Preparation method of sabasola sodium

Abstract

The invention discloses a preparation method of sabesartan sodium in the technical field of medicines, which comprises the following steps of: adding cuprous chloride and a catalyst in the SN2 nucleophilic substitution reaction process of 8-chloro ethyl caprylate serving as a raw material and capralan, so that the reaction selectivity and the reaction yield are improved; a sodium hydroxide hydrolysis reaction is carried out, and a reducing agent is added under an anaerobic condition, so that the formation of colored impurities is minimized; and finally salifying with sodium hydroxide in an alcohol solvent to obtain a final product SNAC. The method has the advantages of high efficiency, simplicity, easiness in factory operation, good product appearance, high purity, economical and easily available raw materials and good industrialization prospect.

Description

Technical Field

[0001] This invention relates to a method for preparing sodium sapoidoxanone (SNAC), belonging to the field of pharmaceutical technology. Background Technology

[0002] The chemical structural formula of sodium shapositories (SNAC), also known as sodium 8-(2-hydroxybenzamide)octanoate (CAS: 203787-91-1), is as follows:

[0003]

[0004] Saponizan sodium is a chemically synthesized fatty acid derivative, initially selected as a highly effective molecule by Emisphere, a foreign company, after screening numerous penetration enhancers. In December 2017, the FDA approved semaglutide injection (trade name: Ozempic) for glycemic control in adults with type 2 diabetes. Novo Nordisk submitted a marketing application to the FDA on December 4, 2020, for semaglutide administered subcutaneously once weekly at a dose of 2.4 mg for weight loss. When discussing semaglutide's development into an oral formulation, the supporting agent N-(8-[2-hydroxybenzoyl]amino)octanoate sodium (SNAC) must be mentioned. For example, when SNAC is administered co-administered with ibandronate, used to treat osteoporosis, it can reduce the recommended daily oral dose of ibandronate by more than half.

[0005] The existing synthetic routes for sodium saboxazole (SNAC) include the following:

[0006] Route 1: World Patent WO00 / 46182, Chinese Patent CN 104974060 A, and NOVARTIS AG[CH]+ published patent WO2006063821 reported methods for preparing sodium 8-(2-hydroxybenzamido)octanoate. All of them use salicylamide as a raw material and react it with ethyl chloroformate to generate the intermediate 2-hydro-benzo[e][1,3]oxazine-2,4(3-hydro)-dione. This intermediate reacts with ethyl 8-bromooctanoate, and then reacts with sodium hydroxide to obtain the final product, sodium 8-(2-hydroxybenzamido)octanoate.

[0007] Reaction equation:

[0008]

[0009] Ethyl chloroformate is highly toxic and genotoxic. Furthermore, this reaction step requires high temperatures, resulting in relatively high energy consumption and numerous side reactions, leading to relatively high production costs. The use of pyridine and acetonitrile as solvents further increases process costs, as these solvents must be disposed of in some way or recycled, both of which incur additional costs.

[0010] Route 2: NOVO NORDISK A / S-WO2009 / 59188 and HOFFMANN LA ROCHE[CH]-CN101506147(A) disclose the production process of sodium 8-(2-hydroxybenzamido)octanoate. The process involves reacting the key starting material carsalam with ethyl 8-bromooctanoate to obtain ethyl 8-(2,4-dicarbonyl-2H-benzo[e][1,3]oxazine-3(4H)-yl)octanoate, followed by hydrolysis with sodium hydroxide and acidification to obtain 8-(2-hydroxybenzamido)octanoic acid. Finally, the product is reacted with sodium hydroxide to obtain the final product, sodium 8-(2-hydroxybenzamido)octanoate.

[0011] Reaction equation:

[0012] This route is the production process of the Swiss pharmaceutical giant Roche. Its technical advantages include the separation and purification of SNAC acids, which greatly improves the quality of the final product. Although it avoids the use of genotoxic ethyl chloroformate, has fewer reaction byproducts, high yield, and a simple process, the starting key raw material ethyl 8-bromooctanoate is expensive, has poor storage stability, and is prone to degradation of bromine to produce impurities such as ethyl 8-hydroxyoctanoate and ethyl 8-olefin octanoate, which will seriously affect the quality of SNAC products and require additional post-processing to obtain products that meet the product quality indicators.

