Preparation method and application of 8-aminocaprylic acid

Abstract

The invention provides a preparation method of 8-amino caprylic acid. The method comprises the following steps: carrying out condensation reaction on 2-(6-halogenated hexyl) ethyl malonate (III) and phthalimide, hydrolyzing with dilute sulphuric acid, decarboxylating, deprotecting to obtain an 8-amino caprylic acid crude product, and recrystallizing with a solvent to obtain the high-purity 8-amino caprylic acid. The method has the advantages of short steps, easily available raw materials, high yield, easily separated and purified products, few three wastes, low cost, easiness in industrialization and the like.

Description

Technical Field

[0001] The present invention belongs to the field of chemical synthesis. Specifically, the present invention relates to a method for synthesizing 8-aminocaprylic acid and a method for preparing sodium 8-(2-hydroxybenzamide)caprylate by using the 8-aminocaprylic acid obtained in this way. Background Art

[0002] Sodium 8-(2-hydroxybenzamido) caprylate, referred to as SNAC, is an oral absorption enhancer that increases the lipophilicity caused by non-covalent macromolecular complexation, thereby increasing the passive transcellular permeation of small intestinal epithelial cells. SNAC can promote the absorption of the oral peptide drug semaglutide and is a delivery excipient in the oral preparation of the drug semaglutide.

[0003] 8-aminocaprylic acid is a key intermediate in the synthesis of sodium 8-(2-hydroxybenzamido)caprylate (SNAC), molecular formula: C 8 H 17 NO 2 ; Molecular weight: 159.23; CAS registration number: 1002-57-9; Its structure is as follows.

[0004]

[0005] There are many reports in the art about the method of synthesizing sodium 8-(2-hydroxybenzamido)octanoate (SNAC) using 8-aminocaprylic acid as an intermediate. For example, Synthetic Communications (2005), 35(12), 1567-1575 discloses a method of synthesizing sodium 8-(2-hydroxybenzamido)octanoate from 8-aminocaprylic acid.

[0006] At present, there are few literature reports on the synthesis of 8-aminocaprylic acid. The main reported synthesis methods are as follows:

[0007] 1) Journal of China Pharmaceutical University 2003 34(6): 496-498 reported that 8-aminooctanoic acid was prepared from cyclooctanone via three steps of oxime formation, cyclic amide, and ring opening. The synthetic route is as follows:

[0008]

[0009] This method uses cyclooctanone as a raw material, which is relatively expensive, and uses a highly toxic reagent, hydroxylamine hydrochloride. The Beckmann rearrangement reaction of ketoxime to generate lactam requires a large amount of polyphosphoric acid and water, which produces a large amount of phosphorus-containing wastewater. The wastewater treatment cost is high, so this method is not suitable for large-scale industrial production.

[0010] 2) 8-bromooctanoic acid is aminated with ammonia water to obtain 8-aminooctanoic acid. The synthetic route is as follows:

[0011]

[0012] The above method uses 8-bromooctanoic acid as a raw material, which is relatively expensive. A large amount of ammonia water is used in the reaction process, which has a great impact on the environment. In addition, the reaction has many by-products, low yield and poor quality. Therefore, this method is not suitable for industrial production.

[0013] 3) CN115557846A reported that 8-aminocaprylic acid was obtained by using N-substituted caprolactam and ethyl acetate as raw materials, ring opening, reduction and hydrolysis by strong base NaHMS. The synthetic route is as follows:

[0014]

[0015] The above method uses N-substituted caprolactam which is also relatively expensive, and uses relatively dangerous and expensive reagents NaHMDS and sodium acetate borohydride during the reaction, which greatly increases the production cost. Therefore, this process is not suitable for large-scale production.

[0016] The 8-aminocaprylic acid synthesis process currently used in the art generally has the problems of expensive raw material prices, a large amount of three wastes, a large impact on the environment, and is not suitable for large-scale industrial production. Therefore, the art is in urgent need of a new 8-amino synthesis route that is low-cost, easy to operate, safe, green and environmentally friendly, and suitable for large-scale industrial production, as well as a method for synthesizing the final 8-(2-hydroxybenzamido) sodium caprylate using the obtained 8-aminocaprylic acid. Summary of the invention

[0017] The purpose of the present invention is to provide a new synthesis method of 8-aminocaprylic acid, which has the advantages of low cost, simple operation, safety, green environmental protection, and suitability for large-scale industrial production.

[0018] The present invention also aims to provide a method for synthesizing sodium 8-(2-hydroxybenzamide)octanoate using 8-aminocaprylic acid obtained by the above method.

[0019] In a first aspect, the present invention provides a method for preparing sodium 8-(2-hydroxybenzamido)octanoate, the method comprising the following steps:

[0020] 1) reacting ethyl 2-(6-halogenohexyl)malonate (compound III) and phthalimide (compound II) in an organic solvent to obtain compound IV;

[0021]

[0022] (wherein X = Br or Cl);

[0023] 2) subjecting compound IV to a decarboxylation reaction to obtain compound VI;

[0024]

[0025] 3) Compound VI is hydrolyzed to obtain compound VII, and compound VII is further hydrolyzed to obtain compound I;

[0026]

[0027] 4) Compound I is used to prepare sodium 8-(2-hydroxybenzamido)octanoate.

[0028] In a specific embodiment, in step 1), ethyl 2-(6-halohexyl)malonate (compound III) is dissolved in an organic solvent S1, phthalimide (compound II) is added, and the temperature is raised to T1 in the presence of a base B1 for reaction, filtered, and concentrated to obtain compound IV.

[0029] In a specific embodiment, in step 2), compound IV is dissolved in dilute acid S2, and the temperature is raised to T2 to reflux for hydrolysis and decarboxylation reaction to obtain intermediate VI.

[0030] In a specific embodiment, step 3-1) is further included between step 3) and step 4), wherein compound I is obtained by crystallization and purification in an organic solvent S3.

[0031] In a preferred embodiment, the solvent S1 is one or more of acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide, preferably N,N-dimethylformamide.

[0032] In a preferred embodiment, the temperature T1 is 80-140°C; preferably 100-120°C.

[0033] In a preferred embodiment, the base B1 is an inorganic base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, etc.; preferably potassium carbonate.

[0034] In a preferred embodiment, the dilute acid S2 is sulfuric acid, hydrochloric acid, phosphoric acid or trifluoroacetic acid; preferably sulfuric acid.

[0035] In a preferred embodiment, the dilute acid S2 is 30%-70% sulfuric acid, preferably 60% sulfuric acid.

[0036] In a preferred embodiment, the temperature T2 is 100-150°C; preferably 125-135°C.

[0037] In a preferred embodiment, the reaction molar ratio of compound IV to dilute acid S2 is 1:1-1:5; preferably 1:2-1:4.

[0038] In a preferred embodiment, the solvent S3 is one or more of methanol, ethanol, isopropanol, n-propanol, and n-butanol; preferably ethanol.

[0039] In a second aspect, the present invention provides a method for preparing a compound of formula I, the method comprising the following steps:

[0040] 1) reacting ethyl 2-(6-halogenohexyl)malonate (compound III) and phthalimide (compound II) in an organic solvent to obtain compound IV;

[0041]

[0042] (wherein X = Br or Cl);

[0043] 2) subjecting compound IV to a decarboxylation reaction to obtain compound VI;

[0044]

[0045] 3) Compound VI is hydrolyzed to obtain compound VII, and compound VII is further hydrolyzed to obtain compound I;

[0046]

[0047] In a specific embodiment, in step 1), ethyl 2-(6-halohexyl)malonate (compound III) is dissolved in an organic solvent S1, phthalimide (compound II) is added, and the temperature is raised to T1 in the presence of a base B1 for reaction, filtered, and concentrated to obtain compound IV.

[0048] In a specific embodiment, in step 2), compound IV is dissolved in dilute acid S2, and the temperature is raised to T2 to reflux for hydrolysis and decarboxylation reaction to obtain intermediate VI.

[0049] In a specific embodiment, after step 3), step 3-1) is further included, in which compound I is obtained by crystallization and purification in an organic solvent S3.

[0050] In a preferred embodiment, the solvent S1 is one or more of acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide, preferably N,N-dimethylformamide.

[0051] In a preferred embodiment, the temperature T1 is 80-140°C; preferably 100-120°C.

[0052] In a preferred embodiment, the base B1 is an inorganic base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, etc.; preferably potassium carbonate.

[0053] In a preferred embodiment, the dilute acid S2 is sulfuric acid, hydrochloric acid, phosphoric acid or trifluoroacetic acid; preferably sulfuric acid.

[0054] In a preferred embodiment, the dilute acid S2 is 30%-70% sulfuric acid, preferably 60% sulfuric acid.

[0055] In a preferred embodiment, the temperature T2 is 100-150°C; preferably 125-135°C.

[0056] In a preferred embodiment, the reaction molar ratio of compound IV to dilute acid S2 is 1:1-1:5; preferably 1:2-1:4.

[0057] In a preferred embodiment, the solvent S3 is one or more of methanol, ethanol, isopropanol, n-propanol, and n-butanol; preferably ethanol.

[0058] In a third aspect, the present invention provides a compound of formula IV,

[0059]

[0060] In a fourth aspect, the present invention provides a compound of formula V,

[0061]

[0062] In a fifth aspect, the present invention provides the use of a compound represented by formula IV or a compound represented by formula V in the preparation of 8-aminocaprylic acid or 8-(2-hydroxybenzamido) sodium caprylate

[0063]

[0064] 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

[0065] Figure 1 The H-NMR spectrum of compound Ⅰ is shown;

[0066] Figure 2 The MS spectrum of compound Ⅰ is shown;

[0067] Figure 3 The HNMR spectrum of compound IV is shown;

[0068] Figure 4 The MS spectrum of compound IV is shown;

[0069] Figure 5 The MS spectrum of compound V is shown;

[0070] Figure 6 The HNMR spectrum of Compound V is shown. DETAILED DESCRIPTION

[0071] After extensive and in-depth research, the inventor unexpectedly discovered a new process route for preparing 8-aminocaprylic acid. The process route has the advantages of short steps, easy availability of raw materials, high yield, easy separation and purification of products, less three wastes, low cost, and easy industrialization. On this basis, the present invention was completed.

[0072] Preparation method of 8-aminocaprylic acid and sodium 8-(2-hydroxybenzamido)caprylate (SNAC)

[0073] In view of the fact that the synthesis process of 8-aminocaprylic acid (compound of formula I) currently used in the art generally has the disadvantages of expensive raw materials, a large amount of three wastes, a large impact on the environment, and being unsuitable for large-scale industrial production, the inventors have developed a new method for preparing 8-aminocaprylic acid, which utilizes the reaction of ethyl 2-(6-halohexyl)malonate and phthalimide to obtain compound IV; then, compound IV is subjected to a decarboxylation reaction to obtain compound VI; and compound VI is hydrolyzed to obtain compound I.

[0074] In a specific embodiment, the method comprises the following steps:

[0075] 1) reacting ethyl 2-(6-halogenohexyl)malonate (compound III) and phthalimide (compound II) in an organic solvent to obtain compound IV;

[0076] 2) subjecting compound IV to a decarboxylation reaction to obtain compound VI;

[0077] 3) Compound VI is hydrolyzed to obtain compound VII, and compound VII is further hydrolyzed to obtain compound I.

[0078] In a preferred embodiment, ethyl 2-(6-halohexyl)malonate (compound III) is dissolved in an organic solvent S1, phthalimide (compound II) is added, and the temperature is raised to T1 in the presence of a base B1 for reaction, filtered, and concentrated to obtain compound IV; then compound IV is dissolved in a dilute acid S2, the temperature is raised to T2, refluxed for hydrolysis and decarboxylation reaction to obtain intermediate VI; after compound VI is hydrolyzed to obtain compound I, compound I can also be crystallized and purified in an organic solvent S3.

[0079] On the basis of the method for preparing 8-aminocaprylic acid of the present invention, the inventors further optimized the reagents and process parameters used therein. In a specific embodiment, the solvent S1 can be one or more of acetone, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide, preferably N,N-dimethylformamide;

[0080] The temperature T1 may be 80-140°C, preferably 100-120°C;

[0081] Base B1 can be an inorganic base such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, etc., preferably potassium carbonate;

[0082] The dilute acid S2 may be sulfuric acid, hydrochloric acid, phosphoric acid or trifluoroacetic acid, preferably sulfuric acid; more preferably, the dilute acid S2 may be 30%-70% sulfuric acid; preferably 60% sulfuric acid;

[0083] The temperature T2 may be 100-150°C, preferably 125-135°C;

[0084] The reaction molar ratio of compound IV to dilute acid S2 can be 1:1-1:5, preferably 1:2-1:4;

[0085] The solvent S3 is one or more of methanol, ethanol, isopropanol, n-propanol, and n-butanol; preferably ethanol.

[0086] Those skilled in the art know how to use the compound shown in formula I, i.e., 8-aminooctanoic acid, to prepare sodium 8-(2-hydroxybenzamido)octanoate. Therefore, the present invention also provides a method for preparing sodium 8-(2-hydroxybenzamido)octanoate.

[0087] In the method of the present invention, the compound represented by formula IV and the compound represented by formula V are novel compounds that can be used to prepare 8-aminocaprylic acid or sodium 8-(2-hydroxybenzamido)caprylate.

[0088] Advantages of the present invention:

[0089] 1. The method of the present invention is easy to operate;

[0090] 2. The raw materials for the method of the present invention are readily available;

[0091] 3. The method of the present invention has a high yield for preparing 8-aminocaprylic acid and 8-(2-hydroxybenzamido) sodium caprylate, and the product is easy to separate and purify;

[0092] 4. The method of the present invention produces less three wastes, has low cost, and is easy to scale up industrially.

[0093] The present invention will be further described below in conjunction with specific examples. 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 without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer.

[0094] Example 1. Synthesis of Compound I Using Diethyl 2-(Bromohexyl)malonate as Raw Material

[0095] Step 1: Add 32.32 g (100.0 mmol) of diethyl 2-(bromohexyl)malonate, 15.4 g (105 mmol) of phthalimide, 20.73 g (150 mmol) of potassium carbonate, 3.22 g (10.0 mmol) of tetrabutylammonium bromide and 300 ml of acetone into a 500 ml three-necked flask, and heat to reflux for 16 hours. Filter the filtrate, and concentrate under reduced pressure to obtain 31.37 g of intermediate IV, with a yield of 80.5%.

[0096] Step 2: Add compound IV (30.00 g, 77.0 mmol) and 50% sulfuric acid 37.73 g (192.5 mmol) into a 500 ml three-necked flask, stir and heat to 120°C for 24 h. Add 150 ml of water to dilute, filter, and add alkali to the filtrate to neutralize pH = 6. Filter, concentrate and dry, add methanol for recrystallization, and obtain 10.08 g of compound I, with a yield of 82.2% and a content of 94.96% (titration).

[0097] Example 2. Synthesis of Compound I from diethyl 2-(chlorohexyl)malonate Step 1: Add 27.88 g (100.0 mmol) of diethyl 2-(chlorohexyl)malonate, 15.4 g (105 mmol) of phthalimide, 20.73 g (150 mmol) of potassium carbonate, 3.22 g (10.0 mmol) of tetrabutylammonium bromide and 300 ml of acetone to a 500 ml three-necked flask, and heat to reflux for 16 hours. After the reaction is complete, filter and concentrate under reduced pressure to obtain 32.4 g of intermediate IV, with a yield of 83.2%.

[0098] Step 2: Add compound IV (30.0 g, 77.0 mmol) and 50% sulfuric acid 37.73 g (192.5 mmol) into a 500 ml three-necked flask, stir and heat to 120 °C for 24 h. Add 150 ml of water to dilute. Filter, add alkali to the filtrate to neutralize pH = 6. Filter, concentrate and dry, add methanol for recrystallization, and obtain 10.12 g of compound I, with a yield of 82.5% and a content of 94.52% (titration).

[0099] Example 3: Comparative Experiment of Different Reaction Solvents and Reaction Temperature in Step 1 (Diethyl 2-(Chlorohexyl)malonate as Raw Material)

[0100] Take 10 three-necked bottles, add 2.51g 2-(chlorohexyl) diethyl malonate (Formula III) (HPLC purity 99.5%), 1.62g phthalimide (Formula II), 2.07g potassium carbonate to each three-necked bottle. Add ①10ml acetone (without phase transfer catalyst tetrabutylammonium bromide), ②10ml acetonitrile, ③10ml tetrahydrofuran, ④10ml dimethyl sulfoxide, ⑤10ml N,N-dimethylacetamide, ⑥10ml N-methylpyrrolidone, ⑦10ml N,N-dimethylformamide, ⑧10ml N,N-dimethylformamide, ⑨10ml N,N-dimethylformamide, ⑩10ml N,N-dimethylformamide. React at different temperatures for 16h. Cool to room temperature, filter and concentrate to dryness, take samples for HPLC detection, and the results are shown in Table 1 below.

[0101] Table 1.

[0102]

[0103]

[0104] Through comparative experiments, it was found that the solvent N,N-dimethylformamide had the highest conversion rate and purity. The optimal condensation reaction temperature was 100℃.

[0105] Example 4. Step 1: Comparative experiment of different bases in condensation reaction (diethyl 2-(chlorohexyl)malonate as raw material)

[0106] Take 6 three-necked bottles, add 2.5g of 2-(chlorohexyl) diethyl malonate (Formula III), 1.6g of phthalimide (Formula II), and 10ml of N,N-dimethylformamide to each three-necked bottle. Add sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide respectively. Heat to 100℃ for reaction for 16h, cool to room temperature, filter and concentrate to dryness. Take samples for HPLC detection, and the results are shown in Table 2 below.

[0107] Table 2.

[0108] Serial number Base type Conversion rate of raw material III (%) Crude IV purity (area%) 1 Sodium bicarbonate 0％ 0％ 2 Potassium bicarbonate 26％ 25.5％ 3 Sodium carbonate 85％ 83％ 4 Potassium carbonate 99.8％ 98.4％ 5 Sodium hydroxide 45.2％ 34.4％ 6 Potassium hydroxide 99.2％ 53.4％

[0109] Through comparative experiments, potassium carbonate was found to have the highest conversion rate and purity when selected as the alkali.

[0110] Example 5. Experimental comparison of hydrolysis and decarboxylation in different dilute acids in step 2

[0111] Take 5 three-necked bottles, add 5g of intermediate IV to each three-necked bottle, add 36% concentrated hydrochloric acid, 60% sulfuric acid, 50% trifluoroacetic acid, 80% acetic acid, 50% phosphoric acid respectively, and the amount of dilute acid is 3 equivalents of compound IV. React at different temperatures for 24h. Cool to room temperature, add alkali to neutralize, filter, concentrate and dry. Add ethanol to crystallize to obtain formula I, the results are shown in Table 3 below.

[0112] Table 3: Hydrolysis and decarboxylation reactions in different acid waters.

[0113] Serial number Hydrolytic decarboxylation reagents Reaction temperature time Formula I Yield (%) 1 36% concentrated hydrochloric acid 110℃ 24h 45％ 2 60% sulfuric acid 130℃ 24h 92％ 3 50% trifluoroacetic acid 70℃ 24h 65％ 4 80% acetic acid 105℃ 24h 18％ 5 50% Phosphoric acid 110℃ 24h 60％

[0114] Through comparative experiments, it was found that the yield of Product I was the highest when 60% sulfuric acid was used.

[0115] Example 6. Experimental comparison of different dilute sulfuric acid concentrations in step 2

[0116] Take 6 three-necked bottles, add 38.95g of intermediate IV to each three-necked bottle, and add 3 equivalents of dilute sulfuric acid respectively. The dilute sulfuric acid is selected from 80% sulfuric acid, 70% sulfuric acid, 65% sulfuric acid, 60% sulfuric acid, 50% sulfuric acid, and 40% sulfuric acid, and the temperature is raised to react at different temperatures for 24h. Cool to room temperature, add alkali to neutralize. Filter, concentrate and dry. Add ethanol for recrystallization to obtain formula I, and the results are shown in Table 4 below.

[0117] Table 4: Effect of sulfuric acid concentration on reaction conditions.

[0118] Serial number Sulfuric acid concentration Reaction temperature Reaction time Formula I Yield (%) 1 80％ 130℃ 24h 35.2％ 2 70％ 130℃ 24h 75.2％ 3 65％ 130℃ 24h 90.3％ 4 60％ 130℃ 24h 92.3％ 5 50％ Reflow 24h 85.3％ 6 40％ Reflow 24h 56.2％

[0119] Through comparative experiments, the hydrolysis decarboxylation yield in 60% sulfuric acid is the highest.

[0120] Example 7: Experimental comparison of the amount of 60% sulfuric acid used in step 2 hydrolysis decarboxylation

[0121] Take 8 three-necked bottles, add 38.95g of intermediate IV to each three-necked bottle, add different amounts of 60% dilute sulfuric acid, and then heat to 130°C for 24h. Cool to room temperature, add alkali to neutralize. Filter, concentrate and dry. Add ethanol for recrystallization to obtain formula I. The results are shown in Table 5 below.

[0122] Table 5.

