Synthesis method of absorption enhancer N-(8-[2-hydroxybenzoyl]-amino) sodium caprylate

Abstract

The invention provides a synthesis method of an absorption enhancer N-(8-[2-hydroxybenzoyl]-amino) sodium caprylate. The method comprises the following steps: dehydrating azelaic acid serving as a raw material to obtain anhydride; the preparation method comprises the following steps: taking 2-aminooctanoic acid as a raw material, reacting with ammonia water to obtain monoamide, concentrating, carrying out Hofmann degradation reaction to obtain an important intermediate 8-aminooctanoic acid, reacting with methyl salicylate in a solvent-free state, and purifying to obtain sodium N-(8-[2-hydroxybenzoyl]-amino) octanoate after the reaction is completed. According to the method, raw materials are easy to obtain, conditions are mild, purification is simple, a high-purity finished product can be obtained, and industrial production is facilitated.

Description

Technical Field

[0001] The invention relates to the field of organic chemistry, and in particular to a method for synthesizing sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate, an absorption enhancer. Background Art

[0002] In September 2019, Novo Nordisk's type 2 diabetes drug, GLP-1 peptide semaglutide It is approved for marketing in the form of an oral preparation. The success of the 18-carbon dicarboxylic acid was due to the lipid modification of the permeation enhancer SNAC (sodium N-(8-(2-hydroxybenzamido)octanoate). ) plays a vital role. SNAC is a dicarbonyl phosphate absorption enhancer, first developed by Emisphere for the treatment of gastrointestinal diseases. The US FDA also designated it as a generally recognized as safe (GRAS) additive. Oral drugs are the target of pharmaceutical companies' research and development because of their convenience and high patient compliance. SNAC, as an excellent enhancer, has broad market prospects when used in combination with drugs.

[0003] At present, there are two difficulties in the synthesis of SNAC. One difficulty is that the key intermediate 8-aminooctanoic acid raw materials are not easy to obtain and the cost is high. For example, the synthesis process involves explosive azide compounds, or the preparation steps contain heavy metals, which are not friendly to the environment; some require low temperature (-70-80°C) reaction (CN115557846), and some require enzyme catalysis (CN118479974). Another difficulty is that the subsequent reaction with salicylic acid is not simple enough, and it is difficult to purify the product. For example, in U.S. Patent US5650386, acyl chloride and amine are used for reaction, the raw materials are not easy to preserve, the reaction activity is high, there are many side reactions, and the impurity content of the finished product is high. The method route of patent WO2000046182 is relatively long, and the reaction raw material ethyl chloroformate is a highly toxic substance, which is not friendly to the environment. The invention patent CN 03114941.3A involves acyl chloride reagents such as thionyl chloride, and the reaction conditions are severe and the pollution is large.

[0004] Therefore, there is an urgent need for a SNAC synthesis method that has readily available raw materials, low cost, mild conditions, simple purification, and is environmentally friendly. Summary of the invention

[0005] The invention aims to provide a SNAC synthesis method with readily available raw materials, low cost, mild conditions, simple purification and environmental friendliness.

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

[0007] Step (1)

[0008]

[0009] Azelaic acid is dehydrated under the action of a catalyst to obtain azelaic anhydride;

[0010] Step (2)

[0011]

[0012] Azelaic anhydride reacts with ammonia water to open the ring to obtain 9-amino-9-oxononanoic acid;

[0013] Step (3)

[0014]

[0015] 9-amino-9-oxononanoic acid was subjected to Hofmann rearrangement to give 8-aminooctanoic acid;

[0016] Step (4)

[0017]

[0018] 8-aminocaprylic acid reacts with methyl salicylate to obtain N-(8-[2-hydroxybenzoyl]-amino)caprylic acid;

[0019] Step (5)

[0020]

[0021] Take the 8-aminocaprylic acid obtained in step (4), add a base, and purify to obtain sodium N-(8-[2-hydroxybenzoyl]-amino)caprylate.

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

[0023] In another preferred embodiment, the method further has one or more characteristics selected from the following group:

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

[0025] (b) the reaction temperature is 10-200° C.;

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

[0027] In another preferred embodiment, in step (1), the amount of the 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 hours.

