How to synthesize Dichlobentiazox?

Brief introduction

Kumiai Chemical Industry announced Dichlobentiazox as a new fungicide in 2016. This active ingredient, which notably contains two distinct isothiazole moieties, has its strength in controlling rice pathogens, especially Magnaporthe oryzae, the causal agent of rice blast. It can also safely be applied to rice seedlings with nursery box cultivation. This fungicide is not permitted for use in Japan.

Synthesis method

The synthesis of dichlobentiazox starts from succinonitrile (92), which, upon treatment with chlorine at elevated temperature, affords a mixture of chlorinated maleonitrile and fumaronitrile (93). Subjecting this mixture to disulfur dichloride and heating yields the trisubstituted isothiazole derivative 94, which is converted by nitrile hydrolysis to the carboxylic acid 95, the acid moiety of the known active ingredient isotianil. Formation of the corresponding acid chloride, followed by its reduction with sodium borohydride, delivers the alcohol derivative 97. Basic treatment of the latter with 3-chloro-1,2-benzothiazole 1,1-dioxide, which can be obtained by chlorination of saccharin, yields dichlobentiazox[1].

Risk assessment

FSCJ conducted the risk assessment of a fungicide, dichlobentiazox, having benzoisothiazole and isothiazole rings, based on results from various studies[2]. The data used in the assessment include fate in animals (rats) and in livestock (goats), fate in plants (paddy rice), residues in crops, subacute toxicity (rats, mice, and dogs), chronic toxicity (dogs), carcinogenicity (rats and mice) and other relevant study results. This chemical showed no carcinogenicity, reproductive toxicity, teratogenicity, or genotoxicity. The lowest no-observed-adverse-effect level (NOAEL) obtained in all studies was 5.03 mg/kg bw per day in a two-year chronic toxicity/carcinogenicity study in rats. FSCJ specified an acceptable daily intake (ADI) of 0.05 mg/kg bw per day by applying a safety factor 100 to the NOAEL.

References

[1] Stephane Jeanmart . “Synthetic approaches to the 2015–2018 new agrochemicals.” Bioorganic & Medicinal Chemistry 39 (2021): Article 116162.

[2] "Dichlobentiazox (Pesticides).” Food safety (Tokyo, Japan) 8 1 (2020): 6–7.