阅读说明：本技术 一种吡啶氮氧化物衍生物中间体的制备方法 (Preparation method of pyridine nitrogen oxide derivative intermediate ) 是由 龚俊 王清枫 姜桥 于 2020-12-30 设计创作，主要内容包括：本发明公开了一种吡啶氮氧化物衍生物中间体的制备方法,合成路线为通过优化反应条件,与高学智等人公开的技术路线相比,出人意料地将氧化反应的时间反由15h缩短到约3小时,同时HPLC纯度可达99％；将溴代反应由15h缩短到约6h,收率由70％提高到92％,HPLC纯度也高达98％。以绿色无污染的水做溶剂,氧化反应无需后处理可直接进行第二步溴代反应,减少了后处理过程,提高了生产效率。(The invention discloses a preparation method of pyridine nitrogen oxide derivative intermediate, which comprises the following synthetic route)

1. A preparation method of pyridine nitrogen oxide intermediate comprises the following steps:

the method comprises the following operations:

and (3) oxidation reaction: dissolving the starting material 1 in water, dropwise adding a mixed solution of hydrogen peroxide and a catalyst, and obtaining a crude product solution of the intermediate 2 after the reaction is finished;

bromination reaction: adding a bromination reagent into the intermediate 2 crude product solution at a temperature not higher than 4 ℃, and heating to perform bromination reaction; after the reaction is finished, adding an alkali quenching bromization reagent, extracting by using an organic solvent, and concentrating to obtain an intermediate 3;

and (3) substitution reaction: dissolving the intermediate 3 and alkali in a solvent for reaction; after the reaction is finished, the solvent is evaporated to dryness, an organic solvent is added to precipitate the inorganic salt, and the intermediate 4 is obtained after post-treatment.

2. The method of claim 1, wherein: the catalyst is at least one of tungstic acid or water-soluble salt thereof.

3. The production method according to claim 1 or 2, characterized in that: the temperature of the oxidation reaction is 25-80 ℃, and preferably 50-60 ℃.

4. The method of claim 1, wherein: the bromination reaction temperature is 20-70 ℃, and preferably 35-40 ℃.

5. The production method according to claim 1 or 4, characterized in that: the agent is selected from hydrogen bromide/hydrogen peroxide, bromine, sulfuric acid/sodium bromide/sodium bromate, and preferably bromine.

6. The method of claim 1, wherein: the mass mixing ratio of the hydrogen peroxide to the catalyst is (4-10): 1.

7. the method of claim 1, wherein: the concentration of the hydrogen peroxide is 25-35 v/v%.

8. The method of claim 1, wherein: the adding temperature of the bromization reagent is 0-4 ℃.

9. The method of claim 1, wherein: the substitution reaction temperature is 40 ℃ to reflux temperature.

10. The method of claim 1, wherein: the organic solvent used for extraction is selected from dichloromethane or chloroform.

Technical Field

The invention relates to the field of pharmacy, in particular to a synthesis process of a medical intermediate, and specifically relates to a preparation method of a pyridine nitrogen oxide intermediate.

Background

The prazole medicine is a kind of Proton Pump Inhibitor (PPI) commonly used in clinic, and inhibits the secretion of hydrogen ions by inhibiting the release of H, K-ATP enzyme, reduces gastric acid secretion, and reduces the stimulation of gastric acid to gastric mucosa, thereby playing a role in treating diseases such as peptic ulcer, gastroesophageal reflux inflammation and the like. 2, 3-dimethyl-4-methoxyl-pyridine-N-oxide is an important medical intermediate, and is mainly used for synthesizing prazole medicines. The main synthetic route reported in domestic and foreign literature is shown as the following formula:

the product is prepared by four steps of reactions of glacial acetic acid and hydrogen peroxide oxidation, mixed acid nitration, acetyl chloride or hydrochloric acid chloride, and methanol and sodium hydroxide substitution. The oxidation of glacial acetic acid and hydrogen peroxide can generate dangerous peroxyacetic acid, and a large potential safety hazard exists under the condition of high-temperature reflux; nitration reactions using concentrated sulfuric acid, fuming nitric acid, and chlorination with acetyl chloride or hydrochloric acid produce large amounts of spent acid solution, and are hazardous; the process route has high temperature and large energy consumption, and has risks in the aspect of safe production.

