阅读说明：本技术 一种甲氨化反应的制备方法 (Preparation method of methylation reaction ) 是由 汪士金 王剑峰 闻鸣 王国华 谭梓骏 于 2021-03-03 设计创作，主要内容包括：本发明涉及甲氨化反应技术领域,且公开了一种甲氨化反应的制备方法,包括以下步骤,S1：在微反应器中加入对氯苯甲酰L-谷氨酸精制品和甲胺水溶液,及氯化亚铜；S2：冷却至室温,放料得对甲氨基苯甲酰L-谷氨酸溶液；S3：对甲氨基苯甲酰L-谷氨酸溶液转移至反应釜中,先加水,NaOH溶液,再加入硫化钠；S4：将滤液减压蒸馏至剩余约2V水；S5：在另一反应釜中加入水和氯化锌,加浓盐酸；S6：滴加浓缩液和浓盐酸,维持pH2.0；S7：室温搅拌0.5h,加入活性炭,继续搅拌；S8：过滤；S9：继续搅拌1h,过滤,70-80℃干燥即可完成。该甲氨化反应的制备方法,通过采用微反应器取代传统常规反应釜进行反应,从而实现工艺时间短、高效、收率高、质量好和三废少的情况。(The invention relates to the technical field of methylation reaction, and discloses a preparation method of methylation reaction, which comprises the following steps of S1: adding a p-chlorobenzoyl L-glutamic acid refined product, a methylamine aqueous solution and cuprous chloride into the microreactor; s2: cooling to room temperature, and discharging to obtain p-methylaminobenzoyl L-glutamic acid solution; s3: transferring the p-toluoyl L-glutamic acid solution to a reaction kettle, adding water, NaOH solution and sodium sulfide; s4: distilling the filtrate under reduced pressure to leave about 2V water; s5: adding water and zinc chloride into another reaction kettle, and adding concentrated hydrochloric acid; s6: dropwise adding the concentrated solution and concentrated hydrochloric acid, and maintaining the pH value at 2.0; s7: stirring at room temperature for 0.5h, adding active carbon, and continuing stirring; s8: filtering; s9: stirring for 1 hr, filtering, and drying at 70-80 deg.C. According to the preparation method of the methylation reaction, a microreactor is adopted to replace a conventional reaction kettle for reaction, so that the conditions of short process time, high efficiency, high yield, good quality and less three wastes are realized.)

1. A preparation method of the methylation reaction is characterized in that: comprises the following steps of (a) carrying out,

the method comprises the following steps: adding a p-chlorobenzoyl L-glutamic acid refined product, a methylamine aqueous solution and cuprous chloride into the microreactor;

step two: cooling the mixed solution to room temperature, and discharging to obtain a p-methylaminobenzoyl L-glutamic acid solution;

step three: transferring the p-toluoyl L-glutamic acid solution into a reaction kettle, adding water, 2.2eq NaOH solution (with the concentration of 30 percent), adding 1.5eq sodium sulfide, and reacting for 3 hours at 90 ℃;

step four: distilling the filtrate under reduced pressure to leave about 2V water;

step five: adding 8V water and 1.1eq zinc chloride into the other reaction kettle, adding concentrated hydrochloric acid to adjust the pH value to 2.0, and dissolving to be clear;

step six: dropwise adding the concentrated solution and concentrated hydrochloric acid into the reaction solution in the fifth step, and maintaining the pH value to be 2.0;

step seven: after the concentrated solution and the concentrated hydrochloric acid are dripped, stirring for 0.5h at room temperature, adding 5% active carbon, and continuously stirring for 0.5 h;

step eight: filtering the solution after reaction;

step nine: stirring for 1 hr, filtering, and drying at 70-80 deg.C.

2. A method for preparing a methylaminomation reaction as claimed in step one of claim 1, wherein: the content of methylamine water solution in the microreactor is 10eq25%, the content of cuprous chloride is 15%, the temperature is controlled to be 130-.

3. The method for preparing a methylaminoylation reaction as claimed in step six of claim 1, wherein: the internal temperature is controlled to be 10-30 ℃ in the process of dropwise adding the concentrated solution and the concentrated hydrochloric acid.

4. The method for preparing a carbamylation reaction according to claim 1, wherein: and the temperature of the filtrate is ensured to be about 25 ℃ in the process of adjusting the pH of the filtrate.

5. The method for preparing a methylaminoylation reaction as claimed in step eight of claim 1, wherein: and adjusting the pH of the filtered filtrate to 5.0-5.5 by using 20% NaOH solution.

Technical Field

The invention relates to the technical field of methylation reaction, in particular to a preparation method of methylation reaction.

Background

Methylamine, chemical formula CH5N, molecular weight 31.06, is an organic compound, is an important organic chemical raw material, belongs to low toxicity, can form explosive mixture when mixed with air, its aqueous solution is a strong base, it is a derivative formed after one hydrogen in ammonia is substituted by methyl, methylamine is the simplest primary amine, the commercial products are generally methanol, ethanol, tetrahydrofuran or aqueous solution, or as anhydrous gas, it is stored under pressure in metal tank, the industrial products usually pressurize the anhydrous gas and transport by trailer, it has very strong fish smell.

Methotrexate, an antifolate antineoplastic agent, inhibits the synthesis of tumor cells mainly through the inhibition of dihydrofolate reductase, thereby inhibiting the growth and reproduction of tumor cells.

The prior art has the following problems:

in the traditional reaction process of preparing methotrexate by using a conventional reaction kettle, the reaction temperature in the step of the methotrexate reaction is higher, the reaction pressure is higher due to the gasification of the methotrexate, meanwhile, the reaction is a liquid-gas two-phase heterogeneous reaction due to the gasification of the methotrexate, and when the reaction is carried out by using the conventional reaction kettle, the reaction time is long, impurities are more, the yield is low, and finally the efficiency is low, so that the preparation method of the methotrexate reaction is provided.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a preparation method of a methylation reaction, which adopts a microreactor to replace the conventional reaction kettle for reaction, solves the problems of long reaction time, more impurities, low yield and low efficiency finally caused by the reaction of the conventional reaction kettle, realizes the advantages of short process time, high efficiency, high yield, good quality, less three wastes and the like by adopting the microreactor, and solves the problems of long time, more impurities, low yield and low yield caused by the reaction of the conventional reaction kettle.

In order to realize the purposes of short process time, high efficiency, high yield, good quality and less three wastes, the invention provides the following technical scheme: a preparation method of the methylation reaction comprises the following steps,

the method comprises the following steps: adding a p-chlorobenzoyl L-glutamic acid refined product, a methylamine aqueous solution and cuprous chloride into the microreactor;

step two: cooling the mixed solution to room temperature, and discharging to obtain a p-methylaminobenzoyl L-glutamic acid solution;

step three: transferring the p-toluoyl L-glutamic acid solution into a reaction kettle, adding water, 2.2eq NaOH solution (with the concentration of 30 percent), adding 1.5eq sodium sulfide, and reacting for 3 hours at 90 ℃;

step four: distilling the filtrate under reduced pressure to leave about 2V water;

step five: adding 8V water and 1.1eq zinc chloride into the other reaction kettle, adding concentrated hydrochloric acid to adjust the pH value to 2.0, and dissolving to be clear;

step six: dropwise adding the concentrated solution and concentrated hydrochloric acid into the reaction solution in the fifth step, and maintaining the pH value to be 2.0;

step seven: after the concentrated solution and the concentrated hydrochloric acid are dripped, stirring for 0.5h at room temperature, adding 5% active carbon, and continuously stirring for 0.5 h;

step eight: filtering the solution after reaction;

step nine: stirring for 1 hr, filtering, and drying at 70-80 deg.C.

Preferably, the content of the methylamine aqueous solution in the microreactor is 10eq25%, the content of cuprous chloride is 15%, the temperature is controlled to be 130-.

Preferably, the internal temperature is controlled to be 10-30 ℃ during the dropwise addition of the concentrated solution and the concentrated hydrochloric acid.