[0013] Route 3:

[0014] Wuxi Zisheng Pharmaceutical Co., Ltd. has publicly disclosed process patents CN111978193A, KURARAY CO LTD-US4510331,1985,A, and NOVO NORDISK A / S-US6346242,2002,B1, which disclose a method for preparing SNAC by reacting a derivative of salicylic acid with 8-aminooctanoic acid.

[0015] Reaction equation:

[0016]

[0017] The starting material used in this method is O-acetyl salicyl chloride, which is difficult to preserve, has high reactivity, many side reactions, and a high content of impurities in the finished product. The raw materials involved are quite special, the yield is generally low, and it is not very suitable for industrial production.

[0018] In summary, current production processes suffer from numerous side reactions and require multiple purification steps. It is necessary to improve the processes, reduce the harshness of the reaction conditions, and thus use efficient and simple processes to prepare high-purity SNAC products. Summary of the Invention

[0019] To overcome the above-mentioned technical problems, the present invention provides a method for preparing sodium saponexa, which results in fewer side reactions, easier product purification, and milder reaction conditions.

[0020] Therefore, the technical solution of the present invention is: a method for preparing sapoid sodium, the reaction process of which is as follows:

[0021] S1:

[0022]

[0023] S2:

[0024]

[0025] S3:

[0026]

[0027] The preparation method of the above-mentioned sodium saponexa (SNAC) specifically includes the following steps:

[0028] S1: Preparation of Compound 4

[0029] S1-1. Under nitrogen protection, add cassalan, ethyl 8-chlorooctanoate, cuprous chloride, catalyst and solvent to the reactor, heat to internal temperature 80-90℃, and mix the solid and liquid systems. Add anhydrous sodium carbonate, and continue to keep the reaction at the temperature for 4 hours after the addition is complete. Take a sample for HPLC control and control cassalan ≤1.0%. The reaction is then complete.

[0030] S1-2. Cool the reaction system to 25°C, add water dropwise to the reaction solution while stirring, stir and filter, wash the filter cake with water, and dry under reduced pressure to obtain the crude product of compound 4.

[0031] Further, in step S1, the catalyst is one of DL-proline, glycine, DL-cysteine, oxaloyldimethylamine and oxaloyldiethylamine, preferably DL-cysteine.

[0032] Furthermore, in step S1, the solvent is one of DMF, NMP, DMSO, ethanol, and acetonitrile, preferably acetonitrile.

[0033] The preparation method of S2: 8-(2-hydroxybenzamido)octanoic acid is as follows:

[0034] S2-1. Under nitrogen protection, add ethyl N-(8-[2-hydroxybenzoyl]-amino)octanoate and water to the reactor. After nitrogen purging, add reducing agent and heat to the internal temperature of 95℃. Add 30% sodium hydroxide solution dropwise. After the addition is complete, continue to keep the reaction at the temperature for 5 hours. Take a sample for HPLC control and control the ethyl N-(8-[2-hydroxybenzoyl]-amino)octanoate ≤1.0%. The reaction is then complete.

[0035] S2-2. Cool the reaction system to 20-25℃, adjust the pH to 4-5, raise the temperature to 65℃ and hold for 0.5h; then slowly cool to 20-25℃ and hold for 2h, filter, and dry under reduced pressure at 40℃ for 3-5h to obtain a white solid.

[0036] Furthermore, in step S2, the reducing agent is one of methoxyphenol, zinc powder, sodium hydrosulfite, sodium metabisulfite, and sodium bisulfite, preferably sodium metabisulfite.

[0037] Preparation method of S3: Sodium 8-(2-hydroxybenzamido)octanoate

[0038] S3-1. Under nitrogen protection, add SNAC free acid and solvent to the reactor and heat to an internal temperature of 40-45℃; add sodium hydroxide solution dropwise, and after the addition is complete, heat to 50-60℃ and keep the reaction at this temperature for 5 hours. Take a sample to check the pH of the solution, which is 8.5-9.5, and the reaction is complete.