Gaozhi, wangqinghe, koozhi, et al, lansoprazole key intermediate 2, 3-dimethyl-4- (2,2, 2-trifluoroethoxy) pyridine-N-oxide synthesis process improvement [ J ] journal of chinese medical industry, 2018, discloses another synthetic route:

the compound 2 is oxidized and oxidized in water by taking sodium tungstate as a catalyst to obtain 3, and the 3 is subjected to oxidation bromination reaction with sodium bromide/sodium bromate in an acidic aqueous solution to generate 4; and reacting with trifluoroethanol in DMF under the action of potassium tert-butoxide to synthesize the intermediate 1. The advantages are that: firstly, water is used as a solvent in the preparation of the compound 3, so that the preparation method is green and environment-friendly, is convenient for post-treatment, and avoids the problem that acetic acid is difficult to recover in the traditional method; the use of the catalyst sodium tungstate shortens the reaction time from 24h to 15h, and improves the yield from 85% to 91%. Secondly, when synthesizing 4, directly taking 3 as a substrate, and carrying out oxidation bromination reaction by using cheap sodium bromide/sodium bromate to generate bromine in situ, so that the reaction steps are shortened, the use of mixed acid in the step of firstly nitrifying and then chlorinating in the literature route is avoided, the reaction conditions are mild, and the method is green and environment-friendly; meanwhile, the use of expensive bromization reagent (NBS) is avoided, and the reaction cost is reduced. ③ when preparing 1, the reaction is completed after 12 hours in DMF under the action of potassium tert-butoxide, thus greatly reducing the reaction time and avoiding the waste of trifluoroethanol. In the preparation of 2, 3-lutidine-N-oxide (3), 30% hydrogen peroxide (125ml, 1.25mol) was added to a solution of sodium tungstate (11.5g, 0.035mol) in water (150ml) at room temperature, and the solution was stirred to become pale yellow. Adding the compound 2(56.5ml, 0.5mol) into the solution, stirring uniformly, heating to 40-45 ℃, and reacting for 15h under the condition of heat preservation. The unreacted hydrogen peroxide was quenched by dropping a saturated sodium hydrogen sulfite solution (10ml) to the above reaction solution, and the reaction solution was white. The specific preparation operation of 4-bromo-2, 3-dimethylpyridine-N-oxide (4) is as follows: sodium bromide (25.7g, 0.25mol), sodium bromate (7.5g, 0.05mol) and intermediate 3(6.1g, 0.05mol) were added to water (150ml) in this order and dissolved at room temperature with stirring. Slowly dripping concentrated sulfuric acid (8.5ml, 0.15mol) at 0-5 ℃, heating to 20 ℃ after dripping, and reacting for 15 hours under the condition of heat preservation.

The preparation process still takes a long time, and meanwhile, the purity and the yield of the product are low. How to further shorten the reaction time and improve the purity of the product is a technical problem to be solved.

Disclosure of Invention

The invention aims to overcome at least one defect of the prior art and provides a preparation method of a pyridine nitrogen oxide intermediate.

The technical scheme adopted by the invention is as follows:

a preparation method of pyridine nitrogen oxide intermediate comprises the following steps:

the method comprises the following operations:

and (3) oxidation reaction: dissolving the starting material 1 in water, dropwise adding a mixed solution of hydrogen peroxide and a catalyst, and obtaining a crude product solution of the intermediate 2 after the reaction is finished;

bromination reaction: adding a bromination reagent into the intermediate 2 crude product solution at a temperature not higher than 4 ℃, and heating to perform bromination reaction; after the reaction is finished, adding an alkali quenching bromization reagent, extracting by using an organic solvent, and concentrating to obtain an intermediate 3;

and (3) substitution reaction: dissolving the intermediate 3 and alkali in a solvent for reaction; after the reaction is finished, the solvent is evaporated to dryness, an organic solvent is added to precipitate the inorganic salt, and the intermediate 4 is obtained after post-treatment.

In some examples, the catalyst is selected from at least one of tungstic acid or a water-soluble salt thereof.

In some examples, the water soluble salt of tungstic acid is selected from sodium tungstate or potassium tungstate.