[0123] Serial number The molar ratio of formula IV to dilute sulfuric acid Reaction time Formula I yield % 1 1.0:1 24h 56.5％ 2 2.0:1 24h 82.2％ 3 2.2:1 24h 85.5％ 4 2.5:1 24h 88.0％ 5 2.8:1 24h 91.8％ 6 3.0:1 24h 92.3％ 7 4.0:1 24h 91.2％ 8 5.0:1 24h 89.5％

[0124] Through comparative experiments, the yield of hydrolysis decarboxylation product with 3.0eq of 60% sulfuric acid was the highest.

[0125] Example 8. Experimental comparison of different hydrolysis decarboxylation reaction temperatures in step 2

[0126] Take 4 three-necked bottles, add 38.95g of intermediate IV to each three-necked bottle, add 60% sulfuric acid, and then heat to 105-115℃, 115-125℃, 125-135℃, 135-145℃ for 24h. Cool to room temperature, add alkali to neutralize. Filter, concentrate and dry, add ethanol to recrystallize to obtain formula I. The results are shown in Table 6 below.

[0127] Table 6. Effect of sulfuric acid concentration on reaction conditions.

[0128] Serial number Reaction temperature℃ Reaction time Formula I yield % 1 135-145 24h 76.2％ 2 125-135 24h 92.3％ 3 115-125 24h 85.4％ 4 105-115 24h 60.2％

[0129] Through comparative experiments, the hydrolysis decarboxylation yield is highest when the reaction temperature is 125-135℃.

[0130] Example 9. Experimental comparison of recrystallization yield and product purity of different solvents in step 2

[0131] Take 389.5g of intermediate IV (R is ethyl), add 3.0eq of 60% dilute sulfuric acid, heat to 125-135℃ and reflux for 24h. Cool to room temperature and add alkali to neutralize. Filter and divide the filtrate into 5 batches. Concentrate and dry under reduced pressure respectively, then add methanol, ethanol, isopropanol, n-propanol and n-butanol respectively to recrystallize to obtain formula I. The results are shown in Table 7 below.

[0132] Table 7.

[0133] Serial number Recrystallization solvent Formula I yield % Formula I content % (titration) 1 Methanol 91.8％ 94.58％ 2 Ethanol 92.3％ 99.52％ 3 Isopropyl alcohol 45.4％ 90.42％ 4 n-Propanol 88.7％ 96.63％ 5 n-Butanol 85.2％ 98.78％

[0134] Through comparative experiments, it was found that recrystallization using ethanol had the highest yield and purity.

[0135] Example 10: Kilogram-level scale-up verification (2-(chlorohexyl) diethyl malonate as raw material)

[0136] Step 1: Add 5.575 kg (20.0 mol) of diethyl 2-(chlorohexyl)malonate, 3.1 kg (21.08 mol) of phthalimide, and 10 L of DMF into a three-necked flask in a 50 L double-layer glass reactor, add 4.14 kg (30.0 mol) of potassium carbonate under stirring, heat to 90-100 ° C and react for 16-18 hours. After the reaction is completed, filter, recover the organic solvent under reduced pressure, and concentrate to obtain 7.52 kg of intermediate IV with a yield of 96.5%.

[0137] Step 2: Add intermediate IV (7.52kg, 19.4mmol) and 60% sulfuric acid 10.0kg (60.0mol) to 50L double-layer glass, stir and heat to 125-135℃, reflux and hydrolyze for decarboxylation reaction for 24h, control the reaction to be complete in HPLC, cool slightly, add 30L of water, stir and cool to room temperature, filter, add alkali to the filtrate to neutralize pH = 6, filter, concentrate and dry, add ethanol for recrystallization, and obtain 2.9kg of Formula I fine product, with a yield of 93.1% and a content of 99.56%.

[0138] Detection method of hydrolysis decarboxylation conversion HPLC: chromatographic column: ZORBAX Eclipse C18 4.6mm*250mm, 5um; column temperature: 30℃; flow rate: 1.0ml / min; detection wavelength: 220nm; injection volume: 5μl; mobile phase: A: water, B: methanol, gradient elution as shown in Table 8 below.

[0139] Table 8.

[0140] Time (min) 0 20 40 41 51 A(％) 20 0 0 20 20 B(％) 80 100 100 80 80

[0141] Example 11: Synthesis of Compound III (X = Br) diethyl 2-(bromohexyl)malonate

[0142]

[0143] In a 2000ml glass three-necked flask, 366g of 1,6-dibromohexane, 100g of anhydrous potassium carbonate, 1.6g of tetrabutylammonium bromide, and 400ml of cyclohexane were added. The temperature was raised to reflux, and 80g of diethyl malonate was slowly added dropwise under reflux. After the addition was completed, the mixture was kept warm for 2 hours. The reaction was completed during GC control. The mixture was cooled to room temperature, filtered, and the filtrate was washed with water once. The solvent was recovered by concentration under reduced pressure, and the residual liquid was distilled under reduced pressure to obtain 123.2g of colorless transparent liquid product compound III (X=Br) 2-(bromohexyl) diethyl malonate with a yield of 76.3% (based on diethyl malonate) and a GC purity of 98.4%.

[0144] Example 12. Synthesis of Compound III (X=Cl) Diethyl 2-(Chlorohexyl)malonate

[0145]

[0146] In a 50L double-layer glass reactor, 9304g of 1,6-dichlorohexane, 3864g of anhydrous potassium carbonate, 32g of tetrabutylammonium chloride, and 16000ml of cyclohexane were added to a three-necked flask, and the temperature was raised to reflux. 3200g of diethyl malonate was slowly added dropwise under reflux. After the addition was completed, the mixture was kept warm for 2 hours. The reaction was completed during GC control. The mixture was cooled to room temperature, filtered, and the filtrate was washed once with 6400ml of water. The organic layer was concentrated under reduced pressure to recover the solvent. The residual liquid was distilled under reduced pressure to obtain 4740.9g of colorless transparent liquid compound III (X=Cl) 2-(chlorohexyl) diethyl malonate with a yield of 85.0% (based on diethyl malonate) and a GC purity of 99.38%.

[0147] 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 preparing 8-(2-hydroxybenzamido) sodium caprylate, the method comprising the following steps: 1) reacting ethyl 2-(6-halogenohexyl)malonate (compound III) and phthalimide (compound II) in an organic solvent to obtain compound IV; (wherein X = Br or Cl); 2) subjecting compound IV to a decarboxylation reaction to obtain compound VI; 3) Compound VI is hydrolyzed to obtain compound VII, and compound VII is further hydrolyzed to obtain compound I; 4) Compound I is used to prepare sodium 8-(2-hydroxybenzamido)octanoate.

2. The preparation method according to claim 1, characterized in that In step 1), ethyl 2-(6-halohexyl)malonate (Compound III) is dissolved in an organic solvent S1, phthalimide (Compound II) is added, and the temperature is raised to T1 in the presence of a base B1 for reaction, and the reaction is filtered and concentrated to obtain Compound IV.

3. The preparation method according to claim 1, characterized in that: In step 2), compound IV is dissolved in dilute acid S2, and the temperature is raised to T2 to reflux for hydrolysis and decarboxylation reaction to obtain intermediate VI.

4. The preparation method according to claim 1, characterized in that: The step 3-1) is included between step 3) and step 4), wherein compound I is obtained by crystallization and purification in an organic solvent S3.

5. A method for preparing a compound of formula I, comprising the following steps: 1) reacting ethyl 2-(6-halogenohexyl)malonate (compound III) and phthalimide (compound II) in an organic solvent to obtain compound IV; (wherein X = Br or Cl); 2) subjecting compound IV to a decarboxylation reaction to obtain compound VI; 3) Compound VI is hydrolyzed to obtain compound VII, and compound VII is further hydrolyzed to obtain compound I; 6. The preparation method according to claim 5, characterized in that: In step 1), ethyl 2-(6-halohexyl)malonate (Compound III) is dissolved in an organic solvent S1, phthalimide (Compound II) is added, and the temperature is raised to T1 in the presence of a base B1 for reaction, and the reaction is filtered and concentrated to obtain Compound IV.

7. The preparation method according to claim 5, characterized in that: In step 2), compound IV is dissolved in dilute acid S2, and the temperature is raised to T2 to reflux for hydrolysis and decarboxylation reaction to obtain intermediate VI.

8. The preparation method according to claim 5, characterized in that: After step 3), the method further comprises step 3-1), wherein compound I is obtained by crystallization and purification in an organic solvent S3.

9. The compound represented by formula IV, 10. The compound represented by formula V, 11. Use of the compound represented by formula IV or the compound represented by formula V in the preparation of 8-aminocaprylic acid or 8-(2-hydroxybenzamido) sodium caprylate

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