Hydrochloric Acid → Isopropyl 4-amino-6-chloro-5-fluoropicolinate

HRID 1424649Notes

Reaction equation

HRID 1424649 reaction equation
[NH2:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1.C([O-])(O)=O.[Na+].[ClH:21]>CCOC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:21])[N:5]=[C:4]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:3]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 516892Sodium BicarbonateHCID 70496176Isopropyl 4-amino-5,6-difluoropicolinate

Product 1

HCID 71551782Isopropyl 4-amino-6-chloro-5-fluoropicolinateYield 46%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
100 °C

Procedure

Propan-2-yl 4-amino-5,6-difluoropicolinate (4.25 g, 19.7 mmol) was dissolved in hydrochloric acid (HCl, 4 M in dioxane; 65 mL) in a 100 mL Hastalloy stiffed Parr reactor. The reactor was heated to 100° C. for 2 h. Upon standing at room temperature overnight, a yellow crystalline solid formed. This solid was not soluble in EtOAc, but did dissolve upon shaking with satd aq NaHCO3 solution (500 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with water (5×50 mL) and then brine. The extracts were dried (MgSO4) and concentrated under vacuum to provide an off-white solid. The crude product was purified by column chromatography (120 g silica column; 0-100% hexane-EtOAc gradient) to give a white solid (2.11 g, 46%): mp 190.7-192.4° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.543 (d, JF-H=5.7 Hz, 1H), 6.91 (br s, 2H, NH2), 5.09 (septet, J=6 Hz, 1H, CHMe2), 1.29 (d, J=6 Hz, 6H, CHMe2); 13C{1H} NMR (101 MHz, DMSO-d6) δ 162.8 (CO2R), 144.8 (d, JF-C=12 Hz, C2/C4), 143.4 (d, JF-C=254 Hz, C5), 142.7 (d, JF-C=4.8 Hz, C2/C4), 136.5 (d, JF-C=17 Hz, C6), 112.8 (d, JF-C=5 Hz, C3), 68.9 (CHMe2), 21.6 (Me); 19F NMR (376 MHz, DMSO-d6) δ −141.0 (d, JF-H=6 Hz). Anal. Calcd for C9H10ClFN2O2: C, 46.47; H, 4.33; N, 12.04. Found: C, 46.50; H, 4.33; N, 11.96.

Workup

  1. customa yellow crystalline solid formed
  2. dissolutiondid dissolve
  3. extractionThe aqueous layer was extracted with EtOAc (2×250 mL)
  4. washThe combined organic extracts were washed with water (5×50 mL)
  5. dry with materialThe extracts were dried (MgSO4)
  6. concentrationconcentrated under vacuum
  7. customto provide an off-white solid
  8. customThe crude product was purified by column chromatography (120 g silica column; 0-100% hexane-EtOAc gradient)

Sources & evidence

ORD record
ord-8d1d159aa9ab4e3ca4268aafd5696d1f
Source dataset
uspto-grants-2015_01
Patent number
US08927731B2

Reaction notes

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