阅读说明：本技术 一种n-(4-甲氧基羰基-3-氨基磺酰基苄基)甲磺酰胺的合成方法 (Synthesis method of N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide ) 是由 唐盈 张晓文 杨杰 陆建国 尤明明 于 2020-06-27 设计创作，主要内容包括：本发明公开了一种N-(4-甲氧基羰基-3-氨基磺酰基苄基)甲磺酰胺的合成方法。本发明通过缩合、脱羧、氨解、重排、开环、酰化反应制得目标化合物,避免了传统工艺中的氯磺化、氧化和氢化步骤,安全性显著提高。本发明反应条件温和、工艺简单,适于工业化生产。(The invention discloses a method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide. The target compound is prepared through condensation, decarboxylation, ammonolysis, rearrangement, ring opening and acylation reactions, chlorosulfonation, oxidation and hydrogenation steps in the traditional process are avoided, and the safety is obviously improved. The invention has mild reaction condition and simple process, and is suitable for industrial production.)

1. A method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide is characterized by comprising the following steps: the structural formula of the N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide is as follows:

the reaction formula of the synthesis method is as follows:

the synthesis method comprises the following specific steps:

step 1: starting a raw material compound II and a compound III, and simultaneously adding a solvent A, a catalyst B and alkali; then heating to a ℃, and keeping the temperature for reaction for b hours to obtain a crude product of the compound IV; adding a proper amount of solvent C and catalyst D into the crude product of the compound IV, heating to C ℃, and carrying out heat preservation reaction for D hours to obtain a compound V;

step 2: carrying out ammonolysis on the compound V, heating to e ℃, and carrying out heat preservation reaction for f hours to obtain a compound VI;

and step 3: adding a solvent E and a degradation reagent into the compound VI, heating to g ℃, and carrying out heat preservation reaction for h to obtain a compound VII;

and 4, step 4: adding a solvent and acid into the compound VII, heating to i ℃, and carrying out heat preservation reaction for j hours to obtain a compound VIII;

and 5: and adding a solvent and an acid-binding agent into the compound VIII, cooling to k ℃, dropwise adding the compound IX, and carrying out heat preservation reaction for m hours to obtain the target compound I.

2. The method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide of claim 1, wherein: the ester R of the compound III is one of methyl, ethyl, propyl, isopropyl, butyl, 1-12 micromolecule alkyl, phenyl, benzyl, 1-5 substituted phenyl and 1-5 substituted benzyl; x of the compound II is F, Cl, Br, I and one of OMs, OTf and OTs.

3. The method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide of claim 1, wherein: the solvent A is an aprotic solvent and is selected from any one or a mixture of two or more of the following solvents: n, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, methyl ethyl ketone, methyl tert-butyl ketone, ethyl acetate, dichloromethane, dichloroethane, carbon tetrachloride, toluene, xylene, benzene, ethylbenzene, cumene, chlorobenzene, N-hexane, cyclohexane, dodecane, tetrahydrofuran, chloroform, acetonitrile, 1, 4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, N-dimethylpropylurea;

the selected range of the temperature a is 30-150 ℃; the selected range of the b hours is 0-12 hours.

4. The method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide of claim 1, wherein: the catalyst B is one of cuprous iodide, cuprous bromide, cuprous chloride, copper powder, copper acetate, copper sulfate, cuprous sulfide and cuprous oxide.

5. The method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide of claim 1, wherein: the alkali is one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia water, potassium phosphate, dipotassium hydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium acetate and potassium acetate.

6. The method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide of claim 1, wherein: the solvent C is an aprotic solvent and is selected from any one or a mixture of two or more of the following solvents: toluene, xylene, benzene, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, methyl ethyl ketone, methyl tert-butyl ketone, ethyl acetate, dichloromethane, dichloroethane, carbon tetrachloride, ethylbenzene, cumene, chlorobenzene, N-hexane, cyclohexane, dodecane, tetrahydrofuran, chloroform, acetonitrile, 1, 4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, N-dimethylpropylurea;

the selected range of c ℃ is 30-150 ℃; the selected range of d hours is 0-12 hours.

7. The method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide of claim 1, wherein: the catalyst D is one of sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide and sodium hydrogen; the selected range of e ℃ is 30-100 ℃; the selected range of f hours is 0-12 hours.

8. The method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide of claim 1, wherein: the E is a protic solvent or an aprotic solvent and is selected from any one or a mixture of two or more of the following: methanol, ethanol, propanol, isopropanol, tert-butanol, water, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, acetone, butanone, methyl tert-butanone, ethyl acetate, dichloromethane, dichloroethane, diethyl ether, carbon tetrachloride, toluene, benzene, xylene, ethylbenzene, cumene, N-hexane, cyclohexane, tetrahydrofuran, chloroform, acetonitrile, 1, 4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane; the degradation reagent is one of sodium hypochlorite and sodium hypobromite;

the g ℃ is selected within the range of 30-120 ℃; the selected range of h hours is 0-12 hours.