Preferably, the temperature of the filtrate is ensured to be about 25 ℃ in the process of adjusting the pH of the filtrate.

Preferably, the pH of the filtered filtrate is adjusted to 5.0-5.5 by using 20% NaOH solution.

Compared with the prior art, the invention provides a preparation method of the methylation reaction, which has the following beneficial effects:

the preparation method of the methylaminoylation reaction comprises the steps of adding a p-chlorobenzoyl L-glutamic acid refined product, a methylamine aqueous solution and cuprous chloride into a microreactor, wherein in the one-step reaction process of methylamine gasification, the reaction temperature is higher, the reaction pressure is higher due to the gasification of the methylamine, and the reaction is a liquid-gas two-phase heterogeneous reaction due to the gasification of the methylamine, so that when a conventional reaction kettle is adopted for reaction, the reaction time is long, impurities are more, the yield is low, and the efficiency is low The method has the advantages of good repeatability, quick system response and convenient operation and control, thereby changing the phenomena of long time, low efficiency, low yield, poor quality and more three wastes of the traditional process.

Drawings

FIG. 1 is a general reaction diagram of methotrexate according to the present invention;

FIG. 2 is a diagram of the methylation reaction of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Referring to fig. 1-2, a method for preparing a carbamylation reaction includes the following steps,

the method comprises the following steps: adding a p-chlorobenzoyl L-glutamic acid refined product, a methylamine aqueous solution and cuprous chloride into the microreactor;

step two: cooling the mixed solution to room temperature, and discharging to obtain a p-methylaminobenzoyl L-glutamic acid solution;

step three: transferring the p-toluoyl L-glutamic acid solution into a reaction kettle, adding water, 2.2eq NaOH solution (with the concentration of 30 percent), adding 1.5eq sodium sulfide, and reacting for 3 hours at 90 ℃;

step four: distilling the filtrate under reduced pressure to leave about 2V water;

step five: adding 8V water and 1.1eq zinc chloride into the other reaction kettle, adding concentrated hydrochloric acid to adjust the pH value to 2.0, and dissolving to be clear;

step six: dropwise adding the concentrated solution and concentrated hydrochloric acid into the reaction solution in the fifth step, and maintaining the pH value to be 2.0;

step seven: after the concentrated solution and the concentrated hydrochloric acid are dripped, stirring for 0.5h at room temperature, adding 5% active carbon, and continuously stirring for 0.5 h;

step eight: filtering the solution after reaction;

step nine: stirring for 1 hr, filtering, and drying at 70-80 deg.C.

According to the preparation method of the carbamylation reaction, the refined p-chlorobenzoyl L-glutamic acid, the methylamine water solution and cuprous chloride are added into the microreactor, and the microreactor is adopted to replace a conventional reaction kettle to perform reaction in the one-step reaction process of the carbamylation, so that the phenomena of long time, low efficiency, low yield, poor quality and more three wastes in the conventional process are changed, and the conditions of short process time, high efficiency, high yield, good quality and less three wastes are realized.

In the first step, the content of methylamine water solution in the microreactor is 10eq25%, the content of cuprous chloride is 15%, the temperature is controlled to be 130-; s6, controlling the internal temperature to be 10-30 ℃ in the process of dropwise adding the concentrated solution and concentrated hydrochloric acid; ensuring the temperature of the filtrate to be about 25 ℃ in the process of adjusting the pH of the filtrate; and (5) adjusting the pH of the filtrate filtered in the step S8 to 5.0-5.5 by using 20% NaOH solution.

When the method works, firstly adding a refined p-chlorobenzoyl L-glutamic acid product, 10eq25% methylamine water solution and 15% cuprous chloride into a microreactor, controlling the temperature at 130-, stirring for 0.5 hr, filtering, adjusting pH of the filtrate to 5.0-5.5 with 20% NaOH solution, controlling temperature to about 25 deg.C, stirring for 1 hr, filtering, and drying at 70-80 deg.C.

It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.