CN112898220B - Preparation method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate and intermediate thereof - Google Patents
Preparation method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate and intermediate thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate and an intermediate thereof, wherein the preparation method of the intermediate comprises the following steps: reacting salicylamide with a protecting group reagent in a first solvent to obtain 2, 2-dimethyl-2, 3-dihydro-4H-benzo [1,3] oxazine-4-ketone, and reacting with 8-bromoethyl octanoate in a second solvent under the action of alkali to generate an intermediate 8- (2, 2-dimethyl-4-oxo-2H-benzo [1,3] oxazine-3 (4H) -yl) ethyl octanoate; the preparation of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate (SNAC) is carried out by hydrolysis and salification on the basis of the intermediate; the method has the advantages of simple and easily obtained raw materials, high safety, simple and mild reaction conditions, simple and easily operated post-treatment, ideal yield and purity, and suitability for large-scale production of the SNAC.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate and an intermediate thereof.
Background
Sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, SNAC for short, is a absorption enhancer of a dicarbonphosphate compound, is used for treating gastrointestinal diseases, and is particularly suitable for gastrointestinal diseases caused by poor absorption of the dicarbonphosphate compound. It has now been demonstrated that oral administration of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate (2.5 mg/day) is effective in the treatment of gastrointestinal disorders caused by the malabsorption of the dicarbophosphate compound. The N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate as a replacement product of the drug for treating the gastrointestinal dicarbophosphate compound malabsorption has higher and safer drug effect than the prior drug and has very considerable application prospect.
However, the current methods for preparing sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate all have some defects, for example, the methods described in patents CN104974060 and WO0046182 all use salicylamide and ethyl chloroformate as starting materials to prepare sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, ethyl chloroformate has genotoxicity, is a highly toxic substance, trace residue affects the quality of the final product, and the process of removing the residue causes the reduction of product yield and the increase of production cost, resulting in poor economic efficiency of the production process.
In patent CN108689876A, salicylamide is condensed with carbonyldiimidazole and then butted with 8-bromooctanoic acid ethyl ester, so that the utilization rate of carbonyldiimidazole atoms is low, which results in large dosage and increased production cost;
disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the prior art and provide an improved method for preparing the intermediate of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate, the method has the advantages of simple and easily obtained raw materials, high safety, simple and mild reaction conditions, simple and convenient post-treatment and easy operation, and simultaneously, the ideal yield and purity can be obtained.
The invention also provides a novel intermediate of the N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate.
The invention also provides a preparation method of the N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate.
In order to solve the technical problems, the invention adopts a technical scheme as follows:
a process for the preparation of an intermediate of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, comprising the steps of:
(1) Reacting salicylamide with a protecting group reagent in a first solvent to obtain 2, 2-dimethyl-2, 3-dihydro-4H-benzo [1,3] oxazine-4-ketone shown as a compound 1; the protecting group reagent is acetone and/or 2, 2-dimethoxypropane;
(2) Reacting the compound 1 with ethyl 8-bromooctanoate in a second solvent under the action of a base to generate an intermediate shown as a compound 2: ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [1,3] oxazin-3 (4H) -yl) octanoate;
according to some preferred and specific aspects of the present invention, in step (1), when the protecting group reagent is acetone, the reaction is performed under reflux; when the protecting group reagent is 2, 2-dimethoxypropane, the reaction is carried out at 65-75 ℃.
According to some preferred aspects of the present invention, in step (1), the reaction is carried out in the presence of a catalyst which is a combination of one or more selected from the group consisting of p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, hydroiodic acid, formic acid, acetic acid and boric acid.
According to some preferred aspects of the present invention, in the step (1), the first solvent is a combination of one or more selected from the group consisting of dichloromethane, chloroform, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile and acetone.
According to some preferred aspects of the invention, in step (2), the reaction is carried out at 50 to 70 ℃.
According to some preferred aspects of the present invention, in the step (2), the second solvent is a combination of one or more selected from the group consisting of dichloromethane, chloroform, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile, acetone and water.
According to some preferred aspects of the invention, in step (2), the base is a combination of one or more selected from the group consisting of lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, lithium diisopropylamide, n-butyllithium, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate.
The invention provides another technical scheme that: an intermediate for the preparation of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, having the structure shown as compound 2 below:
the invention provides another technical scheme that: a process for the preparation of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate comprising:
preparing ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [1,3] oxazin-3 (4H) -yl) octanoate represented by Compound 2 by the method described above;
(ii) hydrolyzing compound 2 in a third solvent in the presence of a hydrolyzing reagent to form 8- (2-hydroxybenzamido) octanoic acid, represented by compound 3;
(iii) reacting compound 3 with a sodium-containing base in a fourth solvent to form sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate;
according to some preferred and specific aspects of the invention, in step (ii), the hydrolysis agent is a combination of one or more selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate.
According to some preferred and specific aspects of the present invention, in step (ii), the third solvent is a combination of one or more selected from methanol, ethanol, isopropanol, butanol, dichloromethane, chloroform, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile, acetone and water;
according to some preferred and specific aspects of the present invention, in step (iii), the sodium-containing base is a combination of one or more selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate and sodium phosphate.
According to some preferred and specific aspects of the present invention, in step (iii), the fourth solvent is a combination of one or more selected from methanol, ethanol, isopropanol, butanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile, acetone and water.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention innovatively takes acetone and/or 2, 2-dimethoxypropane as a protecting group reagent, and the acetone and/or 2, 2-dimethoxypropane are mixed with salicylamide to prepare 2, 2-dimethyl-2, 3-dihydro-4H-benzo [1,3] oxazine-4-ketone, and then the intermediate is used as a base to be mixed with 8-bromoethyl octanoate to synthesize a novel intermediate: 8- (2, 2-dimethyl-4-oxo-2H-benzo [1,3] oxazine-3 (4H) -group) ethyl caprylate, and then preparing the target product of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate (SNAC) by simple hydrolysis and salt formation; according to the route, the used raw materials are cheap and easy to obtain, the market supply is sufficient, the used reagents are common reagents, the safety is good, the related reaction conditions are simple and mild, the post-treatment is simple and convenient, the operation is easy, and the production period is short; the reaction generates few byproducts, and the obtained intermediate and the final product have high purity and high yield, and are suitable for large-scale production.
Drawings
Figure 1 is compound 1 prepared in example 1: nuclear magnetic spectrum of 2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one;
figure 2 is compound 2 prepared in example 1: a nuclear magnetic spectrum of ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [ e ] [1,3] oxazin-3 (4H) -yl) octanoate;
figure 3 is compound 3 prepared in example 1: nuclear magnetic spectrum of 8- (2-hydroxybenzamido) caprylic acid;
FIG. 4 is a high performance liquid chromatogram of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate (SNAC) prepared in example 1.
Detailed Description
For a further understanding of the present invention, reference will now be made to the following preferred embodiments of the invention in conjunction with the examples, but it is to be understood that the description is intended to further illustrate the features and advantages of the invention and is not intended to limit the scope of the claims which follow.
The invention provides a preparation method of an intermediate of N- (8- [ 2-hydroxybenzoyl ] -amino) sodium caprylate, which comprises the following steps:
(1) Reacting salicylamide with a protecting group reagent in a first solvent to obtain 2, 2-dimethyl-2, 3-dihydro-4H-benzo [1,3] oxazine-4-ketone shown as a compound 1; the protecting group reagent is acetone and/or 2, 2-dimethoxypropane;
(2) Reacting the compound 1 with ethyl 8-bromooctanoate in a second solvent under the action of alkali to generate an intermediate shown as a compound 2: ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [1,3] oxazin-3 (4H) -yl) octanoate;
in the present invention, in the step (1), when the protecting group reagent is acetone, the reaction is performed in a reflux state; when the protecting group reagent is 2, 2-dimethoxypropane, the reaction is carried out at 65-75 ℃.
The molar ratio of the protecting group reagent to the salicylamide feed is preferably 0.5-20: 1, more preferably 1-20: 1.
In the present invention, in step (1), the reaction is preferably carried out in the presence of a catalyst which is a combination of one or more selected from the group consisting of p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, hydroiodic acid, formic acid, acetic acid and boric acid. Preferably, the addition amount of the catalyst is 0.01-10% of the feeding mass of the salicylamide in percentage by mass; further 0.1 to 3%.
In the present invention, in the step (1), the reaction time is 2 to 8 hours, and further 3 to 6 hours.
Preferably, in the step (1), the first solvent is one or more selected from the group consisting of dichloromethane, chloroform, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile and acetone.
In the present invention, when the protecting group reagent is acetone, acetone may be used as both the protecting group reagent and the solvent without adding the first solvent, and a larger amount of acetone may be appropriately added.
Preferably, in step (2), the reaction is carried out at 50 to 70 ℃ for 4 to 6 hours. Preferably, in step (2), the reaction is carried out at 55-65 ℃.
In the invention, in the step (2), the feeding molar ratio of the compound 1 to the ethyl 8-bromooctanoate is 1: 0.8-5, preferably 1: 0.9-1.5.
Preferably, in the step (2), the second solvent is one or more selected from the group consisting of dichloromethane, chloroform, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile, acetone and water.
Preferably, in step (2), the base is one or more selected from the group consisting of lithium bistrimethylsilyl amine, sodium bistrimethylsilyl amine, lithium diisopropylamide, n-butyl lithium, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate.
Preferably, in the step (2), the addition amount of the base is 0.1 to 20 times the mass of the compound 1.
The invention also provides an intermediate for preparing the sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, which has the structure shown as the following compound 2:
the invention also provides a preparation method of the sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, which comprises the following steps:
preparing ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [1,3] oxazin-3 (4H) -yl) octanoate represented by Compound 2 by the method described above;
(ii) hydrolyzing compound 2 in a third solvent in the presence of a hydrolyzing reagent to form 8- (2-hydroxybenzamido) octanoic acid represented by compound 3;
(iii) reacting compound 3 with a sodium-containing base in a fourth solvent to form sodium N- (8- [ 2-hydroxybenzoyl ] -amino) octanoate;
preferably, in step (ii), the hydrolysis agent is a combination of one or more selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate.
The hydrolysis in step (ii) is preferably carried out at 30 to 100 ℃, more preferably at 40 to 90 ℃, and still more preferably at 50 to 80 ℃.
In the present invention, in the step (ii), the third solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, butanol, dichloromethane, chloroform, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile, acetone and water.
Preferably, in step (iii), the sodium-containing base is a combination of one or more selected from sodium hydroxide, sodium carbonate, sodium bicarbonate and sodium phosphate.
In this step (iii), the amount of the sodium-containing base added may be slightly insufficient, equivalent, slightly excessive, etc. relative to compound 3.
Specific embodiments of this step (iii) are: mixing sodium-containing alkali and a fourth solvent, dispersing in a heating state, preferably until the solution is clear, adding the compound 3, carrying out heat preservation reaction, cooling for crystallization, filtering, and drying to obtain the compound. Wherein the temperature of heating, in some embodiments, is preferably to 45-85 deg.C, or 50-75 deg.C.
Preferably, in step (iii), the fourth solvent is a combination of one or more selected from methanol, ethanol, isopropanol, butanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile, acetone and water.
The above-described scheme is further illustrated below with reference to specific examples; it is to be understood that these embodiments are provided to illustrate the general principles, essential features and advantages of the present invention, and the present invention is not limited in scope by the following embodiments; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
In the following, all starting materials are either commercially available or prepared by conventional methods in the art, unless otherwise specified.
The reaction scheme for the preparation of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) octanoate (SNAC) in the following examples is as follows:
example 1
Compound 1: preparation of 2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one
Adding 100g of salicylamide, 500mL of acetone and 1g of p-toluenesulfonic acid into a reaction bottle, carrying out reflux reaction for 3h, concentrating to remove most of solvent, separating out a product, filtering, collecting a filter cake, and drying to obtain a compound 1:129g, molar yield of about 100%, purity of 99.4%, NMR spectrum see FIG. 1.
Compound 2: preparation of ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [ e ] [1,3] oxazin-3 (4H) -yl) octanoate
Adding 80g of compound 1, 400mL of acetonitrile, 93g of potassium carbonate and 113.4g of 8-bromoethyl octanoate into a reaction flask, reacting for 5h at 60 ℃, cooling to normal temperature, filtering, and concentrating the filtrate to obtain a compound 2: 156g of ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [ e ] [1,3] oxazin-3 (4H) -yl) octanoate had a purity of 98.7% and was used directly in the next reaction.
Referring to figure 2, nuclear magnetic hydrogen spectroscopy data for compound 2: 1 H NMR(400MHz DMSO-d6)δ7.77-7.75(dd,J＝8Hz,1H)，7.52-7.48(dt,J＝8.4Hz,1H)，7.12-7.08(dd,J＝7.6Hz,1H)，6.97-6.95(d,J＝7.2Hz,1H)，4.07-4.02(q,J＝7.6Hz,2H)，3.44-3.40(q,J＝4Hz,1H)，2.29-2.26(t,J＝7.2Hz,1H)，1.62(s,6H)，1.57-1.48(m,4H)，1.33-1.23(m,6H)，1.19-1.15(t,J＝4Hz,3H)。
compound 3: preparation of 8- (2-hydroxybenzamido) octanoic acid
85g of compound 2, 400mL of ethanol and 10g of hydrochloric acid are added into a reaction bottle to react at 50 ℃ overnight, the mixture is concentrated to obtain a crude product of the compound 3- (2-hydroxybenzamido) caprylic acid, 200mL of acetonitrile is added to be recrystallized to obtain 62.5g of 8- (2-hydroxybenzamido) caprylic acid, the nuclear magnetic spectrum of which is shown in figure 3, the molar yield is 92%, and the purity is 99.7%.
Preparation of the compound sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate (SNAC)
Adding 200mL of ethanol and 1.43g of sodium hydroxide into a reaction bottle, heating to 50-55 ℃ until the mixture is dissolved clearly, continuously adding 10g of the compound 3, keeping the temperature and stirring for 1h after the addition, cooling to 20 +/-5 ℃ for crystallization, rapidly filtering after a large amount of solid is separated out, and drying a filter cake by air blasting to obtain 10.2g of similar white solid SNAC (selective non-catalytic reduction) with a high performance liquid chromatogram of which the high performance liquid chromatogram is shown in figure 4, the molar yield is 95.3% and the purity is 99.6%.
Example 2
Compound 1: preparation of 2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one
Adding 50g of salicylamide, 300mL of 2, 2-dimethoxypropane and 300mL of acetonitrile into a reaction bottle, reacting for 6h at 70 ℃, concentrating to remove most of solvent, separating out a product, filtering, collecting a filter cake, and drying to obtain a compound 1: 63.2g of 2, 2-dimethyl-2H-benzo [1,3] oxazine-4 (3H) -ketone, the molar yield is 98 percent, and the purity is 99.8 percent.
Compound 2: preparation of ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [ e ] [1,3] oxazin-3 (4H) -yl) octanoate
Adding 50g of compound 1, N-dimethylformamide 300mL into a reaction bottle, cooling to 0-10 ℃, adding 16.9g of sodium hydride in batches, continuing to stir for 0.5h after the addition is finished, dropwise adding 70.8g of 8-bromoethyl octanoate, reacting for 5h at 60 ℃, pouring the reaction liquid into water, extracting twice with ethyl acetate, drying an organic phase, filtering, and concentrating the filtrate to obtain a compound 2: 97g of ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [1,3] oxazin-3 (4H) -yl) octanoate having a purity of 98.0% was used directly in the next reaction.
Compound 3: preparation of 8- (2-hydroxybenzamido) octanoic acid
Adding 50g of compound 2, 400mL of methanol and 10g of sodium hydroxide into a reaction bottle, reacting at 80 ℃ overnight, concentrating to remove the solvent, adjusting the pH to acidity by using concentrated hydrochloric acid under cooling, precipitating a solid, filtering to obtain a crude product, adding 120mL of acetonitrile, and recrystallizing to obtain 35.5g of compound 3:8- (2-hydroxybenzamido) caprylic acid, the molar yield is 89%, and the purity is 99.6%.
Preparation of the compound sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate (SNAC)
Adding 200mL of isopropanol and 1.43g of sodium hydroxide into a reaction bottle, heating to 50-55 ℃ until the mixture is dissolved clearly, continuously adding 10g of the compound 3, keeping the temperature and stirring for 1h, cooling to 20 +/-5 ℃ for crystallization, quickly filtering after a large amount of solid is separated out, and drying a filter cake by blowing air to obtain 10.1g of white-like solid SNAC (selective non-catalytic reduction) with the molar yield of 94.4% and the purity of 99.9%.
Example 3
Compound 1: preparation of 2, 2-dimethyl-2H-benzo [ e ] [1,3] oxazin-4 (3H) -one
Adding 100g of salicylamide, 500mL of acetone and 1g of p-toluenesulfonic acid into a reaction bottle, carrying out reflux reaction for 3h, concentrating to remove most of solvent, separating out a product, filtering, collecting a filter cake, and drying to obtain a compound 1:129g of 2, 2-dimethyl-2H-benzo [1,3] oxazine-4 (3H) -ketone, 100 percent of molar yield and 99 percent of purity.
Compound 2: preparation of ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [ e ] [1,3] oxazin-3 (4H) -yl) octanoate
Adding 40g of compound 1, DMF 400mL, cesium carbonate 136g, ethyl 8-bromooctanoate 56.7g into a reaction bottle, reacting at 60 ℃ for 5h, cooling to normal temperature, filtering, adding ethyl acetate into filtrate for extraction twice, and concentrating an organic phase to obtain compound 2: 156g of ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [1,3] oxazin-3 (4H) -yl) octanoate with a purity of 98.7% was used directly in the next reaction.
Compound 3: preparation of 8- (2-hydroxybenzamido) octanoic acid
To a reaction flask were added 50g of compound 2, 200mL of isopropanol, 50g of sulfuric acid, overnight at 80 ℃, concentrated to give a crude product, and recrystallized by adding 120mL of acetonitrile to give 37.5g of compound 3:8- (2-hydroxybenzamido) caprylic acid, the molar yield is 94 percent, and the purity is 99.6 percent.
Preparation of the compound sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate (SNAC)
Adding 300mL of isopropanol and 3.8g of sodium carbonate into a reaction bottle, heating to 70-75 ℃ until the mixture is dissolved clearly, continuously adding 10g of the compound 3, keeping the temperature and stirring for 1h, cooling to 20 +/-5 ℃ for crystallization, quickly filtering after a large amount of solid is separated out, and drying a filter cake by air blast to obtain 9.8g of white-like solid SNAC, wherein the molar yield is 91.5%, and the purity is 99.2%.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (8)
1. A process for the preparation of an intermediate of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that it comprises the following steps:
(1) Reacting salicylamide with a protecting group reagent in a first solvent to obtain 2, 2-dimethyl-2, 3-dihydro-4H-benzo [1,3] oxazine-4-ketone shown as a compound 1; the protecting group reagent is acetone and/or 2, 2-dimethoxypropane;
allowing the reaction to proceed in the presence of a catalyst which is a combination of one or more selected from the group consisting of p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, hydroiodic acid, formic acid, acetic acid, and boric acid;
(2) Reacting the compound 1 with ethyl 8-bromooctanoate in a second solvent under the action of alkali to generate an intermediate shown as a compound 2: ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [1,3] oxazin-3 (4H) -yl) octanoate;
the alkali is one or more of bis-trimethylsilyl amido lithium, bis-trimethylsilyl amido sodium, lithium diisopropyl amido, n-butyl lithium, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate;
2. the process for producing an intermediate of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate according to claim 1, characterized in that, in the step (1), when the protecting group reagent is acetone, the reaction is carried out under reflux; when the protecting group reagent is 2, 2-dimethoxypropane, the reaction is carried out at 65-75 ℃.
3. The process for preparing an intermediate of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate according to claim 1, characterized in that in step (1), the first solvent is one or more selected from the group consisting of dichloromethane, chloroform, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile and acetone.
4. The process for the preparation of the intermediate of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate according to claim 1, characterized in that in step (2), the reaction is carried out at 50-70 ℃.
5. The process for producing an intermediate of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate according to claim 1, characterized in that in step (2), the second solvent is a combination of one or more selected from dichloromethane, chloroform, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile, acetone and water.
6. An intermediate for the preparation of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that it has the structure shown in the following compound 2:
7. a process for the preparation of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate, characterized in that it comprises:
preparing ethyl 8- (2, 2-dimethyl-4-oxo-2H-benzo [1,3] oxazin-3 (4H) -yl) octanoate represented by compound 2 by a process according to any one of claims 1 to 5;
(ii) hydrolyzing compound 2 in a third solvent in the presence of a hydrolyzing reagent to form 8- (2-hydroxybenzamido) octanoic acid represented by compound 3;
(iii) reacting compound 3 with a sodium-containing base in a fourth solvent to form sodium N- (8- [ 2-hydroxybenzoyl ] -amino) octanoate;
8. the process for the preparation of sodium N- (8- [ 2-hydroxybenzoyl ] -amino) caprylate according to claim 7, wherein in step (ii), the hydrolyzing agent is a combination of one or more selected from hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate; the third solvent is one or more selected from methanol, ethanol, isopropanol, butanol, dichloromethane, chloroform, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile, acetone and water;
in step (iii), the sodium-containing base is a combination of one or more selected from sodium hydroxide, sodium carbonate, sodium bicarbonate and sodium phosphate; the fourth solvent is one or more selected from methanol, ethanol, isopropanol, butanol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, 1, 4-dioxane, tetrahydrofuran, acetonitrile, acetone, and water.
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