阅读说明：本技术 一种l-硒代蛋氨酸的制备方法 (Preparation method of L-selenomethionine ) 是由 刘育 王天峰 李明江 刘子博 李仕恒 于 2019-10-22 设计创作，主要内容包括：本发明公开了一种L-硒代蛋氨酸的制备方法,属于添加剂领域,包括以下步骤：A、将化合物1和化合物2在溶剂中进行反应,反应后过滤得到绿色固体化合物3；B、首先将化合物3和硼氢化钠在质子性溶剂中反应1-10小时,到达反应时间后滴加硫酸二甲酯继续反应1-5小时,醋酸淬灭后,过滤、烘干制得L-硒代蛋氨酸。本发明的有益效果是：1、化合物1条件温和,收率高；2、化合物3的反应条件温和,没有剧毒和恶臭的硒甲醇钠生成,有利于劳动保护和环境保护；3、化合物3的分离简单,离心甩滤即可,所得产物纯度高；4、所用原料和试剂均有市售,L-硒代蛋氨酸的制备过程中,中间体不需要分离,操作简单。(The invention discloses a preparation method of L-selenomethionine, belonging to the field of additives and comprising the following steps: A. reacting the compound 1 with the compound 2 in a solvent, and filtering after reaction to obtain a green solid compound 3; B. firstly, reacting the compound 3 with sodium borohydride in a protic solvent for 1-10 hours, dripping dimethyl sulfate after the reaction time is reached, continuing to react for 1-5 hours, quenching acetic acid, filtering and drying to obtain the L-selenomethionine. The invention has the beneficial effects that: 1. the compound 1 has mild condition and high yield; 2. the reaction condition of the compound 3 is mild, no virulent and malodorous selenium sodium methoxide is generated, and the labor protection and the environmental protection are facilitated; 3. the compound 3 is simple to separate and only needs to be centrifugally subjected to spin filtration, and the obtained product has high purity; 4. the raw materials and reagents are commercially available, and in the preparation process of the L-selenomethionine, the intermediate does not need to be separated, so that the operation is simple.)

1. A preparation method of L-selenomethionine is characterized by comprising the following steps:

A. reacting the compound 1 with the compound 2 in a solvent, filtering after the reaction to obtain a green solid compound 3,

wherein the solvent is water, ethanol or methanol, the reaction temperature is 0-60 ℃, the reaction time is 3-10 hours,

compound 1 is

The ratio of the compound 1 to the compound 2 is 1:0.8-4 according to the mol ratio;

B. firstly, reacting the compound 3 with sodium borohydride in a protic solvent for 1-10 hours, dripping dimethyl sulfate after the reaction time is reached to continue reacting for 1-5 hours, filtering and drying after acetic acid quenching to prepare L-selenomethionine,

wherein the protonic solvent is water, absolute ethyl alcohol, 95% ethyl alcohol, methanol or isopropanol, the reaction temperature is 0-80 ℃,

the molar ratio of the compound 3 to the sodium borohydride is 1:8-12, and the ratio of the compound 3 to the dimethyl sulfate is 1: 2-4.

2. The process for producing L-selenomethionine according to claim 1, wherein step a comprises:

preparation of compound 1: adding sodium hydroxide (the equivalent ratio of the sodium hydroxide to the selenium particles is 1: 1) into water at room temperature, adding the selenium particles after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate, reacting under the protection of nitrogen after dropwise adding to obtain a compound 1 solution,

wherein the ratio of the sodium hydroxide to the selenium particles in a molar ratio is 1: 1;

synthesis of Compound 3: and (3) dropwise adding the compound 2 into the solution of the compound 1, reacting after the dropwise adding is finished, cooling the reaction system to 0-5 ℃ after the reaction is finished, performing suction filtration, and drying to obtain a compound 3.

3. The process for producing L-selenomethionine according to claim 1, wherein the ratio of compound 1 to compound 2 in step A is 1: 0.9-2.

4. The method for preparing L-selenomethionine according to claim 1, wherein compound 3 is added to protic solvent under the protection of nitrogen in step B, then sodium borohydride is added in batches for reaction, dimethyl sulfate is added dropwise after the reaction is finished, the reaction is carried out, the system is cooled to 20-25 ℃ after the reaction is completed, glacial acetic acid is added dropwise to adjust the pH value to 5-6, and white solid is obtained after filtering and drying.

Technical Field

The invention belongs to the field of additives, and particularly relates to a preparation method of L-selenomethionine.

Background

Selenium is an indispensable trace element and plays a very important role in human bodies. Selenium cannot be synthesized in human body and is an element easy to excrete, so the human body must keep enough selenium every day to maintain normal metabolism of the human body, and especially people living in low-selenium environment pay more attention to continuously supplementing enough selenium. In human body, the lack of trace element selenium can cause the reduction of the immunity of the human body. With the age, the selenium storage quantity in the human body is reduced in an integrated series. Meanwhile, with the rapid development of economy, the selenium deficiency phenomenon of modern people is more serious due to the change of dietary structure and living habits, environmental pollution and the like (the contemporary chemical research, 2017, 11: 135-136). In order to supplement trace element selenium in human body more effectively and safely, No. 455/2013 regulation issued by european union committee (EU) in 2013 approved L-selenomethionine analogue as animal feed additive (chinese feed additive, 2013,6: 50) to provide safer selenium source for human by increasing selenium content in meat and egg products of poultry. Along with the improvement of living standard of people, the demand of L-selenomethionine is increased, so that the industrialized and environment-friendly preparation process of the L-selenomethionine is developed, and the market prospect is very wide.

At present, the preparation process of selenomethionine is mainly prepared by the following synthetic route (CN 107973733; CN 106220539):

the following problems mainly exist in the rerouting process:

(1) the preparation of the selenium sodium methoxide is carried out by dimethyl diselenyl ether, which is a brownish red viscous oily substance and has high toxicity, and serious rash is easily generated by contact in the production process;

(2) the wastewater amount in the preparation process of the dimethyl diselenyl ether is very large, and the preparation process is not environment-friendly;

(3) in the process of preparing the selenium sodium methoxide from the dimethyl diselenyl ether, the selenium methanol gas with foul smell and high toxicity is very easy to generate, and the labor protection and the environmental protection are extremely not facilitated.

Disclosure of Invention

The invention aims to solve the technical problem of providing a preparation method of L-selenomethionine, which has no production of highly toxic by-products in the process, is environment-friendly, and has good product quality and high yield.

In order to solve the technical problems, the invention adopts the technical scheme that:

a preparation method of L-selenomethionine comprises the following steps:

A. reacting the compound 1 with the compound 2 in a solvent, filtering after the reaction to obtain a green solid compound 3,

wherein the solvent is water, ethanol or methanol, the reaction temperature is 0-60 ℃, the reaction time is 3-10 hours,

compound 1 is

The compound 2 is

The compound 3 is

，

The ratio of the compound 1 to the compound 2 is 1:0.8-4 according to the mol ratio;

B. firstly, reacting the compound 3 with sodium borohydride in a protic solvent for 1-10 hours, dripping dimethyl sulfate after the reaction time is reached to continue reacting for 1-5 hours, filtering and drying after acetic acid quenching to prepare L-selenomethionine,

wherein the protonic solvent is water, absolute ethyl alcohol, 95% ethyl alcohol, methanol or isopropanol, the reaction temperature is 0-80 ℃,

the molar ratio of the compound 3 to the sodium borohydride is 1:8-12, and the ratio of the compound 3 to the dimethyl sulfate is 1: 2-4.

The invention has the beneficial effects that: 1. the compound 1 has mild condition and high yield; 2. the reaction condition of the compound 3 is mild, no virulent and malodorous selenium sodium methoxide is generated, and the labor protection and the environmental protection are facilitated; 3. the compound 3 is simple to separate and only needs to be centrifugally subjected to spin filtration, and the obtained product has high purity; 4. the raw materials and reagents are commercially available, and in the preparation process of the L-selenomethionine, the intermediate does not need to be separated, so that the operation is simple.

Detailed Description

The invention provides a preparation method of L-selenomethionine, wherein a compound 1 and a compound 2 react to generate a compound 3, and the compound 3 is reduced by sodium borohydride and then reacts with dimethyl sulfate to prepare the final product of L-selenomethionine. The synthetic route is

。

The method comprises a step A and a step B.

And step A, reacting the compound 1 with the compound 2 in a solvent, and filtering after reaction to obtain a green solid compound 3, wherein the solvent is water, ethanol or methanol, the reaction temperature is 0-60 ℃ (preferably 20-40 ℃), and the reaction time is 3-10 hours (preferably 4-6 hours).

Compound 1 is

The compound 2 is

The compound 3 is

。

The ratio of the compound 1 to the compound 2 is 1:0.8-4, preferably 1:0.9-2, in terms of molar ratio.

The method specifically comprises the following steps:

preparation of compound 1: adding sodium hydroxide into water at room temperature, adding selenium particles after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate, and reacting under the protection of nitrogen after dropwise adding to obtain a compound 1 solution. The molar ratio of the sodium hydroxide to the selenium particles is 1: 1.

Synthesis of Compound 3: dropwise adding the compound 2 into the solution of the compound 1, reacting after the dropwise adding is finished, cooling a reaction system to 0-5 ℃ after the reaction is finished, performing suction filtration, and drying to obtain a compound 3, namely: (2S, 2 'S) -4' -diselenylbis (2-aminobutyric acid).

Step A embodiment one:

adding sodium hydroxide (4.0 g, 0.1 mol) into water (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (6.4 g, 0.1 mol), slowly heating to 35 ℃ for reaction for 3 hours after dropwise adding, dropwise adding compound 2 (26.3 g, 0.1 mol) at the temperature under the protection of nitrogen, dissolving in 60ml of water, and reacting for 3 hours at 35 ℃ after dropwise adding. After the reaction, the reaction system was cooled to 5 ℃, filtered and dried to obtain 18.76g of green solid, the crude product yield was 79.8%, and the HPLC purity was 95%.

Step a example two:

adding sodium hydroxide (4.0 g, 0.1 mol) into ethanol (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (6.4 g, 0.1 mol), slowly heating to 40 ℃ for reaction for 3 hours after dropwise adding, dropwise adding compound 2 (23.7 g, 0.09 mol) at the temperature under the protection of nitrogen, dissolving in 60ml of ethanol, and reacting for 4 hours at 40 ℃ after dropwise adding. After the reaction, the reaction system was cooled to 5 ℃, filtered and dried to obtain 20.6g of green solid, the crude product yield was 60.4%, and the HPLC purity was 92%.

Step a example three:

adding sodium hydroxide (4.0 g, 0.1 mol) into methanol (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (6.4 g, 0.1 mol), slowly raising the temperature to 35 ℃ for reaction for 3 hours after the dropwise adding is finished, dropwise adding compound 2 (34.2 g, 0.13 mol) at the temperature under the protection of nitrogen, dissolving in 90ml of methanol, and reacting for 3 hours at 20 ℃ after the dropwise adding is finished. After the reaction is finished, the reaction system is cooled to 5 ℃, filtered and dried to obtain 25.3g of green solid, the yield of the crude product is 70.7%, and the HPLC purity is 91%.

Step a example four:

adding sodium hydroxide (8.0 g, 0.2 mol) into water (60 ml) at room temperature, adding selenium particles (15.8 g, 0.2 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (12.6 g, 0.2 mol), and slowly raising the temperature to 35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under nitrogen protection, compound 2 [ 105.2g, 0.4mol ] was added dropwise at this temperature and dissolved in 150ml of water, and after completion of the addition, the reaction was carried out at 35 ℃ for 5 hours. The reaction system is cooled to 5 ℃, filtered and dried to obtain 22.6g of green solid, the yield of crude product is 63.8 percent, and the HPLC purity is 91 percent.

Step a example v:

adding sodium hydroxide (4.0 g, 0.1 mol) into water (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (6.3 g, 0.1 mol), and slowly raising the temperature to 35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under the protection of nitrogen, compound 2 [ 21g, 0.08mol ] was added dropwise at this temperature and dissolved in 60ml of water, and after completion of the addition, the reaction was carried out at 35 ℃ for 5 hours. The reaction system is cooled to 5 ℃, filtered and dried to obtain 9.96g of green solid, the yield of the crude product is 68.8 percent, and the HPLC purity is 93 percent.

Step a example six:

adding sodium hydroxide (4.0 g, 0.1 mol) into water (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (6.3 g, 0.1 mol), and slowly raising the temperature to 35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under nitrogen protection, compound 2 [ 23.7g, 0.09mol ] was added dropwise at this temperature in 60ml of water, and after completion of the addition, the reaction was carried out at 35 ℃ for 6 hours. The reaction system is cooled to 5 ℃, filtered and dried to obtain 26.0g of green solid, the yield of the crude product is 80.3 percent, and the HPLC purity is 95 percent.

Step a example seven:

adding sodium hydroxide (4.0 g, 0.1 mol) into water (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (6.3 g, 0.1 mol), and slowly raising the temperature to 35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under the protection of nitrogen, compound 2 [ 26.3g, 0.11mol ] was added dropwise at this temperature and dissolved in 60ml of water ], followed by reaction at 60 ℃ for 4 hours after completion of the dropwise addition. The reaction system is cooled to 5 ℃, filtered and dried to obtain 14.7g of green solid, the yield of the crude product is 81.2 percent, and the HPLC purity is 93 percent.

Step a example eight:

adding sodium hydroxide (4.0 g, 0.1 mol) into water (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (6.3 g, 0.1 mol), and slowly raising the temperature to 35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under nitrogen protection, compound 2 [ 47.3g, 0.18mol ] was added dropwise at this temperature and dissolved in 120ml of water ], followed by reaction at 45 ℃ for 5 hours after completion of the dropwise addition. The reaction system is cooled to 5 ℃, filtered and dried to obtain 14.7g of green solid, the yield of the crude product is 81.1 percent, and the HPLC purity is 94 percent.

Step a example nine:

adding sodium hydroxide (4.0 g, 0.1 mol) into water (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (6.3 g, 0.1 mol), and slowly raising the temperature to 35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under nitrogen protection, compound 2 [ 39.6g, 0.15mol ] was added dropwise at this temperature and dissolved in 90ml of water ], followed by reaction at 50 ℃ for 5 hours after completion of the dropwise addition. The reaction system is cooled to 5 ℃, filtered and dried to obtain 20.1g of green solid, the yield of the crude product is 81.0 percent, and the HPLC purity is 94 percent.

Step a example ten:

adding sodium hydroxide (4.0 g, 0.1 mol) into water (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (6.3 g, 0.1 mol), and slowly raising the temperature to 35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under the protection of nitrogen, compound 2 [ 45.0g, 0.17mol ] was added dropwise at this temperature and dissolved in 100ml of water ], followed by reaction at 60 ℃ for 7 hours. The reaction system is cooled to 5 ℃, filtered and dried to obtain 17.7g of green solid, the yield of the crude product is 69.2 percent, and the HPLC purity is 98 percent.

Step a example eleven:

adding sodium hydroxide (4.0 g, 0.1 mol) into water (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, stirring for 30min at 15 ℃, then dropwise adding hydrazine hydrate (6.3 g, 0.1 mol), and slowly raising the temperature to 35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under the protection of nitrogen, dropwise adding compound 2 (26.3 g, 0.1 mol) at 20-25 ℃ and dissolving in 60ml of water, and reacting for 2 hours at 60 ℃ after dropwise adding. The reaction system is cooled to 5 ℃, filtered and dried to obtain 19.5g of green solid, the yield of the crude product is 12.7 percent, and the HPLC purity is 93 percent.

Step a example twelve:

adding sodium hydroxide (4.0 g, 0.1 mol) into water (30 ml) at room temperature, adding selenium particles (7.9 g, 0.1 mol) after the sodium hydroxide is completely dissolved, then dropwise adding hydrazine hydrate (6.3 g, 0.1 mol), and slowly raising the temperature to 35 ℃ for reaction for 6 hours after the dropwise adding is finished. Under the protection of nitrogen, compound 2 [ 26.3g, 0.1mol ] was added dropwise at this temperature and dissolved in 60ml of water ], followed by reaction at 60 ℃ for 8 hours after completion of the dropwise addition. The reaction system is cooled to 5 ℃, filtered and dried to obtain 18.1g of green solid, the yield of the crude product is 72.8 percent, and the HPLC purity is 93 percent.

And step B, firstly, reacting the compound 3 with sodium borohydride in a protic solvent for 1-10 hours, adding dimethyl sulfate dropwise after the reaction time is reached, continuing to react for 1-5 hours, quenching acetic acid, filtering and drying to obtain the L-selenomethionine white solid, wherein the protic solvent is water, absolute ethyl alcohol, 95% ethyl alcohol, methanol or isopropanol, and the reaction temperature is 0-80 ℃ (preferably 30-50 ℃).

The molar ratio of the compound 3 to the sodium borohydride is 1: 8-12.

The molar ratio of the compound 3 to the dimethyl sulfate is 1: 2-4.

Specifically, adding the compound 3 into a protic solvent under the protection of nitrogen, then adding sodium borohydride in batches for reaction, dropwise adding dimethyl sulfate after the reaction is finished, reacting, cooling the system to 20-25 ℃ after the reaction is completed, dropwise adding glacial acetic acid to adjust the pH value to 5-6, filtering, and drying to obtain a white solid.

Step B, embodiment one:

compound 3 (20 g, 55.2 mmol) was added to anhydrous ethanol (350 ml) under nitrogen, sodium borohydride (20.9 g, 0.55 mol) was added in portions at 35 ℃ and the reaction was completed for 5 hours at 35 ℃. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise thereto, and the reaction was carried out at 45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain 43.4g of white solid with the HPLC purity of 99.5%.

Step B example two:

compound 3 (20 g, 55.2 mmol) was added to anhydrous ethanol (350 ml) under nitrogen, sodium borohydride (20.9 g, 0.55 mol) was added in portions at 45 ℃ and the reaction was completed for 5 hours at 45 ℃. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise thereto, and the reaction was carried out at 45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain a white solid 16.9g, wherein the yield is 78% and the HPLC purity is 99.3%.

Step B example three:

compound 3 (20 g, 55.2 mmol) was added to anhydrous ethanol (100 ml) under nitrogen, sodium borohydride (16.7 g, 0.44 mol) was added in portions at 55 ℃, and the reaction was completed for 4 hours at 40 ℃. Anhydrous ethanol (250 ml) was added, dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise, and the reaction was carried out at 55 ℃ for 1.5 hours. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain 17.3g of white solid, wherein the yield is as follows: 80% and 99.5% HPLC purity.

Step B example four:

compound 3 (20 g, 55.2 mmol) was added to 95% ethanol (100 ml) under nitrogen, sodium borohydride (23.0 g, 0.60 mol) was added in portions at 35 ℃ and the addition was completed, followed by reaction at 45 ℃ for 5 hours. Dimethyl sulfate (27.9 g, 0.166 mol) was added dropwise thereto, and the reaction was carried out at 30 ℃ for 3 hours after completion of the addition. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain 17.7g of white solid, wherein the yield is 81.8%, and the HPLC purity is 99.7%.

Step B example five:

compound 3 (20 g, 55.2 mmol) was added to anhydrous methanol (100 ml) under nitrogen, sodium borohydride (25.0 g, 0.66 mol) was added in portions at 35 ℃ and the reaction was allowed to proceed for 5 hours at 50 ℃. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise thereto, and the reaction was carried out at 45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain 17.5g of white solid, wherein the yield is 81.5%, and the HPLC purity is 99.6%.

Step B example six:

compound 3 (20 g, 55.2 mmol) was added to anhydrous ethanol (100 ml) under nitrogen, sodium borohydride (8.4 g, 0.22 mol) was added in portions at 45 ℃ and the reaction was completed for 5 hours at 45 ℃. Dimethyl sulfate (13.9 g, 0.11 mol) was added dropwise thereto, and the reaction was carried out at 30 ℃ for 2 hours after completion of the addition. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain 17.5g of white solid, wherein the yield is 81%, and the HPLC purity is 99.6%.

Step B example seven:

compound 3 (20 g, 55.2 mmol) was added to anhydrous ethanol (100 ml) under nitrogen, sodium borohydride (25.0 g, 0.66 mol) was added in portions at 50 ℃ and the addition was completed, followed by reaction at 35 ℃ for 5 hours. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise thereto, and the reaction was carried out at 45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain 17.7g of white solid, wherein the yield is as follows: 82% and 99.3% HPLC purity.

Step B example eight:

compound 3 (20 g, 55.2 mmol) was added to 95% ethanol (100 ml) under nitrogen, sodium borohydride (16.7 g, 0.44 mol) was added in portions at 35 ℃ and the addition was completed, and reacted at 35 ℃ for 5 hours. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise thereto, and the reaction was carried out at 45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain 17.1g of white solid, wherein the yield is as follows: 79% and 99.8% HPLC purity.

Step B example nine:

compound 3 (20 g, 55.2 mmol) was added to 95% ethanol (100 ml) under nitrogen, sodium borohydride (25.1 g, 0.66 mol) was added in portions at 35 ℃ and the addition was completed, followed by reaction at 35 ℃ for 5 hours. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise thereto, and the reaction was carried out at 45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain 17.0 g of white solid, wherein the yield is as follows: 78% and 99.7% HPLC purity.

Step B example ten:

compound 3 (20 g, 55.2 mmol) was added to 95% ethanol (100 ml) under nitrogen, sodium borohydride (20.9 g, 0.55 mol) was added in portions at 35 ℃ and the addition was completed, followed by reaction at 35 ℃ for 5 hours. Dimethyl sulfate (13.9 g, 0.11 mol) was added dropwise thereto, and the reaction was carried out at 45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain 17.1g of white solid, wherein the yield is 79% and the HPLC purity is 99.5%.

Step B example eleven:

compound 3 (20 g, 55.2 mmol) was added to 95% ethanol (100 ml) under nitrogen, sodium borohydride (20.9 g, 0.55 mol) was added in portions at 35 ℃ and the addition was completed, followed by reaction at 35 ℃ for 5 hours. Dimethyl sulfate (20.9 g, 0.17 mol) was added dropwise thereto, and the reaction was carried out at 45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain 17.5g of white solid, wherein the yield is 81%, and the HPLC purity is 99.4%.

Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention and not to limit it; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that: modifications to the specific embodiments of the invention or equivalent substitutions for parts of the technical features may be made; without departing from the spirit of the present invention, it is intended to cover all aspects of the invention as defined by the appended claims.