A method for synthesizing sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate, an absorption enhancer

Abstract

This invention provides a method for synthesizing sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate, an absorption enhancer. The method uses azelaic acid as a raw material, dehydrated to obtain an anhydride; this anhydride is then reacted with ammonia to obtain a monoamide, which is concentrated and subjected to a Hoffmann degradation reaction to obtain the important intermediate 8-aminooctanoic acid. This intermediate is then reacted with methyl salicylate in a solvent-free state. After the reaction is complete, purification yields sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate. The method of this invention uses readily available raw materials, operates under mild conditions, and is simple to purify, yielding a high-purity finished product, which is beneficial for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and specifically to a method for synthesizing sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate, an absorption enhancer. Background Technology

[0002] In September 2019, Novo Nordisk's type 2 diabetes drug, the GLP-1 peptide semaglutide... Approved for marketing in the form of oral formulation, The success was due not only to the esterification modification of 18-carbon dicarboxylic acid, but also to the penetration enhancer SNAC(N-(8-(2-hydroxybenzamido)octanoate sodium), The role of SNAC is crucial. SNAC is a dicarbonate phosphate absorption enhancer, originally developed by Emisphere for the treatment of gastrointestinal diseases. The US FDA has also designated it as a generally recognized as safe (GRAS) additive. Oral medications, due to their convenience and high patient compliance, are a target for pharmaceutical companies' research and development. SNAC, as an excellent enhancer, has a broad market prospect when used in combination with drugs.

[0003] Currently, there are two main challenges in SNAC synthesis. One is the scarcity and high cost of the key intermediate, 8-aminooctanoic acid. For example, the synthesis process may involve explosive azide compounds, or the preparation steps may contain heavy metals, making it environmentally unfriendly. Some methods require low-temperature reactions (-70-80℃) (CN115557846), while others require enzyme catalysis (CN118479974). The other challenge is the less-than-simple subsequent reaction with salicylic acid, leading to difficulties in product purification. For instance, US patent US5650386 uses an acyl chloride reacting with an amine, which results in difficult-to-preserve raw materials, high reactivity, numerous side reactions, and a high impurity content in the finished product. Patent WO2000046182 employs a lengthy route, and the reactant, ethyl chloroformate, is highly toxic and environmentally unfriendly. Invention patent CN 03114941.3A involves acyl chloride reagents such as thionyl chloride, resulting in harsh reaction conditions and significant pollution.

[0004] Therefore, there is an urgent need for a method for synthesizing SNAC that uses readily available raw materials, is low in cost, operates under mild conditions, is easy to purify, and is environmentally friendly. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing SNAC that is easy to obtain, low in cost, mild under mild conditions, simple to purify, and environmentally friendly.

[0006] In a first aspect of the invention, a method for synthesizing sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate is provided, the method comprising the steps of:

[0007] Step (1)

[0008]

[0009] Azelaic acid is dehydrated in the presence of a catalyst to yield azelaic anhydride.

[0010] Step (2)

[0011]

[0012] Azelaic anhydride reacts with ammonia to open the ring, yielding 9-amino-9-oxononanoic acid.

[0013] Step (3)

[0014]

[0015] 9-Amino-9-oxonanoic acid was rearranged by Hofmann to give 8-aminooctanoic acid;

[0016] Step (4)

[0017]

[0018] The reaction of 8-aminooctanoic acid with methyl salicylate yields N-(8-[2-hydroxybenzoyl]-amino)octanoic acid;

[0019] Step (5)

[0020]

[0021] Take the 8-aminooctanoic acid obtained in step (4), add alkali, and purify to obtain sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate.

[0022] In another preferred embodiment, the catalyst in step (1) of the method is selected from the group consisting of acetic anhydride, acetyl chloride, or combinations thereof.

[0023] In another preferred embodiment, the method further comprises one or more features selected from the group consisting of:

[0024] (a) The amount of catalyst used is 0.5-15 eq;

[0025] (b) The reaction temperature is 10-200℃;

[0026] (c) The reaction time is 1-20 hours;

[0027] In another preferred embodiment, in step (1), the amount of catalyst used is 8-12 eq.

[0028] In another preferred embodiment, in step (1), the reaction temperature is 20-160°C.

