Hydrochloric Acid → HCID 131730483, compound

HRID 1963604Notes

Reaction equation

HRID 1963604 reaction equation
[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([OH:13])=O)[CH2:8][CH2:7][N:6]1[C:14]([O:16][CH3:17])=[O:15].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:35]([O:37][C:38](=[O:43])[CH2:39][C:40]([O-:42])=O)[CH3:36].[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.O>[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:13])[CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:43])[CH2:8][CH2:7][N:6]1[C:14]([O:16][CH3:17])=[O:15].[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:40](=[O:42])[CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:43])[CH2:8][CH2:7][N:6]1[C:14]([O:16][CH3:17])=[O:15]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66732104HCID 66732104, compound2×

Product 2

HCID 131730482HCID 131730482, compoundYield 18%HCID 131730483HCID 131730483, compoundYield 69%

Reagents, catalysts & solvents 3

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

Procedure

To a mixture of 2-(2,5-difluorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (7.4 g, 23.62 mmol) (reference compound 54) in anhydrous methyl-THF (150 mL) was added di(1H-imidazol-1-yl)methanone (5.74 g, 35.43 mmol) at room temperature under nitrogen. The suspension was stirred at room temperature for 4 h (flask 1). To a mixture of potassium 3-ethoxy-3-oxopropanoate (7.24 g, 42.52 mmol) in anhydrous methyl-THF (150 mL) was added magnesium chloride (4.05 g, 42.52 mmol) at room temperature under nitrogen. The mixture was heated at 50° C. for 4 h, and then allowed to cool to room temperature (flask 2). The suspension in flask 1 was added to the suspension in flask 2. The reaction mixture was stirred at room temperature for 48 h. The mixture was acidified to pH 1 with 4 M HCl and then water and MTBE was added. The organic phase was separated, washed with water, satd NaHCO3, dried and evaporated. The diastereomers were separated by flash chromatography on silica gel using iso-hexane/EtOAc (100:15 and 100:50) as eluent. Trans-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.6 g, 18%) and cis-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (6.2 g, 69%) were isolated as oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 1.20-1.32 (m, 3H), 1.64-2.00 (m, 4H), 2.67-3.15 (m, 4H), 3.48 (s, 2H), 3.58 (s, 3H), 3.87-3.99 (m, 1H), 4.07-4.32 (m, 3H), 6.82-7.01 (m, 3H). Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.22-1.32 (m, 3H), 1.45-2.01 (m, 4H), 2.52-3.12 (m, 4H), 3.41-3.74 (m, 5H), 4.04-4.34 (m, 3H), 4.48-4.74 (m, 1H), 6.82-7.06 (m, 3H). MS m/z 384 (M+H)+

Workup

  1. temperatureThe mixture was heated at 50° C. for 4 h
  2. temperatureto cool to room temperature (flask 2)
  3. additionThe suspension in flask 1 was added to the suspension in flask 2
  4. stirringThe reaction mixture was stirred at room temperature for 48 h
  5. customThe organic phase was separated
  6. washwashed with water
  7. customdried
  8. customevaporated
  9. customThe diastereomers were separated by flash chromatography on silica gel

Sources & evidence

ORD record
ord-009f25c7cbdc49ae8db7bbb7c15e0317
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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