9. The method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide of claim 1, wherein: the acid is: one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, acetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, perchloric acid, citric acid and tartaric acid;

the selected range of i ℃ is 0-120 ℃; the selected range of the j hours is 0-12 hours.

10. The method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide of claim 1, wherein: the acid-binding agent is: one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, dipotassium hydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium acetate, sodium hydroxide, potassium hydroxide, calcium oxide, ammonia, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, N-dimethylaniline, dimethylisopropylamine, diisopropylethylamine, pyridine, triethylamine, 1, 8-diazacyclo [5,4,0] undecene-7;

the k ℃ is selected within the range of-30 to 120 ℃; the selected range of m hours is 0-12 hours.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonyl benzyl) methanesulfonamide I.

Background

The mesosulfuron-methyl, also called mesosulfuron-methyl, is a novel sulfonylurea herbicide developed by German Bayer crop science company in 2002, has the characteristics of super high efficiency, wide weed control spectrum, environmental friendliness and the like, and can be widely applied to field weeding of crops such as rice, corn, soybean and the like. At present, large-scale production of raw drug manufacturers is not available in China, so that research on the production process of the raw drug is also highly concerned in the field of organic synthesis. The chemical name is 2- [3- (4, 6-dimethoxypyrimidin-2-yl) ureidosulfonyl ] -4-methanesulfonamide methyl benzoate. The structural formula is as follows:

n- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide is a key intermediate for the synthesis of methyldisulfuron, US20170156330 discloses a synthetic route: the target compound is obtained by taking 5-methyl-2-methoxycarbonyl benzene sulfonyl chloride as a raw material through amidation, bromination, azidation, hydrogenation, mesylation and dealkylation reactions, the raw material in the route is not easy to obtain, the operation is complex, and bromination, azidation and hydrogenation belong to high-risk reactions, so that the method is not beneficial to industrial large-scale production.

Another synthesis route is published in Fine chemistry 2013, 30(3):353-356 ]: the p-tolunitrile is used as a raw material, and a target compound is obtained through chlorosulfonation, aminolysis, oxidation, hydrogenation, mesylation and alcoholysis reactions.

Therefore, the method can avoid high-risk reactions such as chlorosulfonation, oxidation and hydrogenation, and is a research hotspot of research and development personnel in the field.

Disclosure of Invention

In order to solve the problems, the invention discloses a method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide, which avoids chlorosulfonation, oxidation and hydrogenation steps and can greatly improve the safety of the reaction.

In order to achieve the above purpose, the invention provides the following technical scheme:

a method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide, wherein the structural formula of the N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide (I) is as follows:

the reaction formula of the synthesis method is as follows:

the synthesis method comprises the following specific steps:

step 1: putting the initial raw material compound II and the compound III into a reaction kettle, a reaction bottle and other containers, and simultaneously adding a proper amount of solvent A, catalyst B and alkali; then heating to a ℃, and keeping the temperature for reaction for b hours to obtain a crude product of the compound IV; adding the crude product of the compound IV into a reaction kettle, a reaction bottle and other containers, simultaneously adding a proper amount of a solvent C and a catalyst D, heating to C ℃, and carrying out heat preservation reaction for D hours to obtain a compound V;

step 2: carrying out ammonolysis on the compound V, heating to e ℃, and carrying out heat preservation reaction for f hours to obtain a compound VI;

and step 3: adding the compound VI into a reaction kettle, a reaction bottle and other containers, simultaneously adding a proper amount of solvent E and a degradation reagent, heating to g ℃, and carrying out heat preservation reaction for h to obtain a compound VII;

and 4, step 4: adding the compound VII into a reaction kettle, a reaction bottle and other containers, simultaneously adding a proper amount of solvent and acid, heating to i ℃, and carrying out heat preservation reaction for j hours to obtain a compound VIII;

and 5: adding the compound VIII into a reaction kettle, a reaction bottle and other containers, simultaneously adding a proper amount of solvent and an acid-binding agent, cooling to k ℃, dropwise adding the compound IX, and carrying out heat preservation reaction for m hours to obtain the target compound I.

The further technical scheme of the invention is as follows: the solvent A is an aprotic solvent and is selected from any one or a mixture of two or more of the following solvents: n, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, methyl ethyl ketone, methyl tert-butyl ketone, ethyl acetate, dichloromethane, dichloroethane, carbon tetrachloride, toluene, xylene, benzene, ethylbenzene, cumene, chlorobenzene, N-hexane, cyclohexane, dodecane, tetrahydrofuran, chloroform, acetonitrile, 1, 4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, N-dimethylpropylurea;

the temperature a is selected from the range of 30-150 ℃, and preferably 80-120 ℃. The temperature may be: 30 ℃, 50 ℃, 80 ℃, 100 ℃, 120 ℃, 150 ℃, etc., but not limited to the recited values.