[0029] In another preferred embodiment, in step (1), the reaction time is 1-14 h.

[0030] In another preferred embodiment, the catalyst in step (1) of the method is acetyl chloride, the amount of which is 8-12 eq, the reaction temperature is 50-70℃, and the reaction time is 10-14h.

[0031] In another preferred embodiment, the catalyst in step (1) of the method is acetic anhydride, the amount is 8-12 eq, the reaction temperature is 140-160℃, and the reaction time is 4-8h.

[0032] In another preferred embodiment, step (2) of the method further comprises one or more features selected from the group consisting of:

[0033] (a) The ammonia solution is a 10-50 wt% ammonia solution;

[0034] (b) The reaction temperature is 10-100℃;

[0035] (c) The weight-to-volume ratio of azelaic anhydride to ammonia is 1:2 to 8 (g / mL).

[0036] In another preferred embodiment, the ammonia solution is a 20-30 wt% ammonia solution.

[0037] In another preferred embodiment, the ammonia solution is a 25-28 wt% ammonia solution.

[0038] In another preferred embodiment, the reaction temperature in step (2) is 20-70°C.

[0039] In another preferred embodiment, the reaction time of step (2) is 2-12 hours.

[0040] In another preferred embodiment, step (3) further includes: dissolving 9-amino-9-oxononanoic acid in a 1-5N alkaline solution and adding an oxidizing agent to react and obtain 8-aminooctanoic acid;

[0041] The alkaline solution is selected from the group consisting of sodium hydroxide, potassium hydroxide, or a combination thereof.

[0042] The oxidant is selected from the group consisting of sodium hypochlorite solution, trichloroisocyanuric acid, sodium dichloroisocyanurate, or combinations thereof.

[0043] The mass-to-volume ratio of 9-amino-9-oxononanoic acid to alkaline solution is 1:1 to 5 g / mL;

[0044] The mass-to-volume ratio of 9-amino-9-oxononanoic acid to sodium hypochlorite solution is 1:1 to 5 g / mL.

[0045] The molar ratio of 9-amino-9-oxononanoic acid to trichloroisocyanuric acid is 1:0.3-2 eq.

[0046] The molar ratio of 9-amino-9-oxononanoic acid to sodium dichloroisocyanurate is 1:0.3-2 eq.

[0047] In another preferred embodiment, step (3) further includes: after the reaction is completed, purifying and drying to obtain 8-aminooctanoic acid.

[0048] In another preferred embodiment, step (3) further includes: after the reaction is completed, adjusting the pH to acidic to precipitate 8-aminooctanoic acid.

[0049] In another preferred embodiment, the pH adjustment to acidity is accomplished by adding an acidic solution dropwise.

[0050] In another preferred embodiment, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, citric acid, or combinations thereof.

[0051] In another preferred embodiment, the acid is hydrochloric acid.

[0052] In another preferred embodiment, step (3) includes: adding NaOH solution to 9-amino-9-oxononanoic acid, adding NaClO aqueous solution dropwise at -10 to 10°C, monitoring the reaction by TLC after the addition is complete, adding sodium sulfite after the reaction is complete, stirring the reaction for 0.1-5 h, and purifying to obtain 8-aminooctanoic acid.

[0053] In another preferred embodiment, step (3) includes: adding methanol to 9-amino-9-oxononanoic acid, stirring to dissolve, then adding trichloroisocyanuric acid or sodium dichloroisocyanurate, and reacting at 15–35°C under TLC monitoring. After the reaction is complete, adding potassium hydroxide aqueous solution at -10–10°C and refluxing for 1–10 h. The resulting product is 8-aminooctanoic acid.

[0054] In another preferred embodiment, the reaction in step (4) is carried out under solvent-free conditions.

[0055] In another preferred embodiment, step (4) further has one or more features selected from the group consisting of:

[0056] (a) The amount of methyl salicylate used is 1-10 eq, based on the amount of 8-aminooctanoic acid used;

[0057] (b) The reaction temperature is 10-150℃;

[0058] (c) The reaction time is 1-25h.

[0059] In another preferred embodiment, the amount of methyl salicylate is 2-5 eq, based on the amount of 8-aminooctanoic acid.

[0060] In another preferred embodiment, the reaction temperature of step (4) is 20-110°C.

[0061] In another preferred embodiment, the reaction time of step (4) is 2-8 hours.

[0062] In another preferred embodiment, the alkaline solution in step (5) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or combinations thereof.

[0063] In another preferred embodiment, the purification in step (5) includes:

[0064] Crystallization is achieved by adding an organic solvent miscible with water, wherein the organic solvent is selected from the group consisting of acetone, acetonitrile, n-propanol, isopropanol, ethanol, or combinations thereof.

[0065] In another preferred embodiment, the purification in step (5) further includes recrystallization, wherein the solvent used for recrystallization is selected from the group consisting of 95% wt ethanol, anhydrous ethanol, and acetonitrile.

[0066] In another preferred embodiment, the solvent used for recrystallization is anhydrous ethanol.

[0067] In a second aspect of the invention, a method for synthesizing sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate using 8-aminooctanoic acid is provided, the method comprising:

[0068]

[0069] 8-Aminooctanoic acid was reacted with methyl salicylate in a solvent-free state, and then a base was added to the reaction system to obtain sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate.

[0070] In another preferred embodiment, the amount of methyl salicylate used is 1-10 eq, more preferably 2-5 eq, based on the amount of 8-aminooctanoic acid.

[0071] In another preferred embodiment, the reaction temperature is 10-150°C, more preferably 20-110°C, and even more preferably 50-100°C.

[0072] In another preferred embodiment, the reaction time is 1-25 hours; more preferably 2-8 hours.

[0073] In another preferred embodiment, the alkaline solution is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or combinations thereof.

[0074] In another preferred embodiment, after the reaction is completed, the product is purified, and the purification includes adding an organic solvent miscible with water to crystallize the system to obtain the product.

[0075] In another preferred embodiment, the organic solvent is selected from the group consisting of acetone, acetonitrile, n-propanol, isopropanol, ethanol, or combinations thereof.

[0076] In another preferred embodiment, the purification further includes recrystallization, wherein the solvent used for recrystallization is selected from the group consisting of 95% wt ethanol, anhydrous ethanol, and acetonitrile.

[0077] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0078] Figure 1 This is a synthesis roadmap for SNAC.

[0079] Figure 2 The HPLC chromatogram of sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate is shown. Detailed Implementation

[0080] Through extensive and in-depth research, and through numerous screenings and tests, the inventors have provided a method for synthesizing SNAC that is readily available, low-cost, mild, simple to purify, and environmentally friendly. The method uses azelaic acid as a raw material, which undergoes acetyl chloride or acetic anhydride-catalyzed ring closure, ammonia-based ring opening, and Hoffmann degradation to obtain the important intermediate 8-aminooctanoic acid. This intermediate is then reacted with methyl salicylate in a solvent-free state, and the resulting SNAC is purified. This invention is based on this method.

[0081] Synthesis of SNAC

[0082] The method of this invention uses azelaic acid as a raw material to obtain an anhydride under the catalysis of acetyl chloride or acetic anhydride; then reacts with ammonia to obtain a monoamide, which is concentrated and then subjected to a Hoffmann degradation reaction to obtain the important intermediate 8-aminooctanoic acid, which is then reacted with methyl salicylate in a solvent-free state. After the reaction is completed, no post-treatment is required; water and alkali are directly added to adjust the pH to alkaline, acetone is added to induce crystallization, the solid is filtered, and further recrystallized to obtain sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate. The raw materials of this invention are readily available, the conditions are mild, and a high-purity finished product can be obtained, which is conducive to industrial production.

[0083] Specifically, the method is as follows:

[0084] Step 1: Azelaic acid is dehydrated to prepare azelaic anhydride, using 2-10 eq of acetyl chloride or 2-10 eq of acetic anhydride as a catalyst. After the reaction is complete, the crude product is obtained by vacuum distillation.

[0085] Step 2: Take the crude product obtained in Step 1 and add it to ammonia water under an ice bath. Then slowly heat it to room temperature to 60°C. After the reaction is complete, concentrate it to obtain the crude product.

[0086] Step 3: Dissolve the crude product obtained in Step 2 in an inert solvent such as an alkaline solution or methanol, and react it with 2-6 eq of sodium hypochlorite, trichloroisocyanuric acid, or sodium dichloroisocyanurate solution. Purify and dry to obtain a white solid.

[0087] Step 4: Suspend the white solid obtained in Step 3 in 2-5 eq of methyl salicylate and react at room temperature to 100°C. After the reaction is complete, concentrate to obtain the crude product.

[0088] Step 5: Add 1-10 eq of alkali to the crude product obtained in Step 4 to react. After the reaction is complete, add an organic solvent miscible with water to crystallize. Filter to obtain the solid. Recrystallize the obtained product to obtain pure sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0089] In another preferred embodiment, in step one, the catalyst is selected from the group consisting of acetyl chloride or acetic anhydride, or combinations thereof.

[0090] In another preferred embodiment, in step one, the amount of catalyst used is 2-10 eq.

[0091] In another preferred embodiment, in step one, the reaction temperature is from room temperature to reflux temperature.

[0092] In another preferred embodiment, the reaction time in step one is 2-12 hours.

[0093] In another preferred embodiment, in step one, the catalyst is acetyl chloride, the reaction temperature is room temperature to 60°C, and the reaction time is 2-12 h.

[0094] In another preferred embodiment, in step one, the catalyst is acetic anhydride, the reaction temperature is room temperature to 150°C, and the reaction time is 2-12 h.

[0095] In another preferred embodiment, in step two, the ammonia water is a commercially available or homemade ammonia water solution with a concentration of 25-28 wt%.

[0096] In another preferred embodiment, in step two, the reaction temperature is from room temperature to 60°C.

[0097] In another preferred embodiment, the reaction time in step two is 2-12 hours.

[0098] In another preferred embodiment, in step three, the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, or combinations thereof.

[0099] In another preferred embodiment, in step three, the acid used to adjust the pH is selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, citric acid, or combinations thereof; preferably hydrochloric acid.

[0100] In another preferred embodiment, in step four, the reaction is a solvent-free reaction.

[0101] In another preferred embodiment, in step four, the reaction temperature is from room temperature to 100°C.

[0102] In another preferred embodiment, the reaction time in step four is 2-12 hours.

[0103] In another preferred embodiment, in step five, the alkali is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or combinations thereof. Sodium hydroxide is preferred.

[0104] In another preferred embodiment, in step five, the organic solvent is selected from the group consisting of acetone, acetonitrile, n-propanol, isopropanol, ethanol, or combinations thereof.

[0105] In another preferred embodiment, in step five, the recrystallization solvent is selected from the group consisting of 95% wt ethanol, anhydrous ethanol, acetonitrile, or combinations thereof; preferably anhydrous ethanol.

[0106] the term

[0107] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0108] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0109] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0110] As used herein, the term “room temperature” or “normal temperature” refers to a temperature of 4–40°C, preferably 25 ± 5°C.

[0111] The main advantages of this invention include:

[0112] 1. Raw materials are readily available: The raw materials for the method are azelaic acid, acetyl chloride or acetic anhydride, which do not contain easily explosive azide compounds or heavy metals, and the raw materials are easy to purchase.

[0113] 2. Mild reaction conditions: Unlike existing technologies that require extremely harsh low-temperature conditions such as -70°C or require the purchase of enzymes as catalysts, the method described in this invention only requires simple heating and reflux, and the reaction conditions are mild.

[0114] 3. Low cost: The raw materials used in the method are simple, the preparation cost is low, and it is easy to scale up production.

[0115] 4. High purity and low pollution: The method involves a solvent-free reaction, avoiding the use of organic solvents, making the preparation process green and environmentally friendly, and reducing solvent pollution.

[0116] The invention is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0117] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0118] Step 1

[0119] Example 1: Preparation of azelaic anhydride

[0120]

[0121] A: Add 100g of azelaic acid to a round-bottom flask, followed by 2-10 eq of acetyl chloride. Control the temperature at room temperature to reflux, and react for 2-12 hours. After the reaction is complete, concentrate to obtain crude intermediate II. The yields are detailed in Table 1.

[0122] B: Add 100g of azelaic acid to a round-bottom flask, followed by 2-10 eq of acetic anhydride. Control the reaction temperature from room temperature to 150℃ and the reaction time for 2-6 hours. After the reaction is complete, concentrate to obtain crude intermediate II. The yields are detailed in Table 1.

[0123] Intermediate II, 1H NMR (400MHz, CDCl3) 2.44 (t, J = 7.4Hz, 4H), 1.60-1.64 (m, 4H), 1.29-1.40 (m, 6H). EI-MS m / z (%): 171 (M+1).

[0124] Table 1. Effect of different conditions on the yield of azelaic anhydride

[0125] No. catalyst Reaction equivalent (eq) Reaction temperature (°C) Reaction time (h) Yield 1 Acetyl chloride 2 60 6 65 2 Acetyl chloride 6 60 6 84 3 Acetyl chloride 10 25 6 56 4 Acetyl chloride 10 60 6 93 5 Acetyl chloride 10 60 12 96 6 Acetic anhydride 2 150 6 72 7 Acetic anhydride 6 150 6 83 8 Acetic anhydride 10 25 6 16 9 Acetic anhydride 10 150 2 91 10 Acetic anhydride 10 150 6 98

[0126] As shown in the table above, the yield of azelaic anhydride is related to the type of catalyst, the amount of catalyst used, the reaction time, and the reaction temperature.

[0127] The preferred catalysts for the reaction are acetyl chloride and acetic anhydride, both of which can achieve yields of >95% under optimal reaction conditions.

[0128] The optimal reaction yield is achieved when the catalyst dosage is around 10 eq. If the catalyst dosage is too low, the reaction may not proceed completely, the substrate may not be fully converted into the product, and the yield may be low.

[0129] Too low a reaction temperature will affect the reaction yield, while a higher reaction temperature is more conducive to the reaction. Experiments at temperatures of 3 and 5, and 8 and 10, show that at temperatures as low as 25°C, the reaction yield is significantly reduced, especially when acetic anhydride is used as the catalyst, with the yield dropping to as low as 16%. Conversely, acetyl chloride performs better at lower temperatures, with a reaction yield of 56%. The reaction yield increases with increasing reaction temperature. When acetic anhydride is used as the catalyst, the yield reaches approximately 98% at 150°C, making 150°C the preferred reaction temperature. When acetyl chloride is used as the catalyst, the yield reaches approximately 96% at 60°C, making 60°C the preferred reaction temperature.

[0130] Extending the reaction time helps to improve the reaction yield. Experiments 4 and 5, and 9 and 10 show that the reaction yield increases with increasing reaction time. When acetic anhydride is used as the catalyst, the yield reaches approximately 98% after 6 hours of reaction, indicating a preferred reaction time of 6 hours. When acetyl chloride is used as the catalyst, the yield reaches approximately 96% after 12 hours, indicating a preferred reaction temperature of 12 hours.

[0131] Step Two

[0132] Example 2: Preparation of 9-amino-9-oxononanoic acid

[0133]

[0134] Add 250 mL of a 25%-28% ammonia solution to 50 g of azelaic anhydride, and maintain the reaction at 60 °C until completion. Concentrate to remove most of the ammonia solution, yielding crude 9-amino-9-oxononanoic acid. No further processing is required; it can be used directly in the next step.

[0135] Step 3

[0136] Example 3: Preparation of 8-Aminooctanoic acid

[0137]

[0138] 300 mL of 2N NaOH solution was added to 100 g of crude 9-amino-9-oxonononic acid, and 300 mL of NaClO aqueous solution was added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to return to room temperature. TLC showed that the reaction was complete. 10.2 g of sodium sulfite was added in portions, and the mixture was stirred for 1 h. Concentrated hydrochloric acid was added dropwise to adjust the pH to 6. Crystallization was carried out under ice bath conditions. The crystals were filtered, and the filter cake was washed with a small amount of ice water. The mixture was dried under reduced pressure to obtain a white solid. The overall yield of the two steps in Examples 2 and 3 was 82%.

[0139] 1 H NMR (500MHz, D2O) δ2.88 (t, J = 7.4Hz, 2H), 2.20 (t, J = 7.4Hz, 2H), 1.35-1.23 (m, 10H).

[0140] Example 4: Preparation of 8-Aminooctanoic acid

[0141]

[0142] 500 mL of methanol was added to 100 g of crude 9-amino-9-oxononic acid, and after stirring to dissolve, 0.5 eq of trichloroisocyanuric acid was added. The reaction was carried out at 25 °C and monitored by TLC. After the reaction was completed, 30% potassium hydroxide aqueous solution was added under ice bath, and then the reaction was refluxed for 3 h. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate, washed with salt, concentrated, and crystallized to give a white solid. The overall yield of the two steps in Examples 2 and 4 was 92%. The HPLC purity was 98.5%.

[0143] Example 5: Preparation of 8-Aminooctanoic acid

[0144]

[0145] 500 mL of methanol was added to 100 g of crude 9-amino-9-oxononic acid, and after stirring to dissolve, sodium dichloroisocyanurate (0.5 eq) was added. The reaction was carried out at 25 °C and monitored by TLC. After the reaction was completed, 30% potassium hydroxide aqueous solution was added under ice bath, and then the reaction was refluxed for 3 h. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate, washed with salt, concentrated, and crystallized to give a white solid. The overall yield of the two steps in Examples 2 and 5 was 95%. The HPLC purity was 98.7%.

[0146] Step Four

[0147] Example 6: Preparation of N-(8-[2-hydroxybenzoyl]amino)octanoic acid

[0148]

[0149] 100 g of 8-aminooctanoic acid was suspended in 2-5 eq of methyl salicylate. The reaction temperature was from room temperature to 100 °C, and the reaction time was 2-12 h. After the reaction was completed, the solution was concentrated under reduced pressure to obtain crude N-(8-[2-hydroxybenzoyl]-amino)octanoic acid. No further processing was required; proceed directly to the next step.

[0150] Step 5

[0151] Example 7: Preparation of sodium N-(8-[2-hydroxybenzoyl]amino)octanoate

[0152]

[0153] Take 100g of crude N-(8-[2-hydroxybenzoyl]-amino)octanoic acid obtained in step 4 and add 1-10 eq of alkali (see Table 2 for specific conditions). Stir the reaction at room temperature for 1 h. After the reaction is complete, add acetone to crystallize, filter, and recrystallize further with anhydrous ethanol. After filtration and drying, obtain pure sodium N-(8-[2-hydroxybenzoyl]-amino)octanoic acid.

[0154] 1 H NMR(300MHz,DMSO-d6)δ:12.73(s,1H),11.94(s,1H),8.81(m,1H),7.83(m,1H),7.38(m,1H),6.8 6(m,2H),2.36(q,J=10.0Hz,2H),2.18(t,J=7.8Hz,2H),1.50(m,4Hm),1.28(m,6H).HPLC purity>98%.

[0155] EI-MS m / z (%): 171 (M+Na)

[0156] Table 2. Effects of different conditions on SNAC yield

[0157]

[0158] As shown in the table above, the reaction yield is related to temperature, type of alkali, reaction time, presence or absence of solvent, and amount of reaction substrate.

[0159] In step four (Example 6), aminooctanoic acid is prepared through multiple steps. There is no industrialized product, and the cost is high and the price is expensive. In contrast, the raw material methyl salicylate is readily available and has been industrialized. Using an excess of methyl salicylate not only increases the yield but also reduces the cost.

[0160] Step four (Example 6) yields higher results when carried out in a solvent-free state. The results from experiments 1 and 2 show that, comparing reactions carried out in solvents such as DMF, isopropanol, and dichloromethane with those carried out in a solvent-free state, the highest yield in the solvent state is only 83%, while the highest yield in the solvent-free state reaches 98%, increasing to 1.2 times the original yield.

[0161] In step four (Example 6), a reaction temperature that is too low will affect the reaction yield, while a higher reaction temperature is more conducive to the reaction. The results of experiments 2, 5, and 6 show that when the reaction temperature is too low, such as 25°C, the reaction yield decreases to about 78%. The reaction yield increases with the increase of the reaction temperature, reaching about 91% at 60°C. The preferred reaction temperature is 100°C.

[0162] Extending the reaction time in step four (Example 6) helps to improve the reaction yield. Results from experiments 2 and 7 show that the reaction yield increases with increasing reaction time; a 98% reaction yield can be obtained at a reaction time of 6 hours. A reaction time of 6 hours is preferred.

[0163] Increasing the amount of reaction substrate can further improve the reaction yield from a high level. Experiments 2, 3, and 4 show that increasing the amount of methyl salicylate added can slightly increase the reaction yield from the high level of 91% to 93%.

[0164] The base used in step five (Example 7) has no special requirements and can achieve the optimal reaction yield. For example, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate used in the examples can all achieve a yield of up to 98% under optimal reaction conditions.

[0165] As can be seen, the preparation method provided by this invention has a high reaction yield and high product purity. It also includes a solvent-free reaction step, which reduces pollution and has a high yield, greatly reducing production costs and making it suitable for large-scale industrial production.

[0166] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for synthesizing sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate, characterized in that, The method includes the following steps: Step (1) Azelaic acid is dehydrated in the presence of acetyl chloride to give azelaic anhydride; The amount of acetyl chloride used was 10 eq, the reaction temperature was 60℃, and the reaction time was 12h. Step (2) Azelaic anhydride reacts with ammonia to open the ring, yielding 9-amino-9-oxononanoic acid; wherein the ammonia is a 10-50 wt% aqueous solution; and the weight-to-volume ratio of azelaic anhydride to ammonia is 1:2-8 (g / mL); Step (3) 9-Amino-9-oxononanoic acid was dissolved in an inert solvent, and sodium dichloroisocyanurate was added dropwise to react and give 8-aminooctanoic acid; wherein the molar ratio of 9-amino-9-oxononanoic acid to sodium dichloroisocyanurate was 1:0.5 eq. Step (4) 8-Aminooctanoic acid reacts with methyl salicylate to obtain N-(8-[2-hydroxybenzoyl]-amino)octanoic acid, and the reaction is carried out under solvent-free conditions; wherein, the amount of methyl salicylate used is 2 eq, based on the amount of 8-aminooctanoic acid; and the reaction in step (4) is carried out under solvent-free conditions; the reaction temperature in step (4) is 60-100℃; and the reaction time is 2-6h. Step (5) Take the compound of formula V obtained in step (4), add alkali, and purify to obtain sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate; the alkali solution in step (5) is selected from the following group: sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate.

2. The method as described in claim 1, characterized in that, The ammonia solution is a 20-30 wt% ammonia solution.

3. The method as described in claim 1, characterized in that, The reaction temperature in step (2) of the method is 10-100℃.

4. The method as described in claim 1, characterized in that, The reaction time for step (2) of the method is 2-12 hours.

5. The method as described in claim 1, characterized in that, In step (3), the inert solvent is methanol.

6. The method as described in claim 1, characterized in that, Step (3) includes: adding methanol to 9-amino-9-oxononanoic acid, stirring to dissolve, adding sodium dichloroisocyanurate, and reacting at 15~35℃. After the reaction is completed, adding potassium hydroxide aqueous solution at -10~10℃ and refluxing for 1-10h. Purification yields 8-aminooctanoic acid.

7. The method as described in claim 1, characterized in that, The reaction time for step (4) is 6 hours.

8. The method as described in claim 1, characterized in that, The reaction temperature in step (4) is 60°C.

9. The method as described in claim 1, characterized in that, The purification step (5) includes: adding an organic solvent miscible with water to induce crystallization, wherein the organic solvent is selected from the group consisting of acetone, acetonitrile, n-propanol, isopropanol, ethanol, or combinations thereof.

10. A method for synthesizing sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate from 8-aminooctanoic acid, characterized in that, The method includes: Step (4) 8-Aminooctanoic acid reacts with methyl salicylate to obtain N-(8-[2-hydroxybenzoyl]-amino)octanoic acid, and the reaction is carried out under solvent-free conditions; wherein, the amount of methyl salicylate used is 2 eq, based on the amount of 8-aminooctanoic acid; and the reaction in step (4) is carried out under solvent-free conditions; the reaction temperature in step (4) is 60-100℃; and the reaction time is 2-6h. Step (5) Take the compound of formula V obtained in step (4), add alkali, and purify to obtain sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate; the alkali solution in step (5) is selected from the following group: sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate.

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