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

HRID 75095Notes

Reaction equation

HRID 75095 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 HCl (4 M in dioxane; 65 mL) in a 100 mL Hastalloy stirred Parr reactor. The reactor was heated at 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 (500 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with H2O (5×50 mL) and then with satd aq NaCl. 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, 13.75. 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 H2O (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-d3fc457dfac44e768f1b84b0b38bd674
Source dataset
uspto-grants-2014_09
Patent number
US08835409B2

Reaction notes

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