CN106749512B - Preparation method of alanyl glutamine - Google Patents
Preparation method of alanyl glutamine Download PDFInfo
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- CN106749512B CN106749512B CN201611264255.4A CN201611264255A CN106749512B CN 106749512 B CN106749512 B CN 106749512B CN 201611264255 A CN201611264255 A CN 201611264255A CN 106749512 B CN106749512 B CN 106749512B
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- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
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Abstract
The invention relates to a preparation method of alanyl glutamine. The preparation method comprises the following specific steps: reacting Boc-alanine in the presence of thionyl chloride to obtain acyl chloride; reacting acyl chloride with N-hydroxysuccinimide under alkaline conditions to obtain Boc-alanyl succinimide, and further reacting with glutamine to obtain Boc-alanyl glutamine; and hydrolyzing the Boc-alanyl glutamine to obtain alanyl glutamine. Compared with the prior art, the invention has the following effects: boc-alanine reacts under the condition of thionyl chloride to obtain acyl chloride, and the raw material is wide and cheap and is simple to operate; acyl chloride and N-hydroxysuccinimide react under alkaline conditions to obtain an active intermediate, and the reaction is simple in post-treatment and does not need to be refined; the synthesis route is short, high-purity alanyl glutamine can be prepared, and powerful guarantee can be provided for the industrial production of alanyl glutamine and intermediates thereof.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of alanyl glutamine.
Background
The alanyl glutamine has the molecular formula of C8H15N3O4, is white or white-like loose block, can be used as an parenteral nutrition medicament, can be used for improving the cellular immune function of patients, effectively reducing the infection risk of critically ill patients, has an important effect on the treatment and recovery of seriously injured patients such as severe infection, malignant tumor and the like, and can shorten the total hospitalization time of the patients. The glutamine dipeptide has wide application in foreign countries, and has larger and larger market demand since the introduction of China, thereby having wide market prospect. Alanyl glutamine, the structure of which is as follows:
the synthesis method reported in the literature includes a DCC coupling method, condensation of Boc-alanine and N-hydroxysuccinimide under DCC condition, removal of Dicyclohexylurea (DCU) generated by the reaction, dropwise addition to glutamine aqueous solution under alkaline condition, acidification, catalytic hydrogenation to remove Boc protecting group and obtain alanyl glutamine. The method has the advantages of simple operation and high yield, but DCU generated by the reaction is difficult to completely remove, has high toxicity and is not suitable for large-scale production.
Reacting alanine with phosgene to obtain N-carboxyl internal anhydride, dripping the N-carboxyl internal anhydride into glutamine water solution under alkaline condition, and acidifying after complete reaction to obtain alanine glutamyl. The process has short steps, but needs violent stirring, and byproducts such as tripeptide, tetrapeptide and the like which are difficult to remove are easily generated in the reaction; phosgene is a toxic gas and is harmful to human bodies when the reaction is incomplete.
Disclosure of Invention
In order to solve the technical problems, the invention provides the preparation method of alanyl glutamine, which has the advantages of easily obtained raw materials, mild reaction conditions, lower cost and higher yield.
The preparation method of alanyl glutamine provided by the invention comprises the following steps:
1) preparation of chloro-Boc-alanine: adding 18.9g of Boc-alanine into a reaction bottle, adding 17.9g of thionyl chloride, adding 0.7g of N, N-dimethylformamide, stirring at 75-85 ℃ for 5 hours, cooling to 40-50 ℃, controlling the temperature to 45-55 ℃, and concentrating under reduced pressure until no fraction exists, so as to obtain an oily substance which is directly used for the next reaction;
2) preparation of Boc-alanyl succinimide: dissolving 13.8g of N-hydroxysuccinimide with 90ml of acetone, then adding 50.5g of triethylamine, dissolving 0.1mol of chloro-Boc-alanine with 40ml of acetone under the condition of ice-water bath, then dropwise adding the mixture into the system, reacting at room temperature for 4 hours after the addition, then adding 400g of purified water into the reaction system, precipitating a large amount of solid, carrying out suction filtration, leaching a filter cake with purified water, and carrying out forced air drying at 50 ℃ to obtain Boc-alanyl succinimide;
3) preparation of Boc-alanylglutamine: adding 10.2g of glutamine and 7mL of water into a reaction bottle, then adding 10g of ammonia water, stirring until the mixture is clear, then adding 10mL of ethanol, dropwise adding a Boc-alanyl succinimide system dissolved by 40mL of ethanol under the stirring condition, and continuing to react for 2 hours at room temperature after the dropwise adding is finished; slowly dropwise adding 2M hydrochloric acid into the system, adjusting the pH to 2-3, stirring for 1h, precipitating a large amount of crystals, performing suction filtration, and drying to obtain a white solid;
4) preparation of alanyl glutamine: removing tert-butyloxycarbonyl.
The preparation method of alanyl glutamine in the step 4) comprises the following steps: 60ml of methylene chloride and 20ml of trifluoroacetic acid were added to a reaction flask containing 19.0g of Boc-alanylglutamine, and the mixture was reacted at room temperature for 5 hours, then 50ml of methyl t-butyl ether was added thereto, and a solid was precipitated, which was filtered by suction and dried to obtain solid alanylglutamine.
The preparation method of alanyl glutamine in the step 4) comprises the following steps: adding 60ml of dichloromethane and 20ml of trifluoroacetic acid into a reaction bottle containing 19.0g of Boc-alanylglutamine, reacting at room temperature for 5 hours, then adding 50ml of methyl tert-butyl ether and 0.1g of lilium B, precipitating a solid, carrying out suction filtration, and drying to obtain solid alanylglutamine.
The synthesis route of the alanyl glutamine is specifically as follows:
compared with the prior art, the preparation method of alanyl glutamine has the following effects: boc-alanine reacts under the condition of thionyl chloride to obtain acyl chloride, and the raw material is wide and cheap and is simple to operate; acyl chloride and N-hydroxysuccinimide react under alkaline conditions to obtain an active intermediate, and the reaction is simple in post-treatment and does not need to be refined; after the lilium brownii element B is added, the substitution effect of methyl tert-butyl ether can be facilitated, and the precipitation of alanyl glutamine can be promoted by a small polar compound inversion method, so that the yield is increased; the synthesis route is short, the high-purity alanyl glutamine can be prepared, the quality reaches the latest standard of pharmacopeia, the industrial production is facilitated, and powerful guarantee can be provided for the industrial production of alanyl glutamine and intermediates thereof.
Drawings
FIG. 1 is an alanylglutamine map. FIG. 2 is a scheme showing the synthesis of alanylglutamine.
Detailed Description
The process for producing alanylglutamine according to the present invention will be further described with reference to the following examples, but the scope of the present invention is not limited thereto.
Example 1
Preparation of chloro-Boc-alanine:
adding Boc-alanine (18.9g, 0.1mol) into a reaction bottle, then adding thionyl chloride (17.9g, 0.15mol), then adding N, N-dimethylformamide (0.7g, 0.01mol), stirring for 5h at 75-85 ℃, then cooling to 40-50 ℃, controlling the temperature to 45-55 ℃, and concentrating under reduced pressure until no fraction is obtained, thus obtaining an oily substance which is directly used for the next reaction.
Preparation of Boc-alanyl succinimide:
dissolving N-hydroxysuccinimide (13.8g, 0.12mol) with 90ml of acetone, then adding triethylamine (50.5g, 0.5mol), dissolving chloro-Boc-alanine (0.1mol) with 40ml of acetone under the condition of ice-water bath, then dropwise adding the mixture into the system, reacting for 4 hours at room temperature after adding, then adding 400g of purified water into the reaction system, precipitating a large amount of solid, performing suction filtration, leaching a filter cake with purified water, and performing forced air drying at 50 ℃ to obtain 22.1g of Boc-alanyl succinimide, wherein the yield of the two steps is 77.2%.
Preparation of Boc-alanylglutamine:
glutamine (10.2g, 0.07mol) and 7mL of water were added to the reaction flask, then 10g of ammonia water was added, stirring was carried out until clarification, then 10mL of ethanol was added, a system of Boc-alanylsuccinimide dissolved in 40mL of ethanol was added dropwise with stirring, and the reaction was continued at room temperature for 2h after the dropwise addition was completed. And then slowly dropwise adding 2M hydrochloric acid into the system, adjusting the pH value to 2-3, stirring for 1h, precipitating a large amount of crystals, performing suction filtration, and drying to obtain 20.0g of white solid with the yield of 90.1%.
Preparation of alanyl glutamine:
to a reaction flask containing Boc-alanylglutamine (19.0g, 0.06mol), 60ml of methylene chloride and 20ml of trifluoroacetic acid were added and reacted at room temperature for 5 hours, and then 50ml of methyl t-butyl ether was added to precipitate a solid, which was filtered with suction and dried to obtain alanylglutamine as a solid in a yield of 82.1%.
Example 2
Preparation of chloro-Boc-alanine:
adding Boc-alanine (18.9g, 0.1mol) into a reaction bottle, then adding thionyl chloride (17.9g, 0.15mol), then adding N, N-dimethylformamide (0.7g, 0.01mol), stirring for 5h at 75-85 ℃, then cooling to 40-50 ℃, controlling the temperature to 45-55 ℃, and concentrating under reduced pressure until no fraction is obtained, thus obtaining an oily substance which is directly used for the next reaction.
Preparation of Boc-alanyl succinimide:
dissolving N-hydroxysuccinimide (13.8g, 0.12mol) with 90ml of acetone, then adding triethylamine (50.5g, 0.5mol), dissolving chloro-Boc-alanine (0.1mol) with 40ml of acetone under the condition of ice-water bath, then dropwise adding the mixture into the system, reacting for 4 hours at room temperature after adding, then adding 400g of purified water into the reaction system, precipitating a large amount of solid, performing suction filtration, leaching a filter cake with purified water, and performing forced air drying at 50 ℃ to obtain 22.1g of Boc-alanyl succinimide, wherein the yield of the two steps is 77.2%.
Preparation of Boc-alanylglutamine:
glutamine (10.2g, 0.07mol) and 7mL of water were added to the reaction flask, then 10g of ammonia water was added, stirring was carried out until clarification, then 10mL of ethanol was added, a system of Boc-alanylsuccinimide dissolved in 40mL of ethanol was added dropwise with stirring, and the reaction was continued at room temperature for 2h after the dropwise addition was completed. And then slowly dropwise adding 2M hydrochloric acid into the system, adjusting the pH value to 2-3, stirring for 1h, precipitating a large amount of crystals, performing suction filtration, and drying to obtain 20.0g of white solid with the yield of 90.1%.
Preparation of alanyl glutamine:
60ml of methylene chloride and 20ml of trifluoroacetic acid were added to a reaction flask containing Boc-alanylglutamine (19.0g, 0.06mol) to react at room temperature for 5 hours, and then 50ml of methyl t-butyl ether and 0.1g of lilium B were added to precipitate a solid, which was then subjected to suction filtration and drying to obtain alanylglutamine as a solid with a yield of 94.3%. After the lily essence B is added, the displacement effect of methyl tert-butyl ether can be facilitated, and the precipitation of alanyl glutamine can be promoted by a small polar compound inversion method, so that the yield is increased.
Claims (1)
1. The preparation method of alanyl glutamine is characterized by comprising the following steps:
1) preparation of chloro-Boc-alanine: adding 18.9g of Boc-alanine into a reaction bottle, adding 17.9g of thionyl chloride, adding 0.7g of N, N-dimethylformamide, stirring at 75-85 ℃ for 5 hours, cooling to 40-50 ℃, controlling the temperature to 45-55 ℃, and concentrating under reduced pressure until no fraction exists, so as to obtain an oily substance which is directly used for the next reaction;
2) preparation of Boc-alanyl succinimide: dissolving 13.8g of N-hydroxysuccinimide with 90ml of acetone, then adding 50.5g of triethylamine, dissolving 0.1mol of chloro-Boc-alanine with 40ml of acetone under the condition of ice-water bath, then dropwise adding the mixture into the system, reacting at room temperature for 4 hours after the addition, then adding 400g of purified water into the reaction system, precipitating a large amount of solid, carrying out suction filtration, leaching a filter cake with purified water, and carrying out forced air drying at 50 ℃ to obtain Boc-alanyl succinimide;
3) preparation of Boc-alanylglutamine: adding 10.2g of glutamine and 7m L g of water into a reaction bottle, then adding 10g of ammonia water, stirring until the mixture is clear, then adding 10ml of ethanol, dropwise adding a Boc-alanyl succinimide system dissolved by 40ml of ethanol under the stirring condition, and continuing the room temperature reaction for 2 hours after the dropwise adding is finished; slowly dropwise adding 2M hydrochloric acid into the system, adjusting the pH to 2-3, stirring for 1h, precipitating a large amount of crystals, performing suction filtration, and drying to obtain a white solid;
4) preparation of alanyl glutamine: adding 60ml of dichloromethane and 20ml of trifluoroacetic acid into a reaction bottle containing 19.0g of Boc-alanylglutamine, reacting at room temperature for 5 hours, then adding 50ml of methyl tert-butyl ether and 0.1g of lilium B, precipitating a solid, carrying out suction filtration, and drying to obtain the solid alanylglutamine.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5032675A (en) * | 1987-07-10 | 1991-07-16 | Ajinomoto Co., Inc. | Process for the production of glutamine derivatives |
| CN1693303A (en) * | 2004-11-01 | 2005-11-09 | 杭州崇舜化学有限公司 | Novel tech. for synthesizing 9-fluorenyl methoxycarbonyl succinic imine |
| CN105085612A (en) * | 2015-06-18 | 2015-11-25 | 海南灵康制药有限公司 | N-(2)-L-alanyl-L-glutamine compound prepared by adopting particle crystal form optimization technique and preparation thereof |
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2016
- 2016-12-31 CN CN201611264255.4A patent/CN106749512B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5032675A (en) * | 1987-07-10 | 1991-07-16 | Ajinomoto Co., Inc. | Process for the production of glutamine derivatives |
| CN1693303A (en) * | 2004-11-01 | 2005-11-09 | 杭州崇舜化学有限公司 | Novel tech. for synthesizing 9-fluorenyl methoxycarbonyl succinic imine |
| CN105085612A (en) * | 2015-06-18 | 2015-11-25 | 海南灵康制药有限公司 | N-(2)-L-alanyl-L-glutamine compound prepared by adopting particle crystal form optimization technique and preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| 甘氨酰_L_谷氨酰胺与甘氨酰_L_酪氨酸的合成工艺研究;陈环宇;《中国优秀硕士学位论文全文数据库 工程科技I辑 第5期》;20160515;第8-9页 * |
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