阅读说明：本技术 一种2-（2,2-二氟乙氧基）-6-（三氟甲基）苯磺酰氯的合成方法 (Synthetic method of 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride ) 是由 郑战江 黄帅帅 徐利文 曹建 杨科芳 崔玉明 徐征 尹官武 郭彬 于 2019-01-28 设计创作，主要内容包括：本发明涉及有机合成技术领域,针对现有2-(2,2-二氟乙氧基)-6-(三氟甲基)苯磺酰氯合成路径较长、总产率较低的问题,本发明公开了一种2-(2,2-二氟乙氧基)-6-(三氟甲基)苯磺酰氯的合成方法,由式I化合物<Image he="114" wi="168" file="DDA0001960710340000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>与非亲核性锂试剂、二丙基二硫醚在非质子试剂中反应得式II化合物<Image he="105" wi="234" file="DDA0001960710340000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>然后由式II化合物在强碱试剂、铜催化剂、助催化剂存在下与二氟乙醇反应得式III化合物<Image he="118" wi="238" file="DDA0001960710340000013.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>再将式III化合物与N-氯代丁二酰亚胺NCS、甲酸或乙酸、水和有机溶剂中氯磺化反应得到2-(2,2-二氟乙氧基)-6-(三氟甲基)苯磺酰氯。本发明的合成方法成本低,反应步骤少,操作方便,目标产物收率可稳定在83％以上。(The invention relates to the technical field of organic synthesis, and discloses a method for synthesizing 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride aiming at the problems of longer synthetic route and lower total yield of the existing 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride, wherein a compound shown in a formula I is used as a raw material Reacting with non-nucleophilic lithium reagent and dipropyl disulfide in non-proton reagent to obtain the compound of formula II Then the compound of the formula II reacts with difluoroethanol in the presence of a strong base reagent, a copper catalyst and a cocatalyst to obtain a compound of a formula III And performing chlorosulfonation reaction on the compound shown in the formula III, N-chlorosuccinimide NCS, formic acid or acetic acid, water and an organic solvent to obtain 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride. The synthesis method has the advantages of low cost, few reaction steps and convenient operation, and the yield of the target product can be stabilized to be more than 83 percent.)

1. A synthetic method of 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride is characterized by comprising the following steps:

(1) reacting the compound shown in the formula I with a non-nucleophilic lithium reagent and dipropyl disulfide in a non-proton reagent to obtain a compound shown in the formula II;

(2) reacting the compound shown in the formula II with difluoroethanol in the presence of a strong base reagent, a copper catalyst and a cocatalyst to obtain a compound shown in the formula III;

(3) performing chlorosulfonation reaction on the compound shown in the formula III with N-chlorosuccinimide, formic acid or acetic acid, water and an organic solvent to obtain a target product 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride.

2. The method for synthesizing 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride as claimed in claim 1, wherein said non-nucleophilic lithium reagent in step (1) is lithium diisopropylamide or lithium hexamethyldisilazide.

3. The method for synthesizing 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride as claimed in claim 1 or 2, wherein the molar ratio of the compound of formula I, the non-nucleophilic lithium reagent and dipropyl disulfide is 1: 1-1.2: 1-1.5.

4. The method for synthesizing 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride as claimed in claim 1 or 2, wherein the reaction temperature in step (1) is-40 to-120 ℃.

5. The method for synthesizing 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride as claimed in claim 1, wherein the strong basic reagent is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride and metallic sodium, the promoter is formate, and the copper catalyst is one of CuI, CuBr and CuCl.

6. The synthesis method of 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride as claimed in claim 1 or 5, wherein the molar ratio of the compound of formula II to the strong base reagent, the copper catalyst, the cocatalyst and the difluoroethanol is 1: 1-5: 0.01-0.3: 0.5-3: 1-100.

7. The method for synthesizing 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride as claimed in claim 1 or 5, wherein the reaction temperature in step (2) is 80-130 ℃.

8. The method for synthesizing 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride as claimed in claim 1, wherein the organic solvent in step (3) is at least one selected from acetonitrile, diethyl ether, tetrahydrofuran, n-hexane, cyclohexane and n-heptane.

9. The method for synthesizing 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride as claimed in claim 1 or 8, wherein the step (3) is carried out at 0-70 ℃ for 1-48 hours.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a synthetic method of 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride.

Background

Penoxsulam (penoxsulam) is a post-emergence herbicide developed by the Dow agriosiences corporation of the united states with the chemical name: 3- (2, 2-difluoroethoxy) -N- (5, 8-dimethoxy- [1,2,4] triazolo [1,5-C ] pyrimidin-2-yl) -alpha, alpha-trifluoromethylphenyl-2-sulfonamide belongs to triazolopyrimidine sulfonamide herbicides, has good control effect on various barnyard grass including instar barnyard grass by inhibiting acetolactate synthase (ALS), has wide herbicidal spectrum, and can be used for preventing and killing barnyard grass and annual sedge and various broad leaf weeds in paddy fields. The synthetic method is that 2- (2, 2-difluoro ethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride and 5, 8-dimethoxy- [1,2,4] triazolo [1,5-c ] pyrimidine-2-amine react in organic solvent by alkali action to prepare the compound. Wherein, the Dow Yinong company discloses a synthesis method of 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride in a U.S. patent US20050215570, and the preparation process is as follows:

however, the synthetic route of the preparation process is complicated, the reaction steps are more, the total yield is lower, and various reagents are used in the preparation process, for example, the introduction of difluoroethoxy requires expensive 2, 2-difluoroiodoethane as a reagent, so the cost is higher. Therefore, a suitable synthesis method of the 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride is found, so that the method has the advantages of few steps, high synthesis yield and low cost, and has positive significance undoubtedly for the marketization application of the penoxsulam.

