Process for the preparation of 8-aminooctanoic acid and uses thereof

Abstract

The present application relates to the field of drug synthesis, and more particularly provides a method for preparing 8-amino octanoic acid with different compounds as starting materials, and the use of 8-amino octanoic acid obtained as an intermediate. The method of the present application has the advantages of cheap and readily available raw materials, simple operation, high product yield and purity, green environmental protection, and suitability for industrial scale-up production.

Description

Process for the preparation of 8-amino octanoic acid and uses thereof

[0001] Cross-reference to related applications

[0002] This application claims priority to Chinese Patent Application No. 202410855409.5, filed on June 28, 2024, to the China Patent Office, which is incorporated herein by reference. TECHNICAL FIELD

[0003] The present application relates to the field of pharmaceutical chemistry synthesis, in particular to a process for the preparation of 8-amino octanoic acid and uses thereof. BACKGROUND

[0004] N-(8-[2-hydroxybenzoyl]-amino) sodium octanoate (SNAC for short) is a chemical synthetic fatty acid sodium salt discovered by Emisphere Corporation in the 1990s, and it is a high-efficiency small molecule penetration enhancer.

[0005] The research team of Emisphere Corporation proposed a SNAC penetration model hypothesis: the carrier molecule SNAC combines with the drug molecule in the form of non-covalent bond, thereby changing the drug molecule configuration to form a transportable complex (hydrophobic lipophilic), thereby performing transcellular transport. At the same time, due to the weak interaction between the two, the carrier molecule and the drug are separated by simple dilution when entering the blood circulation.

[0006] Clinical data shows that SNAC can promote the penetration and absorption of some polypeptide drugs such as semaglutide tablets, and has good stability and safety. Oral polypeptide has gradually become a trend in the development of polypeptide drugs, so SNAC as a penetration enhancer has great application potential in polypeptide drugs.

[0007] 8-amino octanoic acid is a key intermediate for preparing SNAC, and its structure is as follows:

[0008] The reported synthesis methods of 8-amino octanoic acid mainly include the following:

[0009] One method is proposed by Eshghi, Hossein (Journal of Chemical Research, 2006, 4, 218), in which cyclooctanone is used as a raw material, sodium azide and concentrated sulfuric acid are used to rearrange 2-azacyclononanone, and then acid hydrolysis is used to obtain 8-amino octanoic acid, and the synthesis route is as follows:

[0010] The method has the following disadvantages: the raw material cyclooctanone is expensive; sodium azide used in the preparation process is an explosive hazardous material, and it produces toxic azide acid in acid, which makes the industrial production have great safety hazards, etc.

[0011] Another method is proposed by Nanda et al. (Tetrahedron Asymmetry, 2003, 14, 13, 1799), in which octanediol is used as the raw material, 8-bromo-1-octanol is obtained by reaction with hydrobromic acid, 8-bromo-1-octanoic acid is obtained by oxidation with Jones reagent, and finally 8-aminooctanoic acid is obtained by reaction with ammonia water, and the synthetic route is as follows:

[0012] The method has the following disadvantages: the starting material octanediol is expensive; the Jones reagent used as the oxidant contains heavy metal chromium element, and thus produces waste solid containing chromium salt, which pollutes the environment; etc.

[0013] Therefore, there is a need in the art to develop a method for synthesizing 8-aminooctanoic acid using low-cost raw materials, which is simple to operate, green and safe, and suitable for industrial production. SUMMARY

[0014] Therefore, the present application provides a new method for synthesizing 8-aminooctanoic acid of formula I, which has the characteristics of low-cost and easily available raw materials, simple operation, high yield and purity, and can realize industrial production.