In some examples, the mass mixing ratio of the hydrogen peroxide to the catalyst is (4-10): 1.

in some examples, the concentration of the hydrogen peroxide is 25-35 v/v%.

In some examples, the temperature of the oxidation reaction is 25 to 80 ℃, preferably 50 to 60 ℃.

In some examples, the bromination reaction temperature is 20 to 70 ℃, preferably 35 to 40 ℃.

In some examples, the secondary reagent is selected from hydrogen bromide/hydrogen peroxide, bromine, sulfuric acid/sodium bromide/sodium bromate, preferably bromine.

In some examples, the brominating agent is added at a temperature of 0-4 ℃.

In some examples, the substitution reaction temperature is from 40 ℃ to reflux temperature.

In some examples, the organic solvent used for extraction is selected from dichloromethane or chloroform.

The invention has the beneficial effects that:

some embodiments of the present invention, by optimizing the reaction conditions, unexpectedly reduce the oxidation reaction time from 15 hours to about 3 hours, while achieving 99% HPLC purity and increasing the yield from 91% to 99%, compared to the technical route disclosed by highly academic wisdom et al.

Some examples of the present invention, by optimizing the reaction conditions, unexpectedly shorten the bromination reaction from 15h to about 6h, increase the yield from 70% to 92%, and increase the HPLC purity to 98% compared to the technical route disclosed by highly academic wisdom et al.

Some embodiments of the invention have simple steps and safe used raw materials. Compared with the existing route, the first step and the second step of the route of the invention take green pollution-free water as a solvent, thereby avoiding the generation of peroxyacetic acid; the bromination reaction temperature is low, water can play a liquid seal role on bromine on the upper layer, bromine generated by the bromination reagent is not easy to volatilize, and the safety is improved. The oxidation reaction in the first step can directly carry out the bromination reaction in the second step without post-treatment, so that the post-treatment process is reduced, and the production efficiency is improved; the direct bromination replaces the two-step reaction route of nitration and chlorination, so that the generated bromide has higher activity than the chloride, the yield is improved, the steps are simple, the safety is high, the consumption of manpower and material resources is reduced, the reaction condition is mild, and the industrial production is easier to realize.

Drawings

FIG. 1 is a HPLC chart of 2, 3-lutidine-N-oxide;

FIG. 2 is a nuclear magnetic hydrogen spectrum of 2, 3-dimethyl-4-bromo-pyridine-N-oxide;

FIG. 3 is a HPLC plot of 2, 3-dimethyl-4-bromo-pyridine-N-oxide;

FIG. 4 is a nuclear magnetic hydrogen spectrum of 2, 3-dimethyl-4-methoxy-pyridine-N-oxide;

figure 5 is a HPLC diagram of 2, 3-dimethyl-4-methoxy-pyridine-N-oxide.

Detailed Description

A preparation method of pyridine nitrogen oxide intermediate comprises the following steps:

the method comprises the following operations:

and (3) oxidation reaction: dissolving the starting material 1 in water, dropwise adding a mixed solution of hydrogen peroxide and a catalyst, and obtaining a crude product solution of the intermediate 2 after the reaction is finished;

bromination reaction: adding a bromination reagent into the intermediate 2 crude product solution at a temperature not higher than 4 ℃, and heating to perform bromination reaction; after the reaction is finished, adding an alkali quenching bromization reagent, extracting by using an organic solvent, and concentrating to obtain an intermediate 3;

and (3) substitution reaction: dissolving the intermediate 3 and alkali in a solvent for reaction; after the reaction is finished, the solvent is evaporated to dryness, an organic solvent is added to precipitate the inorganic salt, and the intermediate 4 is obtained after post-treatment.

The inventor unexpectedly finds that different from the traditional method that a large amount of impurities are generated due to temperature rise, the reaction time can be unexpectedly and effectively shortened to 3-4 h by dropwise adding a mixed solution of hydrogen peroxide and a catalyst (tungstic acid or a water-soluble salt thereof) and controlling the reaction temperature to be 50-60 ℃, and the HPLC purity of the product is more than 98%

By optimizing the condition of the bromination reaction, particularly by adopting a specific bromination reagent, and simultaneously raising the reaction temperature to 35-40 ℃, the reaction speed can be remarkably improved, the bromination reaction time is shortened to about 6 hours, the product yield is greatly improved, and the HPLC purity is as high as 98%.

In some examples, the catalyst is selected from at least one of tungstic acid or a water-soluble salt thereof.

In some examples, the water soluble salt of tungstic acid is selected from sodium tungstate or potassium tungstate.

In some examples, the mass mixing ratio of the hydrogen peroxide to the catalyst is (4-10): 1. the mixing ratio ensures that the hydrogen peroxide is not decomposed too fast and can play a role in preactivation.

In some examples, the concentration of the hydrogen peroxide is 25-35 v/v%. The hydrogen peroxide with the concentration is low in price and relatively high in safety.

In some examples, the bromination reaction temperature is 20 to 70 ℃, preferably 35 to 40 ℃. At the temperature, the bromine is not easy to volatilize, and the complete reaction can be ensured. Particularly, the reaction can be accelerated and the purity can be very high at 35-40 ℃.

The technical scheme of the invention is further explained by combining the embodiment.

Example 1:

oxidation reaction

Preparation of 2, 3-dimethylpyridine-N-oxide

In a 500mL round-bottom flask, 10g of 2, 3-lutidine and 40mL of purified water are sequentially added, and 15mL of H with the mass fraction of 30% is slowly dropped at 55 DEG C₂O₂And 3.0g of sodium tungstate, and reacting for 3 hours in a heat preservation manner. After the reaction is finished, the reaction can be directly put into the next reaction without post-treatment. Yield 99% and HPLC purity 99% (fig. 1).

MS(m/z)：[M+H]⁺＝124。¹H NMR(600MHz，DMSO-d₆)：8.11-8.12(dd,1H)，7.13-7.17(m,2H)，2.29(s,3H)，2.33(s,3H)。

Bromination reaction

Preparation of 2, 3-dimethyl-4-bromo-pyridine-N-oxide

And adding 100mL of water into the oxidation reaction liquid in the previous step, adding 20mL of bromine under ice bath, heating to 35 ℃, and preserving heat for reaction for 6 hours. After the reaction is finished, slowly adding 40% sodium hydroxide aqueous solution into the bromination reaction solution in an ice bath, adjusting the pH value to be alkalescent, and changing the reaction solution into orange or turquoise; extracting with dichloromethane, dehydrating the organic phase, and concentrating to obtain white 2, 3-dimethyl-4-bromo-pyridine-N-oxide. Yield 92% and HPLC purity 98%.

MS(m/z)：[M+H]⁺＝204；¹H NMR(500MHz，CDCl₃-d₆): 8.01-8.03(d,1H), 7.28-7.33(d,1H), 2.59(s,3H), 2.45(s, 3H). The nuclear magnetic hydrogen spectrum is shown in FIG. 2, and the HPLC is shown in FIG. 3.

Substitution reaction

Preparation of 2, 3-dimethyl-4-methoxy-pyridine-N-oxide

In a 500mL round-bottom flask, 17mL of a 30% by mass methanol solution of sodium methoxide and 40mL of methanol were sequentially added, and 10g of 2, 3-dimethyl-4-bromo-pyridine-N-oxide was added and reacted at 50 ℃ for 4 hours. And after the reaction is finished, spin-drying the solvent, adding 150mL of dichloromethane, stirring, filtering to remove inorganic salts, adding activated carbon into the filtrate for decoloring, filtering, concentrating, and recrystallizing with ethyl acetate and N-heptane to obtain a white solid, namely 2, 3-dimethyl-4-methoxy-pyridine-N-oxide. Yield: 93% and 99% purity by HPLC.

MS(m/z)：[M+H]⁺＝154；¹H NMR(500MHz，CDCl₃-d₆): 8.25(d,1H), 6.74(d,1H), 3.90(s,3H), 2.56(s,3H), 2.20(s, 3H). The nuclear magnetic hydrogen spectrum is shown in FIG. 4, and the HPLC is shown in FIG. 5.

Example 2:

oxidation reaction

Preparation of 2, 3-dimethylpyridine-N-oxide

In a 1000mL round bottom flask, 20g of 2, 3-lutidine and 70mL of purified water are sequentially added, and 30mL of H with the mass fraction of 30% is slowly dropped at 60 DEG₂O₂And 6.5g of tungstic acid, and reacting for 4 hours under the condition of heat preservation. After the reaction is finished, the reaction can be directly put into the next reaction without post-treatment. Yield 98% and HPLC purity 98%.

MS(m/z)：[M+H]⁺＝154；¹H NMR(500MHz，CDCl₃-d₆)：8.25-8.26(d,1H)，6.72-6.74(d,1H)，3.90(s,3H)，2.56(s,3H)，2.20(s,3H)。

Bromination reaction

Preparation of 2, 3-dimethyl-4-bromo-pyridine-N-oxide

And (3) adding 100mL of aqueous hydrogen bromide with the mass fraction of 40% and 50mL of hydrogen peroxide with the mass fraction of 30% into the oxidation reaction liquid in the previous step in sequence under ice bath, and reacting for 6h at 40 ℃. After the reaction is finished, slowly adding 40% sodium hydroxide aqueous solution into the bromination reaction solution in an ice bath, adjusting the pH value to be alkalescent, and changing the reaction solution into orange or turquoise; extracting with dichloromethane, dehydrating the organic phase, and concentrating to obtain yellowish white 2, 3-dimethyl-4-bromo-pyridine-N-oxide. Yield 90% and HPLC purity 98%.

MS(m/z)：[M+H]⁺＝204；¹H NMR(500MHz，CDCl₃-d₆)：8.01-8.03(d,1H)，7.28-7.33(d,1H)，2.59(s,3H)，2.45(s,3H)。

Substitution reaction

2, 3-dimethyl-4-methoxy-pyridine-N-oxide

In a 250mL round bottom flask, 100mL methanol, 10g sodium hydroxide, 20g 2, 3-dimethyl-4-bromo-pyridine-N-oxide was added, stirred at 60 ℃ for 20min, and reacted at 60 ℃ for 4 h. And after the reaction is finished, spin-drying the solvent, adding 200mL of dichloromethane, stirring, filtering to remove inorganic salts, adding activated carbon into the filtrate for decolorization, filtering, concentrating, and recrystallizing with ethyl acetate and N-heptane to obtain a white solid, namely 2, 3-dimethyl-4-methoxy-pyridine-N-oxide. Yield 92% and HPLC purity 99%.

MS(m/z)：[M+H]⁺＝154；¹H NMR(500MHz，CDCl₃-d₆)：8.25-8.26(d,1H)，6.72-6.74(d,1H)，3.90(s,3H)，2.56(s,3H)，2.20(s,3H)。

Example 3

Oxidation reaction

Preparation of 2, 3-dimethylpyridine-N-oxide

15g of 2, 3-lutidine were sequentially added to a 1000mL round-bottom flask,60mL of purified water, and 25mL of 30% H by mass fraction slowly added dropwise at 50 DEG C₂O₂And 5.2g of a mixed solution of potassium tungstate, and reacting for 5 hours in a heat preservation manner. After the reaction is finished, the reaction can be directly put into the next reaction without post-treatment. Yield 98% and HPLC purity 99%.

MS(m/z)：[M+H]⁺＝154；¹H NMR(500MHz，CDCl₃-d₆)：8.25-8.26(d,1H)，6.72-6.74(d,1H)，3.90(s,3H)，2.56(s,3H)，2.20(s,3H)。

Bromination reaction

Preparation of 2, 3-dimethyl-4-bromo-pyridine-N-oxide

Adding 200mL of water into the oxidation reaction liquid in the previous step, adding 33mL of bromine under ice bath, heating to 40 ℃, and preserving heat for reaction for 5 hours. After the reaction is finished, slowly adding 40% sodium hydroxide aqueous solution into the bromination reaction solution in an ice bath, adjusting the pH value to be alkalescent, and changing the reaction solution into orange or turquoise; extracting with dichloromethane, dehydrating the organic phase, and concentrating to obtain white 2, 3-dimethyl-4-bromo-pyridine-N-oxide. The yield was 91% and the HPLC purity was 97%.

MS(m/z)：[M+H]⁺＝204；¹H NMR(500MHz，CDCl₃-d₆)：8.01-8.03(d,1H)，7.28-7.33(d,1H)，2.59(s,3H)，2.45(s,3H)。

Substitution reaction

2, 3-dimethyl-4-methoxy-pyridine-N-oxide

In a 250mL round bottom flask, 130mL of methanol and 15g of sodium hydroxide were added, stirred at 60 ℃ for 20min, and 15g of 2, 3-dimethyl-4-bromo-pyridine-N-oxide was added, and reacted at 60 ℃ for 4 h. And after the reaction is finished, spin-drying the solvent, adding 200mL of dichloromethane, stirring, filtering to remove inorganic salts, adding activated carbon into the filtrate for decolorization, filtering, concentrating, and recrystallizing with ethyl acetate and N-heptane to obtain a white solid, namely 2, 3-dimethyl-4-methoxy-pyridine-N-oxide. The yield was 93% and the HPLC purity was 99%.

Comparative example 1: improvement of a synthesis process of a lansoprazole key intermediate 2, 3-dimethyl-4- (2,2, 2-trifluoroethoxy) pyridine-N-oxide [ J ] J.J. China J.Med.Industrials, 2018, 49(09):1252-1254.

And (3) oxidation reaction:

to a solution of sodium tungstate (11.5g, 0.035mol) in water (150mL) at room temperature was added 30% hydrogen peroxide (125mL, 1.25mol), and the solution was stirred to become pale yellow. Adding the compound 2(56.5mL, 0.5mol) into the solution, stirring uniformly, heating to 40-45 ℃, and reacting for 15h under the condition of heat preservation. The unreacted hydrogen peroxide was quenched by dropping a saturated sodium hydrogen sulfite solution (10mL) to the reaction solution, and the reaction solution was white. The reaction mixture was concentrated under reduced pressure to about 100mL, added with sodium chloride (10g, 0.17mol), and extracted with DCM (100 mL. times.5). After the organic phases were combined, they were dried over anhydrous sodium sulfate (10g) overnight. Filtration and concentration of the filtrate under reduced pressure recovered DCM to give 3 as a white solid (56g, 91%).

Bromination reaction:

sodium bromide (25.7g, 0.25mol), sodium bromate (7.5g, 0.05mol) and intermediate 3(6.1g, 0.05mol) were added to water (150mL) in this order and dissolved at room temperature with stirring. Slowly dripping concentrated sulfuric acid (8.5mL, 0.15mol) at 0-5 ℃, heating to 20 ℃ after dripping, and reacting for 15 hours under the condition of heat preservation. DCM (50mL) was added and then saturated sodium bisulfite solution (about 20mL) was slowly added dropwise under ice water bath conditions to quench the unreacted bromine. Upon completion of the quenching, the solution appeared pale yellow. Separating, separating organic layer, extracting water layer with DCM (100mL × 5), combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure, recovering DCM to obtain light brown crude solid. The crude product was recrystallized from DCM/hexane (2: 1) to give a white solid 4(7.0g, 70%)

And (3) substitution reaction:

after potassium tert-butoxide (2.5g, 0.023mol) was added to trifluoroethanol (2mL, 0.023mol) under the condition of ice-water bath and stirred for 15min, it was slowly added dropwise to a DMF (20mL) solution of 4(3.0g, 0.015mol) and heated to 100 ℃ for 12 h. After the reaction was completed, a little white solid adhered to the wall of the flask, DMF was recovered under reduced pressure (-0.1MPa, 80 ℃) to about 5mL, water (40mL) was added, and extraction was performed with ethyl acetate (40 mL. times.5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to recover ethyl acetate. The resulting concentrate was recrystallized from ethyl acetate and petroleum ether (1: 4) to give 1(2.9g, 89%) as a white solid with a purity of 99.73%.

The comparison of the different processes for the preparation of pyridine nitroxide derivatives is as follows:

as can be seen from the data in the table:

compared to comparative example 1: the total yield of the process is higher (81.1-84.7% VS 56.7%).

By optimizing the process, the reaction time is shortened, and the yield and the purity of the oxidation reaction are improved; the improvement of yield and purity allows direct input into the next reaction without work-up, thus reducing the number of operating steps and consequently the losses of work-up.