Preparation method of 8-aminocaprylic acid

Abstract

The invention provides a preparation method of 8-amino caprylic acid, which comprises the following steps: step S1, carrying out substitution reaction on a halogenated caprylate compound and N-Cbz-acetamide to generate N-Cbz-acetamido caprylate; step S2, carrying out a hydrolysis reaction on the N-Cbz-acetamido octanoate, so as to obtain N-Cbz amino caprylic acid; and S3, carrying out a Cbz protecting group removal reaction on the N-Cbz amino caprylic acid to obtain the 8-amino caprylic acid. The preparation method provided by the embodiment of the invention has the advantages of short synthetic route, high total yield, low raw material cost and higher feasibility of the route, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation, and more specifically, relates to a method for preparing 8-aminocaprylic acid. Background Art

[0002] 8-Aminocaprylic acid is an important raw material for the synthesis of sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate (SNAC). SNAC is a new ω-amino fatty acid derivative. As an oral peptide drug absorption enhancer, it can improve the oral absorption of peptide drugs under physiological pH conditions. It has more advantages than α-amino acids and acetylated amino acids: simple structure, no need for enhanced adhesion function in the process of preparing microspheres, and higher anticoagulant therapeutic level in vivo.

[0003] There are related literature reports on the synthesis of 8-aminocaprylic acid, and the main synthesis routes are as follows:

[0004] Route 1: Cyclooctanone is used as a raw material, reacted with hydroxylamine hydrochloride to obtain cyclooctanone hydrochloride, which is then rearranged with polyphosphoric acid to obtain 2-azacyclononanone, and then hydrolyzed with sodium hydroxide to obtain 8-aminooctanoic acid (the synthesis route is shown in the following formula (1)).

[0005]

[0006] However, the disadvantages of this method are that the raw material cyclooctanone is expensive; a large amount of polyphosphoric acid is required for the reaction, which produces a large amount of phosphorus-containing wastewater, greatly increasing the pressure on the environmental protection; and inorganic salts are produced after neutralization of the sodium hydroxide used for hydrolysis, which are difficult to remove in the product.

[0007] Route 2: Using cyclooctanone as the raw material, firstly use sodium azide and concentrated sulfuric acid for rearrangement reaction to prepare 2-azacyclononanone, and then use hydrochloric acid for hydrolysis to obtain 8-aminooctanoic acid (its synthetic route is shown in the following formula (2)).

[0008]

[0009] However, this method also has the problem of expensive raw material cyclooctanone; in addition, the reaction requires the use of explosive and dangerous goods sodium azide, and there are great safety risks in scale-up production; the hydrolyzed HCl will produce inorganic salts after neutralization with alkali, which is difficult to remove in the product.

[0010] Route 3: Octanediol is used as a raw material, reacted with hydrobromic acid to obtain 8-bromo-1-octanol, then oxidized with Jones reagent to obtain 8-bromo-1-octanoic acid, and finally reacted with ammonia water to obtain the target product (the synthetic route is shown in the following formula (3)).

[0011]

[0012] However, in this method, the raw material octanediol is expensive, and the oxidant Jones reagent will produce waste solids containing chromium salts, which will cause serious environmental pollution when used in large quantities. Similarly, the inorganic salts in the product cannot be completely removed.

[0013] Route 4: N-substituted carbonyl caprolactam is used as a raw material, reacted with ethyl acetate in the presence of potassium bis(trimethylsilyl)amide (KHMDS) to obtain N-substituted carbonyl-6-oxo-8-octanoic acid ethyl ester, then the carbonyl group is reduced with sodium acetate borohydride, and then the N-protecting group and ester group are decomposed with propylene oxide to obtain 8-aminooctanoic acid (the synthesis route is shown in the following formula (4)).

[0014]

[0015] The disadvantages of this method are that KHMDS is very expensive, and the reaction needs to be carried out at -80 to -70°C, and in the absence of water and oxygen. The reaction conditions are harsh and the post-processing is cumbersome. Therefore, this method can only be used for small-scale preparation in the laboratory and is not suitable for large-scale production.

[0016] In summary, although a variety of synthetic routes have been developed, they are not suitable for large-scale production due to their respective shortcomings. Therefore, it is urgent to develop a preparation method of 8-aminocaprylic acid that is simple to operate, low in raw material cost, high in total yield, and more conducive to industrial-scale production. Summary of the invention

[0017] In view of this, the object of the present invention is to provide a method for preparing 8-aminocaprylic acid which has simple operation, low raw material cost, high total yield and is more conducive to industrial-scale production.

[0018] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0019] The preparation method of 8-aminocaprylic acid according to an embodiment of the present invention comprises the following steps:

[0020] Step S1, allowing a halogenated octanoate compound to undergo a substitution reaction with N-Cbz-acetamide to generate N-Cbz-acetylamino octanoate;

[0021] Step S2, hydrolyzing N-Cbz-acetylamino caprylate to obtain N-Cbz amino caprylic acid;

[0022] Step S3, removing the Cbz protecting group from the N-Cbz aminocaprylic acid to obtain 8-aminocaprylic acid.

[0023] In some embodiments of the present invention, in step S1, the halogenated octanoate compound is chlorooctanoate, bromooctanoate, or a mixture thereof, the chlorooctanoate is any one or more of 8-chlorooctanoic acid methyl ester, 8-chlorooctanoic acid ethyl ester, and 8-chlorooctanoic acid isopropyl ester, and the bromooctanoate is any one or more of 8-bromooctanoic acid methyl ester, 8-bromooctanoic acid ethyl ester, and 8-bromooctanoic acid isopropyl ester.

[0024] Furthermore, the substitution reaction is carried out in a first solvent under the action of a first base, the first base is any one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, diethylamine, triethylamine, and diisopropylethylamine, and the first solvent is any one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile, acetone, methanol, and ethanol.

[0025] Furthermore, in the step S1, the molar ratio of the N-Cbz-acetamide: the halogenated octanoate compound: the first base is 1.0:(1.0-1.5):(1.5-3.0), the reaction temperature is 20-60°C, and the reaction time is 8-24h.

[0026] Furthermore, the step S1 further comprises: after the reaction is completed, filtering out the solid, washing the solid with DMF, evaporating the solvent, extracting the residue, drying, filtering, evaporating the solvent, and obtaining the N-Cbz-acetylamino caprylate as an oily substance.

[0027] In some embodiments of the present invention, step S2 includes:

[0028] The N-Cbz-acetylamino caprylate is added to a second solvent, and an aqueous solution of a second base is added dropwise therein to cause the hydrolysis reaction, wherein the second base is sodium hydroxide, potassium hydroxide, or a mixture thereof, and the second solvent is any one or more of methanol, ethanol, isopropanol, and tert-butanol.

[0029] Furthermore, in the step S2, the molar ratio of the N-Cbz-acetylamino caprylate: the second base is 1.0: (1.5-3.0), the reaction temperature is 10-40° C., and the reaction time is 2-8 h.

[0030] Furthermore, the step S2 further comprises: after the reaction is completed, filtering, evaporating the solvent, washing the residue, filtering, washing the filter cake with water and drying, to obtain the N-Cbz aminocaprylic acid as a white solid.

[0031] Furthermore, in step S3, the Cbz protecting group removal reaction is carried out in a third solvent under the action of hydrogen and a catalyst, the third solvent is any one or more of methanol, ethanol, and tetrahydrofuran, and the catalyst is palladium carbon, Raney nickel, or a mixture thereof.

[0032] Furthermore, the step S3 further comprises: after the reaction is completed, filtering, evaporating the solvent, washing the residue, filtering, washing the filter cake with ethanol and drying to obtain the 8-aminocaprylic acid.

