CN102344395A - Synthesis method for bifenazate - Google Patents

Abstract

The invention belongs to the technical field of pesticide and intermediate synthesis, and in particular relates to a preparation method of bifenazate. The invention uses p-hydroxybiphenyl as raw material to synthesize the target product through one-step method of nitration, methylation, hydrogenation reduction, diazotization, diazonium salt reduction and acylation. Among them, the hydrazine salt is not treated and the acylation reaction is directly performed to shorten the experimental steps, the yield is increased from 50% to more than 65%, and the conversion rate of the reaction product is high, which is easy to carry out purification treatment. The method of the invention has the advantages of simple operation, mild conditions, high yield, low cost, etc., is easy for industrial production, and has broad application prospects. The bifenazate synthesized by the invention can be used as a specific acaricide, is active in the active stage of the spider mite, and can also prevent and control the egg stage of pests such as the two-spotted spider mite. For cotton, hops and certain fruit crops, it is effective against mites in all stages of growth.

Description

A kind of synthetic method of bifenazate

technical field

The invention belongs to the technical field of synthesis of pesticides and intermediates, and in particular relates to a method for synthesizing bifenazate.

Background technique

The chemical name of bifenazate is N'-(4-methoxybiphenyl-3-)hydrazine carboxylate isopropyl ester, which is a new type of hydrazine ester compound. It is a specific acaricide, which is active in the active stage of spider mites, and can also control the egg stage of pests such as spider mites. Used in cotton, hops and certain fruit crops to effectively control mites in all growth stages ^[1] . The drug can provide rapid killing and long-residue selective control effect (no harm to beneficial mites and beneficial insects). It has been registered and applied in various states in the United States, but it is not produced in China at present.

Looking at the development history of the pesticide industry, the number of original pesticide varieties has increased from dozens in the 1940s to more than 1,000 now. At the same time, some old varieties are still being eliminated or restricted. By 1995, there were about 100 A number of pesticide varieties have been banned, and the number of pesticide varieties that are currently restricted or banned has risen to several hundred. For example, the European Union recently made a decision to phase out 320 active ingredients of pesticides from July 1, 2003. In terms of absolute figures, ten years have passed when the registration of new pesticide molecules was high, and the number of new molecules of crop protection products emerging in recent years is relatively small. This is mainly because the U.S. Environmental Protection Agency has slowed down the pace of pesticide registration after the implementation of food quality protection regulations, and some manufacturers of basic pesticides and pesticides that have passed the patent period will focus more on products that have been tested and reliable , Constantly upgrade new products, transform them into new preparations and premixes and form a tendency, which has more commercial value than the investment in research and development of new molecules. Although the number of new pesticide molecules to be developed has decreased, there are also potential "giant bombs" among them ^{[2, 3]} . Bifenazate produced by Uniroyal Company is one of them, and its trade name is Acramite.

As a known synthetic pesticide, bifenazate has many synthetic methods. It has been reported that 3-bromo-4-methoxybiphenyl and 5-bromo-2-methoxyaniline were used as the starting point. The target product ^[4-7] was obtained by transition metal catalysis, and the product ^[8,9] was obtained by amination of p-hydroxybiphenyl as raw material with diisopropyl azodicarboxylate, but the cost Too high, more difficult for industrial production. How to reduce the production cost and the difficulty of operation to obtain the target product is of great significance. The invention uses p-hydroxybiphenyl as raw material to synthesize the target product through one-step method of nitration, methylation, hydrogenation reduction, diazotization, diazonium salt reduction and acylation. The method of the invention has the advantages of simple operation, mild conditions, high yield, low cost, etc., is easy for industrialized production, and has broad application prospects. Among them, the hydrazine salt is not treated and the acylation reaction is directly performed to shorten the experimental steps, and the yield is obviously improved, from 50% to more than 65%, and the reaction conversion rate is high, and it is easy to carry out purification treatment.

references:

[1] Technology development. Agricultural market news on the 10th. 2006 , 435, 18-19.

[2] Bautista F. M., et a1 . Applied Catalysis A: General. 1993 , 99, 161-173.

[3] Velu S., et a1 , Applied Catalysis A: General. 1994 , 119, 241-252.

