Pivaloyl chloride → HCID 86674623, compound

HRID 2283184Notes

Reaction equation

HRID 2283184 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11](C(O)=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CC(C)(C)C(Cl)=O.Cl.[CH3:35][O:36][C:37](=[O:40])[CH2:38][NH2:39]>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:17])[C:11]([NH:39][CH2:38][C:37]([O:36][CH3:35])=[O:40])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 62493Pivaloyl chlorideHCID 81531Diisopropylethylamine2×HCID 122755Glycine methyl ester hydrochlorideHCID 672120915-(3-Chlorophenyl)-3-hydroxy-2-pyridinecarboxylic acid

Product 1

HCID 86674623HCID 86674623, compoundYield 91%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
3 °C

Procedure

A 20 L reactor equipped with a mechanical stirrer, condenser, thermometer and nitrogen inlet was charged with 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, 3, (380 g, 1.52 mol) and diisopropylethylamine (DIPEA) (295 g, 2.28 mol). With agitation, the solution was cooled to 3° C. and charged with trimethylacetyl chloride (275.7 g, 2.29 mol) while maintaining a temperature of less than 11° C., The mixture was then agitated at ambient temperature for 2 hours. The mixture was then cooled to 10° C. and charged with a slurry of glycine methyl ester HCl (573.3 g, 4.57 mol) and THF (1689 g, 1900 mL), then charged with DIPEA (590.2 g, 4.57 mol) and agitated at ambient temperature for 16 hours. The mixture was then charged with EtOH (1500 g, 1900 mL) and concentrated under reduced pressure to a reaction volume of about 5.8 L. The EtOH addition and concentration was repeated twice more. Water (3800 g) was then added and the mixture was agitated for 16 hours at ambient temperature. The resulting solid product was isolated by filtration and washed with a mixture of EtOH (300 g, 380 mL) and water (380 g), followed by water (3800 g), dried under reduced pressure for 18 hours at 50° C. to afforded 443 g (91% yield) of the desired product as an off-white solid. Purity by HPLC was 98.9%. 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 9.52 (t, 1H), 8.56 (d, 1H), 7.93 (s, 1H), 7.80 (q, 2H), 7.55 (t, 2H), 4.12 (d, 2H), and 3.69 (s, 3H).

Workup

  1. customA 20 L reactor equipped with a mechanical stirrer, condenser
  2. temperaturewhile maintaining a temperature of less than 11° C.
  3. temperatureThe mixture was then cooled to 10° C.
  4. stirringagitated at ambient temperature for 16 hours
  5. concentrationconcentrated under reduced pressure to a reaction volume of about 5.8 L
  6. additionThe EtOH addition and concentration
  7. additionWater (3800 g) was then added
  8. stirringthe mixture was agitated for 16 hours at ambient temperature
  9. customThe resulting solid product was isolated by filtration
  10. washwashed with a mixture of EtOH (300 g, 380 mL) and water (380 g)
  11. customdried under reduced pressure for 18 hours at 50° C.

Sources & evidence

ORD record
ord-5a68376996cb45b5a97ef34e9a6dac1a
Source dataset
uspto-grants-2015_09
Patent number
US09145366B2

Reaction notes

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