6-Bromoimidazo[1,2-a]pyridine-3-carboxylicacid Chemical Properties

Density 

1.89±0.1 g/cm3(Predicted)

storage temp. 

2-8°C

pka

-0.99±0.41(Predicted)

Appearance

Off-white to light brown Solid

InChI

InChI=1S/C8H5BrN2O2/c9-5-1-2-7-10-3-6(8(12)13)11(7)4-5/h1-4H,(H,12,13)

InChIKey

SDKJLYHPCBMDAD-UHFFFAOYSA-N

SMILES

C12=NC=C(C(O)=O)N1C=C(Br)C=C2

Safety Information

HS Code 

2933399990

6-Bromoimidazo[1,2-a]pyridine-3-carboxylicacid Usage And Synthesis

Uses

6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid belongs to heterocyclic derivatives and can be used as pharmaceutical intermediates.  

Synthesis

1. Ethyl 6-bromoimidazo[1,2-A]pyridine-3-carboxylate (12400 g, dissolved in 51 L of ethanol) was added to a stainless steel reactor of suitable capacity at room temperature and under nitrogen protection. 2. Solid compound 6 (9500 g) was added to the reaction mixture in a single addition. 3. The reaction system was heated to reflux temperature (about 78°C) with continuous stirring for 1 to 2 days. 4. The reaction process was monitored by high performance liquid chromatography (HPLC). 5. Upon completion of the reaction, the reaction mixture was cooled to room temperature. 6. Sodium hydroxide solution (9884 g NaOH solid dissolved in 38 L of water) was added slowly and dropwise over a period of 30 minutes at an internal temperature of less than 35° C. The reaction mixture was heated again for 1 to 2 days with continuous stirring. 7. The reaction mixture was again heated to reflux temperature (about 78°C) and maintained for 3 to 4 hours. 8. The reaction process was monitored by HPLC. 9. Upon completion of the reaction, the reaction mixture was cooled to a suitable temperature and solvent removal was initiated. 10. Ethanol was removed by distillation under reduced pressure at 40 to 45 °C (about 5 volumes). 11. Cool the reaction mixture to room temperature. 12. Add water (57 L; 6 vol) to the reaction mixture. 13. The aqueous phase was washed using ethyl acetate (2 x 38L) to remove organic impurities. 14. cooled the aqueous phase to 0 to 5 °C and adjusted the pH to 1-2 with concentrated hydrochloric acid (~15 L). 15. The reaction mixture was stirred at 0 to 5°C for 1 to 2 hours. 16. The mixture was filtered and the filter cake was washed sequentially with water (2 x 38 L) and acetone (2 x 19 L) and subsequently dried for 1 to 2 hours. 17. The dried solid was retransferred to a reactor of suitable capacity. 18. Heptane (95L; 10 v/v) was added and the suspension was stirred for 4 to 5 hours at room temperature. 19. Collect the solid by filtration and wash with heptane (2 x 19 L). 20. Suspend the solid (15 kg) in methanol (75 L; 5 vol) and stir at room temperature for 2 hours. 21. The suspension was filtered and the collected solid was washed with methanol (2 x 5L). 22. The solid was dried under vacuum at 50 °C to constant weight to afford 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Compound 8) as an off-white to white solid (10169 g, 83.3% yield; 99.2% HPLC purity; 1H NMR (DMSO-d6, 300 MHz) δ 9.4 (s, 1H), 8.3 (s, 1H), 7.85-7.67 (m, 1H). 7.85-7.67 (m, 2H)).

References

[1] Patent: WO2011/50245, 2011, A1. Location in patent: Page/Page column 105
[2] Patent: WO2013/71272, 2013, A1. Location in patent: Paragraph 00298-00320
[3] Patent: WO2014/151147, 2014, A1. Location in patent: Paragraph 00641
[4] Patent: US2015/30588, 2015, A1. Location in patent: Page/Page column 67
[5] Patent: US9295673, 2016, B2. Location in patent: Page/Page column 345

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