[4] Park S. B., et a1 . US 6,706,895 ( 2004 ).

[5] Wang Z. R., et a1 . Tetrahedron Lett ． 1999 , 40, 3543-3546.

[6] Yoshiaki Kitamura, et a1 . Tetrahedron . 2007 , 63: 10596-10602.

[7] Deng C. L., et a1 . Eur． J． Org． Chem . 2007 , 1457-1462.

[8] Chee G. L., et a1 . US 6,093,843 ( 2000 ).

[9] Gaik L., et a1 . Synthetic Commun . 2006 , 36, 2151-2156.

Contents of the invention

The object of the present invention is to provide a kind of synthetic method of novel pesticide bifenazate.

The synthetic method of the bifenazate that the present invention proposes, its synthetic route is as follows:

Specific steps are as follows:

(1) Synthesis of 3-nitro-4-methoxybiphenyl (III)

Dissolve p-hydroxybiphenyl in methyl tert-butyl ether (MTBE), mix and stir evenly, add nitric acid dropwise into the resulting mixed solution, continue stirring for 1-3h after dropping, and control the temperature at 20-40°C throughout the process; TLC Detection, the reaction is over. The system was poured into ice water, and a large amount of solid was precipitated, which was filtered by suction and dried to obtain a yellow solid compound 3-nitro-4-hydroxybiphenyl (II). Among them, the molar ratio of p-hydroxybiphenyl to nitric acid is 1: (1-2).

Add 3-nitro-4-hydroxybiphenyl, dimethyl carbonate, tetrabutylammonium bromide (TBAB) and potassium carbonate into the reaction flask, raise the temperature to 80-100°C, and react for 40-50 hours; TLC detection , the reaction ends. The system was cooled to room temperature, and HCl solution was added dropwise to the system to adjust the pH to 4-6. At this time, no bubbles came out of the system. The system was poured into ice water, a large amount of solids were precipitated, filtered by suction, and dried to obtain tan solid compound 3-nitro-4-methoxybiphenyl (III). The molar ratio of 3-nitro-4-hydroxybiphenyl to dimethyl carbonate is 1:(2-10), and the molar ratio of 3-nitro-4-hydroxybiphenyl to tetrabutylammonium bromide is 1 :(1-3), the molar ratio of 3-nitro-4-hydroxybiphenyl to potassium carbonate is 1:(2-5).

(2) Synthesis of 3-amino-4-methoxybiphenyl (IV)

Add the 3-nitro-4-methoxybiphenyl obtained in step (1) into the reaction flask, use methanol as the solvent and Raney nickel as the catalyst, under the conditions of 1.5MPa pressure and 50-100°C After reacting for 1-3 hours, TLC detection showed that the reaction was completed, and the methanol was removed by vacuum rotary evaporation to obtain 3-amino-4-methoxybiphenyl. Among them, the molar ratio of 3-nitro-4-methoxybiphenyl to Raney nickel is 1: (0.01-0.05).

(3) Synthesis of isopropyl N'-(4-methoxybiphenyl-3-)hydrazinecarboxylate (I)

The 3-amino-4-methoxybiphenyl obtained in the step (2) and the HCl-H ₂ O solution were mixed and stirred evenly at room temperature, and then cooled to 0° C. in an ice-water bath. The aqueous solution of NaNO ₂ was slowly added dropwise to the system, and after 0.5-2 hours of reaction, a diazonium salt solution was obtained, and no raw materials were left after testing. Dissolve tin protochloride in concentrated hydrochloric acid, cool to -20°C, and slowly add it dropwise to the diazonium salt solution. Yellow and turbid, after stirring for 0.5-2h, it becomes off-white and turbid. The solid was filtered and dried in vacuo to give 3-(4-methoxybiphenyl-3-yl)hydrazino hydrochloride. Among them, the molar ratio of 3-amino-4-methoxybiphenyl to sodium nitrite is 1: (1-2), and the molar ratio of 3-amino-4-methoxybiphenyl to stannous chloride is 1 : (2-8).

Mix the obtained 3-(4-methoxybiphenyl-3-yl)hydrazine hydrochloride solid with toluene under ice bath, add pyridine, and add the mixed solution of isopropyl chloroformate and toluene to the system . React at 0° C. for 1 h, detect by TLC, and the reaction ends. Then the system was washed twice with water, the aqueous phase was extracted with toluene, the extract was mixed with the original toluene, and evaporated under reduced pressure to obtain the light brown target product I, namely bifenazate. Among them, the molar ratio of 3-(4-methoxybiphenyl-3-yl)hydrazine hydrochloride to pyridine is 1:(1-3), 3-(4-methoxybiphenyl-3 The molar ratio of -yl) hydrazine hydrochloride to isopropyl chloroformate is 1: (1-3).

In the present invention, the volume ratio of HCl to H ₂ O in the HCl-H ₂ O solution described in step (3) is 1:1, and concentrated hydrochloric acid with a mass fraction of 37.5% is used as HCl.

The advantages of the present invention are:

In the present invention, the acylation reaction of the diazonium salt reduction product-hydrazine salt without treatment shortens the experimental steps, significantly improves the yield from 50% to more than 65%, and the reaction system is not complicated, so post-treatment is easy.

Detailed ways

The present invention is further illustrated by the following examples, but the content of the present invention cannot be limited.

Embodiment 1: Preparation of compound bifenazate (I)

In a 250ml three-necked flask, 5g (29.4mmol) of p-hydroxybiphenyl was dissolved in 25ml of methyl tert-butyl ether (MTBE), mixed and stirred for 5min, and the temperature was controlled at 30°C. Take 4ml (58.8mmol, 2eq.) of nitric acid mixed with 10ml of MTBE and pour it into the dropping funnel, the dropwise addition is completed within 1h, and continue to stir for 3h. TLC detects that the reaction ends. The system was poured into 300ml of ice water and stirred for 5 minutes. At this time, there was no dark orange liquid on the surface of the liquid surface, and a large amount of solids were precipitated. They were suction filtered and dried to obtain 5.9 g of yellow solid 3-nitro-4-hydroxybiphenyl (II). The rate is 93%.

the

5 g (23.2 mmol) of the obtained 3-nitro-4-hydroxybiphenyl solid were mixed with 40 ml of dimethyl carbonate, 8.2 g (1.1 eq.) of tetrabutylammonium bromide (TBAB) and 3.2 g (1 eq.) of carbonic acid Potassium was stirred and mixed, and the temperature was raised to 100°C to reflux. After 48h, TLC detection, the reaction ended. The system was cooled to room temperature, and HCl solution was added dropwise to the system to adjust the pH to 4-6, and no bubbles came out of the system at this time. The system was poured into 200ml of ice water, a large amount of solids were precipitated, filtered by suction, and dried to obtain 5.253g of 3-nitro-4-methoxybiphenyl (III) as a yellowish-brown solid with a yield of 98.7%.

Add 5 g of the obtained 3-nitro-4-methoxybiphenyl (III) into the reaction flask, add 20 ml of methanol, use 5% Raney nickel as a catalyst, and react at 60 °C and 1.5 MPa for 3 h, TLC detection shows After the reaction was completed, methanol was removed by vacuum rotary evaporation to obtain 4.0 g of the desired product compound 3-amino-4-methoxybiphenyl (IV), with a yield of 93%.

the

Mix 3g of 3-amino-4-methoxybiphenyl (IV) with HCl-H ₂ O (30+30ml, hydrochloric acid is concentrated hydrochloric acid with a mass fraction of 37.5%) and mix well at room temperature, then cool in an ice-water bath to 0°C . The aqueous solution of 1.35g NaNO ₂ was slowly added dropwise to the system, after 0.5h, it was detected that no raw material remained. Dissolve 13.56g of stannous chloride in 30ml of concentrated hydrochloric acid, cool to -20°C, and slowly add it dropwise to the diazonium salt solution. At this time, the temperature of the solution rises and becomes viscous gradually. Tin hydrochloric acid solution was yellow and turbid, and after stirring continuously for 1 hour, it was gray-white and turbid. The solid was filtered and dried in vacuo to give 3-(4-methoxybiphenyl-3-yl)hydrazino hydrochloride.

The obtained 3-(4-methoxybiphenyl-3-yl)hydrazine hydrochloride solid was mixed with 20ml of toluene under ice bath, 1.78g of pyridine was added, the system turned yellow, and 2.75g of isopropyl chloroformate A mixed solution with 5 ml of toluene was added to the system. React at 0° C. for 1 h, detect by TLC, and the reaction ends. Then the system was washed twice with water, the aqueous phase was extracted with toluene, the extract was mixed with the original toluene, and evaporated under reduced pressure to obtain 2.97 g of light brown solid bifenazate (I), with a yield of 66%.

The characterization data are as follows:

¹ H NMR (300 MHz, CDCl ₃ , TMS), 6: 1.25 (d, 6H, 2-CH ₃ ), 3.89 (s, 3H, -CH ₃ ), 4.97 (m, 1 H ), 6.40(S, 1H, -NH-), 6.88(d, 1H), 7.07(d, 2H), 7.28(t, 1H), 7.39(t, 2H) , 7.52(d, 2H).

Embodiment 2: the preparation of compound bifenazate (I)

In a 250ml three-necked flask, 5g (29.4mmol) of p-hydroxybiphenyl was dissolved in 25ml of methyl tert-butyl ether (MTBE), mixed and stirred for 5min, and the temperature was controlled at 20°C. Take 2ml (29.4mmol, 1eq.) of nitric acid mixed with 10ml of MTBE and pour it into the dropping funnel, the dropwise addition is completed within 1h, and continue to stir for 3h. TLC detects that the reaction ends. The system was poured into 300ml of ice water and stirred for 5 minutes. At this time, there was no dark orange liquid on the surface of the liquid surface, and a large amount of solids were precipitated. They were suction filtered and dried to obtain 5.9 g of yellow solid 3-nitro-4-hydroxybiphenyl (II). The rate is 80%.

the

5 g (23.2 mmol) of the obtained 3-nitro-4-hydroxybiphenyl solid were mixed with 30 ml of dimethyl carbonate, 8.2 g (1.1 eq.) of tetrabutylammonium bromide (TBAB) and 3.2 g (1 eq.) of carbonic acid Potassium was stirred and mixed, and the temperature was raised to 90°C to reflux. After 48h, TLC detection, the reaction ended. The system was cooled to room temperature, and HCl solution was added dropwise to the system to adjust the pH to 4-6, and no bubbles came out of the system at this time. The system was poured into 200ml of ice water, a large amount of solids were precipitated, filtered by suction and dried to obtain 5.253g of 3-nitro-4-methoxybiphenyl (III) as a yellowish brown solid with a yield of 95%.

Add 5g of the obtained 3-nitro-4-methoxybiphenyl (III) into the reaction flask, add 20ml of methanol, use 5% Raney nickel as a catalyst, and react at 70°C and 1.5MPa for 3h, TLC detection shows After the reaction was completed, methanol was removed by vacuum rotary evaporation to obtain 4.0 g of the desired product compound 3-amino-4-methoxybiphenyl (IV), with a yield of 93%.

the

Mix 3g of 3-amino-4-methoxybiphenyl with HCl-H ₂ O (30+30ml, concentrated hydrochloric acid with a mass fraction of 37.5%) at room temperature and mix well, then cool to 0°C in an ice-water bath. The aqueous solution of 1.35g NaNO ₂ was slowly added dropwise to the system, and no raw material was detected after 1h. Dissolve 16.95g of stannous chloride in 20ml of concentrated hydrochloric acid, cool to -20°C, and slowly add it dropwise to the diazonium salt solution. At this time, the temperature of the solution rises and becomes viscous gradually. Tin hydrochloric acid solution was yellow and turbid, and after stirring continuously for 1 hour, it was gray-white and turbid. The solid was filtered and dried in vacuo to give 3-(4-methoxybiphenyl-3-yl)hydrazino hydrochloride as a solid.

The obtained 3-(4-methoxybiphenyl-3-yl)hydrazine hydrochloride solid was mixed with 20ml of toluene under ice bath, 1.78g of pyridine was added, the system turned yellow, and 3.12g of isopropyl chloroformate A mixed solution with 5 ml of toluene was added to the system. React at 0° C. for 2 h, detect by TLC, and the reaction ends. Then the system was washed twice with water, the aqueous phase was extracted with toluene, the extract was mixed with the original toluene, and evaporated under reduced pressure to obtain 3.1 g of light brown solid bifenazate (I), with a yield of 69%.

Embodiment 3: the preparation of compound bifenazate (I)

In a 250ml three-necked flask, 5g (29.4mmol) of p-hydroxybiphenyl was dissolved in 25ml of methyl tert-butyl ether (MTBE), mixed and stirred for 5min, and the temperature was controlled at 40°C. Take 2ml (58.8mmol, 2eq.) of nitric acid mixed with 10ml of MTBE and pour it into the dropping funnel, the dropwise addition is completed within 1h, and continue to stir for 3h. TLC detects that the reaction ends. The system was poured into 300ml of ice water and stirred for 5 minutes. At this time, there was no dark orange liquid on the surface of the liquid surface, and a large amount of solids were precipitated. They were suction filtered and dried to obtain 5.9 g of yellow solid 3-nitro-4-hydroxybiphenyl (II). The rate is 85%.

the

5 g (23.2 mmol) of the obtained 3-nitro-4-hydroxybiphenyl solid were mixed with 30 ml of dimethyl carbonate, 8.2 g (1.1 eq.) of tetrabutylammonium bromide (TBAB) and 3.2 g (1 eq.) of carbonic acid Potassium was stirred and mixed, and the temperature was raised to 100°C to reflux. After 48h, TLC detection, the reaction ended. The system was cooled to room temperature, and HCl solution was added dropwise to the system to adjust the pH to 4-6, and no bubbles came out of the system at this time. The system was poured into 200ml of ice water, a large amount of solids were precipitated, filtered by suction and dried to obtain 5.253g of 3-nitro-4-methoxybiphenyl (III) as a yellowish brown solid with a yield of 95%.

Add 5g of the obtained 3-nitro-4-methoxybiphenyl (III) into the reaction flask, add 20ml of methanol, use 5% Raney nickel as a catalyst, and react at 70°C and 1.5MPa for 3h, TLC detection shows After the reaction was completed, methanol was removed by vacuum rotary evaporation to obtain 4.0 g of the desired product compound 3-amino-4-methoxybiphenyl (IV), with a yield of 93%.

the

Mix 3g of 3-amino-4-methoxybiphenyl with HCl-H ₂ O (30+30ml, hydrochloric acid is concentrated hydrochloric acid with a mass fraction of 37.5%) at room temperature and mix well, then cool to 0°C in an ice-water bath. The aqueous solution of 1.35g NaNO ₂ was slowly added dropwise to the system, after 0.5h, it was detected that no raw material remained. Dissolve 16.95g of stannous chloride in 25ml of concentrated hydrochloric acid, cool to -20°C, and slowly add it dropwise to the diazonium salt solution. At this time, the temperature of the solution rises and becomes viscous gradually. Tin hydrochloric acid solution was yellow and turbid, and after stirring continuously for 1 hour, it was gray-white and turbid. The solid was filtered and dried in vacuo to give 3-(4-methoxybiphenyl-3-yl)hydrazino hydrochloride.

The obtained 3-(4-methoxybiphenyl-3-yl)hydrazine hydrochloride solid was mixed with 20ml of toluene under ice bath, 3.55g of pyridine was added, the system turned yellow, and 5.12g of isopropyl chloroformate A mixed solution with 5 ml of toluene was added to the system. React at 0° C. for 1 h, detect by TLC, and the reaction ends. Then the system was washed twice with water, the aqueous phase was extracted with toluene, the extract was mixed with the original toluene, and evaporated under reduced pressure to obtain 3.15 g of light brown solid bifenazate (I), with a yield of 70%.