[0033] The above technical solution of the present invention has at least one of the following beneficial effects:

[0034] The preparation method according to the embodiment of the present invention has a short synthetic route, a high total yield, a low raw material cost, a stronger feasibility of the route, and is suitable for industrial production. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0036] The following first describes in detail the preparation method of 8-aminocaprylic acid according to an embodiment of the present invention.

[0037] The preparation method of 8-aminocaprylic acid according to an embodiment of the present invention comprises the following steps:

[0038] Step S1, allowing a halogenated octanoate compound to undergo a substitution reaction with N-Cbz-acetamide to generate N-Cbz-acetylamino octanoate;

[0039] Step S2, hydrolyzing N-Cbz-acetylamino caprylate to obtain N-Cbz amino caprylic acid;

[0040] Step S3, removing the Cbz protecting group from the N-Cbz aminocaprylic acid to obtain 8-aminocaprylic acid.

[0041] That is, according to the preparation method of the present invention, a halogenated octanoate compound is used as a starting raw material, and the halogen group at the end is first replaced by an N-Cbz-acetamide group to protect the terminal alkyl group with Cbz, and then the ester group at the other end is hydrolyzed to form N-Cbz-aminooctanoic acid, and finally, the Cbz protecting group is removed to obtain the target compound 8-aminooctanoic acid. According to the preparation method of the present invention, expensive raw materials are not required; and the N-Cbz-aminooctanoic acid generated by hydrolysis is easily separated from inorganic salts, and the inorganic salts will not be carried to the next step of the reaction; in addition, the three-step reaction is a conventional reaction with a high yield, and the total yield is high; and the reaction route is simple and easy to operate, and no unnecessary impurities are generated, and there are few three wastes.

[0042] Below, each step is described in detail.

[0043] Step S1: a halogenated octanoate compound is subjected to a substitution reaction with N-Cbz-acetamide to generate N-Cbz-acetylamino octanoate.

[0044] Specifically, the reaction formula is shown in the following formula (5):

[0045]

[0046] Wherein, X represents a halogen group, such as -Cl or -Br; R represents a methyl group, an ethyl group, or an isopropyl group.

[0047] In some embodiments of the present invention, the halogenated octanoate compound is chlorooctanoate, bromooctanoate, or a mixture thereof, the chlorooctanoate is any one or more of 8-chlorooctanoic acid methyl ester, 8-chlorooctanoic acid ethyl ester, and 8-chlorooctanoic acid isopropyl ester, and the bromooctanoate is any one or more of 8-bromooctanoic acid methyl ester, 8-bromooctanoic acid ethyl ester, and 8-bromooctanoic acid isopropyl ester. The selected starting material is easier to obtain and cheaper than the starting materials of other routes.

[0048] In some embodiments of the present invention, the substitution reaction is carried out in the first solvent under the action of the first base. On the one hand, the base can promote the removal of the halogen group and promote the Cbz group to bind to the terminal alkyl group to protect the terminal alkyl group. On the other hand, the base as an acid binding agent can keep the reaction system alkaline, which is conducive to promoting the reaction and improving the yield.

[0049] The first base may be any one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, diethylamine, triethylamine, and diisopropylethylamine, preferably potassium carbonate.

[0050] In addition, the first solvent may be any one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile, acetone, methanol, and ethanol, preferably DMF.

[0051] In some embodiments of the present invention, in step S1, the molar ratio of N-Cbz-acetamide: halogenated octanoate compound: first base is 1.0:(1.0-1.5):(1.5-3.0). The halogenated octanoate is slightly excessive and can be easily removed in post-treatment.

[0052] In addition, the reaction temperature of the substitution reaction can be 20-60° C., and the reaction time can be 8-24 hours. The reaction conditions are mild and easy to control.

[0053] In some embodiments of the present invention, step S1 further comprises: after the reaction is completed, filtering out the solid, washing the solid with DMF, evaporating the solvent, extracting the residue, drying, filtering, evaporating the solvent, and obtaining the N-Cbz-acetylamino caprylate as an oily substance.

[0054] That is to say, after the substitution reaction is completed, simple solid-liquid separation and extraction can be performed to effectively remove the residual solvent and the like to obtain the intermediate product N-Cbz-acetylamino caprylate. The post-treatment is simple and easy to operate.

[0055] Step S2: subjecting N-Cbz-acetylamino caprylate to a hydrolysis reaction to obtain N-Cbz amino caprylic acid.

[0056] That is, after the terminal is protected with Cbz, the ester group undergoes a hydrolysis reaction to become an acid.

[0057] Specifically, the reaction formula is shown in the following formula (6):

[0058]

[0059] In some embodiments of the present invention, step S2 includes:

[0060] The N-Cbz-acetylamino caprylate is added to a second solvent, and an aqueous solution of a second base is added dropwise therein to cause the hydrolysis reaction.

[0061] The second alkali may be sodium hydroxide, potassium hydroxide, or a mixture thereof.

[0062] In addition, the second solvent may be any one or more of methanol, ethanol, isopropanol, and tert-butanol, preferably methanol.

[0063] In some embodiments of the present invention, in step S2, the molar ratio of N-Cbz-acetylamino caprylate: the second base is 1.0: (1.5-3.0), the reaction temperature is 10-40° C., and the reaction time is 2-8 h.

[0064] In some embodiments of the present invention, step S2 further comprises: after the reaction is completed, filtering, evaporating the solvent, washing the residue, filtering, washing the filter cake with water and drying to obtain the N-Cbz aminocaprylic acid as a white solid.

[0065] That is to say, after the hydrolysis reaction is completed, simple solid-liquid separation and extraction can be performed to effectively remove the residual solvent and the like to obtain the intermediate product N-Cbz amino caprylic acid. The post-treatment is simple and easy to operate.

[0066] Step S3: subjecting the N-Cbz aminocaprylic acid to a Cbz protecting group removal reaction to obtain 8-aminocaprylic acid.

[0067] That is to say, after conversion into acid, the target product 8-aminooctanoic acid can be obtained by removing the terminal Cbz protecting group.

[0068] Specifically, the reaction formula is shown in the following formula (7):

[0069]

[0070] In some embodiments of the present invention, in step S3, the Cbz protecting group removal reaction is carried out in a third solvent under the action of hydrogen and a catalyst.

[0071] Wherein, the third solvent is any one or more of methanol, ethanol, and tetrahydrofuran.

[0072] The catalyst may be palladium on carbon, Raney nickel, or a mixture thereof.

[0073] In some embodiments of the present invention, the step S3 further comprises: after the reaction is completed, filtering, evaporating the solvent, washing the residue, filtering, washing the filter cake with ethanol and drying to obtain the 8-aminocaprylic acid.

[0074] In summary, the preparation method according to the embodiment of the present invention has a short synthetic route, a high total yield, a low raw material cost, a stronger feasibility of the route, and is suitable for industrial production.

[0075] Below, the preparation method of 8-aminocaprylic acid of the present invention is further described in detail by specific examples.

[0076] Example 1

[0077] (a) Synthesis of N-tert-butyloxycarbonyl-8-aminooctanoic acid methyl ester

[0078] In a 100 mL round-bottom flask, 10 g (0.052 mol, 1.0 eq) of N-Cbz-acetamide was dissolved in 50 mL of DMF, 14.3 g (0.104 mol, 2.0 eq) of potassium carbonate was added, and 13.0 g (0.068 mol, 1.3 eq) of 8-chlorooctanoic acid methyl ester was added dropwise at room temperature. After the addition was complete, the temperature was raised to 50°C and the reaction was continued for 24 hours. After the reaction was completed, the solid was filtered out, the solid was washed with DMF, the solvent was evaporated, water was added to the residue, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 18.1 g of an oily substance. (b) Synthesis of N-tert-butyloxycarbonyl-8-aminooctanoic acid