[0015] In one aspect, a method for preparing 8-aminooctanoic acid of formula I is provided, which comprises the following steps:

[0016] Step 1: reacting a compound of formula IV with a compound of formula III in the presence of a base in an organic solvent and / or water to obtain a compound of formula II; and

[0017] Step 2: hydrolyzing the compound of formula II in the presence of an acid in an organic solvent and / or water to obtain the desired target product 8-aminooctanoic acid,

[0018] wherein R1 is a hydroxyl protecting group selected from methylsulfonyl, ethylsulfonyl, phenylsulfonyl, 2-methylphenylsulfonyl, 3-methylphenylsulfonyl, 4-methylphenylsulfonyl, 4-nitrophenylsulfonyl or 4-chlorophenylsulfonyl;

[0019] R2 is independently selected from CN or -CO2R4, wherein R4 is independently selected from H, substituted or unsubstituted C 1-9 alkyl, substituted or unsubstituted C 3-9 cycloalkyl or substituted or unsubstituted C 6-10 aryl;

[0020] R3is independently selected from H, substituted or unsubstituted C 1-9 alkyl, substituted or unsubstituted C 3-9 cycloalkyl, or substituted or unsubstituted C 6-10 aryl; and

[0021] R5is an amino protecting group selected from methoxycarbonyl, ethoxycarbonyl, n- propyloxycarbonyl, i-propyloxycarbonyl, n-butyloxycarbonyl, t-butyloxycarbonyl, or benzyloxycarbonyl.

[0022] In another aspect, there is provided a process for preparing 8-aminooctanoic acid of formula I, the process comprising the steps of:

[0023] Step 3: reacting the compound of formula V in an organic solvent in the presence of a reducing agent to obtain a compound of formula VI;

[0024] Step 4: reacting the compound of formula VI with a sulfonylating agent R1X in the presence of an organic amine in an organic solvent to obtain a compound of formula IV;

[0025] Step 1: reacting the compound of formula IV with a compound of formula III in the presence of a base in an organic solvent and / or water to obtain a compound of formula II; and

[0026] Step 2: hydrolyzing the compound of formula II in the presence of an acid in an organic solvent and / or water to obtain the desired target product 8-aminooctanoic acid,

[0027] wherein R1, R2, R3and R5are as defined above, and X is a halogen selected from chlorine, bromine or iodine.

[0028] In a preferred embodiment, the base used in step 1 is one or more selected from n-butyllithium, t-butyllithium, sodium t-butoxide, potassium t-butoxide, methylmagnesium chloride, ethylmagnesium chloride, lithium diisopropylamide, lithium hydride, sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium i-propoxide, and sodium n-butoxide.

[0029] In a preferred embodiment, the acid used in step 2 is one or more selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, formic acid, and acetic acid.

[0030] In a preferred embodiment, the above process further comprises quenching the reaction with a weak acid prior to step 2.

[0031] In a preferred embodiment, the above process further comprises solvent extraction and crystallization of the resulting target compound after step 2.

[0032] In a preferred embodiment, the reducing agent used in step 3 is one or more selected from borane, lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, lithium triethylborohydride and sodium triacetylborohydride; preferably, the reaction in step 3 is carried out at 0-75 °C.

[0033] In a preferred embodiment, the organic amine used in step 4 is one or more selected from methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tributylamine, pyridine, piperidine, ethylenediamine, morpholine and piperazine.

[0034] In a preferred embodiment, the same or different organic solvents are used in steps 1 to 4.

[0035] In yet another aspect, there is provided a use of 8-aminooctanoic acid prepared by the process of the present application as an intermediate for the preparation of N-(8-[2-hydroxybenzoyl]-amino)octanoic acid sodium salt (SNAC). DETAILED DESCRIPTION

[0036] The present application provides a process for the synthesis of 8-aminooctanoic acid using different starting compounds as the raw material. More particularly, the present application provides a first reaction scheme and a second reaction scheme as shown below for the synthesis of the target compound 8-aminooctanoic acid:

[0037] (first reaction scheme)

[0038] (second reaction scheme)

[0039] The first reaction scheme directly uses a compound of formula IV as the raw material and comprises the following steps 1 and 2:

[0040] Step 1: reacting a compound of formula IV with a compound of formula III in the presence of a base in an organic solvent and / or water to obtain a compound of formula II; and

[0041] Step 2: hydrolyzing the compound of formula II in the presence of an acid in an organic solvent and / or water to obtain the desired target product 8-aminooctanoic acid.

[0042] In the compound of formula IV used, R1 is a hydroxyl protecting group selected from methanesulfonyl, ethanesulfonyl, benzenesulfonyl, 2-methylbenzenesulfonyl, 3-methylbenzenesulfonyl, 4-methylbenzenesulfonyl, 4-nitrobenzenesulfonyl or 4-chlorobenzenesulfonyl; and R5 is an amino protecting group selected from methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, t-butyloxycarbonyl or benzyloxycarbonyl.

[0043] In the used compound of formula III, R2is independently selected from cyano (CN) or -CO2R4, wherein R4is independently selected from H, substituted or unsubstituted C 1-9 alkyl, substituted or unsubstituted C 3-9 cycloalkyl or substituted or unsubstituted C 6-10 aryl; and R3is independently selected from H, substituted or unsubstituted C 1-9 alkyl, substituted or unsubstituted C 3-9 cycloalkyl or substituted or unsubstituted C 6-10 aryl.

[0044] The inventors surprisingly found that by specifically selecting the hydroxyl protecting group R1of the compound of formula IV to be the above mentioned sulfonyl group, the reaction of the compound of formula IV with the compound of formula III (in the presence of a base) can be accomplished under milder reaction conditions (e.g. without the use of expensive and / or hazardous and / or environmentally unfriendly chemicals etc.) in high yield (90% or more) and the resulting compound of formula II can subsequently be subjected to a simple acidic hydrolysis to obtain the target compound in high yield (90% or more) and high purity (99% or more), thereby making the overall procedure of the present application simple, cost-effective and environmentally friendly.

[0045] The second reaction scheme starts with a compound of formula V and, in contrast to the above described first scheme, it comprises additional steps 3 and 4 for the synthesis of the compound of formula IV:

[0046] Step 3: reacting the compound of formula V in the presence of a reducing agent in an organic solvent to obtain a compound of formula VI; and

[0047] Step 4: reacting the compound of formula VI with a sulfonylating reagent R1X in the presence of an organic amine in an organic solvent to obtain the compound of formula IV.

[0048] In the used compound of formula V and in the obtained compound of formula VI, R5is as defined above for the compound of formula IV; and in the used sulfonylating reagent R1X, R1is as defined above for the compound of formula IV, and X is a halogen selected from chlorine (CI), bromine (Br) or iodine (I), preferably CI. As it is well known to the skilled person, the used compound of formula V can be readily prepared from commercially available caprolactam by a conventional reaction with the amino protecting group R5.

[0049] The present inventors have found that the compound of formula V with the above-mentioned amino protecting group R5 can be easily obtained, for example, by protecting the amino group of a caprolactam compound by a method well known in the art. Moreover, in the case where the amino group is protected, the compound of formula V can be obtained as a ring-opened product, i.e., a compound of formula VI, using a reducing agent such as a boron-based reducing agent under mild conditions (e.g., at ordinary temperature and pressure, without using a toxic or hazardous chemical, etc.) with a high yield (up to 100%). Further, the obtained compound of formula VI can also be obtained as a desired compound of formula IV by reacting with a sulfonylating agent R1X under mild conditions (e.g., at ordinary temperature and pressure, without using a toxic or hazardous chemical, etc.) with a high yield (up to 100%).

[0050] As used herein, C 1-9 Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-butyl, and the like. C 3-9 Examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, methylcyclopentyl, ethylcyclopentyl, methylcyclohexyl, ethylcyclohexyl, and the like. C 6-10 Examples of the aryl group include, but are not limited to, phenyl, tolyl, ethylphenyl, benzyl, naphthyl, and the like. Moreover, in the present application, the above-mentioned C 1-9 Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-butyl, and the like. C 3-9 Examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, methylcyclopentyl, ethylcyclopentyl, methylcyclohexyl, ethylcyclohexyl, and the like. C 6-10 The aryl group can be unsubstituted or substituted with a substituent such as a halogen, and is preferably unsubstituted.

[0051] In step 1 of the method of the present application, preferably, the base used can be one or more selected from the group consisting of n-butyllithium, t-butyllithium, sodium t-butoxide, potassium t-butoxide, methylmagnesium chloride, ethylmagnesium chloride, lithium diisopropylamide, lithium hydride, sodium hydride, potassium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide.

[0052] In step 2 of the method of the present application, preferably, the acid used can be one or more selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, formic acid, acetic acid.