The b hour is selected within the range of 0-12 hours, preferably 0.5-5 hours. The reaction time may be 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, etc., but is not limited to the exemplified values.

The further technical scheme of the invention is as follows: the catalyst B is one of cuprous iodide, cuprous bromide, cuprous chloride, copper powder, copper acetate, copper sulfate, cuprous sulfide and cuprous oxide.

The further technical scheme of the invention is as follows: the alkali is one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia water, potassium phosphate, dipotassium hydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium acetate and potassium acetate.

The further technical scheme of the invention is as follows: the solvent C is an aprotic solvent and is selected from any one or a mixture of two or more of the following solvents: toluene, xylene, benzene, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, methyl ethyl ketone, methyl tert-butyl ketone, ethyl acetate, methylene chloride, dichloroethane, carbon tetrachloride, ethylbenzene, cumene, chlorobenzene, N-hexane, cyclohexane, dodecane, tetrahydrofuran, chloroform, acetonitrile, 1, 4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, N-dimethylpropylurea.

The temperature of c is selected from the range of 30-150 ℃, and preferably 60-110 ℃. The temperature may be: 30 ℃, 60 ℃, 80 ℃, 100 ℃, 110 ℃, 150 ℃, etc., but are not limited to the recited values.

The selected range of d hours is 0-12 hours, and preferably 0.5-5 hours. The reaction time may be 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, etc., but is not limited to the exemplified values.

The further technical scheme of the invention is as follows: the catalyst D is one of sodium ethoxide, sodium methoxide, potassium tert-butoxide, sodium tert-butoxide and sodium hydrogen.

The temperature of e is selected from the range of 30-100 ℃, and preferably 30-60 ℃. The temperature may be: 30 ℃, 60 ℃, 80 ℃, 100 ℃, 110 ℃, etc., but are not limited to the recited values.

The selected range of f hours is 0-12 hours, and preferably 0.5-5 hours. The reaction time may be 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, etc., but is not limited to the exemplified values.

The further technical scheme of the invention is as follows: the E is a protic solvent or an aprotic solvent and is selected from any one or a mixture of two or more of the following: methanol, ethanol, propanol, isopropanol, tert-butanol, water, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, acetone, butanone, methyl tert-butanone, ethyl acetate, dichloromethane, dichloroethane, diethyl ether, carbon tetrachloride, toluene, benzene, xylene, ethylbenzene, cumene, N-hexane, cyclohexane, tetrahydrofuran, chloroform, acetonitrile, 1, 4-dioxane, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane; the degradation reagent is one of sodium hypochlorite and sodium hypobromite.

The g ℃ is selected from the range of 30-120 ℃, and preferably 60-120 ℃. The temperature may be: 30 ℃, 60 ℃, 80 ℃, 100 ℃, 120 ℃, etc., but are not limited to the recited values.

The selected range of the h hour is 0-12 hours, and preferably 0.5-5 hours. The reaction time may be 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, etc., but is not limited to the exemplified values.

The further technical scheme of the invention is as follows: the acid is: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, acetic acid, formic acid, methanesulfonic acid, p-toluenesulfonic acid, perchloric acid, citric acid, tartaric acid.

The temperature of i ℃ is selected from the range of 0-120 ℃, and preferably 60-120 ℃. The temperature may be: 0 ℃, 30 ℃, 60 ℃, 80 ℃, 100 ℃, 120 ℃, etc., but not limited to the recited values.

The selected range of the j hour is 0-12 hours, and preferably 0.5-5 hours. The reaction time may be 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, etc., but is not limited to the exemplified values.

The further technical scheme of the invention is as follows: the acid-binding agent is: sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, dipotassium hydrogen phosphate, sodium phosphate, disodium hydrogen phosphate, sodium acetate, sodium hydroxide, potassium hydroxide, calcium oxide, ammonia, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, N, N-dimethylaniline, dimethylisopropylamine, diisopropylethylamine, pyridine, triethylamine, and one of 1, 8-diazacyclo [5,4,0] undecene-7.

The k ℃ is selected from-30 to 120 ℃, and preferably from-30 to 0 ℃. The temperature may be: -30 ℃,0 ℃, 30 ℃, 60 ℃, 90 ℃, 120 ℃ and the like, but is not limited to the recited values.

The selected range of m hours is 0-12 hours, and preferably 0.5-5 hours. The reaction time may be 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, etc., but is not limited to the exemplified values.

The invention has the following beneficial effects: compared with the prior art, the method has the advantages that chlorosulfonation, oxidation and hydrogenation reactions are not used, so that the safety of industrial production is improved by a large side effect, and the method is convenient for large-scale industrial production.

Detailed Description

The present invention will be further illustrated below with reference to specific embodiments, which are to be understood as merely illustrative and not limitative of the scope of the present invention.

The invention discloses a method for synthesizing N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide, wherein the structural formula of the N- (4-methoxycarbonyl-3-aminosulfonylbenzyl) methanesulfonamide (I) is as follows:

the reaction formula of the synthesis method is as follows: