2,6-Dichlorobenzoyl chloride

Chemical Properties

Clear slightly yellow liquid

Uses

2,6-Dichlorobenzoyl chloride acts as an important intermediate in organic synthesis, pharmaceuticals, agrochemicals and dyestuffs. It is employed in the substrate activity screening method for the rapid development of novel substrates and their conversion into non-peptidic inhibitors of Cys and Ser proteases. It is also used in the preparation of 1-acyliridoles and (-)-aspicilin. In addition to this, it undergoes esterification of (fluoren-9-ylmethoxy)carbonyl (Fmoc)-amino acids to 4-alkoxybenzyl alcohol polystyrene.

Uses

2,6-Dichlorobenzoyl chloride was used:

• in substrate activity screening method for the rapid development of novel substrates and their conversion into non-peptidic inhibitors of Cys and Ser proteases
• in the synthesis of 1-acyliridoles
• in enantiocontrolled total synthesis of (-)-aspicilin

General Description

2,6-Dichlorobenzoyl chloride participates in esterification of (fluoren-9-ylmethoxy)carbonyl (Fmoc)-amino acids to 4-alkoxybenzyl alcohol polystyrene.

Synthesis

50-30-6

4659-45-4

At 0 °C and under nitrogen protection, 2,6-dichlorobenzoic acid (0.1 g, 0.52 mmol) was dissolved in dichloromethane (5 mL), N,N-dimethylformamide (3.83 mg, 52.35 μmol) was added as a catalyst, followed by the slow addition of oxalyl dichloride (0.20 g, 1.57 mmol). The reaction mixture was added dropwise at 0 °C and stirred in the range of 0 to 20 °C for 2 hours. The progress of the reaction was monitored by thin layer chromatography (TLC, unfolding reagent ratio of petroleum ether:ethyl acetate=5:1, Rf=0.77) and after confirming the complete consumption of the feedstock, the solvent was removed under reduced pressure to afford 2,6-dichlorobenzoyl chloride (0.11 g, 0.37 mmol, 70% yield), and the product was ready to be used in the next step of the reaction without further purification. 28g-int (65 mg, 0.17 mmol, in hydrochloride form) and N,N-diisopropylethylamine (DIEA, 87.3 mg, 0.68 mmol) were dissolved in dichloromethane (10 mL), and dichloromethane (5 mL) was slowly added dropwise at 0 °C and under nitrogen protection to a 2,6-dichlorobenzoyl chloride (88.43 mg, 0.42 mmol) solution. The reaction mixture was stirred at 0-20 °C for 16 h. Liquid chromatography-mass spectrometry (LCMS) analysis showed that 28g-int was completely consumed and 28h-int was produced.After removing the solvent under reduced pressure, the crude product was purified by preparative high-performance liquid chromatography (HPLC) to give pure 28h-int.LCMS (electrospray ionization in positive ion mode, ESI+) data: m/ z 521.3 ([M+H]+), retention time (RT): 1.1 min. HPLC purification conditions: a Gilson 281 semi-preparative HPLC system was used; mobile phase A: an aqueous solution containing 0.075% trifluoroacetic acid (TFA, v/v), mobile phase B: acetonitrile (ACN) with a gradient elution program (phase B ratio: 20% at 0 min, 40% at 12 min ); column: YMC-Actus Triart C18 (150 mm×30 mm, 5 μm); flow rate: 20 mL/min; detection wavelength: 220 nm and 254 nm.

Purification Methods

Reflux the acid chloride for 2hours with excess of acetyl chloride (3 volumes), distil off AcCl followed by the benzoyl chloride. Store it away from moisture. It is an IRRITANT.[Beilstein 9 III 1377.]

References

[1] Patent: WO2018/49068, 2018, A1. Location in patent: Paragraph 0430; 0431
[2] Journal of the American Chemical Society, 1940, vol. 62, p. 1432,1434
[3] Journal of the Chemical Society, 1903, vol. 83, p. 1213
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2843 - 2852
[5] Journal of Medicinal Chemistry, 1982, vol. 25, # 11, p. 1280 - 1286