirred at room temperature for 72 h. 3.8 M HCl was added (ca. 200 mL) and the resulting biphasic mixture stirred vigorously for 30 min. MTBE was added and the phases separated. The organic phase was washed with water, satd NaHCO3 and water, then dried over MgSO4 and evaporated. The residue was purified via Biotage (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes, then 20%=>60% over 7 CV). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-5-(trifluoromethyl)benzyl)-piperidine-1-carboxylate (758 mg, 14%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.52 g, 46%) were isolated. Cis-isomer: 1H NMR (600 MHz, cdcl3) δ 1.20-1.28 (m, 3H), 1.64-1.95 (m, 4H), 2.68-2.81 (m, 2H), 2.95 (dd, 1H), 3.02 (ddd, 1H), 3.45 (s, 2H), 3.59 (s, 3H), 3.84-3.96 (m, 1H), 4.06-4.23 (m, 3H), 7.04-7.11 (m, 1H), 7.15 (d, 1H), 7.19-7.24 (m, 1H). MS m/z 434 (M+H)+. Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 1.20-1.29 (m, 3H), 1.43-1.99 (m, 4H), 2.75-2.89 (m, 1H), 2.89-3.04 (m, 3H), 3.36-3.72 (m, 5H), 4.03-4.33 (m, 3H), 4.49-4.72 (m, 1H), 6.98-7.20 (m, 2H), 7.20-7.28 (m, 1H).

Workup

  1. temperaturecooled to room temperature (flask 1)
  2. stirringThe resulting mixture was stirred at room temperature for 2 h (flask 2)
  3. customThe contents of flask 2 is transferred into flask
  4. washWash with methyl THF (30 mL)
  5. customResulting suspension
  6. stirringstirred at room temperature for 72 h
  7. stirringthe resulting biphasic mixture stirred vigorously for 30 min
  8. customthe phases separated
  9. washThe organic phase was washed with water
  10. dry with materialdried over MgSO4
  11. customevaporated
  12. customThe residue was purified via Biotage (Biotage® KP-SIL 340 g column, 1 CV 20% EtOAc in heptanes

Sources & evidence

ORD record
ord-67732ab87283415f8419881702169f67
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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