Hydrochloric Acid → HCID 67495464, compound

HRID 1411345Notes

Reaction equation

HRID 1411345 reaction equation
F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([Mg]Cl)(C)C.Cl>O1CCCC1.O.CC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[C@H:20]([CH3:24])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 2428196-Fluoronicotinic AcidHCID 2756811(R)-1-Boc-3-methylpiperazineHCID 178418918HCID 178418918, compound

Product 1

HCID 67495464HCID 67495464, compoundYield 96.3%

Reagents, catalysts & solvents 3

HCID 180AcetoneSolventHCID 962WaterSolvent4×HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-40 °C

Procedure

A mixture of 6-fluoronicotinic acid (150 g, 1.063 mol) and (R)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (234.2 g, 1.169 mol) in tetrahydrofuran (1.75 L) was cooled to −40° C. and then 2 M isopropylmagnesium chloride in tetrahydrofuran (1.196 L, 2.39 mol) was added slowly maintaining the temperature less than −20° C. The reaction mixture was slowly warmed to RT, stirred at RT for 4 h and then 1 N HCl (1.75 L) and water (1.175 L) were added. The reaction mixture was extracted with ethyl acetate (4 L). The organic phase was evaporated to provide crude solid (534 g). To the crude solid was added acetone (2 L) and water (200 mL). The resulting reaction mixture was heated to 50° C. and then water (2.8 L) was added slowly. Seed crystals from a previous run at smaller scale were added after ˜1 L of water. The reaction mixture was cooled to 20° C. over 3 h, stirred at 20° C. overnight and filtered. The solid was washed with 2:3 acetone:water (2×500 mL) and dried under vacuum to provide the title compound (329 g, 96% yield) as an off-white solid. HPLC Method A: Retention time 9.73 min.

Workup

  1. temperaturemaintaining the temperature less than −20° C
  2. temperatureThe reaction mixture was slowly warmed to RT
  3. extractionThe reaction mixture was extracted with ethyl acetate (4 L)
  4. customThe organic phase was evaporated
  5. customto provide crude solid (534 g)
  6. customThe resulting reaction mixture
  7. temperaturewas heated to 50° C.
  8. temperatureThe reaction mixture was cooled to 20° C. over 3 h
  9. stirringstirred at 20° C. overnight
  10. filtrationfiltered
  11. washThe solid was washed with 2:3 acetone
  12. dry with materialwater (2×500 mL) and dried under vacuum

Sources & evidence

ORD record
ord-d3a0fe2d83734b8b8a5bffbc4b874c77
Source dataset
uspto-grants-2014_12
Patent number
US08921372B2

Reaction notes

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