阅读说明：本技术 一种氟雷拉纳中间体的制备方法 (Preparation method of flurarana intermediate ) 是由 刘雄 阮张寅 刘文金 黄想亮 周国斌 曹雨倩 曹倩 于 2020-09-30 设计创作，主要内容包括：本发明涉及一种氟雷拉纳中间体的制备方法,其以4-氰基-2-甲基苯甲酸甲酯作为起始反应物,与羟胺发生加成反应得到4-甲酰胺肟-2-甲基苯甲酸甲酯,再依次经重氮化和脱氮反应得到卤肟类化合物,最后卤肟类化合物与1,3-二氯-5-(1-三氟甲基-乙烯基)苯进行加成环合反应得到目标产物弗雷拉纳中间体。本发明先通过加成反应制备酰胺肟,再经重氮化反应制备卤代肟,相较于现有技术中的还原、肟化和氯化反应,制备过程大大简化,且工艺条件温和、安全、绿色环保,收率可达到70％以上,适应于工业化生产。(The invention relates to a preparation method of a flurandrine intermediate, which takes 4-cyano-2-methyl benzoate as an initial reactant to perform addition reaction with hydroxylamine to obtain 4-formamide oxime-2-methyl benzoate, then performs diazotization and denitrification reaction in sequence to obtain a halogen oxime compound, and finally performs addition cyclization reaction on the halogen oxime compound and 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to obtain the target product of the flurandrine intermediate. According to the invention, amide oxime is prepared through an addition reaction, and then halogenated oxime is prepared through a diazotization reaction, compared with reduction, oximation and chlorination reactions in the prior art, the preparation process is greatly simplified, the process conditions are mild, safe, green and environment-friendly, the yield can reach more than 70%, and the method is suitable for industrial production.)

1. A preparation method of a flurarana intermediate is characterized by comprising the following steps:

(1) carrying out addition reaction on a compound 5 shown in the following formula and hydroxylamine to obtain a compound 4 shown in the following formula;

(2) carrying out diazotization and denitrification reaction on the compound 4 obtained in the step (1) to obtain a compound 3 shown in the following formula, wherein X in the compound 3 is Cl or Br;

(3) performing addition cyclization reaction on the compound 3 obtained in the step (2) and a compound 2 shown in the following formula to obtain a target product, namely a compound 1 shown in the following formula,

2. the process for the preparation of a frataxin intermediate according to claim 1, wherein: the reaction in the step (2) comprises a first stage and a second stage, wherein the first stage is that a diazotization reaction is carried out on a compound 4 and sodium nitrite to obtain a compound 6 shown in the following formula,

the second stage is that the compound 6 and cuprous halide are subjected to sandmeyer denitrification reaction to obtain a compound 3,

3. the process for the preparation of a frataxin intermediate according to claim 1, wherein: in the step (1), methanol or ethanol is used as a solvent, and a catalyst, hydroxylamine hydrochloride and the compound 5 are placed in the solvent for reaction at the temperature of 50-65 ℃ for 3-5 hours.

4. The process for the preparation of a frataxin intermediate according to claim 3, wherein: the catalyst is triethylamine or N, N-diisopropylethylamine.

5. The process for the preparation of a frataxin intermediate according to claim 3, wherein: and (2) after the reaction in the step (1) is finished, concentrating the reaction system under reduced pressure to 0.2-0.45 time of the volume of the original reaction system, stirring for 2-3 h at room temperature, filtering and drying to obtain the compound 4.

6. The process for the preparation of a frataxin intermediate according to claim 2, wherein: in the first stage, acetonitrile or ethylene glycol dimethyl ether is used as a solvent, concentrated hydrochloric acid, a 30% sodium nitrite solution and the compound 4 are placed in the solvent for reaction, the reaction temperature is 0-5 ℃, and the reaction time is 0.8-1.2 h.

7. The process for the preparation of a frataxin intermediate according to claim 6, wherein: and in the second stage, adding a cuprous chloride hydrochloric acid solution into the reaction system in the first stage, reacting for 3-5 h at 0-5 ℃, and after the reaction is finished, carrying out reduced pressure concentration and layering treatment to obtain the compound 3.

8. The process for the preparation of a frataxin intermediate according to claim 2, wherein: in the first stage, acetonitrile or ethylene glycol dimethyl ether is used as a solvent, hydrobromic acid, a 30% sodium nitrite solution and the compound 4 are placed in the solvent for reaction, the reaction temperature is 0-5 ℃, and the reaction time is 0.8-1.2 h.

9. The process for the preparation of a frataxin intermediate according to claim 8, wherein: and in the second stage, adding a hydrobromic acid solution of cuprous bromide into the reaction system in the first stage, reacting for 3-5 h at 0-5 ℃, and after the reaction is finished, carrying out reduced pressure concentration and layering treatment to obtain the compound 3.

10. The process for producing a frainer intermediate as claimed in any one of claims 1 to 9, wherein: in the step (3), the organic solvent solution of the compound 3 is cooled to-5-0 ℃, then the catalyst and the compound 2 are added, and the reaction is carried out for 3-5 hours at-5 ℃.

Technical Field

The invention relates to a preparation method of a flurandrine key intermediate, in particular to a preparation method of 4- [5- (3, 5-dichlorophenyl) -5-trifluoromethyl-4, 5-dihydroisoxazol-3-yl ] -2-trifluoromethyl methyl benzoate.

Background

Flurarana (english name:Fluralaner) The chemical name is 4, 5- [ (3, 5-dichlorophenyl) -4, 5-dihydro-5-trifluoromethyl-3-isoxazolyl]-2-methyl-aza- [ 2-oxo-2- [ (2, 2, 2-trifluoroethyl) amino]Ethyl radical]-benzamide. In 2004, frairana was successfully synthesized by japanese nippon chemical industries co. In 2014, frailamide was approved by the U.S. food and drug administration for marketing (trade name braveco) in the european and american market, with quarterly sales amounting to $ 1 billion.

The loratadine mainly plays a role by interfering GABA gated chloride ion channels, and is similar to the action targets of pesticides such as cyclopentadiene, phenylpyrazole and macrolide. The successful research and development of the loratadine creates a brand-new research direction of GABA (gamma-aminobutyric acid) gated chloride channel interfering agents, and draws the attention and favor of animal medicine and pesticide science workers. The fraxidin is a broad-spectrum pesticide, has good insecticidal activity on pests of the orders of tick, flea, louse, hemiptera, diptera and the like, and has higher toxicity or equivalent toxicity to that of a common pesticide. The activity of the frailana fluoride to Ctenocephalides (Ctenocephalides felis) is superior to that of the traditional insecticides fipronil and imidacloprid; the activity to the copper green fly (Lucilia cuprina) is higher than that of fipronil, dieldrin, imidacloprid and deltamethrin; the activity of the compound on Boophilus microplus (Rhipicephalus microplus) is far higher than that of deltamethrin, and the insecticidal activity of the compound on Laodelphax striatellus (Laodelphax striatellus) and Tetranychus urticae (Tetranychus urticae) of fipronil is better. The fraxidin has no obvious cross resistance with the existing pesticide, and even has better insecticidal activity to partially resistant pests.

Fraserpine was first disclosed in international patent application EP1731512B 1. International application WO2008122375a2 discloses a process for the preparation of fraxidin.

Patent EP1731512B1 in example 3 uses 2-methyl-4-formaldoxime methyl benzoate as a raw material, firstly an oxime chloride compound is obtained under the action of NCS, and then 1, 3-dipolar addition cyclization is performed with 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to obtain a key intermediate 4- [5- (3, 5-dichlorophenyl) -5-trifluoromethyl-4, 5-dihydroisoxazol-3-yl ] -2-trifluoromethyl methyl benzoate, and after a series of reactions, fluranide is obtained; example 5 discloses that 4-bromo-3-methylbenzaldehyde is used as a raw material, reacted with hydroxylamine to obtain 4-bromo-3-methylbenzaldehyde oxime, reacted with NCS to obtain an oxime chloride compound, subjected to 1, 3-dipolar addition cyclization with 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene, and subjected to a carbon insertion reaction to obtain a key intermediate, thereby obtaining flurandrine. The preparation method disclosed above is not only difficult in raw material preparation, but also dangerous in carbon insertion reaction conditions, and liable to cause explosion and poisoning.

International publication WO2008122375A2 discloses that 4-bromo-3-methylbenzoic acid is used as a starting material, 4-formyl-2-methylbenzoic acid is obtained under the action of n-butyl lithium, then the 4-formyl-2-methylbenzoic acid reacts with methanol to generate methyl 4-formyl-2-methylbenzoate, and an intermediate is obtained through hydroxylamine reaction, chlorination and 1, 3-dipolar addition cyclization. The 4-position formylation condition in the method is harsh, and the method needs to be acted with a metal catalyst n-butyl lithium at the temperature of minus 70 ℃.

It can be known from the prior art that the intermediate compound 4- [5- (3, 5-dichlorophenyl) -5-trifluoromethyl-4, 5-dihydroisoxazol-3-yl ] -2-trifluoromethyl benzoic acid methyl ester has a parent nucleus structure of the flurorana, and the target product flurorana can be obtained by hydrolysis reaction and then amidation reaction with 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide, so that the intermediate compound is an extremely important intermediate product for synthesizing the flurorana.

However, according to the methods disclosed in the prior art, the preparation of 4-formyl-2-methylbenzoic acid is difficult, a carbon insertion reaction requires special equipment, a gas source is very inconvenient, the operation is very dangerous in large-scale preparation, explosion is easy to occur, poisoning is easy to occur once leakage occurs, serious pollution is easily caused, in addition, the reaction time of the above methods is long, usually several days are required, the reaction is incomplete, and the separation and purification of the product are difficult, and the yield is low.

Disclosure of Invention

The invention aims to solve the technical problem of providing a preparation method of a flurarana intermediate, which has the advantages of safe and pollution-free preparation process, short reaction time and high yield, aiming at the current situation of the prior art.

The technical scheme adopted by the invention for solving the technical problems is as follows: a preparation method of a flurarana intermediate is characterized by comprising the following steps:

(1) carrying out addition reaction on a compound 5 shown in the following formula and hydroxylamine to obtain a compound 4 shown in the following formula;

(2) carrying out diazotization and denitrification reaction on the compound 4 obtained in the step (1) to obtain a compound 3 shown in the following formula, wherein X in the compound 3 is Cl or Br;

(3) performing addition cyclization reaction on the compound 3 obtained in the step (2) and a compound 2 shown in the following formula to obtain a target product, namely a compound 1 shown in the following formula,

in the scheme, the reaction of the step (2) comprises a first stage and a second stage, wherein the first stage is that the compound 4 and sodium nitrite are subjected to diazotization reaction to obtain a compound 6 shown in the following formula,

the second stage is that the compound 6 and cuprous halide are subjected to sandmeyer denitrification reaction to obtain a compound 3,

preferably, in the step (1), methanol or ethanol is used as a solvent, and a catalyst, hydroxylamine hydrochloride and the compound 5 are placed in the solvent to react at the temperature of 50-65 ℃ for 3-5 hours.

Further preferably, the catalyst is triethylamine or N, N-diisopropylethylamine.

Preferably, after the reaction in the step (1) is finished, the reaction system is decompressed and concentrated to 0.2-0.45 time of the volume of the original reaction system, stirred for 2-3 hours at room temperature, filtered and dried to obtain the compound 4.

Preferably, in the first stage, acetonitrile or ethylene glycol dimethyl ether is used as a solvent, concentrated hydrochloric acid, a 30% sodium nitrite solution and the compound 4 are placed in the solvent for reaction, the reaction temperature is 0-5 ℃, and the reaction time is 0.8-1.2 h. And in the second stage, adding a cuprous chloride hydrochloric acid solution into the reaction system in the first stage, reacting for 3-5 h at 0-5 ℃, and after the reaction is finished, carrying out reduced pressure concentration and layering treatment to obtain the compound 3.

Preferably, in the first stage, acetonitrile or ethylene glycol dimethyl ether is used as a solvent, and hydrobromic acid, a 30% sodium nitrite solution and the compound 4 are placed in the solvent for reaction at a temperature of 0-5 ℃ for 0.8-1.2 h. And in the second stage, adding a hydrobromic acid solution of cuprous bromide into the reaction system in the first stage, reacting for 3-5 h at 0-5 ℃, and after the reaction is finished, carrying out reduced pressure concentration and layering treatment to obtain the compound 3.

Preferably, in the step (3), after the compound 3 is cooled to-5 to 0 ℃ by using an organic solvent, the catalyst and the compound 2 are added to react for 3 to 5 hours at-5 to 5 ℃.

Compared with the prior art, the invention has the advantages that: according to the invention, amide oxime is prepared through an addition reaction, and then halogenated oxime is prepared through a diazotization reaction, compared with reduction, oximation and chlorination reactions in the prior art, the preparation process is greatly simplified, the process conditions are mild, safe, green and environment-friendly, the yield can reach more than 70%, and the method is suitable for industrial production.

Drawings

FIG. 1 is an ESI-MS diagram of Compound 4 in example 1 of the present invention;

FIG. 2 is an HPLC chromatogram of Compound 1 of example 1 of the present invention.

Detailed Description

The invention is described in further detail below with reference to the accompanying examples.

Example 1:

the preparation method of the frataxin intermediate in the embodiment comprises the following steps:

(1) adding 0.1moL of compound 5 (4-cyano-2-methyl benzoate) and 150mL of methanol into a 500mL four-mouth bottle with a thermometer and mechanical stirring, adding 25mL of triethylamine and 10.5g of hydroxylamine hydrochloride, reacting for 3 hours at 50-55 ℃, cooling to room temperature after TCL detection reaction is completed, concentrating under reduced pressure to 50-75 mL, stirring for 2-3 hours at room temperature, filtering, and drying in vacuum to obtain 20.1g of white-like solid, wherein the white-like solid is compound 4. The yield was 96%, and ESI-MS (m/z): 209[ M + H ] +, the sample molecular weight 208 is consistent with the target object;

(2) adding 15.6g of compound 4 (4-formamide oxime-2-methyl benzoate) into a 500mL reaction bottle, adding 100mL of acetonitrile, stirring to dissolve, adding 7mL of 36% concentrated hydrochloric acid at 5-10 ℃, adding 20g of 30% sodium nitrite solution at 0-5 ℃, and carrying out heat preservation reaction for 1 h; dropwise adding a solution prepared from 7.5g of cuprous chloride and 25mL of 36% hydrochloric acid at 0-5 ℃, and reacting for 3-5 h under heat preservation; after the TCL monitoring reaction is finished, carrying out reduced pressure concentration, adding 100mL of ethyl acetate, standing for layering, washing an organic layer with water, and layering again to obtain an ethyl acetate solution of a compound 3;

(3) cooling the ethyl acetate solution of the compound 3 to-5-0 ℃, adding 15mL of triethylamine, adding 21.7g of a compound 2(1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene) at-5 ℃, and reacting for 3-5 hours in a heat preservation manner; and after the TCL monitoring reaction is finished, washing the organic layer with water, standing and layering to obtain an organic layer, concentrating under reduced pressure, adding 100mL of methanol for crystallization, stirring at room temperature for 2-3 hours, filtering, and drying in vacuum to obtain 22.7g of a white-like solid, wherein the white-like solid is a compound 1. The yield was 70%, and the product purity was 96.85% as shown in fig. 2.

Example 2:

the preparation method of the frataxin intermediate in the embodiment comprises the following steps:

(1) adding 0.2moL of compound 5 (4-cyano-2-methyl benzoate) and 400mL of ethanol into a 500mL four-mouth bottle with a thermometer and mechanical stirring, adding 50mL of N, N-diisopropylethylamine and 28g of hydroxylamine hydrochloride, reacting for 5 hours at 60-65 ℃, cooling to room temperature after TCL detection reaction is completed, concentrating under reduced pressure to 100-150 mL, stirring for 2-3 hours at room temperature, filtering, and drying in vacuum to obtain 40.6g of white-like solid, wherein the white-like solid is compound 4, and the yield is 98%;

(2) adding 20.8g of compound 4 (4-formamidooxime-2-methyl benzoate) into a 500mL reaction bottle, adding 100mL of ethylene glycol dimethyl ether, stirring to dissolve, adding 10mL of 47% hydrobromic acid at 5-10 ℃, adding 25g of 30% sodium nitrite solution at 0-5 ℃, and reacting for 1h under the condition of heat preservation; dropwise adding a solution prepared from 14g of cuprous bromide and 40ml of 48% hydrobromic acid at 0-5 ℃, and reacting for 3-5 hours in a heat preservation manner; after the TCL monitoring reaction is finished, carrying out reduced pressure concentration, adding 100mL of methyl tert-butyl ether, standing for layering, washing an organic layer with water, and layering again to obtain a methyl tert-butyl ether solution of a compound 3;

(3) cooling the methyl tert-butyl ether solution of the compound 3 to-5-0 ℃, adding 21mLN, N-diisopropylethylamine, adding 27.1g of the compound 2(1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene) at-5 ℃, and reacting for 3-5 h under heat preservation; and after the TCL monitoring reaction is finished, washing the organic layer with water, standing for layering to obtain an organic layer, concentrating under reduced pressure, adding 100mL of ethanol for crystallization, stirring at room temperature for 2-3 hours, filtering, and drying in vacuum to obtain 31.5g of a white-like solid, wherein the white-like solid is a compound 1, and the yield is 73%.