Synthesis method of L-selenomethionine
阅读说明：本技术 一种l-硒代蛋氨酸的合成方法 (Synthesis 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-硒代蛋氨酸的合成方法,属于添加剂领域,包括以下步骤：A、化合物1和化合物2在溶剂中反应,反应完成后过滤、烘干后得到绿色固体化合物3；B、将化合物3和硼氢化钠在质子性溶剂中反应1-10小时,反应完成后滴加硫酸二甲酯继续反应1-5小时,然后醋酸淬灭,过滤,制得L-硒代蛋氨酸。本发明的有益效果是：1、化合物1有文献报道,条件温和,收率高；2、化合物2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2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 method for synthesizing L-selenomethionine, which belongs to the field of additives and comprises the following steps: A. reacting the compound 1 with the compound 2 in a solvent, and filtering and drying after the reaction is finished to obtain a green solid compound 3; B. reacting the compound 3 with sodium borohydride in a protic solvent for 1-10 hours, dripping dimethyl sulfate after the reaction is finished, continuing the reaction for 1-5 hours, then quenching with acetic acid, and filtering to obtain the L-selenomethionine. The invention has the beneficial effects that: 1. the compound 1 is reported in documents, the conditions are mild, and the yield is high; 2. the reaction condition of the compound 2 is mild, no virulent and malodorous selenium sodium methoxide is generated, and the labor protection and the environmental protection are facilitated; 3. the compound 2 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 method for synthesizing L-selenomethionine is characterized by comprising the following steps:
A. reacting the compound 1 with the compound 2 in a solvent, filtering and drying after the reaction is finished 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 molar ratio of the compound 1 to the compound 2 is 1: 0.8-4;
B. reacting the compound 3 with sodium borohydride in a protic solvent for 1-10 hours, dripping dimethyl sulfate after the reaction is finished to continue the reaction for 1-5 hours, then quenching with acetic acid, filtering to prepare L-selenomethionine,
wherein the protonic solvent is water, absolute ethyl alcohol, 95% ethyl alcohol, methanol or isopropanol, the reaction temperature is 30-50 ℃,
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 method for synthesizing L-selenomethionine according to claim 1, wherein the ratio of compound 1 to compound 2 in step A is 1: 0.9-2.
3. The method for synthesizing L-selenomethionine according to claim 1, wherein in step A, sodium hydroxide is added into a solvent at room temperature, selenium particles and hydrazine hydrate are added dropwise after the sodium hydroxide is completely dissolved, and the reaction is carried out for 3-6 hours after the completion of the dropwise addition;
adding the compound 2 in batches under the protection of nitrogen, reacting after the dropwise addition is finished, cooling the reaction system to 0-5 ℃ after the reaction is finished, performing suction filtration, and drying to obtain a green solid.
4. The method for synthesizing L-selenomethionine according to claim 1, wherein in step B, compound 3 is added into a protic solvent under the protection of nitrogen, then sodium borohydride is added in batches, after the addition, the reaction is carried out for 1 to 10 hours, then dimethyl sulfate is added dropwise and the reaction is carried out for 1 to 5 hours, after the reaction is completed, the system is cooled to 20 to 25 ℃, glacial acetic acid is added dropwise to adjust the pH value to 5 to 6, and the white solid is obtained after filtration and drying.
Technical Field
The invention belongs to the field of additives, and particularly relates to a method for synthesizing L-selenomethionine.
Background
Since the discovery that selenium is a necessary trace element in animals in the late 50 s of this century, scientists have been making continuous efforts to reveal the relationship between selenium and life. It is clear that most of the selenium in organisms exists in the form of selenocysteine, and the active part of catalytic oxidoreductase is focused, wherein glutathione peroxidase, which has a radical scavenging function, is studied more clearly and deeply, and protects red blood cells from being damaged by peroxidation, which indicates that selenium is an essential vital element of organisms. In addition, research shows that selenium has peculiar efficacy in the aspects of cancer prevention, cancer resistance, aging resistance, virus resistance, prevention and treatment of cardiovascular diseases, keshan disease, Kaschin-Beck disease and the like. L-selenomethionine, i.e., methionine replaced by a selenium atom, can be synthesized by introducing methylseleno groups into appropriate molecules (Synthesis, 1984, 439-442).
Currently, the preparation process of selenomethionine mainly uses homoserine lactone hydrobromide as a starting material (CN 106928110; CN 102558005):
homoserine lactone hydrobromide was synthesized by a route (Tetrahedron, 43(22): 5341-5349) in which dimethyl sulfide as a leaving group undergoes a nucleophilic substitution reaction with a hydroxyl group. The specific reaction route is as follows:
Disclosure of Invention
The invention aims to solve the technical problem of synthesizing L-selenomethionine, a compound 1 reacts with diselenyl disodium to generate a compound 3, the compound 3 is reduced by sodium borohydride and then reacts with dimethyl sulfate to prepare the L-selenomethionine product, an intermediate does not need to be separated, and the operation is simple.
In order to solve the technical problems, the invention adopts the technical scheme that:
a method for synthesizing L-selenomethionine comprises the following steps:
A. reacting the compound 1 with the compound 2 in a solvent, filtering and drying after the reaction is finished 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
B. reacting the compound 3 with sodium borohydride in a protic solvent for 1-10 hours, dripping dimethyl sulfate after the reaction is finished to continue the reaction for 1-5 hours, then quenching with acetic acid, filtering to prepare L-selenomethionine,
wherein the protic solvent is water, absolute ethyl alcohol, 95% ethyl alcohol, methanol or isopropanol, the reaction temperature is 30-50 ℃, 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 is reported in documents, the conditions are mild, and the yield is high; 2. the reaction condition of the compound 2 is mild, no virulent and malodorous selenium sodium methoxide is generated, and the labor protection and the environmental protection are facilitated; 3. the compound 2 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 method for synthesizing L-selenomethionine, based on the discovery that quaternized trimethylamine can also be used as a leaving group in the preparation process of tetrabenazine, and electrophilic substitution reaction is carried out with electrophilic reagents (org. process Res. Dev., 2018, 22, 520-526), and the specific reaction route is as follows:
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 and drying after the reaction is finished to obtain a green solid compound 3.
Wherein the solvent is water, ethanol or methanol, the reaction temperature is 0-60 deg.C (preferably 20-40 deg.C), the reaction time is 3-10 hr (preferably 4-6 hr), and compound 1 is
In detail, adding sodium hydroxide into a solvent at room temperature, adding selenium particles and dropwise adding hydrazine hydrate after the sodium hydroxide is completely dissolved, and reacting for 3-6 hours after dropwise adding is finished to generate a compound 1;
adding the compound 2 in batches under the protection of nitrogen, reacting after the dropwise addition is finished, cooling the reaction system to 5 ℃ after the reaction is finished, performing suction filtration, and drying to obtain a green solid.
Wherein, the molar ratio of the sodium hydroxide to the selenium particles to the hydrazine hydrate is 1: 1: 1.
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 30-35 ℃ for reaction for 3 hours after the dropwise adding is finished, adding compound 2 (29.1 g, 0.1 mol) in batches at the temperature under the protection of nitrogen, and reacting for 2 hours at 30-35 ℃ after the feeding is finished. After the reaction, the reaction system is cooled to 0-5 ℃, filtered, dried to obtain 18.76g of green solid, the yield of the crude product is 79.8%, and the HPLC purity is 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 40-45 ℃ for reaction for 3 hours after the dropwise adding is finished, adding a compound 2 (26.2 g, 0.09 mol) in batches at the temperature under the protection of nitrogen, and reacting for 4 hours at 40-45 ℃ after the dropwise adding is finished. After the reaction, the reaction system is cooled to 0-5 ℃, filtered, dried to obtain 20.6g of green solid, the yield of the crude product is 60.4%, and the HPLC purity is 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 heating to 30-35 ℃ for reaction for 3 hours after the dropwise adding is finished, adding a compound 2 (37.83 g, 0.13 mol) in batches at the temperature under the protection of nitrogen, and reacting for 3 hours at 15-20 ℃ after the dropwise adding is finished. After the reaction is finished, the reaction system is cooled to 0-5 ℃, filtered, 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 35-40 ℃ for reaction for 5 hours after the dropwise adding is finished. Under nitrogen protection, compound 2 (116.4 g, 0.4 mol) was added in portions at this temperature, and reacted at 35-40 ℃ for 5 hours after the addition was complete. And (3) reducing the temperature of the reaction system to 0-5 ℃, performing suction filtration and drying to obtain 22.6g of green solid, wherein the yield of the crude product is 63.8 percent, and the purity of HPLC 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 35-40 ℃ for reaction for 5 hours after the dropwise adding is finished. Under the protection of nitrogen, adding the compound 2 (23.28 g, 0.08 mol) in portions at the temperature, and reacting for 2 hours at 35-40 ℃ after the dropwise addition is finished. And (3) cooling the reaction system to 0-5 ℃, carrying out suction filtration and drying to obtain 9.96g of green solid, wherein the yield of the crude product is 68.8 percent, and the purity of HPLC 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 35-40 ℃ for reaction for 5 hours after the dropwise adding is finished. Under the protection of nitrogen, adding the compound 2 (26.2 g, 0.09 mol) in portions at the temperature, and reacting for 2 hours at 35-40 ℃ after the dropwise addition is finished. And (3) cooling the reaction system to 0-5 ℃, carrying out suction filtration and drying to obtain 26.0g of green solid, wherein the yield of the crude product is 80.3%, and the purity of HPLC is 95%.
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 30-35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under the protection of nitrogen, compound 2 (32.0 g, 0.11 mol) was added in portions at this temperature, and after completion of the dropwise addition, the reaction was carried out at 55 to 60 ℃ for 4 hours. And (3) reducing the temperature of the reaction system to 0-5 ℃, performing suction filtration and drying to obtain 14.7g of green solid, wherein the yield of the crude product is 81.2 percent, and the purity of HPLC 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 30-35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under nitrogen protection, compound 2 (52.4 g, 0.18 mol) was added in portions at this temperature, and after completion of the addition, the reaction was carried out at 40 to 45 ℃ for 5 hours. And (3) reducing the temperature of the reaction system to 0-5 ℃, performing suction filtration and drying to obtain 14.7g of green solid, wherein 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 30-35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under nitrogen protection, compound 2 (43.6 g, 0.15 mol) was added in portions at this temperature, and after completion of the dropwise addition, the reaction was carried out at 45 to 50 ℃ for 5 hours. And (3) reducing the temperature of the reaction system to 0-5 ℃, performing suction filtration and drying to obtain 20.1g of green solid, wherein 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 30-35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under nitrogen protection, compound 2 (49.5 g, 0.17 mol) was added in portions at this temperature, and reacted at 55-60 ℃ for 7 hours after the addition was completed. And (3) reducing the temperature of the reaction system to 0-5 ℃, carrying out suction filtration and drying to obtain 17.7g of green solid, wherein the yield of the crude product is 69.2 percent, and the purity of HPLC 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 15-20 ℃, then dropwise adding hydrazine hydrate (6.3 g, 0.1 mol), and slowly raising the temperature to 30-35 ℃ for reaction for 5 hours after the dropwise adding is finished. Under the protection of nitrogen, adding the compound 2 (29.1 g, 0.1 mol) in batches at 20-25 ℃, and reacting for 2 hours at 55-60 ℃ after dropwise addition. And (3) reducing the temperature of the reaction system to 0-5 ℃, carrying out suction filtration and drying to obtain 19.5g of green solid, wherein the yield of the crude product is 12.7 percent, and the purity of HPLC 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 30-35 ℃ for reaction for 6 hours after the dropwise adding is finished. Under the protection of nitrogen, adding the compound 2 (29.1 g, 0.1 mol) in portions, and reacting for 2 hours at 55-60 ℃ after the dropwise addition is finished. And (3) reducing the temperature of the reaction system to 0-5 ℃, carrying out suction filtration and drying to obtain 18.1g of green solid, wherein the yield of the crude product is 72.8 percent, and the purity of HPLC is 93 percent.
And step B, reacting the compound 3 with sodium borohydride in a protic solvent for 1-10 hours, dropwise adding dimethyl sulfate after the reaction is finished, continuing the reaction for 1-5 hours, then quenching with acetic acid, and filtering to obtain the L-selenomethionine white solid.
Wherein the protic solvent is water, absolute ethyl alcohol, 95% ethyl alcohol, methanol or isopropanol, the reaction temperature is 30-50 ℃, 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.
In detail, adding a compound 3 into a protic solvent under the protection of nitrogen, then adding sodium borohydride in batches, reacting for 1-10 hours after the addition is finished, then dropwise adding dimethyl sulfate and reacting for 1-5 hours, 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:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into absolute ethyl alcohol (350 ml), sodium borohydride (20.9 g, 0.55 mol) is added in portions at 30-35 ℃, and reaction is carried out for 5 hours at 30-35 ℃ after the addition is finished. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise and the reaction was carried out at 40-45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20-25 ℃, dropwise adding glacial acetic acid (15 g), adjusting the pH value to 5-6, filtering, and drying to obtain white solid 43.4g with the HPLC purity of 99.5%.
Step B example two:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into absolute ethyl alcohol (350 ml), sodium borohydride (20.9 g, 0.55 mol) is added in portions at 40-45 ℃, and reaction is carried out for 5 hours at 40-45 ℃ after the addition is finished. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise and the reaction was carried out at 40-45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20-25 ℃, 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:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into absolute ethyl alcohol (100 ml), sodium borohydride (16.7 g, 0.44 mol) is added in portions at 40-45 ℃, and reaction is carried out for 4 hours at 40-45 ℃ after the addition is finished. Adding absolute ethyl alcohol (250 ml), dropwise adding dimethyl sulfate (27.9 g, 0.22 mol), and reacting at 50-55 ℃ for 1.5 hours after dropwise adding. And (3) completely reacting, cooling the system to 20-25 ℃, 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:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into 95% ethanol (100 ml), sodium borohydride (23.0 g, 0.60 mol) is added in portions at 30-35 ℃, and reaction is carried out for 5 hours at 40-45 ℃ after the addition is finished. Dimethyl sulfate (27.9 g, 0.166 mol) was added dropwise and reacted at 25-30 ℃ for 3 hours. And (3) completely reacting, cooling the system to 20-25 ℃, 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:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into absolute methanol (100 ml), sodium borohydride (25.0 g, 0.66 mol) is added in portions at 30-35 ℃, and reaction is carried out for 5 hours at 45-50 ℃ after the addition is finished. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise and the reaction was carried out at 40-45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20-25 ℃, 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:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into absolute ethyl alcohol (100 ml), sodium borohydride (8.4 g, 0.22 mol) is added in portions at 40-45 ℃, and reaction is carried out for 5 hours at 40-45 ℃ after the addition is finished. Dimethyl sulfate (13.9 g, 0.11 mol) was added dropwise and the reaction was carried out at 25-30 ℃ for 2 hours after completion of the addition. And (3) completely reacting, cooling the system to 20-25 ℃, 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:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into absolute ethyl alcohol (100 ml), sodium borohydride (25.0 g, 0.66 mol) is added in portions at 40-45 ℃, and reaction is carried out for 5 hours at 30-35 ℃ after the addition is finished. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise and the reaction was carried out at 40-45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20-25 ℃, 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:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into 95% ethanol (100 ml), sodium borohydride (16.7 g, 0.44 mol) is added in portions at 30-35 ℃, and reaction is carried out for 5 hours at 30-35 ℃ after the addition is finished. Dimethyl sulfate (27.9 g, 0.22 mol) was added dropwise and the reaction was carried out at 40-45 ℃ for 1.5 hours after completion of the addition. And (3) completely reacting, cooling the system to 20-25 ℃, 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:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into 95% ethanol (100 ml), sodium borohydride (25.1 g, 0.66 mol) is added in portions at 30-35 ℃, and reaction is carried out for 5 hours at 30-35 ℃ after the addition is finished. 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:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into 95% ethanol (100 ml), sodium borohydride (20.9 g, 0.55 mol) is added in portions at 30-35 ℃, and reaction is carried out for 5 hours at 30-35 ℃ after the addition is finished. Dimethyl sulfate (13.9 g, 0.11 mol) was added dropwise, and the reaction was carried out at 40-45 ℃ for 1.5 hours after the addition. And (3) completely reacting, cooling the system to 20-25 ℃, 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:
under the protection of nitrogen, compound 3 (20 g, 55.2 mmol) is added into 95% ethanol (100 ml), sodium borohydride (20.9 g, 0.55 mol) is added in portions at 30-35 ℃, and reaction is carried out for 5 hours at 30-35 ℃ after the addition is finished. Dimethyl sulfate (20.9 g, 0.17 mol) was added dropwise, and the reaction was carried out at 40-45 ℃ for 1.5 hours after the addition. And (3) completely reacting, cooling the system to 20-25 ℃, 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.
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