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

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

[0032] In another preferred embodiment, step (2) of the method further has one or more characteristics selected from the following group:

[0033] (a) aqueous ammonia is 10 to 50 wt % aqueous ammonia solution;

[0034] (b) the reaction temperature is 10-100° C.;

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

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

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

[0038] In another preferred embodiment, the reaction temperature of 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, the step (3) further comprises: dissolving 9-amino-9-oxononanoic acid in a 1-5N alkaline solution, and adding an oxidant dropwise to react to obtain 8-aminooctanoic acid;

[0041] Wherein, 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 a combination thereof;

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

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

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

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

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

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

[0049] In another preferred embodiment, the pH is adjusted to be acidic by dripping an acid solution.

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

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

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

[0053] In another preferred embodiment, the step (3) comprises: adding methanol to 9-amino-9-oxononanoic acid, stirring and dissolving, adding trichloroisocyanuric acid or sodium dichloroisocyanurate, and reacting at 15 to 35° C., and tracking by TLC. After the reaction is completed, adding potassium hydroxide aqueous solution at -10 to 10° C., and reflux reaction for 1 to 10 hours. Purification yields 8-aminooctanoic acid.

[0054] In another preferred embodiment, the reaction in step (4) is carried out in the absence of a solvent.

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

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

[0057] (b) the reaction temperature is 10-150° C.;

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

[0059] In another preferred embodiment, the amount of methyl salicylate used is 2-5 eq, calculated based on the amount of 8-aminocaprylic 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 a combination thereof.

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

[0064] An organic solvent miscible with water is added for crystallization, wherein the organic solvent is selected from the group consisting of acetone, acetonitrile, n-propanol, isopropanol, ethanol, or a combination thereof.

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

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

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

[0068]

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

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

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

[0072] In another preferred embodiment, the reaction time is 1-25 hours; 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 a combination 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, and crystallizing the system to obtain the product.

[0075] In another preferred embodiment, the organic solvent is selected from the following group: acetone, acetonitrile, n-propanol, isopropanol, ethanol, or a combination thereof.

[0076] In another preferred embodiment, the purification further comprises: recrystallization, wherein the solvent used for recrystallization is selected from the following group: 95%wt ethanol, anhydrous ethanol, acetonitrile.

[0077] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 This is the synthetic route of SNAC.

[0079] Figure 2 This is the HPLC spectrum of sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate. DETAILED DESCRIPTION

[0080] After extensive and in-depth research, the inventors have provided a method for synthesizing SNAC with easy-to-obtain raw materials, low cost, mild conditions, simple purification and environmental friendliness through a large number of screening and testing. The method uses azelaic acid as a raw material, and obtains an important intermediate 8-aminooctanoic acid through acetyl chloride or acetic anhydride catalytic ring closure, ammonia ring opening, and Hofmann degradation reaction, and then reacts with methyl salicylate in a solvent-free state, and purifies to obtain SNAC after the reaction is completed. The present invention was completed on this basis.

[0081] Synthesis of SNAC

[0082] The method of the present invention uses azelaic acid as a raw material to obtain anhydride under the catalysis of acetyl chloride or acetic anhydride; then reacts with ammonia water to obtain monoamide, and after concentration, obtains an important intermediate 8-aminooctanoic acid through Hofmann degradation reaction, and then reacts with methyl salicylate in a solvent-free state. After the reaction is completed, no post-treatment is required, and water and alkali are directly added to adjust the pH to alkaline, acetone is added for crystallization, solids are filtered, and further recrystallized to obtain sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate. The raw materials of the present invention are easy to obtain, 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: Dehydrating azelaic acid to prepare azelaic anhydride, the catalyst used is 2-10eq of acetyl chloride or 2-10eq of acetic anhydride. After the reaction is completed, the crude product is obtained by vacuum distillation.

[0085] Step 2: Take the crude product obtained in step 1 and add it into ammonia water under ice bath, then slowly heat it to room temperature to 60°C, and after the reaction is completed, concentrate it to obtain the crude product.

[0086] Step 3: The crude product obtained in step 2 is dissolved in an inert solvent such as an alkaline solution or methanol, and reacted with 2-6 eq of sodium hypochlorite, trichloroisocyanuric acid, or sodium dichloroisocyanurate solution, and purified and dried to obtain a white solid.

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

[0088] Step 5: Add 1-10eq of a base to the crude product obtained in step 4 to react, add a water-miscible organic solvent for crystallization after the reaction, filter out the solid, and recrystallize the obtained product to obtain pure sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate.

[0089] In another preferred embodiment, in step 1, the catalyst is selected from the following group: acetyl chloride or acetic anhydride, or a combination thereof.

[0090] In another preferred embodiment, in step 1, the amount of the catalyst is 2-10 eq.

[0091] In another preferred embodiment, in step 1, the reaction temperature is from room temperature to reflux temperature.

[0092] In another preferred embodiment, in step 1, the reaction time is 2-12 hours.

[0093] In another preferred embodiment, in step 1, 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 1, the catalyst is acetic anhydride, the reaction temperature is from room temperature to 150° C., and the reaction time is 2-12 h.

[0095] In another preferred embodiment, in step 2, 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 2, the reaction temperature is room temperature to 60°C.

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

[0098] In another preferred embodiment, in step three, the base is selected from the following group: sodium hydroxide, potassium hydroxide, or a combination thereof.

[0099] In another preferred embodiment, in step three, the acid for adjusting pH is selected from the following group: hydrochloric acid, sulfuric acid, acetic acid, citric acid, or a combination thereof; preferably hydrochloric acid.

[0100] In another preferred embodiment, in step 4, the reaction is a solvent-free reaction.

[0101] In another preferred embodiment, in step 4, the reaction temperature is room temperature to 100°C.

[0102] In another preferred embodiment, in step 4, the reaction time is 2-12 hours.

[0103] In another preferred embodiment, in step 5, the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or a combination thereof, preferably sodium hydroxide.

[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 a combination thereof.

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

[0106] the term

[0107] Unless defined otherwise, 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 belongs.

[0108] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. 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 term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting 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 the present invention include:

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

[0113] 2. Mild reaction conditions: Different from the prior art which requires extremely harsh low temperature conditions such as -70°C or requires the purchase of enzymes as catalysts, the method of the present invention only requires simple heating and reflux, and the reaction conditions are mild.

[0114] 3. Low cost: The method has simple raw materials, low preparation cost, and is easy to scale up production.

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

[0116] The present invention will be further described below in conjunction with specific implementation. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually 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 according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0117] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration 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, then add 2-10eq of acetyl chloride, control the temperature from room temperature to reflux, and the reaction time is 2-12h. After the reaction is completed, concentrate to obtain the crude intermediate II. The yield is shown in Table 1.

[0122] B: Add 100g of azelaic acid to a round-bottom flask, then add 2-10eq of acetic anhydride, control the reaction temperature from room temperature to 150°C, and the reaction time is 2-6h. After the reaction is completed, concentrate to obtain the crude intermediate II. The yield is shown 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]

[0126] It can be seen from the above table that the yield of azelaic anhydride is related to the type of catalyst, catalyst dosage, reaction time and reaction temperature.

[0127] The catalysts in the reaction are preferably acetyl chloride and acetic anhydride, both of which can achieve a yield of about >95% under optimal reaction conditions.

[0128] The amount of catalyst used in the reaction is about 10eq, and the reaction yield is optimal. When the amount of catalyst used is too small, the reaction may not be complete, the substrate is not completely converted into the product, and the yield is low.

[0129] Too low a reaction temperature will affect the reaction yield, and an increase in the reaction temperature is more conducive to the reaction. From the experimental results of No. 3 and No. 5, No. 8 and No. 10, it can be found that when the reaction temperature is too low, such as 25°C, the reaction yield is greatly reduced, especially when the catalyst is acetic anhydride, the impact is greater, and the yield is as low as 16%. On the contrary, acetyl chloride performs better at low temperatures, with a reaction yield of 56%. The reaction yield increases with increasing reaction temperature. When the catalyst is acetic anhydride, the yield reaches about 98% at 150°C, and the preferred reaction temperature is 150°C. When the catalyst is acetyl chloride, the yield reaches about 96% at 60°C, and the preferred reaction temperature is 60°C.

[0130] Prolonging the reaction time helps to improve the reaction yield. From the results of experiments No. 4 and No. 5, No. 9 and No. 10, it can be found that the reaction yield increases with the extension of the reaction time. When the catalyst is acetic anhydride, the yield reaches about 98% after 6 hours of reaction, and the preferred reaction time is 6 hours. When the catalyst is acetyl chloride, the yield reaches about 96% after 12 hours, and the preferred reaction temperature is 12 hours.

[0131] Step 2

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

[0133]

[0134] 250 mL of 25%-28% ammonia solution was added to 50 g of azelaic anhydride, and the reaction was carried out at 60°C until completion, and most of the ammonia solution was removed by concentration to obtain a crude compound 9-amino-9-oxononanoic acid, which was used directly in the next step without further treatment.

[0135] Step 3

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

[0137]

[0138] 300 mL of 2N NaOH solution was added to 100 g of crude 9-amino-9-oxononanoic acid, and 300 mL of NaClO aqueous solution was added dropwise under ice bath. After the addition was completed, the mixture returned to room temperature naturally. After TLC showed that the reaction was complete, 10.2 g of sodium sulfite was added in batches, stirred for 1 h, concentrated hydrochloric acid was added dropwise, pH was adjusted to 6, crystallized under ice bath, filtered, the filter cake was rinsed with a small amount of ice water, and dried under reduced pressure to obtain a white solid. The total yield of Example 2 and Example 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-aminocaprylic acid

[0141]

[0142] Add 500 mL of methanol to 100 g of crude 9-amino-9-oxononanoic acid, stir and dissolve, then add trichloroisocyanuric acid (0.5 eq), keep warm at 25 ° C and follow up with TLC. After the reaction is completed, add 30% potassium hydroxide aqueous solution under ice bath, and then reflux for 3 hours. After the reaction is completed, cool to room temperature, extract with ethyl acetate, wash with salt, concentrate, and crystallize to obtain a white solid. The total yield of Example 2 and Example 4 is 92%. The HPLC content is 98.5%.

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

[0144]

[0145] Add 500 mL of methanol to 100 g of crude 9-amino-9-oxononanoic acid, stir and dissolve, then add sodium dichloroisocyanurate (0.5 eq), keep warm at 25 ° C and follow up with TLC. After the reaction is completed, add 30% potassium hydroxide aqueous solution under ice bath, and then reflux for 3 hours. After the reaction is completed, cool to room temperature, extract with ethyl acetate, wash with salt, concentrate, and crystallize to obtain a white solid. The total yield of Example 2 and Example 5 is 95%. The HPLC content is 98.7%.

[0146] Step 4

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

[0148]

[0149] Suspend 100g of 8-aminocaprylic acid in 2-5eq of methyl salicylate, the reaction temperature is room temperature to 100°C, and the reaction time is 2-12h. After the reaction is completed, concentrate under reduced pressure to obtain a crude product of N-(8-[2-hydroxybenzoyl]-amino)caprylic acid. No treatment is required, and the product is directly used in the next step.

[0150] Step 5

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

[0152]

[0153] Take 100 g of the crude N-(8-[2-hydroxybenzoyl]-amino) caprylic acid obtained in step 4, add 1-10 eq of a base (see Table 2 for specific conditions), stir and react at room temperature for 1 h, add acetone to crystallize after the reaction, filter, further recrystallize with anhydrous ethanol, filter, and dry to obtain pure sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate.

[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. Effect of different conditions on SNAC yield

[0157]

[0158] It can be seen from the above table that the reaction yield is related to temperature, type of base, reaction time, presence or absence of solvent and amount of reaction substrate.

[0159] In step 4 (Example 6), aminocaprylic acid is prepared through multiple steps, there is no industrialized product, the cost is high, and the price is expensive. Relatively speaking, the raw material methyl salicylate is easy to obtain and has been industrialized. Using an excess of methyl salicylate not only improves the yield but also reduces the cost.

[0160] Step 4 (Example 6) has a higher yield when carried out in a solvent-free state. From the results of Experiments 1 and 2, it can be found that when the reaction is carried out in a solvent such as DMF, isopropanol, and dichloromethane and when the reaction is carried out in a solvent-free state, the maximum yield of the reaction in the solvent state is only 83%, while the maximum yield in the solvent-free state can reach 98%, which is 1.2 times the original yield.

[0161] The reaction temperature of step 4 (Example 6) is too low to affect the reaction yield, and an increase in the reaction temperature is more conducive to the reaction. From the experimental results of No. 2, No. 5 and No. 6, it can be found that when the reaction temperature is too low, such as 25°C, the reaction yield is reduced to about 78%, and the reaction yield increases with the increase in reaction temperature. At 60°C, the yield reaches about 91%, and the preferred reaction temperature is 100°C.

[0162] Prolonging the reaction time of step 4 (Example 6) helps to improve the reaction yield. From the results of experiments No. 2 and No. 7, it can be found that the reaction yield increases with the extension of the reaction time. When the reaction time is 6 hours, a reaction yield of 98% can be obtained. The preferred reaction time is 6 hours.

[0163] Increasing the amount of reaction substrate can further improve the reaction yield on a high basis. From the experimental results of No. 2, No. 3 and No. 4, it can be found that increasing the amount of methyl salicylate can slightly increase the reaction yield from the high level of 91% to 93%.

