2-Chloro-5-fluoronicotinic acid Chemical Properties

Melting point:

141-142°C

Boiling point:

297.0±35.0 °C(Predicted)

Density 

1.576±0.06 g/cm3(Predicted)

storage temp. 

under inert gas (nitrogen or Argon) at 2-8°C

pka

1.67±0.25(Predicted)

form 

powder

color 

Off-white

InChI

InChI=1S/C6H3ClFNO2/c7-5-4(6(10)11)1-3(8)2-9-5/h1-2H,(H,10,11)

InChIKey

WMADTZFXZAITIR-UHFFFAOYSA-N

SMILES

C1(Cl)=NC=C(F)C=C1C(O)=O

CAS DataBase Reference

38186-88-8(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38

Safety Statements 

7/9-24/25-26-36/37-38-51

WGK Germany 

3

HazardClass 

IRRITANT

HS Code 

2933399990

2-Chloro-5-fluoronicotinic acid Usage And Synthesis

Application

2-Chloro-5-fluoronicotinic acid possesses unique chemical properties and pharmaceutical activity, making it an intermediate in many pharmaceuticals and pesticides with a very broad application prospect. It can also be used as a pharmaceutical and pharmaceutical intermediate, a hair dyeing auxiliary agent, a polymer stabilizer, an antioxidant in photosensitive materials, and an anti-fogging agent, among other applications. 2-Chloro-5-fluoronicotinic acid is also an intermediate in many high-value-added drugs, including diabetes medications, antidepressants, antitumor drugs, local anesthetics, and antihypertensive drugs, and it has applications in the fields of antihypertensive, antitumor, and anticoccosis treatments.

Synthesis Reference(s)

The Journal of Organic Chemistry, 71, p. 4021, 2006 DOI: 10.1021/jo0602571

Synthesis

The general procedure for the synthesis of 2-chloro-5-fluoronicotinic acid from 2,6-dichloro-5-fluoropyridine-3-carboxylic acid is as follows: 1. Synthesis of the intermediate 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine: - Reagents and conditions: i. Pd(OAc)2, PPh3, Et3N, HCOOH. ii. 1) (COCl)2, CH2Cl2, catalytic amount of DMF; 2) NH3(g), Dioxane; iii. iii. TFAA, Et3N, CH2Cl2, 0 °C. H2NNH2-H2O, n-butanol, reflux. iv. 2. Synthesis of 2-chloro-5-fluoronicotinic acid (6): - Degassed DMF (270 μL), Pd(OAc)2 (0.05 eq, 2.7 g, 11.9 mmol), PPh3 (0.1 eq, 6.2 g, 23.8 mmol), and degassed Et3N (6 eq, 200 mL, 1428.6 mmol) were added to a round-bottomed flask under N2 atmosphere. - The mixture was stirred for 20 min and then HCOOH (3 eq, 28 mL, 714.3 mmol) was added. - After 5 min, 2,6-dichloro-5-fluoronicotinic acid (50 g, 238.1 mmol) was added. - The mixture was stirred at 50 °C and the progress of the reaction was monitored by 1H NMR analysis. - When all ingredients were consumed (~24 h), the mixture was cooled to 0 °C and water (500 mL) was added. - After 20 minutes, the mixture was filtered through a diatomaceous earth pad and rinsed with water. - The mixture was alkalized to pH 9 with 30% NaOH aqueous solution and then washed with EtOAc (2x). - 12N HCl was added slowly to pH 1 and treated with a saturated solution of NaCl. - The mixture was extracted with EtOAc (3x), the organic phases were combined, washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give 37 g (88% yield) of a beige solid, which could be used in the next step without further purification. - 1H NMR (DMSO-d6, 300MHz): δ 8.16 (dd, 1H); 8.58 (d, 1H).

References

[1] Patent: WO2008/77086, 2008, A1. Location in patent: Page/Page column 56-57
[2] Patent: WO2009/18415, 2009, A1. Location in patent: Page/Page column title page; 35
[3] Patent: WO2008/112642, 2008, A1. Location in patent: Page/Page column 50; 50-51
[4] Patent: WO2008/112646, 2008, A1. Location in patent: Page/Page column 49-50
[5] Patent: WO2009/145814, 2009, A2. Location in patent: Page/Page column 49

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