Acetonitrile → Isopropyl 4-(amino)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate

HRID 541042Notes

Reaction equation

HRID 541042 reaction equation
O.O.[F-].[K+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9](B2OCCCO2)=[C:8]([F:18])[C:7]=1[O:19][CH3:20].[NH2:21][C:22]1[C:27]([F:28])=[C:26](Br)[N:25]=[C:24]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH:23]=1.CC#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:21][C:22]1[C:27]([F:28])=[C:26]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[C:7]([O:19][CH3:20])[C:8]=2[F:18])[N:25]=[C:24]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH:23]=1

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 23708904Potassium fluoride dihydrateHCID 577824192-(4-Chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinaneHCID 86709864Isopropyl 4-amino-6-bromo-5-fluoropicolinate

Product 1

HCID 70497595Isopropyl 4-(amino)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
69 °C

Procedure

In a 50 mL three-neck round bottom flask was charged potassium fluoride dihydrate (12.0 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (5.40 mmol), isopropyl 4-amino-6-bromo-5-fluoropicolinate (4.0 mmol), MeCN (15 mL), and H2O (5 mL). The resulting mixture was sparged with N2 for 15 min then Pd(PPh3)2Cl2 (0.006-0.08 mmol) was added. The resulting suspension was sparged for 20 min then heated to 68-70° C. After 1 h of stirring, an aliquot (1-2 μL) was taken and diluted with MeCN (2 mL). The aliquot was analyzed by HPLC by monitoring the consumption of starting material 4-(acetylamido)-5-fluoropicolinate ester. After the reaction was deemed complete the heating mantle was removed and the mixture was cooled to ambient temperature and was diluted with MeCN/toluene/H2O (75 mL, 3/1/1); if needed, extra volume of the solvent mixture was added to dissolve the solids. The layers were then separated using a reparatory funnel. The product assay was then determined using an internal standard (hexanophenone): mp=177-179° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, JF-H=6.8 Hz, 1H), 7.47 (dd, J=8.4, 1.6 Hz, 1H), 7.29 (dd, J=8.4, 7.2 Hz, 1H), 6.70 (s, 2H), 5.12 (p, J=6.4 Hz, 1H), 3.93 (s, 3H), 1.30 (d, J=6.4 Hz, 6H); 13C NMR (100.6 MHz, DMSO-d6) δ 163.6, 154.4, 151.2, 148.0, 145.5, 144.0 (dd, JF-C=38.3, 4.2 Hz), 143.7 (d, JF-C=2.9 Hz), 139.0 (d, JF-C=13.6 Hz), 128.2 (d, JF-C=3.1 Hz), 126.0 (d, JF-C=3.4 Hz), 125.4 (d, JF-C=3.5 Hz), 123.9 (dd, JF-C=14.2, 3.5 Hz), 112.5 (d, JF-C=5.1 Hz), 68.5, 61.5 (d, JF-C=4.0 Hz), 21.6; 19F {1H} NMR (376.5 MHz, DMSO-d6) δ −129.4 (d, JF-F=25.6 Hz), −142.8 (d, JF-F=25.6 Hz); MS Calcd. for C16H15ClF2N2O3: 356.1. Found: 356 (M+), 270.

Workup

  1. customThe resulting mixture was sparged with N2 for 15 min
  2. customThe resulting suspension was sparged for 20 min
  3. additiondiluted with MeCN (2 mL)
  4. customthe consumption of starting material 4-(acetylamido)-5-fluoropicolinate ester
  5. customwas removed
  6. temperaturethe mixture was cooled to ambient temperature
  7. additionwas diluted with MeCN/toluene/H2O (75 mL, 3/1/1)
  8. additionextra volume of the solvent mixture was added
  9. dissolutionto dissolve the solids
  10. customThe layers were then separated

Sources & evidence

ORD record
ord-b30fa14854a442d08f386561640c6d5c
Source dataset
uspto-grants-2014_10
Patent number
US08871943B2

Reaction notes

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