Claims (2)

1. a synthetic method of bifenazate is characterized in that the synthetic route is as follows: Specific steps are as follows: (1) Synthesis of 3-nitro-4-methoxybiphenyl (III) Dissolve p-hydroxybiphenyl in methyl tert-butyl ether, mix and stir evenly, drop nitric acid into the resulting mixed solution, continue stirring for 1-3 hours after the drop, and control the temperature during the whole process at 20-40°C; TLC detection, reaction End; the system is poured into ice water, a large amount of solids are precipitated, suction filtered, and dried to obtain a yellow solid compound 3-nitro-4-hydroxybiphenyl (II); wherein, the mol ratio of p-hydroxybiphenyl to nitric acid is 1 :(1-2); Add 3-nitro-4-hydroxybiphenyl, dimethyl carbonate, tetrabutylammonium bromide and potassium carbonate into the reaction flask, raise the temperature to 80-100°C, and react for 40-50 hours; TLC detection, the reaction is over ; Cool the system to room temperature, add HCl solution dropwise to the system, adjust the pH to 4-6, and no bubbles emerge from the system at this time; pour the system into ice water, a large amount of solid precipitates, filter with suction, and dry to obtain a yellow-brown solid Compound 3-nitro-4-methoxybiphenyl (III); wherein the molar ratio of 3-nitro-4-hydroxybiphenyl to dimethyl carbonate is 1:(2-10), 3-nitro- The molar ratio of 4-hydroxybiphenyl to tetrabutylammonium bromide is 1: (1-3), and the molar ratio of 3-nitro-4-hydroxybiphenyl to potassium carbonate is 1: (2-5); (2) Synthesis of 3-amino-4-methoxybiphenyl (IV) Add the 3-nitro-4-methoxybiphenyl obtained in step (1) into the reaction flask, use methanol as the solvent and Raney nickel as the catalyst, under the conditions of 1.5MPa pressure and 50-100°C Reaction 1-3h, TLC detection shows that after the reaction is completed, the methanol is removed by vacuum rotary evaporation to obtain 3-amino-4-methoxybiphenyl; wherein, 3-nitro-4-methoxybiphenyl and Raney nickel The molar ratio is 1: (0.01-0.05); (3) Synthesis of isopropyl N'-(4-methoxybiphenyl-3-)hydrazinecarboxylate (I) Mix and stir the 3-amino-4-methoxybiphenyl and HCl-H ₂ O solution obtained in step (2) at room temperature, then cool in an ice-water bath to 0°C; slowly add NaNO ₂ aqueous solution to the system dropwise After reacting for 0.5-2h, the diazonium salt solution was obtained, and no raw materials were left after testing; dissolving stannous chloride in concentrated hydrochloric acid, cooled to -20°C, and slowly added dropwise to the diazonium salt solution. When the temperature of the solution rises, it becomes viscous gradually, and the stannous chloride hydrochloric acid solution is continuously added dropwise, which turns yellow and turbid. After stirring for 0.5-2 hours, it becomes off-white and turbid; the solid is filtered and vacuum-dried to obtain 3-(4-methoxybis Phenyl-3-yl)hydrazine hydrochloride; wherein, the molar ratio of 3-amino-4-methoxybiphenyl to sodium nitrite is 1:(1-2), 3-amino-4-methoxy The molar ratio of biphenyl to stannous chloride is 1: (2-8); Mix the obtained 3-(4-methoxybiphenyl-3-yl)hydrazine hydrochloride solid with toluene under ice bath, add pyridine, and add the mixed solution of isopropyl chloroformate and toluene to the system ; reacted at 0°C for 1 h, detected by TLC, and the reaction was completed; then the system was washed twice with water, the aqueous phase was extracted with toluene, the extract was mixed with the original toluene, and evaporated under reduced pressure to obtain the light brown target product I, namely Phenylhydrazine ester; wherein, the molar ratio of 3-(4-methoxybiphenyl-3-yl)hydrazine hydrochloride to pyridine is 1:(1-3), 3-(4-methoxybiphenyl The molar ratio of phenyl-3-yl)hydrazine hydrochloride to isopropyl chloroformate is 1:(1-3). 2. The method according to claim 1, characterized in that the volume ratio of HCl and H ₂ O in the HCl-H ₂ O solution described in step (3) is 1:1, and HCl adopts concentrated hydrochloric acid with a mass fraction of 37.5%. .