Analysis of triazole fungicides and their intermediates

Discovery process

In the mid-1960s, Philiph-Dupher of the Netherlands developed the first 1, 2, 4 triazole fungicide - Vermecillin, but the subsequent 1, 2, 4 - triazole fungicide has not attracted enough attention due to its narrow antibacterial spectrum. The bactericidal activity of 1-substituted azole derivatives was first reported by Bayer and Janssen Pharmaceuticals in Belgium in the late 1960s. The Bayer researchers studied the bactericidal activity of azole compounds from the structural assumption that "any compound capable of producing highly reactive carbyl ions in living organisms must have some activity." It has significant antibacterial activity against yeast and plant pathogens by biological identification. The experimental results showed that when the azole components were mainly imidazole and 1, 2, 4-triazole as the basic structure, the biological activity would not be lost even if the substituents were changed. Therefore, the representative compound flutriazole was developed and has been used as a medicine to control powdery mildew in cereals and vegetables.

In the 1970s, the high efficient bactericidal activity of triazole compounds caused great attention of the international pesticide community, the major companies have developed research shows that phenyl can be widely replaced by other groups, its biological activity remains unchanged, or more improved. The biological activity of these compounds is very high, and has since been developed into the most representative endogenic fungicides such as triazolone and triazolol series of excellent varieties. In practice, it has been found that some triazole compounds not only have bactericidal activity, but also have certain regulatory activity on plant growth. B¨uchel et al. first reported that triazole compounds with plant growth activity could increase soybean yield by 40% at 0.05 %. The discovery of plant growth regulation activity of triazole derivatives has made the research of this kind of fungicides more active. Major companies have developed and introduced high-efficient plant growth retarder PP333, plant growth inhibitor "bud inhibition" and other triazole compounds. The special properties of these compounds in plant growth regulation have opened up a new field for the study of plant growth regulators.

A common triazole fungicide

Structural characteristics

Triazole fungicides are a class of broad-spectrum and endogenic fungicides composed of imidazole ring, hydroxyl (ketone group) and substituted benzyl group, etc. Most triazole fungicides have a chiral center and belong to chiral pesticides. Their general structure is as follows:

1, 2, 4-triazole is an important intermediate in the synthesis of this bactericide:

Typical structure of triazole fungicides

Common triazole fungicide structure

About triazole

Triazole (1,2, 4-triazole) is a colorless acicular crystal or crystalline powder. It is an important fine chemical raw material and widely used in pesticide, medicine, dyes and rubber auxiliary industries. It can also be used as photoconductor of replication system and an important intermediate of organic chemical industry. As early as the 2030s, triazole preparation research has begun.

In recent decades, heterocyclic compounds have played an important role in the development of medicine, pesticide and chemical industry. In particular, many heterocyclic derivatives of triazole have become the focus of research in recent years because of their good biological activities, high efficacy and wide effects. In-depth studies have found that triazole compounds as fungicides are favored for their broad spectrum, low toxicity and high efficiency. Not only that, triazole compounds also have antibacterial, anti-spasming, anti-platelet aggregation, anti-inflammatory and other functions in medicine, causing extensive research. For example, 3-amino-1,2, 4-triazole and many of its derivatives have insecticidal, antibacterial, weeding, promoting and regulating the growth of crops, and have been widely used in agriculture and medicine. At the same time, as an important functional group, triazoles have strong complexing ability of metal ions and hydrogen bond formation, which has attracted much attention in the field of chemistry.

Common synthesis methods of triazolium compounds

1. Formamide method

Hydrazine hydrate is gradually added to hot formamide to directly synthesize triazole.

60kg formamide was first heated to 175-185℃, and then slowly added 30kg80% hydrazine hydrate. The mixture was heated and dehydrated at 180-185℃ for 30min after dripping, and the yield of triazole was 91%. Formamide process is one of the commonly used methods for triazole production.

2. Formic acid method

The ammonia gas is passed into 130g 85% formic acid. When the temperature of the reactant rises to 130℃ and pH=7-8, the ammonia gas is finished. When the temperature was raised to 155℃, 59g of 80% hydrazine hydrate was added for 2-3h, and the water was removed by distillation while the drops were added. After the addition of hydrazine hydrate, the water was kept for 3h, and then the temperature was raised to 210℃ to obtain 75g triazole with yield of 91.08%. Formic acid process is also one of the commonly used methods to produce triazoles.

Examples of triazole fungicides

1 phenyloxyconazole

difenoconazole, also known as difenoconazole, is a triazole fungicide. Phenoxyconazole has the characteristics of high efficiency, wide spectrum, safety, long duration and strong endoscopicity. It can destroy the structure and function of fine cell membrane by inhibiting the biosynthesis of ergosterol in fungi and cells, so as to achieve the purpose of sterilization.

