阅读说明：本技术 一种4-甲氧基-2,3,5-三甲基-吡啶氮氧化物的合成方法 (Synthetic method of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide ) 是由 李立威 李莹 周江洪 许方亮 于 2021-02-23 设计创作，主要内容包括：本发明公开了一种4-甲氧基-2,3,5-三甲基-吡啶氮氧化物的合成方法,包括以下步骤：S1、2,3,5-三甲基吡啶-N-氧化物经溴代反应、甲氧基取代得到4-溴-2,3,5-三甲基-吡啶氮氧化物；S2、4-溴-2,3,5-三甲基-吡啶氮氧化物经甲醇钠取代反应生成奥美拉唑的重要中间体4-甲氧基-2,3,5-三甲基-吡啶氮氧化物。本发明工艺路线中先采用了溴酸盐和溴化盐这种温和的溴化反应条件,然后再利用溴代物中间体进行甲氧基取代反应,整个工艺设计简单,反应条件温和,操作简便易行。(The invention discloses a synthetic method of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide, which comprises the following steps: s1, carrying out bromination reaction and methoxy substitution on the 2,3, 5-trimethylpyridine-N-oxide to obtain 4-bromo-2, 3, 5-trimethylpyridine oxynitride; s2, 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide is subjected to sodium methoxide substitution reaction to generate an important intermediate 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide of omeprazole. The process route of the invention adopts the mild bromination reaction condition of bromate and bromide salt, and then utilizes the bromide intermediate to carry out methoxy substitution reaction, the whole process design is simple, the reaction condition is mild, and the operation is simple and easy to implement.)

1. A synthetic method of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide is characterized by comprising the following steps:

s1, carrying out bromination reaction and methoxy substitution on the 2,3, 5-trimethylpyridine-N-oxide to obtain 4-bromo-2, 3, 5-trimethylpyridine oxynitride;

s2, 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide is subjected to sodium methoxide substitution reaction to generate an important intermediate 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide of omeprazole; the chemical reaction formula is as follows:

。

2. the method for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide according to claim 1, wherein in S1 bromination reaction, the bromination reagent is sodium bromate or sodium bromide under the synthesis conditions of 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide.

3. The method for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide according to claim 1, wherein in S1 bromination reaction, sulfuric acid is adopted as the synthesis condition of 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide.

4. The method according to claim 1, wherein in the substitution reaction of S2, the substitution reagent is sodium methoxide, and the solvent is methanol, N-dimethylformamide or dimethylsulfoxide.

5. The method for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide according to claim 1, wherein tetrabutylammonium bromide or triethylbenzylammonium chloride is added as a phase transfer catalyst in the S2 substitution reaction for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide.

6. The method for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitroxide as claimed in claim 1, wherein the bromination reaction in S1 comprises: adding sodium bromide, sodium bromate and 2,3, 5-trimethylpyridine-N-oxide into water, stirring and dissolving at room temperature, slowly dropwise adding concentrated sulfuric acid at 0-5 ℃, and stirring and reacting for 15 hours at room temperature after dropwise adding.

7. The method for synthesizing 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide according to claim 1, wherein the substitution reaction in S2 comprises: adding 4-bromo-2, 3, 5-trimethylpyridine-N-oxide into anhydrous DMF or anhydrous methanol, adding sodium methoxide at room temperature, adding tetrabutylammonium bromide or triethylbenzylammonium chloride as a phase transfer catalyst, heating to 80-100 ℃, and stirring for reacting for 6 hours.

Technical Field

The invention belongs to the field of pharmacy, and relates to synthesis of a compound 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide.

Background

The omeprazole with the chemical name of 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl ] -1H-benzimidazole is applied to clinically treating acid-related diseases such as gastric ulcer, duodenal ulcer and gastroesophageal reflux disease. 4-methoxy-3, 5-dimethyl-2-pyridinemethanol generated by rearrangement reaction of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide is an important intermediate for synthesizing omeprazole.

Junggren et al in U.S. Pat. No. 4,55431, Brandstrom et al in U.S. Pat. No. 4,4620008 describe that 2,3, 5-trimethylpyridine is subjected to nitroxidation, nitration, methoxy substitution under sodium methoxide conditions to give 4-methoxy-2, 3, 5-trimethyl-pyridine nitroxide.

In 2004, xu baocai et al described that 2,3, 5-trimethylpyridine first produced pyridine-N-oxide by oxynitridation with hydrogen peroxide/glacial acetic acid, and through nitration, methoxy substitution under sodium hydrogen conditions produced 4-methoxy-2, 3, 5-trimethyl-pyridine nitroxide. (Fine chemical engineering, 2004, 21 (1): 67-69)

The method adopts 2,3, 5-trimethylpyridine as a starting material to prepare the 4-methoxy-2, 3, 5-trimethyl-pyridine oxynitride through nitrogen oxidation, bromination and methoxy substitution, avoids the use of dangerous processes such as nitration reaction and the like, ensures safer production operation, simultaneously can recycle and reuse sodium bromide serving as a byproduct generated after the methoxylation of bromide, reduces the cost of production raw materials, has simple two-step synthesis operation and mild reaction conditions, does not need to adopt a dangerous chemical process which is seriously regulated in China, reduces the difficulty in treating a large amount of wastewater generated by nitration of mixed acid, and is very suitable for industrial production.

Disclosure of Invention

The invention aims to provide a synthetic method of a compound 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide, which has the advantages of simple synthetic process, mild reaction conditions, no need of dangerous chemical process, small waste water production amount, high overall yield and suitability for industrial scale-up production.

The purpose of the invention is realized by the following technical scheme: 2,3, 5-trimethyl pyridine is taken as a starting material, and is subjected to nitrogen oxidation reaction, bromination reaction and methoxy substitution to obtain 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide, wherein the reaction formula of each step is as follows,

。

in the bromination reaction, the bromination reagent is sodium bromate or sodium bromide under the synthesis condition of 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide.

In the bromination reaction, the synthesis condition of 4-bromo-2, 3, 5-trimethyl-pyridine nitrogen oxide adopts sulfuric acid catalytic reaction.

In the methoxy substitution reaction, in the synthesis of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide, sodium methoxide is adopted as a substitution reagent, and methanol or N, N-dimethylformamide or dimethyl sulfoxide is adopted as a solvent.

In the methoxy substitution reaction, tetrabutylammonium bromide or triethylbenzylammonium chloride is added as a phase transfer catalyst in the synthesis of 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide.

The bromination reaction in S1 includes: adding sodium bromide, sodium bromate and 2,3, 5-trimethylpyridine-N-oxide into water, stirring and dissolving at room temperature, slowly dropwise adding concentrated sulfuric acid at 0-5 ℃, and stirring and reacting for 15 hours at room temperature after dropwise adding.

The substitution reaction in S2 includes: adding 4-bromo-2, 3, 5-trimethylpyridine-N-oxide into anhydrous DMF or anhydrous methanol, adding sodium methoxide at room temperature, adding tetrabutylammonium bromide or triethylbenzylammonium chloride as a phase transfer catalyst, heating to 80-100 ℃, and stirring for reacting for 6 hours.

In the process route, mild bromination reaction conditions of bromate and bromide are adopted, and then a bromide intermediate is used for carrying out methoxy substitution reaction, so that the whole process is simple in design, mild in reaction conditions and simple and easy to operate, meanwhile, the critical chemical process of national key supervision of nitration reaction is avoided, the generation of mixed acid wastewater which is difficult to treat is reduced, and sodium bromide serving as a byproduct can be recycled and reused. Therefore, the process has the advantages of safety, environmental protection, lower production cost and the like when being used for industrial production.

Detailed Description

The present invention will be further illustrated with reference to the following examples.

Example 1: synthesis of 2,3, 5-trimethylpyridine-N-oxide

2,3, 5-trimethylpyridine oxide (30.00g,0.248mol) is added to DCM (150g) and dissolved with stirring at room temperature, and m-chloroperoxybenzoic acid (51.43g,0.298mol) is added in portions at 0 ℃. After the addition, the reaction was stirred at room temperature for 1.5 hours, and after monitoring the completion of the reaction, a saturated sodium bisulfite solution was dropped into the above reaction solution to quench. Extracting with dichloromethane for 5 times, mixing organic phases, drying with anhydrous sodium sulfate, filtering, and spin-drying solvent to obtain light yellow solid 2,3, 5-trimethylpyridine-N-oxide.

1HNMR(CDCl₃) δ 8.03(s,1H), 6.91(s,1H), 2.46(s,3H), 2.30(s, 3H),2.23 (s, 3H).

Example 2: 4-bromo-2, 3, 5-trimethylpyridine-N-oxide

Sodium bromide (13.63g,0.1325mol), sodium bromate (4.00g,0.0265mol) and 2,3, 5-trimethylpyridine-N-oxide (3.64g,0.0265mol) were added to water (80ml) and dissolved with stirring at room temperature. Slowly dropwise adding concentrated sulfuric acid (7.80g,0.0795mol) at 0-5 ℃, stirring and reacting for 15h at room temperature after dropwise adding. After completion of the reaction, the reaction mixture was quenched by addition of a saturated sodium hydrogen sulfite solution under ice-water conditions, and then stirred for 1 hour by addition of methylene chloride (40 ml). Separating, separating organic layer, extracting water layer with DCM for 6 times, mixing organic phases, adding anhydrous sodium sulfate, drying, filtering, concentrating filtrate under reduced pressure to obtain light yellow solid crude product, pulping crude product with dichloromethane/petroleum ether (2: 1), and purifying to obtain white solid 4-bromo-2, 3, 5-trimethylpyridine-N-oxide.

1HNMR(CDCl₃)δ 8.55(s,1H), 2.73(s,3H), 2.56(s, 3H),2.46 (s, 3H).Ms=216,218.

Example 3: 4-methoxy-2, 3, 5-trimethylpyridine-N-oxide

4-bromo-2, 3, 5-trimethylpyridine-N-oxide (40 g,0.2 mol) was taken, anhydrous DMF (400 ml) was added, sodium methoxide (54g, 1mol) and tetrabutylammonium bromide (4 g) were added at room temperature, and the mixture was heated to 80 ℃ and stirred for reaction for 6 hours. After the reaction is finished, the solvent DMF is evaporated by reduced pressure, dichloromethane is added, stirring is carried out for 1 hour, filtering and spin-drying are carried out, dichloromethane/petroleum ether (1:1) is added, stirring and filtering are carried out, and petroleum ether is washed to obtain light yellow solid 4-methoxy-2, 3, 5-trimethylpyridine-N-oxide.

1HNMR(CDCl₃)δ 8.03(s,1H), 3.68(s,3H), 2.42(s, 3H),2.14-2.18 (d, 6H).Ms=168.

Example 4: 4-methoxy-2, 3, 5-trimethyl-pyridine nitroxide

4-bromo-2, 3, 5-trimethyl-pyridine oxynitride (32 g,0.16 mol) was taken and added to anhydrous methanol (320 ml), sodium methoxide (43.2g, 0.8mol) and triethylbenzylammonium chloride (3.2 g) were added at room temperature, the autoclave was sealed and reacted, and the temperature was raised to 100 ℃ and stirred for 6 hours. After the detection reaction is finished, the solvent is evaporated to dryness under reduced pressure, dichloromethane is added, stirring is carried out, filtering is carried out, filtrate is dried in a spinning mode, dichloromethane/petroleum ether (1:1) is added, stirring is carried out for 1 hour, filtering is carried out, and air blowing and drying are carried out at the temperature of 50 ℃ to obtain light yellow solid 4-methoxy-2, 3, 5-trimethyl-pyridine nitrogen oxide.

The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention.