Method for synthesizing Boc-AEA-AEA-OH
Through simplified synthesis steps, reactants such as (Boc)2O and diethylene glycolamine are used to generate intermediates a and b in an organic solvent, and finally react in concentrated alkaline water, successfully reducing the synthesis cost and step complexity of Boc-AEEA-AEEA-OH, and solving the problems of low yield and high cost in the prior art.
Patent Information
- Application Number
- CN202510325778.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-19
- Publication Date
- 2025-06-20
AI Technical Summary
The existing Boc-AEEA-AEEA-OH synthesis method has complex steps, low yield and high cost, which makes the semegglutide expensive and difficult to meet the needs.
(Boc)2O and diethylene glycolamine were used to react in an organic solvent to form intermediate a, followed by H-AEEA-OH or H-AEEA-OH.HCl and chloroacetyl chloride to form intermediate b, and finally intermediate a reacts with intermediate b in concentrated alkaline water to synthesize the target product Boc-AEEA-AEEA-OH.
This method simplifies the synthesis steps, improves yield, reduces costs, is suitable for large-scale and industrial production, and significantly reduces the production cost of semegglutide.
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Figure CN120172882A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceuticals, and specifically to a method for synthesizing Boc-AEEA-AEEA-OH. Background Art
[0002] Boc-AEEA-AEEA-OH is an important organic compound, which is widely used in the fields of medicine, materials science, etc.
[0003] Boc-AEEA-AEEA-OH is one of the important structures of the second-generation GLP-1 (glucagon-like peptide-1) analogue semaglutide. It can mediate and promote the strong binding of semaglutide to albumin, reduce the renal clearance rate, and the peptide modified with AEEA-AEEA makes the insolubility easier to dissolve and the fluidity enhanced.
[0004] Another pharmacological effect of semaglutide has a weight loss effect. However, the existing synthesis methods of the important structure AEEA-AEEA have problems such as complex steps, low yield, and high cost, making the cost price of semaglutide expensive, which discourages some obese patients who need to lose weight.
[0005] There is a patent-disclosed method for synthesizing Boc-AEEA-AEEA-OH, which uses Hosu to synthesize the activated ester intermediate Boc-AEEA-Osu under the action of the condensing agent DCC, and then reacts with H-AEEA-OH to synthesize the final product.
[0006]
[0007] However, experiments show that the substrate reaction of this method is incomplete, and Boc-AEEA-Osu is extremely easy to hydrolyze in a humid and high-temperature environment in summer. The introduction of structurally similar impurities and other generated impurities are not easy to remove, which increases the difficulty of purification.
[0008] Therefore, this process provides a simple and low-cost synthesis of Boc-AEEA-AEEA-OH, indirectly greatly reducing the cost of semaglutide, benefiting the patient population, and having important significance for reducing the economic burden on patients. Summary of the Invention
[0009] The technical problem to be solved by the present invention is to provide a method for efficiently and simply synthesizing Boc-AEEA-AEEA-OH, and to solve the problems of complex synthesis steps, low yield, high cost, etc.
[0010] To solve the above problems, the technical solution provided by the present invention is as follows:
[0011] A method for synthesizing Boc-AEEA-AEEA-OH, comprising the following steps:
[0012] (1) (Boc)2O and diethanolamine are added to an organic solvent, and a certain amount of catalyst is added. The reaction is carried out at a certain temperature for a certain time to synthesize intermediate a; the structural formula of intermediate a is
[0013] (2) H-AEEA-OH or H-AEEA-OH·HCl is dissolved in alkaline water. After adding a solvent, chloroacetyl chloride is added dropwise at a certain temperature and reacted for a certain time to synthesize intermediate b;
[0014] The structural formula of intermediate b is
[0015] (3) Intermediate a is dissolved in a solvent, intermediate b is added, and concentrated alkaline water is added. The reaction is carried out at a certain temperature for a certain time to finally synthesize the target product Boc-AEEA-AEEA-OH.
[0016] Preferably, the solvent used for synthesizing intermediate a is one or more of ethyl acetate, tetrahydrofuran, dichloromethane, acetone, N,N-dimethylformamide, and acetonitrile. The catalyst is DMAP, and the amount of catalyst used is 0.2 - 0.3 times the molar amount of diethanolamine.
[0017] Preferably, the solvent used for synthesizing intermediate b is one or more of acetone, tetrahydrofuran, dioxane, and acetonitrile.
[0018] Preferably, the reaction temperature for synthesizing intermediate a is 5 - 20 °C, and the reaction time is 3 - 7 h.
[0019] Preferably, the molar ratio of diethanolamine to (Boc)2O for synthesizing intermediate a is 1:0.9 - 1.
[0020] Preferably, for synthesizing intermediate b, the molar ratio of H-AEEA-OH or H-AEEA-OH·HCl to chloroacetyl chloride is 1:1.5 - 2.5, preferably 1:1.5 - 2.
[0021] Preferably, for synthesizing intermediate b, the molar ratio of H-AEEA-OH or H-AEEA-OH·HCl to the base is 1:1.5 - 3.5, preferably 1:1.5 - 3.
[0022] Preferably, the reaction temperature for synthesizing intermediate b is -10 - 0 °C, and the reaction time is 1 - 5 h.
[0023] Preferably, the base used for synthesizing intermediate b is one of potassium carbonate, sodium carbonate, and sodium bicarbonate.
[0024] Preferably, the base used for synthesizing the final product Boc-AEEA-AEEA is one of sodium hydroxide, potassium hydroxide, and lithium hydroxide.
[0025] Preferably, the molar ratio a:b of the intermediate materials fed for synthesizing the final product Boc-AEEA-AEEA is 1:1.1 to 1.3.
[0026] Preferably, the solvent used for synthesizing the final product Boc-AEEA-AEEA is one or more of acetone, tetrahydrofuran, dioxane, and acetonitrile.
[0027] Preferably, the concentrated alkaline water for synthesizing the final product Boc-AEEA-AEEA is 50% alkaline water prepared from an alkali of 3 to 7N.
[0028] Preferably, the reaction temperature for synthesizing the final product Boc-AEEA-AEEA is -10 to 0 °C, and the reaction time is 1 to 5 h.
[0029] Preferably, the reaction formula can be:
[0030]
[0031] In the present invention, if there is a conflict between the Chinese name and the structural formula of the compound, the structural formula shall prevail, except when there is an obvious error in the structural formula.
[0032] The present invention provides an efficient and simple method for synthesizing Boc-AEEA-AEEA-OH. It solves the problems of complex synthesis steps, low yield, high cost, etc., and is very suitable for large-scale and industrial production. Description of the Drawings
[0033] Figure 1 . Nuclear magnetic resonance spectrum of Boc-AEEA-AEEA-OH in Example 1. Detailed Description of the Invention
[0034] The following examples illustrate the present invention, but do not limit the present invention. In the art, simple substitutions or improvements made by those skilled in the art to the present invention fall within the scope of the technical solutions protected by the present invention.
[0035] Example 1:
[0036] 100 g (0.95 mol) of diethanolamine was added to a three-necked flask, 300 ml of dichloromethane was added, 23.18 g (0.19 mol) of DMAP was added, the external cooling temperature was adjusted to 5 °C to 10 °C, and (Boc)2O, 197.2 g (0.90 mol), was slowly added. The reaction was carried out for 3 h. After confirming the completion of the reaction by TLC plate spotting, after the reaction was completed, it was washed with a sodium bicarbonate solution, the organic phase was dried with anhydrous sodium sulfate, and the intermediate a was obtained by vacuum distillation in an amount of 186.18 g.
[0037] Add 103.08 g (1.23 mol) of sodium bicarbonate and 500 ml of water into a three-necked flask. Start stirring and add 100 g (0.61 mol) of H-AEEA-OH. Then add 500 ml of tetrahydrofuran. Start stirring and cool the external temperature to -5°C to 0°C. Slowly add 103.82 g (0.92 mol) of chloroacetyl chloride dropwise. React for 2 h. Confirm that the reaction of the materials is complete by TLC plate. After the reaction, extract impurities with petroleum ether, acidify to pH = 3 with 2N hydrochloric acid, extract the product with ethyl acetate, dry the organic phase with anhydrous magnesium sulfate, and distill under reduced pressure to obtain 105.74 g of intermediate b.
[0038] Add 50 g (0.24 mol) of intermediate a into a three-necked flask, add 125 g of tetrahydrofuran, and add 64.21 g (0.27 mol) of intermediate b. Start stirring and cool the external temperature to -5 to 0°C. Prepare 50% concentrated alkali water with 29.23 g (0.733 mol) of sodium hydroxide and drop it into the reaction system. React for 2 h. Confirm that the reaction of the materials is complete by TLC plate. After the reaction, extract impurities with petroleum ether, acidify to pH = 3 with 2N hydrochloric acid, extract the product with dichloromethane, wash the organic phase twice with saturated sodium chloride water, dry the organic phase with anhydrous magnesium sulfate, and distill under reduced pressure to obtain 75.47 g of finished product Boc-AEEA-AEEA with a purity of 99.65% and a yield of 77%. Mass spectrum [M+H]+409.3.
[0039] Example 2:
[0040] Add 100 g (0.95 mol) of diethylene glycol amine into a three-necked flask, add 300 ml of ethyl acetate, and add 23.18 g (0.19 mol) of DMAP. Start stirring and cool the external temperature to 5°C to 10°C. Slowly add 207.58 g (0.95 mol) of (Boc)2O. React for 3 h. Confirm that the reaction of the materials is complete by TLC plate. After the reaction, wash with sodium bicarbonate solution, dry the organic phase with anhydrous sodium sulfate, and distill under reduced pressure to obtain 180.18 g of intermediate a.
[0041] Add 103.08 g (1.23 mol) of sodium bicarbonate and 500 ml of water into a three-necked flask. Start stirring and add 100 g (0.61 mol) of H-AEEA-OH. Then add 500 ml of tetrahydrofuran. Start stirring and cool the external temperature to -5°C to 0°C. Slowly add 138.43 g (1.23 mol) of chloroacetyl chloride dropwise. React for 2 h. Confirm that the reaction of the materials is complete by TLC plate. After the reaction, extract impurities with petroleum ether, acidify to pH = 3 with 2N hydrochloric acid, extract the product with ethyl acetate, dry the organic phase with anhydrous magnesium sulfate, and distill under reduced pressure to obtain 107.95 g of intermediate b.
[0042] Add 50 g of intermediate a (0.24 mol) into a three-necked flask, add 140 g of acetone, add 64.21 g of intermediate b (0.27 mol), start stirring, start external cooling to a temperature of -5 to 0 °C. Take 23.34 g of lithium hydroxide (2.68 mol) and prepare it into 50% concentrated alkali water, and drop it into the reaction system. React for 2 h, confirm that the materials have reacted completely by TLC plate. After the reaction is completed, extract impurities with petroleum ether, acidify to pH = 3 with 2N hydrochloric acid, extract the product with dichloromethane, wash the organic phase with saturated sodium chloride water twice, dry the organic phase with anhydrous magnesium sulfate, and perform vacuum distillation to obtain the finished product Boc-AEEA-AEEA, 73.51 g, with a purity of 99.35% and a yield of 75.2%.
[0043] Example 3:
[0044] Add 100 g (0.95 mol) of diethylene glycol amine into a three-necked flask, add 450 ml of tetrahydrofuran, add 23.18 g (0.19 mol) of DMAP, start stirring and external cooling to a temperature of 5 to 10 °C, slowly add (Boc)2O, 197.2 g (0.90 mol), react for 5 h, confirm that the materials have reacted completely by TLC plate. After the reaction is completed, dry the organic phase with anhydrous sodium sulfate and perform vacuum distillation to obtain 179.97 g of intermediate a.
[0045] Add 127.05 g (0.92 mol) of potassium carbonate into a three-necked flask, add 600 ml of water, start stirring, add 100 g (0.61 mol) of H-AEEA-OH, add 450 ml of acetonitrile, start stirring and external cooling to a temperature of -5 to 0 °C, slowly drop 138.43 g (1.23 mol) of chloroacetyl chloride, react for 1.5 h, confirm that the materials have reacted completely by TLC plate. After the reaction is completed, extract impurities with petroleum ether, acidify to pH = 3 with 2N hydrochloric acid, extract the product with ethyl acetate, dry the organic phase with anhydrous magnesium sulfate, and perform vacuum distillation to obtain 106.03 g of intermediate b.
[0046] Add 50 g of intermediate a (0.24 mol) into a three-necked flask, add 150 g of dioxane, add 70 g of intermediate b (0.29 mol), start stirring, start external cooling to a temperature of -5 to 0 °C. Take 23.34 g of lithium hydroxide (0.98 mol) and prepare it into 50% concentrated alkali water, and drop it into the reaction system. React for 2 h, confirm that the materials have reacted completely by TLC plate. After the reaction is completed, extract impurities with petroleum ether, acidify to pH = 3 with 2N hydrochloric acid, extract the product with dichloromethane, wash the organic phase with saturated sodium chloride water twice, dry the organic phase with anhydrous magnesium sulfate, and perform vacuum distillation to obtain the finished product Boc-AEEA-AEEA, 74.39 g, with a purity of 99.53% and a yield of 76.1%.
[0047] Example 4:
[0048] Add 100 g (0.95 mol) of diethanolamine to a three-necked flask, add 600 ml of acetone, add DMAP, 23.18 g (0.19 mol), start stirring, cool the external temperature to 5 °C - 10 °C, slowly add (Boc)₂O, 186.82 g (0.86 mol), react for 4 h, confirm the completion of the reaction by TLC plate spotting. After the reaction is completed, dry the organic phase with anhydrous sodium sulfate and distill under reduced pressure to obtain 183.24 g of intermediate a.
[0049] Add 97.43 g (0.92 mol) of sodium carbonate to a three-necked flask, add 700 ml of water, start stirring, add H-AEEA-OH. 100 g (0.61 mol), add 500 ml of tetrahydrofuran, start stirring, cool the external temperature to -5 °C - 0 °C, slowly dropwise add 138.43 g (1.23 mol) of chloroacetyl chloride, react for 1 h, confirm the completion of the reaction by TLC plate spotting. After the reaction is completed, extract impurities with petroleum ether, acidify to pH = 3 with 2N hydrochloric acid, extract the product with ethyl acetate, dry the organic phase with anhydrous magnesium sulfate and distill under reduced pressure to obtain 108.01 g of intermediate b.
[0050] Add 50 g of intermediate a (0.24 mol) to a three-necked flask, add 160 g of dioxane, add 70 g of intermediate b, (0.29 mol), start stirring, cool the external temperature to -5 - 0 °C, take 68.34 g of potassium hydroxide (1.22 mol) and prepare it into 50% concentrated alkali water, drop it into the reaction system, react for 2 h, confirm the completion of the reaction by TLC plate spotting. After the reaction is completed, extract impurities with petroleum ether, acidify to pH = 3 with 2N hydrochloric acid, extract the product with dichloromethane, wash the organic phase twice with saturated sodium chloride water, dry the organic phase with anhydrous magnesium sulfate and distill under reduced pressure to obtain 75.22 g of finished product Boc-AEEA-AEEA, with a purity of 99.46% and a yield of 76.95%.
[0051] Example 5:
[0052] Add 100 g (0.95 mol) of diethanolamine to a three-necked flask, add 550 ml of acetonitrile, add DMAP, 23.18 g (0.19 mol), start stirring, cool the external temperature to 5 °C - 10 °C, slowly add (Boc)₂O, 201.35 g (0.92 mol), react for 4 h, confirm the completion of the reaction by TLC plate spotting. After the reaction is completed, dry the organic phase with anhydrous sodium sulfate and distill under reduced pressure to obtain 184.17 g of intermediate a.
[0053] Add 154.46 g (1.84 mol) of sodium bicarbonate and 700 ml of water into a three-necked flask. Start stirring and add 100 g (0.61 mol) of H-AEEA-OH. Then add 500 ml of tetrahydrofuran. Start stirring and cool the external temperature to -5°C to 0°C. Slowly add dropwise 138.42 g (1.23 mol) of chloroacetyl chloride. React for 5 h. Confirm that the materials have reacted completely by TLC spotting. After the reaction is completed, extract the impurities with petroleum ether, acidify to pH = 3 with 2N hydrochloric acid, extract the product with ethyl acetate. Dry the organic phase with anhydrous magnesium sulfate and distill under reduced pressure to obtain 106.27 g of intermediate b.
[0054] Add 50 g (0.24 mol) of intermediate a into a three-necked flask, add 135 g of acetonitrile, add 75.89 g (0.32 mol) of intermediate b. Start stirring and cool the external temperature to -5 to 0°C. Prepare 50% concentrated alkali water with 48.72 g (1.22 mol) of sodium hydroxide and add it dropwise to the reaction system. React for 2 h. Confirm that the materials have reacted completely by TLC spotting. After the reaction is completed, extract the impurities with petroleum ether, acidify to pH = 3 with 2N hydrochloric acid, extract the product with dichloromethane. Wash the organic phase twice with saturated sodium chloride water. Dry the organic phase with anhydrous magnesium sulfate and distill under reduced pressure to obtain 76.35 g of Boc-AEEA-AEEA as the finished product, with a purity of 99.47% and a yield of 77.9%.
[0055] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the inventive concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention.
Claims
1. A method for synthesizing Boc-AEEA-AEEA-OH, characterized in that: The steps include: (1) (Boc)2O and diglycolamine are added to an organic solvent, and a certain amount of catalyst is added to react at a certain temperature for a certain time to synthesize intermediate a; the structural formula of intermediate a is (2) H-AEEA-OH or H-AEEA-OH.HCl is dissolved in alkaline water, and after adding a solvent, chloroacetyl chloride is added dropwise at a certain temperature and reacted for a certain period of time to synthesize intermediate b; The structural formula of intermediate b is (3) Intermediate a is dissolved in a solvent, intermediate b is added, concentrated alkaline water is added, and the mixture is reacted at a certain temperature for a certain time to finally synthesize the target product Boc-AEEA-AEEA-OH.
2. The method according to claim 1, characterized in that The organic solvent used in the synthesis of intermediate a in step (1) is one or more of ethyl acetate, tetrahydrofuran, dichloromethane, acetone, N,N-dimethylformamide, and acetonitrile; the catalyst is DMAP, and the amount of the catalyst used is 0.2-0.3 times the molar amount of diglycolamine.
3. The method according to claim 1, characterized in that The solvent used to synthesize the intermediate b in step (2) is one or more of acetone, tetrahydrofuran, dioxane and acetonitrile.
4. The method according to claim 1, characterized in that In the step (1), the reaction temperature for synthesizing intermediate a is 5 to 20° C. and the reaction time is 3 to 7 hours.
5. The method according to claim 1, characterized in that In the step (1) for synthesizing the intermediate a, the molar ratio of diglycolamine and (Boc)2O is 1:0.9-1.
6. The method according to claim 1, characterized in that In the step (2) for synthesizing intermediate b, the molar ratio of H-AEEA-OH or H-AEEA-OH.HCl to chloroacetyl chloride is 1:1.5-2.0, and the molar ratio of H-AEEA-OH or H-AEEA-OH.HCl to alkali is 1:1.5-3.
5.
7. The method according to claim 1, characterized in that The base used to synthesize the intermediate b in step (2) is one of potassium carbonate, sodium carbonate and sodium bicarbonate.
8. The method according to claim 1, characterized in that The alkali used in step (3) is one of sodium hydroxide, potassium hydroxide and lithium hydroxide.
9. The method according to claim 1, characterized in that In the step (3), the molar ratio of intermediate a to intermediate b is 1:1.1-1.5, and the solvent used is one or more of acetone, tetrahydrofuran, dioxane, and acetonitrile.
10. The method according to claim 1, characterized in that The concentrated alkaline water for synthesizing the final product Boc-AEEA-AEEA in step (3) is 3-7N alkali prepared into 50% alkaline water, the reaction temperature is -10-0°C, and the reaction time is 1-5h.