Disclosure of Invention

Aiming at the problems that the existing synthesis route of 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride is long, and the overall yield is low due to the complicated route, the invention aims to provide the synthesis method of 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride, which has the advantages of few reaction steps, short synthesis route and high synthesis yield of 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride.

The invention provides the following technical scheme:

a synthetic method of 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride is characterized by comprising the following steps:

(1) reacting the compound shown in the formula I with a non-nucleophilic lithium reagent and dipropyl disulfide in a non-proton reagent to obtain a compound shown in the formula II;

(2) reacting the compound shown in the formula II with difluoroethanol in the presence of a strong base reagent, a copper catalyst and a cocatalyst to obtain a compound shown in the formula III;

(3) performing chlorosulfonation reaction on the compound shown in the formula III, N-chlorosuccinimide NCS, formic acid or acetic acid, water and an organic solvent to obtain a target product 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride.

The aprotic solvent used in step (1) may be one or more of diethyl ether, tetrahydrofuran, cyclohexane, n-hexane, and n-heptane.

Preferably, in the method of the present invention, the non-nucleophilic lithium reagent in step (1) is lithium diisopropylamide or lithium hexamethyldisilazide.

Preferably, the molar ratio of the compound of formula I, the non-nucleophilic strong base lithium reagent and the dipropyl disulfide is 1: 1-1.2: 1-1.5.

As a preference of the process of the present invention, the reaction temperature in step (1) is from-40 to-120 ℃. The reaction temperature in step (1) is more preferably from-78 to-100 ℃.

Preferably, the strong alkali reagent is one of sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride and metallic sodium, the promoter is formate, and the copper catalyst is one of CuI, CuBr and CuCl. The formate is preferably methyl formate or ethyl formate.

Preferably, the molar ratio of the compound shown in the formula II to the strong alkali reagent, the copper catalyst, the cocatalyst and the difluoroethanol is 1: 1-5: 0.01-0.3: 0.5-3: 1-100.

Preferably, the reaction temperature in step (2) is 80-130 ℃. In the step (2), the reaction temperature is preferably 100-130 ℃.

In the method of the present invention, the organic solvent in the step (3) is preferably at least one selected from the group consisting of acetonitrile, diethyl ether, tetrahydrofuran, n-hexane, cyclohexane and n-heptane.

Preferably, the reaction in step (3) is carried out at 0 to 70 ℃ for 1 to 48 hours. In the step (3), the reaction temperature is further preferably 10-50 ℃, the reaction time is 10-36 hours, and the preferable molar ratio of the compound shown in the formula III to NCS is 1: 1-10.

The synthesis method of the 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride can be realized through three steps of operation. The method comprises the following steps of firstly using a compound shown in a formula I as a substrate, forming lithium salt with lithium diisopropylamide or lithium hexamethyldisilazide, reacting with dipropyl disulfide in situ to obtain a compound shown in a formula II, and then carrying out etherification reaction on the prepared compound shown in the formula II with difluoroethanol by utilizing the relative activity of a C-Br bond under the catalytic action of a copper catalyst, a cocatalyst methyl formate or ethyl formate in the presence of alkali, thereby preparing the compound shown in the formula III. And then reacting the compound shown in the formula III with N-chlorosuccinimide/acetic acid/water in an organic solvent or N-chlorosuccinimide/formic acid/water in an organic solvent to obtain a target product.

The synthesis method of the 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride can be realized through three steps of operation, the reaction steps are greatly reduced compared with those of US20050215570, the reaction path is simpler, the yield of the 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride is above 83%, the price of the compound of the formula I is lower, and the preparation cost is reduced.

The invention has the following beneficial effects:

the synthesis method of the 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride has the advantages of low price of raw materials, low cost, few reaction steps, concise reaction path and convenient operation, and the yield of the 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride is high and can be stabilized to be more than 83%.

Drawings

FIG. 1 shows the preparation of the compound of formula II obtained in example 1¹H NMR spectrum.

FIG. 2 shows the preparation of the compound of the formula III obtained in example 1¹H NMR spectrum.

FIG. 3 is a drawing showing 2- (2, 2-difluoroethoxy) -6- (trifluoromethyl) benzenesulfonyl chloride obtained in example 1¹H NMR spectrum.

Detailed Description

The following further describes the embodiments of the present invention.

The starting materials used in the present invention are commercially available or commonly used in the art, unless otherwise specified, and the methods in the following examples are conventional in the art, unless otherwise specified.