[0079] The oily substance obtained in the previous step was added to 100 ml of methanol. Under cooling, 26 g (0.13 mol, 2.5 eq) of 20% sodium hydroxide solution was added dropwise at 0-10°C. After completion of the addition, the mixture was stirred at 25°C for 4 hours. The solvent was evaporated, 100 ml of water was added to the residue, and the mixture was washed twice with 100 ml of ethyl acetate. The pH value of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, and the mixture was filtered with suction. The filter cake was washed with water and dried to obtain 12.5 g of a white solid with a yield of 82%.

[0080] (c) Synthesis of 8-aminooctanoic acid

[0081] In a 250mL round-bottom flask, dissolve 10g (0.034mol, 1.0eq) of N-tert-butyloxycarbonyl-8-aminooctanoic acid in 150mL of methanol, add 1g of 5% palladium on carbon, stir at room temperature for 24 hours through hydrogen, filter with suction, evaporate the solvent, add 20ml of 95% ethanol to the residue, stir at room temperature for 1 hour, filter with suction, wash with 95% ethanol, and dry to obtain 4.9g of white solid with a yield of 91%.

[0082] The NMR results of the product are as follows:

[0083] 1 H-NMR (400MHz, D2O): δ3.01(t,J=7.5Hz,2H), 2.19(t,J=7.4Hz,2H), 1.62(dp,J=41.5,7.1Hz,4H), 1.38(dt,J=18.5,8.5Hz,6H).

[0084] The results showed that its structure was consistent with that of the target product 8-aminocaprylic acid.

[0085] Example 2

[0086] (a) Synthesis of N-tert-butyloxycarbonyl-8-aminooctanoic acid ethyl ester

[0087] In a 100 mL round-bottom flask, 10 g (0.052 mol, 1.0 eq) of N-Cbz-acetamide was dissolved in 50 mL of DMF, 18 g (0.13 mol, 2.5 eq) of potassium carbonate was added, and 14 g (0.068 mol, 1.3 eq) of 8-chlorooctanoic acid ethyl ester was added dropwise at room temperature. After the addition was complete, the temperature was raised to 60°C and the mixture was reacted for 24 hours. After the reaction was completed, the solid was filtered out, washed with DMF, the solvent was evaporated, water was added to the residue, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 18.7 g of an oily substance. (b) Synthesis of N-tert-butyloxycarbonyl-8-aminooctanoic acid

[0088] The oily substance obtained in the previous step was added to 100 ml of methanol. Under cooling, 31.2 g (0.156 mol, 3.0 eq) of 20% sodium hydroxide solution was added dropwise at 0-10°C. After completion of the addition, the mixture was stirred at 25°C for 8 hours. The solvent was evaporated, 100 ml of water was added to the residue, and the mixture was washed twice with 100 ml of ethyl acetate. The pH value of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, and the mixture was filtered with suction. The filter cake was washed with water and dried to obtain 13.0 g of a white solid with a yield of 85%.

[0089] (c) Synthesis of 8-aminooctanoic acid

[0090] In a 250mL round-bottom flask, dissolve 10g (0.034mol, 1.0eq) of N-tert-butyloxycarbonyl-8-aminooctanoic acid in 150mL of methanol, add 2g of 5% palladium on carbon, stir at room temperature for 24 hours through hydrogen, filter with suction, evaporate the solvent, add 20ml of 95% ethanol to the residue, stir at room temperature for 1 hour, filter with suction, wash with 95% ethanol, and dry to obtain 5.0g of white solid with a yield of 93%.

[0091] The NMR results of the product are the same as those in Example 1, and their detailed description is omitted here.

[0092] Example 3

[0093] (a) Synthesis of Isopropyl N-tert-Butyloxycarbonyl-8-aminooctanoate

[0094] In a 100mL round-bottom flask, 10g (0.052mol, 1.0eq) of N-Cbz-acetamide was dissolved in 50mL of DMF, and 14.3g (0.104mol, 2.0eq) of potassium carbonate was added. 13.8g (0.062mol, 1.2eq) of 8-chlorooctanoic acid isopropyl was added dropwise at room temperature. After the addition, the temperature was raised to 50°C and the reaction was carried out for 24 hours. After the reaction was completed, the solid was filtered out, washed with DMF, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted twice with 100ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 19.6g of an oily substance.

[0095] (b) Synthesis of N-tert-butyloxycarbonyl-8-aminooctanoic acid

[0096] The oily substance obtained in the previous step was added to 100 ml of methanol. Under cooling, 43.7 g (0.156 mol, 3.0 eq) of 20% potassium hydroxide solution was added dropwise at 0-10°C. After completion of the addition, the mixture was stirred at 10°C for 3 hours. The solvent was evaporated, 100 ml of water was added to the residue, and the mixture was washed twice with 100 ml of ethyl acetate. The pH value of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, and the mixture was filtered with suction. The filter cake was washed with water and dried to obtain 11.0 g of a white solid with a yield of 72%.

[0097] (c) Synthesis of 8-aminooctanoic acid

[0098] In a 250mL round-bottom flask, dissolve 10g (0.034mol, 1.0eq) of N-tert-butyloxycarbonyl-8-aminooctanoic acid in 200mL of methanol, add 1g of Raney nickel, stir at room temperature for 24 hours under hydrogen, filter with suction, evaporate the solvent, add 20ml of 95% ethanol to the residue, stir at room temperature for 1 hour, filter with suction, wash with 95% ethanol, and dry to obtain 4.7g of white solid with a yield of 87%.

[0099] The NMR results of the product are the same as those in Example 1, and their detailed description is omitted here.

[0100] Example 4

[0101] (a) Synthesis of N-tert-butyloxycarbonyl-8-aminooctanoic acid methyl ester

[0102] In a 100 mL round-bottom flask, 10 g (0.052 mol, 1.0 eq) of N-Cbz-acetamide was dissolved in 50 mL of DMF, 14.3 g (0.104 mol, 2.0 eq) of potassium carbonate was added, and 14.8 g (0.062 mol, 1.2 eq) of methyl 8-bromooctanoate was added dropwise at room temperature. After the addition was complete, the temperature was raised to 50°C and the reaction was continued for 8 hours. After the reaction was completed, the solid was filtered out, the solid was washed with DMF, the solvent was evaporated, water was added to the residue, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 18.3 g of an oily substance. (b) Synthesis of N-tert-butyloxycarbonyl-8-aminooctanoic acid

[0103] The oily substance obtained in the previous step was added to 100 ml of methanol. Under cooling, 26 g (0.13 mol, 2.5 eq) of 20% sodium hydroxide solution was added dropwise at 0-10°C. After completion of the addition, the mixture was stirred at 25°C for 4 hours. The solvent was evaporated, 100 ml of water was added to the residue, and the mixture was washed twice with 100 ml of ethyl acetate. The pH value of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, and the mixture was filtered with suction. The filter cake was washed with water and dried to obtain 12.6 g of a white solid with a yield of 83%.

[0104] (c) Synthesis of 8-aminooctanoic acid

[0105] In a 250mL round-bottom flask, dissolve 10g (0.034mol, 1.0eq) of N-tert-butyloxycarbonyl-8-aminooctanoic acid in 150mL of methanol, add 1g of 5% palladium on carbon, stir at room temperature for 24 hours through hydrogen, filter with suction, evaporate the solvent, add 20ml of 95% ethanol to the residue, stir at room temperature for 1 hour, filter with suction, wash with 95% ethanol, and dry to obtain 4.7g of white solid with a yield of 87%.

[0106] The NMR results of the product are the same as those in Example 1, and their detailed description is omitted here.

[0107] Example 5

[0108] (a) Synthesis of N-tert-butyloxycarbonyl-8-aminooctanoic acid methyl ester

[0109] In a 100 mL round-bottom flask, 10 g (0.052 mol, 1.0 eq) of N-Cbz-acetamide was dissolved in 50 mL of DMF, 14.3 g (0.104 mol, 2.0 eq) of potassium carbonate was added, and 19.6 g (0.078 mol, 1.5 eq) of ethyl 8-bromooctanoate was added dropwise at room temperature. After the addition was complete, the temperature was raised to 50°C and the mixture was reacted for 24 hours. After the reaction was completed, the solid was filtered out, washed with DMF, the solvent was evaporated, water was added to the residue, and the mixture was extracted twice with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 18.9 g of an oily substance. (b) Synthesis of N-tert-butyloxycarbonyl-8-aminooctanoic acid

[0110] The oily substance obtained in the previous step was added to 100 ml of methanol. Under cooling, 26 g (0.13 mol, 2.5 eq) of 20% sodium hydroxide solution was added dropwise at 0-10°C. After completion of the addition, the mixture was stirred at 25°C for 8 hours. The solvent was evaporated, 100 ml of water was added to the residue, and the mixture was washed twice with 100 ml of ethyl acetate. The pH value of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, and the mixture was filtered with suction. The filter cake was washed with water and dried to obtain 13.7 g of a white solid with a yield of 90%.

[0111] (c) Synthesis of 8-aminooctanoic acid

[0112] In a 250mL round-bottom flask, dissolve 10g (0.034mol, 1.0eq) of N-tert-butyloxycarbonyl-8-aminooctanoic acid in 150mL of methanol, add 2g of 5% palladium on carbon, stir at room temperature for 24 hours through hydrogen, filter with suction, evaporate the solvent, add 20ml of 95% ethanol to the residue, stir at room temperature for 1 hour, filter with suction, wash with 95% ethanol, and dry to obtain 4.9g of white solid with a yield of 90%.

[0113] The NMR results of the product are the same as those in Example 1, and their detailed description is omitted here.

[0114] Example 6

[0115] (a) Synthesis of Isopropyl N-tert-Butyloxycarbonyl-8-aminooctanoate

[0116] In a 100mL round-bottom flask, 10g (0.052mol, 1.0eq) of N-Cbz-acetamide was dissolved in 50mL of DMF, and 14.3g (0.104mol, 2.0eq) of potassium carbonate was added. 16.5g (0.062mol, 1.2eq) of 8-bromooctanoic acid isopropyl was added dropwise at room temperature. After the addition, the temperature was raised to 50°C and the reaction was carried out for 24 hours. After the reaction was completed, the solid was filtered out, washed with DMF, and the solvent was evaporated. Water was added to the residue, and the mixture was extracted twice with 100ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain 19.7g of an oily substance.

[0117] (b) Synthesis of N-tert-butyloxycarbonyl-8-aminooctanoic acid

[0118] The oily substance obtained in the previous step was added to 100 ml of methanol. Under cooling, 36.5 g (0.13 mol, 2.5 eq) of 20% potassium hydroxide solution was added dropwise at 0-10° C. After completion of the addition, the mixture was stirred at 25° C. for 3 hours. The solvent was evaporated, 100 ml of water was added to the residue, and the mixture was washed twice with 100 ml of ethyl acetate. The pH value of the aqueous phase was adjusted to 2-3 with concentrated hydrochloric acid, and the mixture was filtered with suction. The filter cake was washed with water and dried to obtain 12.3 g of a white solid with a yield of 81%.

[0119] (c) Synthesis of 8-aminooctanoic acid

[0120] In a 250mL round-bottom flask, dissolve 10g (0.034mol, 1.0eq) of N-tert-butyloxycarbonyl-8-aminooctanoic acid in 200mL of methanol, add 1.5g of palladium carbon, stir at room temperature for 24 hours through hydrogen, filter with suction, evaporate the solvent, add 20ml of 95% ethanol to the residue, stir at room temperature for 1 hour, filter with suction, wash with 95% ethanol, and dry to obtain 4.8g of white solid with a yield of 89%.

[0121] The NMR results of the product are the same as those in Example 1, and their detailed description is omitted here.

[0122] In summary, the preparation method of 8-aminocaprylic acid of the present invention has the advantages of short synthesis route, simple operation, low cost and high yield.

[0123] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 8-aminocaprylic acid, characterized in that: The steps include: Step S1, allowing a halogenated octanoate compound to undergo a substitution reaction with N-Cbz-acetamide to generate N-Cbz-acetylamino octanoate; Step S2, hydrolyzing N-Cbz-acetylamino caprylate to obtain N-Cbz amino caprylic acid; Step S3, removing the Cbz protecting group from the N-Cbz aminocaprylic acid to obtain 8-aminocaprylic acid.

2. The preparation method according to claim 1, characterized in that: In the step S1, the halogenated octanoate compound is chlorooctanoate, bromooctanoate, or a mixture thereof; the chlorooctanoate is any one or more of 8-chlorooctanoic acid methyl ester, 8-chlorooctanoic acid ethyl ester, and 8-chlorooctanoic acid isopropyl ester; the bromooctanoate is any one or more of 8-bromooctanoic acid methyl ester, 8-bromooctanoic acid ethyl ester, and 8-bromooctanoic acid isopropyl ester.

3. The preparation method according to claim 2, characterized in that: The substitution reaction is carried out in a first solvent under the action of a first base, wherein the first base is any one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, diethylamine, triethylamine, and diisopropylethylamine, and the first solvent is any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetone, methanol, and ethanol.

4. The preparation method according to claim 3, characterized in that: In the step S1, the molar ratio of the N-Cbz-acetamide: the halogenated octanoate compound: the first base is 1.0:(1.0-1.5):(1.5-3.0), the reaction temperature is 20-60° C., and the reaction time is 8-24 hours.

5. The preparation method according to claim 1, characterized in that: The step S1 further comprises: after the reaction is completed, filtering out the solid, washing the solid with DMF, evaporating the solvent, extracting the residue, drying, filtering, and evaporating the solvent to obtain the N-Cbz-acetylamino caprylate as an oily substance.

6. The preparation method according to claim 1, characterized in that: The step S2 comprises: The N-Cbz-acetylamino caprylate is added to a second solvent, and an aqueous solution of a second base is added dropwise therein to cause the hydrolysis reaction, wherein the second base is sodium hydroxide, potassium hydroxide, or a mixture thereof, and the second solvent is any one or more of methanol, ethanol, isopropanol, and tert-butanol.

7. The preparation method according to claim 6, characterized in that: In the step S2, the molar ratio of the N-Cbz-acetylamino caprylate: the second base is 1.0: (1.5-3.0), the reaction temperature is 10-40° C., and the reaction time is 2-8 hours.

8. The preparation method according to claim 7, characterized in that: The step S2 further comprises: after the reaction is completed, filtering with suction, evaporating the solvent, washing the residue, filtering with suction, washing the filter cake with water and drying, to obtain the N-Cbz aminocaprylic acid as a white solid.

9. The preparation method according to claim 1, characterized in that: In the step S3, the Cbz protecting group removal reaction is carried out in a third solvent under the action of hydrogen and a catalyst, the third solvent is any one or more of methanol, ethanol, and tetrahydrofuran, and the catalyst is palladium carbon, Raney nickel, or a mixture thereof.

10. The preparation method according to claim 9, characterized in that: The step S3 further comprises: after the reaction is completed, filtering with suction, evaporating the solvent, washing the residue, filtering with suction, washing the filter cake with ethanol and drying to obtain the 8-aminocaprylic acid.

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