A method for preparing 8-(2-hydroxybenzamido)octanoic acid

Abstract

This invention discloses a novel method for preparing 8-(2-hydroxybenzamido)octanoic acid in the field of biomedical technology. The method uses 2-hydroxybenzaldehyde and 8-aminooctaldehyde as raw materials, chloroform as solvent, and tert-butanol peroxide as oxidant, to prepare 8-(2-hydroxybenzamido)octanoic acid via an oxidation-free radical reaction. The route provided by this invention is concise, the conditions are mild, and the product yield is high, offering a general new method for the preparation of 8-(2-hydroxybenzamido)octanoic acid.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a novel method for synthesizing 8-(2-hydroxybenzamido)octanoic acid. Background Technology

[0002] Because peptide and protein drugs have large molecular weights and poor lipid solubility, they are difficult to cross biological membrane barriers. Clinically, most peptide and protein drugs are administered via non-gastrointestinal routes, often causing significant inconvenience to patients. Sodium 8-(2-hydroxybenzamido)octanoate has certain hydrophilic and lipophilic properties and a high electron density, making it suitable as an absorption enhancer for peptide and protein drugs, improving their absorption capacity for large molecule drugs.

[0003] Currently, the following methods for preparing 8-(2-hydroxybenzamido)octanoic acid have been reported in the literature:

[0004] (1) In patent CN108689876A, salicylamide is used as a raw material to react with N'N-carbonyldiimidazole to generate the intermediate 2H-benzo[e][1,3]oxazine-2,4(3H)-dione, which then undergoes a nucleophilic substitution reaction with ethyl 8-bromooctanoate to obtain ethyl 8-(2,4-dicarbonyl-2H-benzo[e][1,3]oxazine-3(4H)-yl)octanoate. After hydrolysis with sodium hydroxide and acidification, 8-(2-hydroxybenzamido)octanoic acid is obtained. Finally, ring-opening is performed in the sodium hydroxide system to obtain sodium 8-(2-hydroxybenzamido)octanoate. This reaction route is cumbersome, and the use of sodium hydroxide to promote ring-opening and crystallization carries the risk of forming a disodium salt.

[0005]

[0006] (2) Patent WO2022 / 162132 uses potassium methoxide to promote the nucleophilic substitution reaction of methyl 2-hydroxybenzoate with 8-aminooctanoic acid to obtain 8-(2-hydroxybenzoamide)octanoic acid.

[0007]

[0008] (3) Ding Ya et al. prepared 8-aminooctanoic acid by cyclooctanone as raw material through a three-step reaction of oxime formation, rearrangement and hydrolysis, and then carried out an acylation reaction with salicylic acid low polyester to obtain 8-salicylamidooctanoic acid.

[0009]

[0010] This technical approach is cumbersome and results in low reaction yield. Summary of the Invention

[0011] The present invention aims to provide a method for preparing 8-(2-hydroxybenzamido)octanoic acid, which has a short reaction procedure, mild reaction conditions, low synthesis cost, and high yield.

[0012] The technical solution adopted in this invention is as follows: A method for preparing 8-(2-hydroxybenzamido)octanoic acid, which uses 2-hydroxybenzaldehyde and 8-aminooctanoic acid as starting materials, chloroform as solvent, and tert-butanol peroxide (TBHP) as oxidant, to obtain 8-(2-hydroxybenzamido)octanoic acid (I) through an oxidation-free radical reaction, the reaction formula of which is:

[0013]

[0014] Furthermore, the molar ratio of tert-butanol peroxide (TBHP) to 2-hydroxybenzaldehyde is (1-3.5):1; preferably 3:1.

[0015] A further improvement of the present invention is that the molar ratio of 2-hydroxybenzaldehyde and 8-aminooctaldehyde is 1:(1-2), preferably 1:1.5.

[0016] The reaction temperature of this invention is 70-90℃, preferably 80℃.

