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. 2017 Jun 30;22(7):1086.
doi: 10.3390/molecules22071086.

A Novel Synthesis of the Efficient Anti-Coccidial Drug Halofuginone Hydrobromide

Junren Zhang  1   2 , Qizheng Yao  3 , Zuliang Liu  4
Affiliations

A Novel Synthesis of the Efficient Anti-Coccidial Drug Halofuginone Hydrobromide

Junren Zhang et al. Molecules. .

Abstract

Background: Halofuginone hydrobromide (1) is recognized as an effective drug against several species of Eimeria (E.) in poultry. In this paper, we describe a convenient and low cost preparation method for the compound, as well as primary validation of its activity. Methods: First, 7-bromo-6-chloroquinazolin-4(3H)-one (2) was prepared from m-chlorotoluene by a conventional process, and then chloroacetone was creatively introduced in two steps. Finally, halofuginone hydrobromide (1) was obtained from 7-bromo-6-chloro-3-(3-cholroacetonyl) quinazolin-4(3H)-one (4) by a four-step reaction sequence including condensation, cyclization, deprotection and isomerization. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS and ¹H-NMR. Besides, the protective effect of compound 1-supplemented chicken diet at doses of 6, 3 and 1.5 mg per 1 kg were evaluated on chickens infected with E. tenella, by reduction in mortality, weight loss, fecal oocyst excretion and gut pathology, respectively. Results: Halofuginone hydrobromide (1) was prepared successfully by and improved and innovative method based on traditional research. Moreover, the synthesized halofuginone hydrobromide significantly exhibited an anti-coccidial property. Conclusions: The fruitful work described in this Communication has resulted in halofuginone hydrobromide, which has a good pharmaceutical development prospects, becoming more available for large-scale production.

Keywords: 4(3H)-quinazolinone; asymmetric synthesis; febrifugine; halofuginone hydrobromide; piperidine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of febrifugine, isofebrifugine, and halofuginone hydrobrimide (1).
Figure 2
Figure 2
4(3H)-Quinazolinone (L) and piperidine (R) derivative.
Scheme 1
Scheme 1
Route A: Synthesis of 7-bromo-6-chloroquinazolin-4(3H)-one: The separation and purification of bromo-substituted 2,3-indolinedione proved hard, leading to low total recovery.
Scheme 2
Scheme 2
Route B: synthesis of 7-bromo-6-chloroquinazolin-4(3H)-one: by choosing 3-chlorotoluene as the starting material, the intermediate was produced with a reduced number of reaction steps and cost.
Scheme 3
Scheme 3
Synthesis of 2-acetonyl-3-methoxyl piperidine involving the application of pyridine derivatives.
Scheme 4
Scheme 4
First asymmetric synthesis of the piperidine ring.
Scheme 5
Scheme 5
The shortest preparation of the piperidine derivative.
Scheme 6
Scheme 6
Total synthesis process to halofuginone hydrobromide 1.
Scheme 7
Scheme 7
Two unsatisfactory routes to substituted products.
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References

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