[0039] S3-2. Cool the reaction system to 30-35℃, add white SNAC sodium salt seed crystals; cool the suspension to 0℃ and age it at this temperature for 20 hours, filter, and dry under reduced pressure to obtain a white solid.

[0040] Furthermore, in step S3, the solvent is one of methanol, ethanol, isopropanol, propanol, and n-butanol, preferably isopropanol.

[0041] The source and theoretical basis of the innovative technical method of the invention are as follows: Most existing production technologies use the reaction of ethyl 8-bromooctanoate and the intermediate cassalan. However, the starting key raw material ethyl 8-bromooctanoate is expensive, has poor storage stability, and is prone to degradation of bromine to produce impurities such as ethyl 8-hydroxyoctanoate and ethyl 8-olefin octanoate. Obviously, ethyl 8-bromooctanoate is not a suitable starting material.

[0042] The side reaction equation is as follows:

[0043]

[0044] From an organic synthesis perspective, since Buchwald and Hartwig published their groundbreaking report in 1995, palladium catalysis has enabled the synthesis of aromatic amine structural units from the reaction of aryl halides and amines, greatly enhancing the synthetic capability and efficiency. However, the high price of palladium and ligands has limited its large-scale production application. Copper-mediated Ullmann coupling between amines and aryl halides utilizes the stable ethyl 8-chlorooctanoate. Due to the low reactivity of chlorine, cuprous chloride is added during the reaction, which synergistically enhances the reaction selectivity and yield, significantly reducing production costs.

[0045] During ester hydrolysis, colored impurities are easily generated, resulting in a slightly pink product. To minimize the formation of colored impurities, anaerobic conditions are adopted and additives are added.

[0046] In the preparation of SNAC products from acids, denatured ethanol is currently used in production. However, the high solubility of ethanol in the product leads to low yields. Isopropanol and n-butanol, with their low solubility in the product, are ideal crystallization solvents. Through extensive experimental research, the preparation method of this invention was developed.

[0047] The beneficial effects of this invention are:

[0048] This invention uses ethyl 8-chlorooctanoate as a raw material. During the bimolecular nucleophilic substitution reaction with cassalan, cuprous chloride and the catalyst synergistically improve reaction selectivity and yield. Following a sodium hydroxide hydrolysis reaction under anaerobic conditions with the addition of a reducing agent, the formation of colored impurities is minimized. Finally, the product SNAC is formed as a salt with sodium hydroxide in an alcohol solvent. This method is highly efficient and simple, easy to operate in factories, produces a product with good appearance and high purity, and uses readily available and economical raw materials, demonstrating promising prospects for industrialization. Attached Figure Description

[0049] Figure 1 This is an HPLC chromatogram for the purity detection of compound 1 in Example 1. Detailed Implementation

[0050] The following examples will help researchers understand the key points of the preparation technology of this invention, but they cannot limit the scope of this invention.

[0051] Example 1

[0052] This embodiment provides a method for preparing sodium saponexa (SNAC), comprising the following steps:

[0053] S1: Preparation of Compound 4

[0054] Under nitrogen protection, add 20.0g of cassalan, 25.3g of ethyl 8-chlorooctanoate, 1g of cuprous chloride, 2.3g of DL-cysteine, and 100ml of acetonitrile to the reactor. Heat to an internal temperature of 80-90℃ to form a solid-liquid mixture. Add 9.0g of anhydrous sodium carbonate. After the addition is complete, continue to maintain the temperature for 4 hours. Take a sample for HPLC control and ensure that the cassalan content is ≤1.0%. The reaction is then complete.

[0055] The reaction system was cooled to 25°C, and 100 ml of water was added dropwise to the reaction solution while stirring. The mixture was stirred and filtered, and the filter cake was washed with water. The product was dried under reduced pressure at 40°C for 3-5 hours to obtain 40.1 g of crude product, with a yield of 98.2% and a purity of 98.5% as determined by HPLC.

[0056] Preparation of S2: 8-(2-hydroxybenzamido)octanoic acid

[0057] Under nitrogen protection, 40.0 g of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid ethyl ester and 120 ml of water were added to the reactor. After nitrogen purging, 2.0 g of sodium metabisulfite was added, and the temperature was raised to 95 °C. 50 g of 30% sodium hydroxide solution was added dropwise, and the reaction was continued at this temperature for 5 h. A sample was taken for HPLC control, and the concentration of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid ethyl ester was controlled to be ≤1.0%. The reaction was then terminated.

[0058] The reaction system was cooled to 20-25℃, the pH was adjusted to 4-5, the temperature was raised to 65℃ and held for 0.5 h; then the temperature was slowly lowered to 20-25℃ and held for 2 h, filtered, and dried under reduced pressure at 40℃ for 3-5 h to obtain 19.9 g of white solid, with a yield of 82.8% and a purity of 99.2% as determined by HPLC.

[0059] Preparation of S3: Sodium 8-(2-hydroxybenzamido)octanoate

[0060] Under nitrogen protection, add 28.0g of SNAC free acid and 200ml of isopropanol to the reactor and heat to an internal temperature of 40-45℃; add 20g of sodium hydroxide solution dropwise, and after the addition is complete, heat to 50-60℃ and keep the reaction at this temperature for 5 hours. Take a sample to check the pH of the solution, which is 8.5-9.5, and the reaction is complete.

[0061] The reaction system was cooled to 30-35℃, and 0.1g of white SNAC sodium salt seed crystals were added. The suspension was cooled to 0℃ and aged at this temperature for 20 hours. After filtration, the solution was dried under reduced pressure at 40℃ for 3-5 hours to obtain 27.6g of white solid, with a yield of 91.7% and a purity of 99.8% as determined by HPLC.

[0062] With all other substances remaining unchanged, the catalyst in step S1 was changed to DL-proline, glycine, DL-cysteine, oxaloyldimethylamine, or oxaloyldiethylamine, resulting in the data listed in Table 1 below:

[0063] Experiment number raw material S1 product yield (%) Purity (%) of product from step S1 1 DL-proline 90.6 98.5 2 glycine 89.3 98.4 3 DL-cysteine 98.7 98.6 4 Oxalodimethylamine 93.2 97.6 5 Oxalate diethylamine 92.9 97.3 6 none 56.5 90.2

[0064] With all other substances remaining unchanged, the solvent in step S1 was changed to DMF, NMP, DMSO, or acetonitrile, resulting in the data listed in Table 2 below:

[0065] Experiment number reaction solvent S1 product yield (%) Purity (%) of product from step S1 1 DMF 85.6 96.1 2 NMP 96.1 97.6 3 DMSO 91.3 97.2 4 Acetonitrile 98.7 98.6

[0066] Selection of reducing agent in step S2:

[0067] With other substances remaining constant, the inventors compared p-methoxyphenol, zinc powder, sodium hydrosulfite, sodium metabisulfite, and sodium bisulfite, obtaining the data listed in Table 3 below:

[0068] Experiment number reducing agent S2 product yield (%) S2 Product Appearance 1 Zinc powder 78.3 grayish white 2 Sodium hydrosulfite 75.6 grayish white 3 Sodium metabisulfite 82.8 White 4 Sodium bisulfite 72.6 off-white 5 p-Methoxyphenol 73.5 off-white 6 none 75.8 pink

[0069] Solvent selection in step S3:

[0070] With all other substances remaining constant, the inventors compared methanol, ethanol, isopropanol, propanol, and n-butanol, obtaining the data listed in Table 4 below:

[0071] Experiment number solvent S3 product yield (%) S3 product purity (%) 1 methanol 75.2 99.2 2 ethanol 79.6 98.8 3 Isopropanol 91.7 99.9 4 propanol 87.5 99.3 5 n-Butanol 93.1 96.5

[0072] Tables 1 to 4 above indicate that in step S1, the catalyst can be one of DL-proline, glycine, DL-cysteine, oxaloyldimethylamine, and oxaloyldiethylamine, with DL-cysteine ​​being preferred. The solvent is one of DMF, NMP, DMSO, ethanol, and acetonitrile, with acetonitrile being preferred.

[0073] In step S2, the reducing agent is one of methoxyphenol, zinc powder, sodium hydrosulfite, sodium metabisulfite, and sodium bisulfite, preferably sodium metabisulfite.

[0074] In step S3, the solvent is one of methanol, ethanol, isopropanol, propanol and n-butanol, preferably isopropanol.

[0075] This invention is not limited to the above embodiments. Based on the technical solutions disclosed in this invention, those skilled in the art can make some substitutions and modifications to some of the technical features without creative effort, and all such substitutions and modifications are within the protection scope of this invention.

Claims

1. A method for preparing sodium sapoid, characterized in that, The reaction formula is as follows: S1： ； S2: ； S3: 。 2. The method for preparing sodium sapoidoxane according to claim 1, characterized in that, In step S1, the preparation steps of compound 4 are as follows: S1-1. Under nitrogen protection, add cassalan, ethyl 8-chlorooctanoate, cuprous chloride, catalyst and solvent to the reactor, heat to the internal temperature of 80-90 ℃, and mix the solid and liquid systems; add anhydrous sodium carbonate, and continue to keep the reaction at the temperature for 4 h after the addition is complete. Take a sample for HPLC control, and control the cassalan ≤1.0%. The reaction is then complete. S1-2. Cool the reaction system to 25 °C, add water dropwise to the reaction solution while stirring, stir and filter, wash the filter cake with water, and dry under reduced pressure to obtain crude compound 4.

3. The method for preparing sodium sapoidoxane according to claim 1, characterized in that, In step S2, the preparation steps of 8-(2-hydroxybenzamido)octanoic acid are as follows: S2-1. Under nitrogen protection, add ethyl N-(8-[2-hydroxybenzoyl]-amino)octanoate and water to the reactor. After nitrogen purging, add reducing agent and heat to an internal temperature of 95 °C. Add 30% sodium hydroxide solution dropwise. After the addition is complete, continue to maintain the temperature for 5 h. Take a sample for HPLC control and control the ethyl N-(8-[2-hydroxybenzoyl]-amino)octanoate ≤1.0%. The reaction is then complete. S2-2. Cool the reaction system to 20-25 ℃, adjust the pH to 4-5, raise the temperature to 65 ℃ and hold for 0.5 h; then slowly cool to 20-25 ℃ and hold for 2 h, filter, and dry under reduced pressure at 40 ℃ for 3-5 h to obtain a white solid.

4. The method for preparing sodium sapoidoxane according to claim 1, characterized in that, In step S3, the preparation steps of sodium 8-(2-hydroxybenzamido)octanoate are as follows: S3-1. Under nitrogen protection, add SNAC free acid and solvent to the reactor and heat to an internal temperature of 40-45 ℃; add sodium hydroxide solution dropwise, and after the addition is complete, heat to 50-60 ℃ and keep the reaction at this temperature for 5 h. Take a sample to check the pH of the solution, which is 8.5-9.5, and the reaction is complete. S3-2. Cool the reaction system to 30-35 °C, add white SNAC sodium salt seed crystals; cool the suspension to 0 °C and age it at this temperature for 20 hours, filter, and dry under reduced pressure to obtain a white solid.

5. The method for preparing sodium sapoidoxane according to claim 2, characterized in that, In step S1, the catalyst is one of DL-proline, glycine, DL-cysteine, oxaloyl dimethylamine, and oxaloyl diethylamine; the solvent is one of DMF, NMP, DMSO, ethanol, and acetonitrile.

6. The method for preparing sodium sapoidoxane according to claim 5, characterized in that, Its features are, The catalyst is DL-cysteine, and the solvent is acetonitrile.

7. The method for preparing sodium sapoidoxane according to claim 3, characterized in that, In step S2, the reducing agent is one of methoxyphenol, zinc powder, sodium hydrosulfite, sodium metabisulfite, and sodium bisulfite.

8. The method for preparing sodium sapoidoxane according to claim 7, characterized in that, The reducing agent is sodium metabisulfite.

9. The method for preparing sodium sapoidoxane according to claim 4, characterized in that, In step S3, the solvent is one of methanol, ethanol, isopropanol, propanol, and n-butanol.

10. The method for preparing sodium sapoidoxane according to claim 9, characterized in that, The solvent is isopropanol.

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