[0053] The organic solvent used in step 1 or step 2 of the process of the present application can be the same or different. For example, the organic solvent used can be one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, water, acetonitrile, hexane, n-heptane, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, toluene, xylene, chlorobenzene, ethyl formate, ethyl acetate, isopropyl acetate.

[0054] In a preferred embodiment, after the compound of formula IV and the compound of formula III (preferably in a molar excess) are added to the organic solvent in step 1, the reaction can be stirred at 0-85°C, preferably 10-70°C, more preferably 30-65°C, under normal pressure and in the presence of a base for 1-12 hours, preferably 2-10 hours, more preferably 3-5 hours, until the compound of formula IV is completely reacted.

[0055] In a preferred embodiment, the reaction mixture obtained after completion of step 1 can be directly used in step 2. Conventionally, after the compound of formula IV is completely reacted in step 1, the reaction can be quenched with an acid such as formic acid, acetic acid, citric acid, succinic acid, etc., and then the reaction solution can be extracted several times with an organic solvent (such as one or more selected from the group consisting of toluene, xylene, chlorobenzene, hexane, n-heptane, ethyl acetate, isopropyl acetate, isopropyl ether, methyl tert-butyl ether), and the obtained organic phase can be concentrated, for example, by rotary evaporation, an acidic solution of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. is added, and then the reaction of step 2 is performed.

[0056] In a more preferred embodiment, in step 1, the compound of formula III can be first dissolved in an organic solvent at 15-70°C, a base is added thereto, and then stirred for 0.5-2.0 hours, and then the compound of formula IV is added to react. After the reaction is completed, an acidic solution of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. is directly added and stirred to perform acidic hydrolysis, whereby the desired target compound of formula I can be obtained.

[0057] In a preferred embodiment, after completion of step 2, an organic solvent can be added to the solution containing the target compound of formula I to extract and crystallize to obtain the compound of formula I. Preferably, the organic solvent used here can be one or more selected from the group consisting of toluene, xylene, chlorobenzene, hexane, n-heptane, ethyl acetate, isopropyl acetate, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methanol, ethanol, isopropanol.

[0058] In step 3 of the process of the present application, preferably, the compound of formula V is dissolved in an organic solvent (such as one or more selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, isopropyl acetate) and then a reducing agent is added to perform the reduction reaction. After the reaction is completed, another organic solvent (such as one or more selected from the group consisting of ethyl formate, ethyl acetate, isopropyl acetate, toluene, hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, methyltetrahydrofuran) can be added to perform extraction, concentrated under reduced pressure, and then crystallized, thereby obtaining the compound of formula VI.

[0059] In step 3 of the process of the present application, preferably, the reducing agent used can be a boron reagent, including but not limited to one or more of borane, lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, lithium triethylborohydride, sodium triacetylborohydride, and the like.

[0060] In step 3 of the process of the present application, preferably, the reduction reaction can be performed at 0-85°C, preferably at 10-40°C, more preferably at room temperature (typically 15-25°C) and under normal pressure.

[0061] In step 4 of the process of the present application, after the reaction of the compound of formula VI with R1Cl in the presence of an organic solvent and an organic amine is completed, post-treatment such as extraction is performed, concentrated, to obtain a concentrated solution of the compound of formula IV, which is directly used for the next step reaction.

[0062] In step 4 of the process of the present application, preferably, the organic solvent used can be one or more selected from the group consisting of dichloromethane, trichloromethane, tetrahydrofuran, methyltetrahydrofuran, ethyl acetate, isopropyl acetate, toluene, hexane, n-heptane, isopropyl ether, methyl tert-butyl ether.

[0063] In step 4 of the process of the present application, preferably, the organic amine used can be one or more selected from the group consisting of methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tributylamine, pyridine, piperidine, ethylenediamine, morpholine, piperazine, and the like.

[0064] In addition, the 8-aminooctanoic acid prepared by the above-mentioned process of the present application can be used as an intermediate compound for preparing the high-efficiency small-molecule penetration enhancer N-(8-[2-hydroxybenzoyl]-amino)octanoic acid sodium. For example, as is apparent to those skilled in the art, the 8-aminooctanoic acid can be first formed into its sodium salt (i.e., 8-aminooctanoic acid sodium), and then reacted with 2-hydroxybenzoyl chloride to obtain the target product N-(8-[2-hydroxybenzoyl]-amino)octanoic acid sodium.

[0065] The method of the present application is further exemplified below by way of examples. It should be understood that the examples below are provided merely to enable a better understanding of the present application, and are not intended to limit the scope of the present application in any way.

[0066] Unless otherwise indicated, the various solvents and reagents are commercially available. The starting materials used are either commercially available or are prepared by further processing of commercially available materials by simple and routine reactions well known in the art. A few reagents directly commercially available are exemplified, such as caprolactam purchased from Zhejiang Risheng Fine Chemical Co., Ltd., ethyl cyanoacetate purchased from Rudong Tongyuan Chemical Co., Ltd., sodium borohydride purchased from Zhejiang Risheng Fine Chemical Co., Ltd., methanesulfonyl chloride purchased from Hubei Xingchi Science and Technology Co., Ltd., p-toluenesulfonyl chloride purchased from Nantong Volan Chemical Co., Ltd., sodium ethoxide purchased from Shandong Langheng Chemical Co., Ltd., acetyl chloride purchased from Zouping Qili Auxiliary Co., Ltd., and the like.

[0067] In addition, in light of the actual laboratory or industrial production operation needs and taking into account the approximation or error in operation and control, some of the reaction condition parameters in the following examples are listed in a range available in practice. As understood by those skilled in the art, such a range (especially the middle value or median range of the range) indicates that the experimental purpose can be achieved and the corresponding results can be obtained within the range listed (without being accurate to a certain specific value). Similarly, for the operations that are conventional in the art, the corresponding operations can be understood and implemented by those skilled in the art without being explicitly stated herein.

[0068] Example 1: Preparation of a compound of Formula VI-a (i.e., an example in which R5 is tert-butyloxycarbonyl)

[0069] Into a reaction flask, 213.3 g of the compound of Formula V-a and 1600 g of methanol were added and stirred to dissolve. While controlling the temperature at 10-30 °C, 75.6 g of sodium borohydride was added in batches, after the addition was completed, the reaction was stirred for 4.0-5.0 hours, then the temperature was raised to 50-65 °C and the reaction was stirred for 2.0-3.0 hours until the reaction was completed. After the temperature was lowered to room temperature, 8% ammonium chloride solution was added to quench the reaction, and the reaction solvent was recovered by concentration under reduced pressure. Finally, ethyl acetate was added to the obtained concentrated solution for extraction three times (260 g each time), and the combined organic phase was concentrated to dryness under reduced pressure to obtain 217.3 g of the compound of Formula VI-a (yield 100%), which was directly used in the next step reaction.

[0070] Example 2: Preparation of a compound of Formula VI-b (i.e., an example in which R5 is ethoxycarbonyl)

[0071] Into a reaction flask, under nitrogen protection, was placed 185.2 g of the compound of Formula V-b and 1500 g of ethanol, and the mixture was stirred until dissolved. Then, the temperature was controlled at 15-25 °C, and 76.5 g of sodium borohydride was added in portions. After the addition was completed, the mixture was stirred for 3.0-4.5 hours, and then the temperature was raised to 55-65 °C. The mixture was stirred for 3.0-4.0 hours until the reaction was completed. The temperature was then lowered to room temperature, 8% ammonium chloride solution was added to quench the reaction, and the reaction solvent was recovered by concentration under reduced pressure. Finally, the concentrated solution was extracted with ethyl acetate three times (230 g each time), and the combined organic phase was concentrated to dryness under reduced pressure to obtain 189.3 g of the compound of Formula VI-b (yield 100%), which was directly used in the next reaction.

[0072] Example 3: Preparation of the compound of Formula IV-a

[0073] Into a reaction flask, under nitrogen protection, was placed 185.2 g of the compound of Formula V-b and 1500 g of ethanol, and the mixture was stirred until dissolved. Then, the temperature was controlled at 15-25 °C, and 76.5 g of sodium borohydride was added in portions. After the addition was completed, the mixture was stirred for 3.0-4.5 hours, and then the temperature was raised to 55-65 °C. The mixture was stirred for 3.0-4.0 hours until the reaction was completed. The temperature was then lowered to room temperature, 8% ammonium chloride solution was added to quench the reaction, and the reaction solvent was recovered by concentration under reduced pressure. Finally, the concentrated solution was extracted with ethyl acetate three times (230 g each time), and the combined organic phase was concentrated to dryness under reduced pressure to obtain 189.3 g of the compound of Formula VI-b (yield 100%), which was directly used in the next reaction.

[0074] Example 4: Preparation of the compound of Formula IV-b

[0075] Into a reaction flask, under nitrogen protection, was placed 185.2 g of the compound of Formula V-b and 1500 g of ethanol, and the mixture was stirred until dissolved. Then, the temperature was controlled at 15-25 °C, and 76.5 g of sodium borohydride was added in portions. After the addition was completed, the mixture was stirred for 3.0-4.5 hours, and then the temperature was raised to 55-65 °C. The mixture was stirred for 3.0-4.0 hours until the reaction was completed. The temperature was then lowered to room temperature, 8% ammonium chloride solution was added to quench the reaction, and the reaction solvent was recovered by concentration under reduced pressure. Finally, the concentrated solution was extracted with ethyl acetate three times (230 g each time), and the combined organic phase was concentrated to dryness under reduced pressure to obtain 189.3 g of the compound of Formula VI-b (yield 100%), which was directly used in the next reaction.

[0076] Example 5: Preparation of the compound of Formula IV-c

[0077] Into a reaction flask under nitrogen atmosphere, 18.9 g of compound of formula VI-a, 6.5 g of triethylamine and 190 g of dichloromethane were taken. Then, temperature was controlled between -5 to 5 °C, 21.5 g of p-toluenesulfonyl chloride was added in portions and after completion of addition, the reaction was allowed to stir for 3.0 to 3.5 hours. After completion of the reaction, 5% potassium carbonate solution was added to quench the reaction and the organic layer was separated. The combined organic layer was washed with 2 x 90 g of water and concentrated to dryness under reduced pressure to obtain 37.1 g of compound of formula IV-c (yield 100%) which was used as such for the next step.

[0078] Example 6: Preparation of 8-aminooctanoic acid compound of formula I from compound of formula IV-a

[0079] Into a reaction flask under nitrogen atmosphere, 18.9 g of compound of formula VI-a, 6.5 g of triethylamine and 190 g of dichloromethane were taken. Then, temperature was controlled between -5 to 5 °C, 21.5 g of p-toluenesulfonyl chloride was added in portions and after completion of addition, the reaction was allowed to stir for 3.0 to 3.5 hours. After completion of the reaction, 5% potassium carbonate solution was added to quench the reaction and the organic layer was separated. The combined organic layer was washed with 2 x 90 g of water and concentrated to dryness under reduced pressure to obtain 37.1 g of compound of formula IV-c (yield 100%) which was used as such for the next step.

[0080] Then, 150 g of concentrated hydrochloric acid was added to the obtained concentrated solution and the reaction was allowed to stir at 100 to 110 °C for 9 to 10 hours. After completion of the reaction, it was concentrated to dryness under reduced pressure and then 50 g of acetonitrile was added for crystallization. It was filtered under suction and dried at 45 to 50 °C to obtain 7.23 g of the target compound of formula I with a yield of 90.8% and HPLC purity of 99.8%.

[0081] Example 7: Preparation of 8-aminooctanoic acid compound of formula I from compound of formula IV-b

[0082] Into a reaction flask under nitrogen atmosphere, 18.9 g of compound of formula VI-a, 6.5 g of triethylamine and 190 g of dichloromethane were taken. Then, temperature was controlled between -5 to 5 °C, 21.5 g of p-toluenesulfonyl chloride was added in portions and after completion of addition, the reaction was allowed to stir for 3.0 to 3.5 hours. After completion of the reaction, 5% potassium carbonate solution was added to quench the reaction and the organic layer was separated. The combined organic layer was washed with 2 x 90 g of water and concentrated to dryness under reduced pressure to obtain 37.1 g of compound of formula IV-c (yield 100%) which was used as such for the next step.

[0083] Then, 220 g of 25% hydrochloric acid was added to the obtained concentrated solution and the reaction was allowed to stir at 100 to 105 °C for 10.0 to 11.0 hours. After completion of the reaction, it was concentrated to dryness under reduced pressure and then 30 g of ethanol and 50 g of n-heptane were added for crystallization. It was filtered under suction and dried at 45 to 50 °C to obtain 14.5 g of the target compound of formula I with a yield of 91.2% and HPLC purity of 99.9%.

[0084] While the specific embodiments of the application have been described in detail, that is not intended to limit the application in any way. Any modification, substitution and improvement made on the details within the spirit and principle of the application shall be included in the scope of the protection of the application. The scope of the application is defined by the appended claims and any equivalents thereof.

Claims

1. A method for preparing 8-aminooctanoic acid of formula I, the method comprising the following steps: Step 1: In an organic solvent and / or water, in the presence of a base, react compound IV with compound III to give compound II; and Step 2: Hydrolyze the compound of formula II in an organic solvent and / or water in the presence of an acid to obtain the desired target product, 8-aminooctanoic acid. Wherein, R1 is a hydroxyl protecting group selected from methanesulfonyl, ethanesulfonyl, benzenesulfonyl, 2-methylbenzenesulfonyl, 3-toluenesulfonyl, 4-toluenesulfonyl, 4-nitrobenzenesulfonyl or 4-chlorobenzenesulfonyl; R2 is independently selected from CN or -CO2R4, wherein R4 is independently selected from H, substituted or unsubstituted C. 1-9 Alkyl, substituted or unsubstituted C 3-9 Cycloalkyl or substituted or unsubstituted C 6-10 Aryl; R3 is independently selected from H, substituted or unsubstituted C. 1-9 Alkyl, substituted or unsubstituted C 3-9 Cycloalkyl or substituted or unsubstituted C 6-10 Aryl; and R5 is an amino protecting group selected from methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl.

2. A method for preparing 8-aminooctanoic acid of formula I, the method comprising the following steps: Step 3: In an organic solvent, in the presence of a reducing agent, react compound V to obtain compound VI; Step 4: In an organic solvent, in the presence of an organic amine, the compound of formula VI is reacted with the sulfonating agent R1X to obtain the compound of formula IV; Step 1: In an organic solvent and / or water, in the presence of a base, react compound IV with compound III to give compound II; and Step 2: Hydrolyze the compound of formula II in an organic solvent and / or water in the presence of an acid to obtain the desired target product, 8-aminooctanoic acid. R1, R2, R3 and R5 are as defined in claim 1, and X is a halogen selected from chlorine, bromine or iodine.

3. The method according to claim 1 or 2, characterized in that, The base used in step 1 is selected from one or more of the following: n-butyllithium, tert-butyllithium, sodium tert-butoxide, potassium tert-butoxide, methyl magnesium chloride, ethyl magnesium chloride, diisopropylaminolithium, lithium hydride, sodium hydride, potassium hydride, bis(trimethylsilyl)aminolithium, sodium bis(trimethylsilyl)aminobis, potassium bis(trimethylsilyl)aminobis, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, and sodium n-butoxide.

4. The method according to claim 1 or 2, characterized in that, The acid used in step 2 is selected from one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, formic acid, and acetic acid.

5. The method according to claim 1 or 2, characterized in that, It also includes quenching the reaction with acid before step 2.

6. The method according to claim 1 or 2, characterized in that, It also includes solvent extraction and crystallization of the obtained target compound after step 2.

7. The method according to claim 1 or 2, characterized in that, The reducing agent used in step 3 is selected from one or more of borane, lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, lithium triethylborohydride, and sodium triacetylborohydride; preferably, the reaction in step 3 is carried out at 0-75°C.

8. The method according to claim 1 or 2, characterized in that, The organic amine used in step 4 is selected from one or more of methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, tributylamine, pyridine, piperidine, ethylenediamine, morpholine, and piperazine.

9. The method according to claim 1 or 2, characterized in that, The same or different organic solvents may be used in steps 1 through 4.

10. Use of 8-aminooctanoic acid prepared by the method of any one of claims 1 to 9 as an intermediate for the preparation of sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate.