4-Pyrimidinecarboxylic acid

4-Pyrimidinecarboxylic acid Property

Melting point:

229.8-231.9°C

Boiling point:

318.7±15.0 °C(Predicted)

Density 

1.403±0.06 g/cm3(Predicted)

storage temp. 

Keep in dark place,Sealed in dry,Room Temperature

solubility 

DMF: 5 mg/ml; DMSO: 20 mg/ml; Ethanol: 0.25 mg/ml; PBS (pH 7.2): 1 mg/ml

form 

powder to crystal

pka

2.81±0.10(Predicted)

color 

White to Light yellow

InChI

InChI=1S/C5H4N2O2/c8-5(9)4-1-2-6-3-7-4/h1-3H,(H,8,9)

InChIKey

YPOXGDJGKBXRFP-UHFFFAOYSA-N

SMILES

C1=NC=CC(C(O)=O)=N1

CAS DataBase Reference

31462-59-6(CAS DataBase Reference)

EPA Substance Registry System

4-Pyrimidinecarboxylic acid (31462-59-6)

Safety

Hazard Codes 

Xi,Xn

Risk Statements 

36

Safety Statements 

26

WGK Germany 

3

TSCA 

Yes

HazardClass 

IRRITANT

HS Code 

29339900

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H319Causes serious eye irritation

Precautionary statements

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

4-Pyrimidinecarboxylic acid Chemical Properties,Usage,Production

Chemical Properties

white solid

Uses

4-?Pyrimidinecarboxylic Acid is a reactant in copper-catalyzed heteroaryl carboxamide-directed ortho-amination of anilines with cyclic alkylamines.

Synthesis

1. Oxidation reaction: Selenium dioxide (8.82 g, 0.079 mol) was slowly added to a stirred solution of 4-methylpyrimidine (5.0 g, 0.053 mol) in pyridine (55 mL) at room temperature. The reaction mixture was stirred at 55°C for 2 hours, then warmed to 80°C and continued stirring for 3.5 hours. After completion of the reaction, it was cooled to room temperature and stirred overnight, the reaction mixture was filtered and the residue was washed with pyridine. The pyridine solution was combined and concentrated, and the resulting pyrimidine-4-carboxylic acid was washed with water to remove traces of selenium dioxide. Yield: 5.3 g, 80.5% yield. 2. Esterification reaction: Concentrated pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) was dissolved in methanol (170 mL) and hydrochloric acid (2 mL, room temperature) was added. After refluxing overnight, the reaction mixture was cooled to room temperature, neutralized with 10% sodium bicarbonate solution and concentrated. The esterified product was extracted with ether, dried over anhydrous sodium sulfate and concentrated to give methyl pyrimidine-4-carboxylate as a yellow solid. Yield: 3.3 g, yield 57.55%. 3. Amidation reaction: Trimethylacetyl chloride (11.30g, 0.093mol) was added dropwise to a solution of triethylamine (15.75g, 0.155mol) and 4-chloroaniline (10.0g, 0.078mol) in benzene (500mL) at 0℃. The reaction mixture was gradually warmed to room temperature and stirred for 3 hours. Upon completion of the reaction, it was quenched with water, extracted with ethyl acetate, washed sequentially with water and brine, and dried over anhydrous sodium sulfate. The resulting solid product was recrystallized from petroleum ether. Yield: 14.0 g, 84.43% yield. 4. Lithiation reaction: To a solution of N-(4-chlorophenyl)-2,2-dimethylpropanamide (3.5 g, 0.0165 mol) in tetrahydrofuran (50 mL) was added a hexane solution of n-butyllithium (2.64 g, 1.2 M, 0.041 mol) at 0 °C. The reaction was followed by stirring for 2 hours. After stirring at 0 °C for 2 h, the reaction was cooled to -70 °C and a tetrahydrofuran (25 mL) solution of methyl pyrimidine-4-carboxylate (3.18 g, 0.023 mol) was slowly added. The reaction mixture was then warmed to room temperature and stirred overnight. Ether (50 mL) and water (50 mL) were added and the organic layer was separated. The aqueous layer was further extracted with ether and the organic layers were combined, washed sequentially with water and brine and dried over anhydrous sodium sulfate. After concentration, the product was purified by column chromatography. Yield: 1.7 g, yield 32.69%. 5. Deprotection reaction: 70% sulfuric acid solution (10 mL) of protected aminoketone (1.7 g, 0.0054 mol) was heated at 95 °C overnight. After cooling to room temperature, it was alkalized with 10% sodium hydroxide solution, extracted with dichloromethane, washed sequentially with water and brine, and dried over anhydrous sodium sulfate. After concentration, the product was purified by basic alumina column chromatography to obtain the target compound. Yield: 0.20 g, 16% yield.

References

[1] Patent: WO2004/46092, 2004, A2. Location in patent: Page 52-53
[2] Patent: WO2008/23239, 2008, A1. Location in patent: Page/Page column 21
[3] Heterocycles, 2003, vol. 60, # 4, p. 953 - 957
[4] PLoS ONE, 2016, vol. 11, # 5,
[5] Patent: WO2008/70150, 2008, A1. Location in patent: Page/Page column 59