A process for the preparation of a somatostatin intermediate

Abstract

The application provides a preparation method of a somatuline peptide intermediate, which comprises the following steps: S1. using a compound of formula I as raw material, reacting in the presence of a reducing agent to generate an intermediate of formula II; S2. reacting the compound of formula II in the presence of a substitution reagent and an alkaline condition in an organic solvent A to generate an intermediate of formula III; S3. reacting the compound of formula III in the presence of an iodine salt reagent and an organic solvent B to generate an intermediate of formula IV; S4. reacting the compound of formula IV in the presence of diethyl malonate, an alkaline and an organic solvent C to generate an intermediate of formula V; and S5. hydrolyzing and deacidifying the compound of formula V under an acidic condition to obtain a somatuline peptide intermediate, wherein the synthesis method is stable and reliable, and the reaction condition is mild; the obtained product has high conversion rate and high purity; and the reaction route is as follows:

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and more specifically, to a method for preparing a semaglutide intermediate. Background Technology

[0002] Semaglutide, developed by Novo Nordisk, was originally intended to treat diabetes. It is a glucagon-like peptide-1 (GLP-1) receptor agonist that mimics GLP-1's action, reducing hunger, food intake, and calorie consumption, thus demonstrating significant effectiveness in weight loss. The intermediate octadecanoic acid used in the synthesis of semaglutide is employed to produce the active pharmaceutical ingredient (API).

[0003] First, a method for producing octadecanoic acid is disclosed in Chinese patent application CN112939762 A:

[0004]

[0005] Starting with hexadecanoic acid, this route involves three steps to obtain an intermediate. However, the condensation reaction involves double condensation, resulting in low yields. Furthermore, hexadecanoic acid is expensive, leading to high costs and making it unsuitable for industrial application. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing a semaglutide intermediate. The synthesis method is simple to operate, the process is stable and reliable, the obtained semaglutide intermediate has high purity and the reaction conditions are mild, making it suitable for industrial production.

[0007] The embodiments of the present invention are achieved through the following technical solutions:

[0008] A method for preparing a semaglutide intermediate includes the following steps:

[0009] S1. Using the compound of formula I as a starting material, in the presence of a reducing agent, the reaction produces the intermediate of formula II;

[0010] S2. The compound of formula II reacts with organic solvent A under substituted reagent and alkaline conditions to generate the intermediate of formula III;

[0011] S3. The compound of formula III reacts with iodine salt reagent and organic solvent B to produce the intermediate of formula IV;

[0012] S4. The compound of formula IV reacts with diethyl malonate in the presence of a base and organic solvent C to produce the intermediate of formula V;

[0013] The compound described in S5.V, under acidic conditions, is hydrolyzed and deacidified to give the compound of S5.V, namely the key intermediate of semaglutide: octadecanoic acid.

[0014] The reaction route is as follows:

[0015]

[0016] Preferably, in S2, the substitution reagent is TsCl or MsCl, with MsCl being the most preferred.

[0017] Preferably, in S2, the molar ratio of the substituted reagent to Formula II is 2.2-3:1, and most preferably 3:1.

[0018] Preferably, in S2, the alkaline reagent is Et3N, K2CO3, or t-BuOK, with potassium carbonate being the most preferred.

[0019] Preferably, in S2, the organic solvent A is DMF, DCM, or THF, with THF being the most preferred.

[0020] Preferably, in S3, the molar ratio of the iodine salt reagent to Formula III is 3-5:1, and most preferably 4:1.

[0021] Preferably, in S3, the iodine salt reagent is NaI or KI, with KI being the most preferred.

[0022] Preferably, in S3, the organic solvent B is acetone, THF, or ethyl acetate, with acetone being the most preferred.

[0023] Preferably, in step S4, the alkaline reagent is sodium ethoxide ethanol solution, K2CO3, or sodium methoxide, with potassium carbonate being the most preferred.

[0024] Preferably, in S4, the organic solvent C is ethanol, DMF, or methanol, with DMF being the most preferred.

[0025] The technical solutions of the embodiments of the present invention have at least the following advantages and beneficial effects:

[0026] 1. The synthesis method of the semaglutide intermediate of the present invention is simple to operate, stable and reliable, safe and effective, can significantly inhibit the generation of by-products, and has good selectivity, high conversion rate and high purity of the obtained semaglutide intermediate.

[0027] 2. The raw materials and auxiliary materials of this invention are readily available and inexpensive, and no heavy metals or precious metals are used in the synthesis process, so it will not cause too much pollution to the environment. Compared with the existing production routes, it has low cost, mild reaction conditions, and short cycle, making it suitable for industrial production. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0029] Example 1: Synthesis of Intermediate II

[0030] Add 500 ml of THF to a 1 L three-necked flask, cool to 0 ± 5 °C, slowly add 11.72 g of sodium borohydride, controlling the temperature at 0 ± 5 °C, slowly add 44 g of boron trifluoride diethyl ether solution, controlling the temperature at 0 ± 5 °C, slowly add 20 g of tetradecanoic acid, and after the addition is complete, raise the temperature to 50 °C and react overnight. Post-treatment: cool to 0-5 °C, slowly add 100 ml of water to quench the reaction, slowly add 6 M HCl to adjust the pH to 1-2, raise the temperature to reflux for 4 h, concentrate the THF, cool to 0 ± 5 °C, crystallize for 4 h, filter, and obtain 15.1 g, with a yield of 85%.

[0031] Example 2: Synthesis of Intermediate III

[0032] In a 1L three-necked flask, 20g of intermediate II prepared in Example 1, 400ml of THF, and 36g of potassium carbonate were added sequentially. Then, 25g of MsCl was slowly added dropwise while maintaining the temperature at 0±5℃. After the addition was complete, the mixture was moved to room temperature and reacted overnight. Post-treatment: The filter cake was washed with 50ml of THF, and the filtrate was collected and concentrated to dryness to obtain 30g of white solid, with a yield of 90%.

[0033] Example 3: Synthesis of Intermediate III

[0034] In a 1L three-necked flask, 20g of intermediate II prepared in Example 1, 400ml of DCM, and 31g of triethylamine were added sequentially. Then, 30g of MsCl was slowly added dropwise while maintaining the temperature at 0±5℃. After the addition was complete, the mixture was moved to room temperature and reacted overnight. Post-treatment: The mixture was filtered, and the filter cake was washed with 50ml of DCM. The filtrate was collected and concentrated to dryness to obtain 28.3g of white solid, with a yield of 85%.

[0035] Example 4: Synthesis of Intermediate III

[0036] In a 1L three-necked flask, 20g of intermediate II prepared in Example 1, 400ml of THF, and 36g of potassium carbonate were added sequentially. Then, 30g of MsCl was slowly added dropwise while maintaining the temperature at 0±5℃. After the addition was complete, the mixture was moved to room temperature and reacted overnight. Post-treatment: The filter cake was washed with 50ml of THF, and the filtrate was collected and concentrated to dryness to obtain 31.7g of white solid, with a yield of 95%.

[0037] Example 5: Synthesis of Intermediate IV

[0038] 20g of intermediate III prepared in Example 2, 400ml of THF, and 38.78g of sodium iodide were added sequentially to a 1L three-necked flask. The mixture was heated to reflux and reacted overnight. Post-treatment: filtration was performed, and the filtrate was concentrated to an oily substance to obtain 18.63g, with a yield of 80%.

[0039] Example 6: Synthesis of Intermediate IV

[0040] 20g of intermediate III prepared in Example 3, 400ml of acetone, and 34.36g of potassium iodide were added sequentially to a 1L three-necked flask. The mixture was heated to reflux and reacted overnight. Post-treatment: filtration was performed, and the filtrate was concentrated to an oily substance to obtain 21.66g, with a yield of 93%.

[0041] Example 7: Synthesis of Intermediate V

[0042] In a 500 mL three-necked flask, 240 mL of DMF, 20 g of intermediate IV prepared in Example 5, 15.63 g of diethyl malonate, and 18.39 g of potassium carbonate were added sequentially. The mixture was stirred and heated to 60 ± 5 °C and reacted overnight. Post-treatment: The mixture was cooled to room temperature, and 80 mL of purified water and 60 mL of ethyl acetate were added for extraction. The aqueous phase was extracted twice with 60 mL of ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to an oily state to obtain 22.16 g, with a yield of 97%.

[0043] Example 8: Synthesis of Intermediate V

[0044] In a 500mL three-necked flask, 240mL of methanol, 20g of intermediate IV prepared in Example 6, 15.63g of diethyl malonate, and 7.2g of sodium methoxide were added sequentially. The mixture was stirred and heated to 60±5℃ and reacted overnight. Post-treatment: The mixture was cooled to room temperature, and 80mL of purified water and 60mL of ethyl acetate were added for extraction. The aqueous phase was extracted twice with 60mL of ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to an oily state to obtain 20.1g, with a yield of 88%.

[0045] Example 9: Synthesis of Intermediate VI

[0046] 20g of intermediate V prepared in Example 8, 80ml of acetic acid, and 80ml of concentrated hydrochloric acid were added sequentially to a 500mL three-necked flask. The mixture was stirred and heated to reflux and reacted overnight. Post-treatment: When the reaction solution was cooled to room temperature, a solid precipitated out. The mixture was filtered, and the filter cake was collected to obtain 10.75g, with a yield of 88% and a purity of 99.5%.

[0047] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a semaglutide intermediate, characterized in that: Includes the following steps: S1. Using compound I as a starting material, under reducing conditions, the reaction produces intermediate II. The reaction equation is as follows: ， S2. The intermediate of formula II reacts with organic solvent A, a substituent, and alkaline conditions to generate intermediate of formula III, wherein the molar ratio of the substituent to formula II is 2.2-3:

1. The reaction equation is as follows: Where R represents Ts and Ms; S3. The intermediate of formula III reacts with an iodine salt reagent under organic solvent B to generate the intermediate of formula IV, wherein the molar ratio of the iodine salt reagent to formula III is 3-5:1, and the reaction equation is as follows: Where R represents Ts and Ms; S4. The intermediate of formula IV is reacted with diethyl malonate in organic solvent C under alkaline conditions to generate intermediate of formula V. The reaction equation is as follows: ， The compound described in formula V, under acidic conditions, undergoes deacidification to produce the compound of formula VI, as shown in the following reaction equation: 。 2. The method for preparing the semaglutide intermediate according to claim 1, characterized in that, In S1, the reducing agent is one or both of sodium borohydride and lithium aluminum hydride.

3. The method for preparing the semaglutide intermediate according to claim 1, characterized in that, In S2, the substitution reagent is TsCl or MsCl; the basic reagent is Et3N, K2CO3 or t-BuOK; and the organic solvent A is DMF, DCM or THF.

4. The method for preparing the semaglutide intermediate according to claim 1, characterized in that, In S3, the iodine salt reagent is NaI or KI.

5. The method for preparing the semaglutide intermediate according to claim 1, characterized in that, In S3, the organic solvent B is acetone, THF, or ethyl acetate.

6. The method for preparing the semaglutide intermediate according to claim 1, characterized in that, In S4, the alkaline reagent is sodium ethoxide solution, K2CO3, or sodium methoxide.

7. The method for preparing the semaglutide intermediate according to claim 1, characterized in that, In S4, the organic solvent C is ethanol, DMF, or methanol.

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