[0017] The oxidant of this invention is selected from m-chloroperoxybenzoic acid (m-CPBA), tert-butanol peroxide (TBHP), hydrogen peroxide (H2O2), cerium ammonium nitrate (CAN), potassium persulfate (K2S2O8), and sodium persulfate (Na2S2O8), with tert-butanol peroxide (TBHP) ultimately selected as the oxidant. The reaction solvent of this invention is selected from chloroform, acetonitrile, dichloromethane, tetrahydrofuran, methanol, and purified water, with chloroform ultimately selected as the reaction solvent.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0019] (1) The preparation route of this invention is simple, and the reaction solvent is chloroform, which is inexpensive and readily available.

[0020] (2) The route provided by the present invention has mild reaction conditions, simple operation, and good promotion and application value. Attached Figure Description

[0021] Figure 1 The target compound's 1H NMR spectrum is shown.

[0022] Figure 2 The carbon NMR spectrum of the target compound. Detailed Implementation

[0023] The analytical instruments and equipment used in the examples are: nuclear magnetic resonance spectrometer (AVANCE DMXⅡⅠ400M, Bruker); three-way ultraviolet analyzer (ZF-6); and micro melting point apparatus (SGW X-4A).

[0024] Example 1: Preparation of 8-(2-hydroxybenzamido)octanoic acid

[0025] 2-hydroxybenzaldehyde (1.22 g, 10 mmol), 8-aminooctaldehyde (2.18 g, 15 mmol), 20 ml chloroform, and TBHP (2.70 g, 30 mmol) were added sequentially to a 100 ml pressure-resistant sealed tube. The reaction was heated at 80 °C for 26 h (TLC was used to monitor the reaction progress); the reaction formula is as follows:

[0026]

[0027] After the reaction was completed, the reaction system was concentrated using a rotary evaporator. 4 ml of ethanol solution and 4 ml of saturated sodium bicarbonate aqueous solution were added to the reaction system, and the mixture was stirred overnight. The solid was filtered and dried to obtain 1.61 g of pure sodium 8-(2-hydroxybenzamide)octanoate, with a yield of 53.6%.

[0028] Its 1H NMR and 1C NMR data are as follows:

[0029] 1 H NMR(400MHz,D2O)δ7.77(dd,J=7.9,2.0Hz,1H),7.26(ddd,J=8.7,7.0,2.0Hz,1H),6.73(dd,J=8.3,1.2Hz,1H),6 .66–6.57(m,1H),3.35(t,J=6.8Hz,2H),2.15(t,J=7.5Hz,2H),1.56(dp,J=26.2,7.1Hz,4H),1.44–1.26(m,6H).

[0030] 13 C NMR (100MHz, D2O) δ184.28,170.39,168.74,133.45,129.36,121.96,118.41,113.74,38.97,37.65,28.66,28.54,28.19,26.24,25.86.

[0031] Example 2: Screening of Oxidizing Agents

[0032] The experimental conditions and feed amounts in this embodiment are the same as in Example 1, but different oxidants are selected. The amount of oxidant used is 3 times that of 2-hydroxybenzaldehyde (molar ratio) for the experiment, as shown in Table 1:

[0033] Table 1: Screening of Oxidizing Agents

[0034] Oxidizing agent yield 1 m-CPBA 42％ 2 TBHP 53.6％ 3 <![CDATA[H2O2]]> Trace% 4 CAN 17.5％ 5 <![CDATA[K2S2O8]]> 28.5％ 6 <![CDATA[Na2S2O8]]> 23.2％

[0035] As shown in Table 1, hydrogen peroxide is not suitable for this catalytic system. During the homolytic cracking process of hydrogen peroxide, water molecules or protons are generated, thus inhibiting the occurrence of free radical reactions. When sodium persulfate and potassium persulfate are used as oxidants, the reaction yields are 23.2% and 28.5%, respectively. However, when tert-butanol peroxide (TBHP) is used as the oxidant, the reaction yield is the highest, at 53.6%. Therefore, this invention selects tert-butanol peroxide (TBHP) as the oxidant.

[0036] Example 3: Screening of TBHP Dosage

[0037] The experimental conditions and dosage in this embodiment are the same as in Example 1. Different doses of TBHP were selected for the experiment, as shown in Table 2.

[0038] Table 2: Screening of Oxidant Dosage

[0039] Dosage (mmol) yield 1 10 25.6％ 2 20 47.5％ 3 30 53.6％ 4 35 54.0％ 5 40 54.1％ 6 50 53.9％

[0040] As shown in Table 2, the reaction yield continued to increase with the increase of TBHP. When the amount of TBHP added was 3 times that of 2-hydroxybenzaldehyde (molar ratio), the reaction yield reached a peak of 53.6%. Further increasing the dosage of TBHP did not significantly improve the yield.

[0041] Example 4: Solvent Screening

[0042] The experimental conditions and feed amounts in this embodiment are the same as in Example 1, but different reaction solvents are selected for the experiments, as shown in Table 3:

[0043] Table 3: Solvent Screening

[0044]

[0045]

[0046] As shown in Table 3, acetonitrile, dichloromethane, and purified water are not suitable for this catalytic system. When methanol and tetrahydrofuran are used as solvents, the yields are 7.5% and 6.2%, respectively. When chloroform is used as the solvent, the reaction yield is the highest at 53.6%, which may be related to the oxidation of chloroform chlorine radicals. In this invention, chloroform is selected as the reaction solvent.

[0047] Example 5: Molar ratio screening of 2-hydroxybenzaldehyde and 8-aminooctaldehyde

[0048] The experimental conditions and feed amounts in this embodiment are the same as in Example 1. Different molar ratios of 2-hydroxybenzaldehyde and 8-aminooctaldehyde were selected for the experiment, as shown in Table 4.

[0049] Table 4: Screening of molar ratios of 2-hydroxybenzaldehyde and 8-aminooctaldehyde

[0050] 2-Hydroxybenzaldehyde and 8-Aminooctaldehyde (mmol) yield 1 1:0.5 16.8％ 2 1:0.75 31.5％ 3 1:1 43.0％ 4 1:1.25 45.3％ 5 1:1.5 53.6％ 6 1:1.8 53.6％ 7 1:2 53.4％ 8 1:3 53.4％ 9 1:4 53.0％

[0051] As shown in Table 4, when the molar ratio of 2-hydroxybenzaldehyde to 8-aminooctaldehyde is 1:0.5, the reaction yield is 16.8%; when the molar ratio of 2-hydroxybenzaldehyde to 8-aminooctaldehyde is 1:1.5, the reaction yield is 53.6%. Therefore, the preferred molar ratio of 2-hydroxybenzaldehyde to 8-aminooctaldehyde in this invention is 1:1.5.

[0052] Example 6: Screening of reaction temperature

[0053] The experimental conditions and feed amounts in this embodiment are the same as in Example 1, but different reaction temperatures are selected for the experiments, as shown in Table 5:

[0054] Table 5: Screening of reaction temperatures

[0055] Reaction temperature (°C) yield 1 30 Trace% 2 45 8.6％ 3 60 29.1％ 4 70 48.2％ 5 80 50.1％ 6 90 53.6％ 7 100 53.6％

[0056] As can be seen from Table 5, the reaction temperature of the present invention can be selected from 70-90℃, preferably 80℃.

[0057] 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 8-(2-hydroxybenzamido)octanoic acid, characterized in that: Starting with 2-hydroxybenzaldehyde and 8-aminooctaldehyde, using chloroform as solvent and tert-butanol peroxide as oxidant, 8-(2-hydroxybenzamido)octanoic acid (I) was obtained via an oxidation-free radical reaction. The reaction formula is as follows: ; The molar ratio of tert-butanol peroxide to 2-hydroxybenzaldehyde is (1-3.5):1; the molar ratio of 2-hydroxybenzaldehyde to 8-aminooctaldehyde is 1:(1-2); and the reaction temperature is 70-90℃.

2. The method for preparing 8-(2-hydroxybenzamido)octanoic acid according to claim 1, characterized in that, The molar ratio of tert-butanol peroxide to 2-hydroxybenzaldehyde is 3:

1.

3. The method for preparing 8-(2-hydroxybenzamido)octanoic acid according to claim 1, characterized in that: The molar ratio of 2-hydroxybenzaldehyde to 8-aminooctaldehyde is 1:1.

5.

4. The method for preparing 8-(2-hydroxybenzamido)octanoic acid according to claim 1, characterized in that: The reaction temperature is 80℃.

Images