Hydrochloric Acid → HCID 131730399, compound

HRID 1963399Notes

Reaction equation

HRID 1963399 reaction equation
[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH:6]1[C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1)=[O:4].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:36]([O:38][C:39](=[O:44])[CH2:40][C:41]([O-:43])=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.CCCCCCC.CCOC(C)=O.O.CC(OC)(C)C>[CH2:36]([O:38][C:39](=[O:44])[CH2:40][C:11]([C@@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[CH2:7]1)=[O:13])[CH3:37].[CH2:36]([O:38][C:39](=[O:44])[CH2:40][C:41]([C@H:8]1[CH2:9][CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[C@@H:6]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[CH2:7]1)=[O:43])[CH3:37]

Participants

12

Reactant 5

HCID 313Hydrochloric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 66731982HCID 66731982, compound2×

Product 2

HCID 131730398HCID 131730398, compoundYield 5%HCID 131730399HCID 131730399, compoundYield 72%

Reagents, catalysts & solvents 5

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 8900HeptaneSolventHCID 15413tert-Butyl methyl etherSolventHCID 178479889HCID 178479889, compoundSolvent2×

Procedure

1-(Methoxycarbonyl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid (2.5 g, 3.76 mmol) (reference compound 17) was dissolved in methyl THF (80 mL) then di(1H-imidazol-1-yl)methanone (1.098 g, 6.77 mmol) was added. The mixture was stirred at room temperature under nitrogen for 3 h (flask 1). In a separate flask potassium 3-ethoxy-3-oxopropanoate (1.153 g, 6.77 mmol) was suspended in methyl THF (80 mL), then magnesium chloride (0.645 g, 6.77 mmol) was added. The suspension was stirred at 50° C. under nitrogen for 3 h using a large magnetic stirring bar (flask 2). After 3 h, the contents of flask 1 was transferred into 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, then MTBE (50 mL) and water (50 mL) was added. The phases were separated and the organic layer was washed with water, satd NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated leaving a slightly yellow oil. The product was flashed on Biotage (340 g) with 1 CV at 20% followed by a gradient of 20-60% EtOAc in n-heptane (8 CV). Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (70 mg, 5%) and cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(6-(trifluoro-methyl)pyridin-3-yl)piperidine-1-carboxylate (1.085 g, 72%) were isolated. Cis-isomer: MS m/z 403 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 1.18-1.31 (m, 3H), 1.53-1.72 (m, 1H), 1.82-1.93 (m, 1H), 2.00-2.13 (m, 1H), 2.49-2.69 (m, 2H), 2.82 (dt, 1H), 3.46 (d, 2H), 3.76 (s, 3H), 4.10-4.40 (m, 3H), 5.72 (s, br., 1H), 7.64-7.77 (m, 2H), 8.63 (s, 1H). MS m/z 403 (M+H)+

Workup

  1. stirringThe suspension was stirred at 50° C. under nitrogen for 3 h
  2. waitAfter 3 h
  3. customthe contents of flask 1 was transferred into flask
  4. stirringThe resulting white suspension was stirred under nitrogen at room temperature overnight
  5. customThe phases were separated
  6. washthe organic layer was washed with water
  7. dry with materialThe organic layer was dried over Na2SO4
  8. filtrationfiltered
  9. customevaporated
  10. customleaving a slightly yellow oil

Sources & evidence

ORD record
ord-531096da75b8470a828c30ff18e34948
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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