The chemical formula is C19H17Cl2N3O3, and the structural formula is as follows:

Physical and chemical properties: Pure white powder, slight fragrance, melting point 78.6℃, 20℃ density of 1.37 g/cm3; The original drug was a pale powder with a density of 1.40g /cm3, melting point 76.0℃, vapor pressure 3.3×10-8 Pa (25℃), solubility (20℃) : water 3.3 mg/L, easy to dissolve in organic solvents. It has little mobility and degrades slowly in soil.

Synthesis process: Using m-dichlorobenzene as raw material, through acylation, etherification, bromination, cyclization and condensation reaction, the final synthesis of phenyloconazole.

Key intermediates: m-dichlorobenzene, 1, 2, 4-triazole

2 tricyclic azole

Tricyclozole, also known as beam, crepyrazole, chemical name 5-methyl-1, 2, 4-triazole and (3, 4-b) benpropithiazole, molecular formula is C9H7N3S, molecular weight 189.237, chemical structure formula is as follows:

Tricyclazole has strong internal absorption and low toxicity, so it can only be used as a protective agent for rice blast in agricultural production. The main dosage forms include 20%, 40% and 70% wettable powder and 20% sol, which can be used for root immersion or leaf spray treatment. Developed by Eli Lilly in 1974, the drug has special effect on rice blast control. It was registered in 1979 and sold in the world pesticide market.

Synthesis process: Using o-toluidine as raw material, tricyclic azole was prepared by four steps of addition, ring closure, substitution and ring expansion.

(1). Addition reaction

In the presence of solvent, o-toluidine was added with sulfuric acid, and then sodium thiocyanate was added, and the reaction was heated. After solvent recovery, cooling, filtration and drying, o-methyl phenyl thiourea was obtained at m.p. 154-160 ℃ with a yield of 93% ~ 95%.

(2). Loop closure reaction

In the presence of solvent, the o-methyl phenyl thiourea and chlorine reaction, attention to control the reaction temperature. After the insulation reaction, the solvent was recovered, alkali was added to neutralize, cooling, filtration, and drying to obtain 2-amino-4-methylbenzothiazole. The yield of m.p. was 90%-91% at 134 ~ 136℃.

(3). Substitution reaction

After mixing appropriate amount of solvent, hydrochloric acid and water, adding 2-amino-4-methylbenzothiazole, reacting with hydrazine hydrochloride, heating reaction to the end point, cooling, filtration, drying to obtain 2-hydrazyl-4-methylbenzothiazole. The yield was 85-87% at m.p. 167 ~ 170℃.

(4). Ring enlargement reaction

2-hydrazyl-4-methylbenzothiazole was added into a reactor with a certain amount of solvent and formic acid under stirring, heated to the end of the reaction, decompressed to recover the solvent and excess formic acid, at the same time, dilute and cool with water, filtered, washed to neutral, and dried to obtain tricyclic azole original. At 184-186 ℃, the yield was 90%-93%.

Key intermediates: o-toluidine, 4-methyl-2-hydrazine benzothiazole (1, 2, 4-triazole is not required for the synthesis of tricyclic azole)

3 pentazolol

Pentazolol is a kind of high efficiency, low toxicity, broad spectrum and endogenic triazole bactericide developed by Bayer in Germany in 1986. It has protection, treatment, eradication of three functions, is a kind of ergosterol demethylation inhibitors, mainly used in wheat, vegetables, bananas, apple and other crops on the seed treatment and foliar spray, sterilization spectrum, high activity, and long duration, for many crops including mono cotyledon plants and dicotyledon plants are relatively safe.

Ethyltrianol, Tebuconazole, chemical name: 1-(4-chlorophenyl)-3-(1h-1, 2, 4-triazol-1-methyl)-4, 4-dimethylpentylene 3-alcohol, alias: Rickethu Corail, Ethyltrianol, Folicur. Molecular formula: C16H22ClN3O; Molecular weight: 307.82.

Compared with traditional triazole fungicides, there are other sites of action, so the bactericidal spectrum of tetrazolol is wider. Since its release in 1988, it has quickly surpassed the sales volume of other triazole fungicides (such as triazolone, pyrazolol, phyllobacterazole, triazolol, nitrile, propionazole, tefluranazole, phenyloconazole, etc.) varieties, and has the highest sales volume and annual growth rate (16.8% in 1999/2005) among more than 20 varieties of triazole fungicides. In 1998, global sales reached 278 million US dollars, and it was the first in the fungicide market until 2003. In 2003, the global sales volume reached $360 million, which rose to the peak of $505 million in 2005. Then, with the entry of pyrimethanil, pyrazole ether ester and other products into the market, the market share of pentazolol declined. But it is still one of the world's leading fungicides.

Synthesis: At present, tetracolol is synthesized by condensation, hydrogenation, epoxidation using p-chlorobenzaldehyde and acetone as raw materials, and finally by a four-step ring opening reaction with 1,2, 4-triazole.

Important intermediates: p-chlorobenzaldehyde, acetone, 1,2, 4-triazole

Source: Leizkan pesticide