[0164] There is no special requirement for the base used in step 5 (Example 7), and the optimal reaction yield can be achieved. For example, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate in the example can achieve a yield of up to 98% under the optimal reaction conditions.

[0165] It can be seen that the preparation method provided by the present invention has a high reaction yield and a high product purity, and there is also a solvent-free reaction step, which reduces pollution, has a high yield, and greatly reduces production costs, and is suitable for large-scale industrial production.

[0166] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for synthesizing sodium N-(8-[2-hydroxybenzoyl]-amino)caprylate, characterized in that: The method comprises the steps of: Step (1) Azelaic acid is dehydrated under the action of a catalyst to obtain azelaic anhydride; Step (2) Azelaic anhydride reacts with ammonia water to open the ring to obtain 9-amino-9-oxononanoic acid; Step (3) 9-amino-9-oxononanoic acid was subjected to Hofmann rearrangement to give 8-aminooctanoic acid; Step (4) 8-aminocaprylic acid reacts with methyl salicylate to obtain N-(8-[2-hydroxybenzoyl]-amino)caprylic acid; Step (5) Take the 8-aminocaprylic acid obtained in step (4), add a base, and purify to obtain sodium N-(8-[2-hydroxybenzoyl]-amino)caprylate.

2. The method according to claim 1, characterized in that In step (1) of the method, the catalyst is selected from the group consisting of acetic anhydride, acetyl chloride, or a combination thereof.

3. The method according to claim 1, characterized in that The method also has one or more features selected from the following group: (a) the amount of the catalyst is 0.5-15eq; (b) the reaction temperature is 10-200° C.; (c) The reaction time is 1-20h.

4. The method according to claim 1, characterized in that The catalyst in step (1) of the method is acetyl chloride, the amount used is 8-12 eq, the reaction temperature is 50-70° C., and the reaction time is 10-14 h; and / or The catalyst in step (1) of the method is acetic anhydride, the dosage is 8-12 eq, the reaction temperature is 140-160° C., and the reaction time is 4-8 h.

5. The method according to claim 1, characterized in that Step (2) of the method further has one or more features selected from the following group: (a) aqueous ammonia is 10 to 50 wt % aqueous ammonia solution; (b) the reaction temperature is 10-100° C.; (c) The weight volume ratio of azelaic anhydride to ammonia water is 1:2-8 (g / mL).

6. The method according to claim 1, characterized in that The step (3) further comprises: dissolving 9-amino-9-oxononanoic acid in an inert solvent, adding an oxidant dropwise, and reacting to obtain 8-aminooctanoic acid; Wherein, the inert solvent is selected from the following group: alkaline solution, methanol; The alkaline solution is selected from the group consisting of sodium hydroxide, potassium hydroxide, or a combination thereof; The oxidant is selected from the group consisting of sodium hypochlorite, trichloroisocyanuric acid, sodium dichloroisocyanurate, or a combination thereof; The mass volume ratio of 9-amino-9-oxononanoic acid to the alkaline solution is: 1:1-10 g / mL; The mass volume ratio of 9-amino-9-oxonanoic acid to methanol is: 1:1-5 g / mL; The mass volume ratio of 9-amino-9-oxononanoic acid to sodium hypochlorite solution is 1:1-5 g / mL; The molar ratio of 9-amino-9-oxonanoic acid to trichloroisocyanuric acid is 1:0.3-2eq; The molar ratio of 9-amino-9-oxonanoic acid to sodium dichloroisocyanurate is 1:0.3-2eq.

7. The method according to claim 1, characterized in that The reaction in step (4) is carried out in the absence of a solvent.

8. The method according to claim 1, characterized in that The step (4) further has one or more characteristics selected from the following group: (a) the amount of methyl salicylate is 1-10 eq, based on the amount of 8-aminocaprylic acid; (b) the reaction temperature is 10-150° C.; (c) The reaction time is 1-25h.

9. The method according to claim 1, characterized in that The alkaline solution in step (5) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or a combination thereof; The purification in step (5) comprises: adding an organic solvent miscible with water for crystallization, wherein the organic solvent is selected from the group consisting of acetone, acetonitrile, n-propanol, isopropanol, ethanol, or a combination thereof.

10. A method for synthesizing sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate using 8-amino caprylic acid, characterized in that: The method comprises: 8-aminocaprylic acid is reacted with methyl salicylate in a solvent-free state, and then a base is added to the reaction system to obtain sodium N-(8-[2-hydroxybenzoyl]-amino)caprylate.

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