CN114920747B - Method for synthesizing fluxapyroxad intermediate - Google Patents
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Abstract
The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing a fluxapyroxad pali intermediate, which comprises the following steps ofN‑The ethyl tert-butoxycarbonyl glycinate is taken as a raw material, and is reacted with hydrazine hydrate under the reflux of ethanol to obtain an intermediate (I); at the same time, 2-trifluoroacetamide is reacted with alcohols to obtain an intermediate (II), then the intermediate (I) and the intermediate (II) are cyclized under the action of alkali to obtain an intermediate (III), and the intermediate (III) is reacted with 1, 2-dibromoethane or 1, 2-dichloroethane to obtain the fluxapari intermediate 2- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [1,5-A ]]Pyrazine, formula (IV). Compared with the prior art, the method avoids the hydrogenation reaction step in the traditional method for synthesizing the compound, and has the advantages of milder reaction conditions, simple and convenient operation, no need of special equipment, high reaction yield and the like.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a fluxapyroxad intermediate.
Background
Cancer is one of several major diseases that are currently relevant to human life and health. The current treatment schemes are still focused on several aspects such as 'operation', 'radiotherapy and chemotherapy', 'molecular targeted therapy', 'biological immunotherapy', and the like. Compared with other schemes, the molecular targeted therapy has the advantages of small damage, combination, local effect, rapidness, safety, minimally invasive and repeatable treatment, and has become the development focus of the current anticancer drugs. The PARP inhibitor, namely the poly (adenosine diphosphate) ribose polymerase inhibitor, is a novel targeted anticancer drug. The mechanism of action of PARP inhibitors is to inhibit repair of DNA damage of tumor cells, and the inhibitors are also the first anticancer drugs obtained by synthetic lethal way. The market for global PARP inhibitors is around dollars 10 billion, and currently, there are many drugs approved for the market, such as rupa 1, olapa 2, nilapari 3, and fluxapa 4. The fluxapyroxad is a drug with the first target point in China, is a new drug sponsored in important special terms in China, and is concerned by people.Wherein the synthesis route of the fluxapyropali 4 is 2- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [1,5-A ]]Pyrazine (IV) and 5- [ (3, 4-dihydro-4-oxo-1-phthalazinyl) methyl]-2-fluorobenzoic acid (US 2013131068 A1). It is readily apparent that 2- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [1,5-A ]]Pyrazine (IV) is a key intermediate in the synthesis of fluxapyroxadThe current literature about the synthesis of the intermediate is not quite extensive, mainly 2-aminopyrazine is taken as a substrate, and a final product is obtained through trifluoroacetylation, phosphorus pentachloride to form oxime, polyphosphoric acid cyclization and palladium carbon reduction of pyrimidine ring, and the specific route is as follows (CN 102686591B, WO2012019427A1 and the like): />It is readily apparent that the above synthetic routes exist for a variety of highly contaminating, corrosive reagents, such as: trifluoroacetic anhydride, phosphorus pentachloride, polyphosphoric acid and the like, and reagent-like agents are used for equipmentHigh requirements and high cost. Meanwhile, the palladium-carbon hydrogenation reduction process has high requirements on equipment and personnel. Therefore, aiming at the defects, the development of a synthetic route which has simple process route, higher yield and lower cost and meets the requirement of industrial production is particularly necessary.
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description summary and in the title of the application, to avoid obscuring the purpose of this section, the description summary and the title of the invention, which should not be used to limit the scope of the invention.
The present invention has been made in view of the problems occurring in the prior art.
It is therefore an object of the present invention to provide a novel process for the synthesis of fluxapyroxad intermediate-2- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [1,5-a ] pyrazine.
In order to solve the technical problems, according to one aspect of the present invention, the following technical solutions are provided:
a method of synthesizing a fluxapyroxad intermediate comprising the steps of:
step 1: raw materials are mixedN-Dissolving tert-butyloxycarbonyl glycine ethyl ester in alcohol solvent, adding hydrazine hydrate to 80 o C, overnight, and carrying out post-treatment on the reaction liquid to obtain an intermediate (I);the step 1 specifically comprises the following steps:
1) Will beN-Placing tert-butoxycarbonyl glycine ethyl ester into a solvent A, adding hydrazine hydrate, reacting for 10-24 hours at 40-90 ℃, tracking by gas chromatography, concentrating the reaction solution after the reaction is finished, and recrystallizing to obtain a formula (In-I);2) 2,2, 2-trifluoro acetamide is placed in a solvent B, cooled to-50-10 ℃ under the protection of inert gas, thionyl chloride and alkali C are slowly added for reaction at the same temperatureAfter 0.5 hour, the bases D and R are slowly added 1 OH, slowly recovering the room temperature after adding, reacting for 10-24 hours at the room temperature, concentrating to obtain the formula (In-II), R 1 Is alkyl, phenyl or heteroaryl, preferably benzyl; />3) Dissolving the formula (In-I) and the formula (In-II) In a solvent F, adding alkali G, reacting for 10-24 hours at 50-110 ℃, detecting that the reaction is complete, cooling to room temperature, adding a 2N hydrochloric acid solution, and recrystallizing to obtain the formula (In-III);
4) Dissolving the formula (In-III) In a solvent H, adding alkali I and a phase transfer catalyst, stirring at 10-50 ℃ for 0.5-3 hours, slowly dropwise adding 1, 2-dichloroethane or 1, 2-dibromoethane solution, preserving heat at 10-50 ℃ for 10-24 hours after adding, and recrystallizing to obtain the fluxapyroxad intermediate, namely the formula (IV).As a preferred embodiment of the method for synthesizing fluxapyroxad intermediate according to the present invention, wherein: in the step 1), the solvent A is tetrahydrofuran, dichloromethane, ethyl acetate,N, NDimethylformamide (DMA),N, N-dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxane, 1, 2-dichloroethane, acetonitrile or a mixture of two. Preferably ethanol;N-the ratio of the quantity of the tert-butyloxycarbonyl glycine ethyl ester to the quantity of the hydrazine hydrate substance is 1:6-1:15, preferably 1:10; volume of solvent AN-The ratio of the amount of the substance of the tert-butyloxycarbonyl glycine ethyl ester is 1:1-4:1, preferably 4:1, the volume unit is mL, and the amount of the substance is mmol.
As a preferred embodiment of the method for synthesizing fluxapyroxad intermediate according to the present invention, wherein: in the step 2), the solvent B is tetrahydrofuran, dichloromethane, ethyl acetate,N, NDimethylformamide (DMA),N, N-dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxyOne or two mixtures of hexacyclic, 1, 2-dichloroethane, acetonitrile, preferably dimethyl sulfoxide; base C and base D are sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium bicarbonate, triethylamine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene,N,N-dimethylaniline, 1, 4-diazabicyclo [2.2.2]One of the octanes, preferably base C is triethylamine and base D is 1, 8-diazabicyclo [5.4.0]Undec-7-ene. R is R 1 OH is one of ethanol, isopropanol, n-butanol, benzyl alcohol, phenol, p-methylphenol, 2-hydroxythiophene, 2-hydroxypyridine, 1-naphthol and 2-naphthol, and preferably benzyl alcohol; in step 2), 2,2, 2-trifluoroacetamide and R 1 The ratio of OH substances is 1:1-1:3, preferably 1:2, and the dosage of thionyl chloride and alkali C is 1-2 times, preferably 1.2 times of that of 2, 2-trifluoroacetamide; the amount of material is in mmol.
As a preferred embodiment of the method for synthesizing fluxapyroxad intermediate according to the present invention, wherein: the solvent F in the step 3) is tetrahydrofuran, methylene dichloride, ethyl acetate,N, NDimethylformamide (DMA),N, N-dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxane, 1, 2-dichloroethane, acetonitrile or a mixture of two thereof, preferably ethanol; the base G is sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium bicarbonate, triethylamine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene,N, N-dimethylaniline, 1, 4-diazabicyclo [2.2.2]One of the octanes, preferably triethylamine; the mass ratio of the substances of the formula (In-I) to the formula (In-II) In the step 3) is 1.2:1-1.5:1, preferably 1.2:1; the amount of the base F is 1 to 2 times, preferably 1.2 times, that of the formula (In-I); the amount of material is in mmol.
As a preferred embodiment of the method for synthesizing fluxapyroxad intermediate according to the present invention, wherein: the solvent H in the step 4) is tetrahydrofuran, dichloromethane, ethyl acetate,N, NDimethylformamide (DMA),N, NOne or two mixtures of dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxane, 1, 2-dichloroethane, acetonitrile, preferablyN, N-dimethylformamide; the alkali I is sodium carbonate,Potassium carbonate, cesium carbonate, potassium acetate, sodium bicarbonate, sodium hydroxide, triethylamine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene,N, N-dimethylaniline, 1, 4-diazabicyclo [2.2.2]One of the octanes, preferably sodium hydroxide; the mass ratio of (In-III) to 1, 2-dichloroethane or 1, 2-dibromoethane In step 4) is 1:1 to 1:1.1, preferably 1:1.05; the amount of the base I is 1 to 2 times, preferably 2 times, that of the formula (In-III); the phase transfer catalyst is 10-30%, preferably 20% of the amount of the substance of formula (In-III); the amount of material is in mmol.
As a preferred embodiment of the method for synthesizing fluxapyroxad intermediate according to the present invention, wherein: the reaction temperature in the step 1) is 40-90 ℃, the reaction time is 10-24 hours, preferably the reaction temperature is 80 ℃, and the reaction time is 16 hours.
As a preferred embodiment of the method for synthesizing fluxapyroxad intermediate according to the present invention, wherein: the reaction temperature in the step 2) is-50-10 ℃, the reaction time is 10-24 hours, preferably-40 ℃, and the reaction time is 12 hours.
As a preferred embodiment of the method for synthesizing fluxapyroxad intermediate according to the present invention, wherein: the reaction temperature in the step 3) is 10-50 ℃, the reaction time is 10-24 hours, preferably the reaction temperature is 30 ℃, and the reaction time is 16 hours.
As a preferred embodiment of the method for synthesizing fluxapyroxad intermediate according to the present invention, wherein: the structure of the compound obtained by the above steps is that 1 Methods such as H NMR and HRMS are characterized and confirmed.
Compared with the prior art, the invention has the beneficial effects that: the prior art does not meet the requirements of green chemistry while using a large amount of reagents with high pollution and high corrosiveness. The synthesis method of the invention not only avoids the use of noble metal palladium catalyst, but also has low pollution of the reaction reagent, high reaction yield and milder condition, and meets the requirements of green chemistry.
Detailed Description
The following detailed description of the present invention will provide further details in order to make the above-mentioned objects, features and advantages of the present invention more comprehensible.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in further detail below.
Example 1
Step one, takingN-2.03g of ethyl tert-butoxycarbonyl glycinate is placed In 40mL of ethanol, 5.01g of hydrazine hydrate is added, the reaction is carried out for 16 hours at 80 ℃, gas chromatography tracking is carried out, after the reaction is finished, the reaction solution is concentrated, and then the recrystallization is carried out, thus obtaining 1.68g of the formula (In-I) with 89% yield. White solid. 1 H NMR (400 MHz, CD 3 OD) δ 3.70 (s, 2H), 1.46 (s, 9H)；EI-HRMS calcd for C 8 H 17 N 3 O 3 (M+) 203.1270, found 203.1272；
Step two, 3.73g of 2,2, 2-trifluoroacetamide is placed In 10mL of dimethyl sulfoxide, the temperature is reduced to-40 ℃ under the protection of inert gas, 4.26g of thionyl chloride and 10.0g of triethylamine are slowly added to react for 0.5 hour at the same temperature, 3.31g of DBU and 1.08g of benzyl alcohol are slowly added, the reaction is slowly restored to room temperature after the addition and is carried out for 12 hours at room temperature, 1.77g of formula (In-II) is obtained by concentration, and the yield is 88%. An oily liquid. 1 H NMR (400 MHz, CDCl3) δ 8.36 (1H, s), 7.43 (5H, m), 5.34 (2H, s); 19 F NMR (376 MHz, CDCl3) −74.7; EI-HRMS calcd for C 9 H 8 F 3 NO (M+) 203.0558, found 203.0532；
Step three, 2.24g of formula (In-I) and 2.03g of formula (In-II) are dissolved In ethanol 10mL, 2.02g of triethylamine is added, after the reaction is completed at 80 ℃ for 12 hours, the reaction is cooled to room temperature, 30mL of 2N hydrochloric acid solution is added, and 1.78g of formula (In-III) can be obtained through recrystallization, and the yield is 80%. An off-white solid. 1 H NMR (400 MHz, CDCl3) δ 4.83 (brs, 2H), EI-HRMS calcd for C 4 H 6 F 3 N 4 (M + ) 167.0539, found 167.0542;
Step four, 2.33g of the formula (In-III) is placed In 15mL of water, 15g of sodium hydroxide and 185mg of tetrabutylammonium bromide are added, stirring is carried out for 0.5 hour at 30 ℃, then a mixed solution of 5.38g of 1, 2-dibromoethane and 10mL of DMF is slowly added dropwise, the temperature is kept for 12 hours at 30 ℃ after the addition, and 1.48g of fluxapyroxad intermediate can be obtained after recrystallization, and the yield is 55%. An oily liquid. 1 H NMR (500 MHz, CDCl 3 ) δ 4.29-4.16 (m, 4H), 3.38 (t, J = 5.5 Hz, 2H). ESI-HRMS calcd for C 6 H 8 F 3 N 4 (M+H) + 193.0696, found 193.0695。
Example 2
The synthesis of formula (In-I) was performed according to the synthesis method of example 1, and the reaction conditions were selected by changing only the reaction solvent, the reaction temperature and the reaction time, and the results are shown In Table 1. Table 1:
example 3
Synthesis of formula (In-I) according to the Synthesis method of example 1, usingN-Boc glycine ethyl ester 2.03g and hydrazine hydrate 6.25g gave 1.69g of the formula (In-I) In 89% yield.
Example 4
Synthesis of formula (In-I) according to the Synthesis method of example 1, usingN-Boc glycine ethyl ester 2.03g and hydrazine hydrate 3.75g gave 1.69g of the formula (In-I) In 62% yield.
Example 5
The synthesis of formula (In-I) was performed according to the synthesis method of example 1, and using ethanol 10. 10mL, 0.95g of formula (In-I) was obtained In 50% yield.
Example 6
In the second step, 3.73g of 2,2, 2-trifluoroacetamide is placed In 10mL of dimethyl sulfoxide, the temperature is reduced to-40 ℃ under the protection of inert gas, 4.26g of thionyl chloride and 10.0g of triethylamine are slowly added for reaction for 0.5 hour at the same temperature, 2.20 g g g of triethylamine and 1.08g of benzyl alcohol are slowly added, after the addition, the reaction is slowly resumed at room temperature for 12 hours at room temperature, 0.93g of formula (In-II) is obtained by concentration, and the yield is 46%.
Example 7
In the second step, 3.73g of 2,2, 2-trifluoroacetamide is placed In 10mL of dimethyl sulfoxide, the temperature is reduced to-40 ℃ under the protection of inert gas, 4.26g of thionyl chloride and 15.0g of DBU are slowly added, the reaction is carried out for 0.5 hour at the same temperature, 3.31 and g g of DBU and 1.08g of benzyl alcohol are slowly added, the reaction is slowly restored to room temperature after the addition and carried out for 12 hours at room temperature, 1.42g of formula (In-II) is obtained by concentration, and the yield is 70%.
Example 8
In the second step, 3.73g of 2,2, 2-trifluoroacetamide is placed In 10mL of dimethyl sulfoxide, the temperature is reduced to-40 ℃ under the protection of inert gas, 4.26g of thionyl chloride and 15.0g of DBU are slowly added to react for 0.5 hour at the same temperature, 3.00 g of potassium carbonate g and 1.08g of benzyl alcohol are slowly added, the reaction is slowly resumed at room temperature and carried out for 12 hours at room temperature after the addition, and the concentration is carried out to obtain the compound of formula (In-II) 0g, wherein the yield is 0%.
Example 9
In the second step, 3.73g of 2,2, 2-trifluoroacetamide is placed In 10mL of dimethyl sulfoxide, the temperature is reduced to-40 ℃ under the protection of inert gas, 4.26g of thionyl chloride and 15.0g of DBU are slowly added for reaction for 0.5 hour at the same temperature, 2.65 g g of DMAP and 1.08g of benzyl alcohol are slowly added, after the addition, the reaction is slowly restored to room temperature and carried out for 12 hours at room temperature, the concentration is carried out, and the formula (In-II) 0.65 g is obtained, and the yield is 32%.
Example 10
In the third step, 2.24g of the formula (In-I) and 2.03g of the formula (In-II) are dissolved In tetrahydrofuran 10mL, 2.02g of triethylamine is added, the reaction is carried out at 80 ℃ for 12 hours, after the reaction is detected to be complete, the temperature is cooled to room temperature, 30mL of a 2N hydrochloric acid solution is added, and 1.33g of the formula (In-III) can be obtained through recrystallization, and the yield is 60%.
Example 11
In the third step, 2.24g of the formula (In-I) and 2.03g of the formula (In-II) are dissolved In acetonitrile 10mL, 2.02g of triethylamine is added, the reaction is carried out at 80 ℃ for 12 hours, after the reaction is detected to be complete, the reaction is cooled to room temperature, 30mL of a 2N hydrochloric acid solution is added, and 1.60g of the formula (In-III) can be obtained through recrystallization, and the yield is 72%.
Example 12
In the third step, 2.24g of formula (In-I) and 2.03g of formula (In-II) were dissolved In DMF 10mL, 2.02g of triethylamine was added, the reaction was allowed to react at 80℃for 12 hours, after completion of the reaction, the reaction was cooled to room temperature, and 30mL of a 2N hydrochloric acid solution was added, and 1.80g of formula (In-III) was obtained by recrystallization In 81%.
Example 13
In the third step, 2.24g of formula (In-I) and 2.03g of formula (In-II) are dissolved In ethanol 10mL, 3.04 g of DBU is added, after the reaction is completed at 80 ℃ for 12 hours, the reaction is cooled to room temperature, 30mL of 2N hydrochloric acid solution is added, and 0.80 g of formula (In-III) can be obtained through recrystallization, and the yield is 36%.
Example 14
In the third step, 2.24g of formula (In-I) and 2.03g of formula (In-II) are dissolved In ethanol 10mL, 2.76 g of potassium carbonate is added, the reaction is carried out at 80 ℃ for 12 hours, after the reaction is detected to be complete, the temperature is cooled to room temperature, 30mL of 2N hydrochloric acid solution is added, and the recrystallization is carried out, so that the formula (In-III) 1.02 g is obtained, and the yield is 46%.
Example 15
In the third step, 2.24g of the formula (In-I) and 2.03g of the formula (In-II) are dissolved In ethanol 10mL, 2.02g of triethylamine is added, the reaction is carried out at 50 ℃ for 12 hours, after the reaction is detected to be complete, the temperature is cooled to room temperature, 30mL of a 2N hydrochloric acid solution is added, and 1.38g of the formula (In-III) can be obtained through recrystallization, and the yield is 62%.
Example 16
In the third step, 2.24g of formula (In-I) and 2.03g of formula (In-II) are dissolved In ethanol 10mL, 2.02g of triethylamine is added, the mixture is placed In a pressure-resistant tube at 110 ℃ for reaction for 12 hours, after the reaction is detected to be complete, the mixture is cooled to room temperature, 30mL of 2N hydrochloric acid solution is added, and 1.78g of formula (In-III) is obtained through recrystallization, wherein the yield is 80%.
Example 17
In the third step, 2.84g of the formula (In-I) and 2.03g of the formula (In-II) were dissolved In acetonitrile 10mL, 2.02g of triethylamine was added, the reaction was allowed to react at 80℃for 12 hours, after completion of the reaction, the reaction was cooled to room temperature, 30mL of a 2N hydrochloric acid solution was added, and 1.80g of the formula (In-III) was obtained by recrystallization In 81%.
Example 18
In the fourth step, 2.33g of the formula (In-III) is placed In 15mL of water, 15g of sodium hydroxide and 185mg of tetrabutylammonium bromide are added, the mixture is stirred for 0.5 hour at 30 ℃, then a mixed solution of 5.38g of 1, 2-dibromoethane and 10mL of toluene is slowly added dropwise, the mixture is kept at 30 ℃ for 12 hours after the addition, and 0.83g of fluxapyroxad intermediate can be obtained after recrystallization, and the yield is 31%.
Example 19
In the fourth step, 2.33g of the formula (In-III) is placed In 15mL of water, 15g of sodium hydroxide and 185mg of tetrabutylammonium bromide are added, the mixture is stirred for 0.5 hour at 30 ℃, then a mixed solution of 5.38g of 1, 2-dibromoethane and 10mL of ethyl acetate is slowly added dropwise, the mixture is kept at 30 ℃ for 12 hours after the addition, and 1.05g of the fluxapyroxad intermediate can be obtained after recrystallization, and the yield is 39%.
Example 20
In the fourth step, 2.33g of the formula (In-III) is placed In 15mL of water, 51.8 g mg of potassium carbonate and 185mg of tetrabutylammonium bromide are added, the mixture is stirred for 0.5 hour at 30 ℃, then 5.38g of 1, 2-dibromoethane and 10mL of DMF are slowly added dropwise, the mixture is kept at 30 ℃ for 12 hours after the addition, and 0.73g of fluxapyropalide intermediate can be obtained after recrystallization, and the yield is 27%.
Example 21
In the fourth step, 2.33g of the formula (In-III) is placed In 15mL of water, 51.8 g mg of sodium hydroxide and 185mg of tetrabutylammonium bromide are added, the mixture is stirred for 0.5 hour at 50 ℃, then 5.38g of 1, 2-dibromoethane and 10mL of DMF are slowly added dropwise, the mixture is kept at 50 ℃ for 12 hours after the addition, and 1.53g of the fluxapyroxad intermediate can be obtained after recrystallization, and the yield is 57%.
Although the invention has been described hereinabove with reference to embodiments, various modifications thereof may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In particular, the features of the disclosed embodiments may be combined with each other in any manner as long as there is no structural conflict, and the exhaustive description of these combinations is not given in this specification merely for the sake of omitting the descriptions and saving resources. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed, but that the invention will include all embodiments falling within the scope of the appended claims. .
Claims (5)
1. A method for synthesizing fluxapyroxad intermediate, which is characterized in that: the method comprises the following steps:
1) Will beN-Placing tert-butyloxycarbonyl glycine ethyl ester in solvent A, wherein the solvent A is tetrahydrofuran, dichloromethane, ethyl acetate,N, N-Dimethylformamide (DMA),N, N-Adding hydrazine hydrate into one or two mixtures of dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxane, 1, 2-dichloroethane and acetonitrile, reacting for 10-24 hours at 40-90 ℃, tracking by gas chromatography, concentrating the reaction solution after the reaction is finished, and recrystallizing to obtain the formula (In-I); the reaction formula is as follows:2) 2,2, 2-trifluoroacetamide is placed in a solvent B, wherein the solvent B is tetrahydrofuran, dichloromethane, ethyl acetate,N, NDimethylformamide (DMA),N, N-one or two mixtures of dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxane, 1, 2-dichloroethane and acetonitrile, cooling to-50-10 ℃ under the protection of inert gas, and slowly adding thionyl chloride and alkali C, wherein the alkali C is triethylamine, 4-dimethylaminopyridine and 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene,N, N-dimethylaniline, 1, 4-diazabicyclo [2.2.2]One of the octanes is reacted for 0.5 hour at the same temperature, and then the alkali D and R are slowly added 1 OH, wherein the base D is triethylamine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene,N, N-dimethylaniline, 1, 4-diazabicyclo [2.2.2]Slowly recovering the octane from the mixture to room temperature after adding the octane, reacting at the room temperature for 10-24 hours, concentrating to obtain the compound shown In the formula (In-II), and R 1 Is alkyl, phenyl or benzyl; the reaction formula is as follows: />3) Dissolving the formula (In-I) and the formula (In-II) In a solvent F, wherein the solvent F is hydrofuran, dichloromethane, ethyl acetate,N, NDimethylformamide (DMA),N, N-one of dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxane, 1, 2-dichloroethane, acetonitrile, adding a base G, wherein the base G is sodium carbonate, potassium carbonate, cesium carbonate, potassium acetate, sodium bicarbonate, triethylamine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene,N, N-dimethylaniline, 1, 4-diazabicyclo [2.2.2]One of the octanes reacts for 10-24 hours at 50-110 ℃, after the reaction is detected to be complete, the reaction is cooled to room temperature, and 2N hydrochloric acid solution is added, and the formula (In-III) is obtained through recrystallization; the reaction formula is as follows:
4) Dissolving the formula (In-III) In water, adding one of alkali potassium carbonate or sodium hydroxide and tetrabutylammonium bromide, stirring at 10-50 ℃ for 0.5-3 hours, slowly dropwise adding 1, 2-dichloroethane or 1, 2-dibromoethane solution, preserving heat at 10-50 ℃ for 10-24 hours after adding, and recrystallizing to obtain a fluxapyropalide intermediate, namely the formula (IV); the reaction formula is as follows:
。
2. a method of synthesizing fluxapyroxad intermediate according to claim 1, wherein: in the step 1), the solvent A is ethanol;N-the ratio of the quantity of the tert-butyloxycarbonyl glycine ethyl ester to the quantity of the hydrazine hydrate substance is 1:10; volume of solventN-The ratio of the amounts of the materials of the ethyl t-butoxycarbonyl glycinate was 4:1, the unit of volume was mL, and the unit of the amount of the materials was mmol.
3. A method of synthesizing a fluxapyroxad intermediate according to claim 1, which comprisesIs characterized in that: in the step 2), the solvent B is dimethyl sulfoxide; base C and base D are triethylamine or 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene; r is R 1 OH is benzyl alcohol; in step 2), 2,2, 2-trifluoroacetamide and R 1 The ratio of OH substances is 1:2, and the dosage of thionyl chloride and alkali C is 1.2 times of that of 2,2, 2-trifluoroacetamide; the amount of material is in mmol.
4. A method of synthesizing fluxapyroxad intermediate according to claim 1, wherein: the solvent F in the step 3) is ethanol; the base G is triethylamine; the mass ratio of the substances of the formula (In-I) to the formula (In-II) is 1.2:1; the amount of base G used is 1.2 times that of formula (In-I); the amount of material is in mmol.
5. A method of synthesizing fluxapyroxad intermediate according to claim 1, wherein: the alkali in the step 4) is sodium hydroxide; the mass ratio of the substances of the formulae (In-III) and 1, 2-dichloroethane or 1, 2-dibromoethane is 1:1.05; the amount of base used is 2 times that of formula (In-III); tetrabutylammonium bromide was 20% of the amount of the substance of the formula (In-III); the amount of material is in mmol.
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