阅读说明：本技术 一种那拉曲坦制备用中间体化合物的制备方法 (Preparation method of intermediate compound for preparing naratriptan ) 是由 郭伟 张鹏飞 李尚立 于 2020-06-19 设计创作，主要内容包括：本发明提供一种那拉曲坦制备用中间体化合物的制备方法,包括采用结构如式VI所示的化合物与氢气反应得到结构如式VII所示的中间体化合物。本发明提供的上述制备方法能够获得高品质的中间体化合物,中间体无需使用硅胶柱分离纯化,也无需繁琐的后处理操作,避免了繁琐的分离提纯步骤,也避免了原料的浪费,降低了生产成本,更适用于工业化生产。(The invention provides a preparation method of an intermediate compound for preparing naratriptan, which comprises the step of reacting a compound with a structure shown in a formula VI with hydrogen to obtain an intermediate compound with a structure shown in a formula VII. The preparation method provided by the invention can obtain a high-quality intermediate compound, the intermediate compound does not need to be separated and purified by using a silica gel column, and complicated post-treatment operation is not needed, so that complicated separation and purification steps are avoided, waste of raw materials is avoided, the production cost is reduced, and the preparation method is more suitable for industrial production.)

1. A preparation method of an intermediate compound for preparing naratriptan comprises the step of carrying out hydrogenation reaction on a compound with a structure shown in a formula VI and hydrogen to obtain an intermediate compound with a structure shown in a formula VII, wherein the reaction route is as follows:

2. the production method according to claim 1,

the reaction system of the hydrogenation reaction also contains a reaction medium, and the reaction medium is a first organic solvent;

and/or, a catalyst is adopted in a reaction system of the hydrogenation reaction, and the catalyst is palladium carbon or Raney nickel;

and/or, the hydrogenation reaction is carried out in a hydrogen atmosphere;

and/or the hydrogenation reaction temperature is 20-60 ℃;

and/or, after the hydrogenation reaction is finished, the method also comprises a post-treatment step, wherein the post-treatment step comprises suction filtration, concentration, pulping and suction filtration.

3. The production method according to claim 2,

the first organic solvent is one or more selected from tetrahydrofuran, ethanol and methanol;

and/or the hydrogen pressure is 0.1MPa to 1 MPa;

and/or the reaction temperature is 20-40 ℃;

and/or adding a mixed solvent of ethyl acetate and petroleum ether for pulping.

4. The preparation method of claim 1, wherein a compound with a structure shown in formula V is adopted to perform deprotection reaction under an acidic condition to obtain a compound with a structure shown in formula VI, and the reaction route is as follows:

5. the production method according to claim 4,

the reaction system of the deprotection reaction contains a second organic solvent, and the second organic solvent is one or two of dichloromethane and methanol;

and/or, the reaction system of the deprotection reaction also contains one or more selected from hydrochloric acid and trifluoroacetic acid for providing acidic conditions;

and/or the reaction temperature of the deprotection reaction is 20-60 ℃;

and/or the reaction time of the deprotection reaction is 15-20 h;

and/or after the reaction of the deprotection reaction is finished, the method also comprises a post-treatment step, wherein the post-treatment step comprises cooling and suction filtration.

6. The preparation method of claim 4, wherein the compound with the structure shown in formula IV is subjected to condensation reaction with tetrahydrofuran solution of methylamine to obtain the compound with the structure shown in formula V, and the reaction route is as follows:

7. the production method according to claim 6,

dropping a compound with a structure shown in a formula IV into a tetrahydrofuran solution of methylamine or dropping the tetrahydrofuran solution of methylamine into the compound with the structure shown in the formula IV for condensation reaction;

and/or the condensation reaction temperature is-20-10 ℃;

and/or the condensation reaction time is not more than 1 h;

and/or after the condensation reaction is finished, the method also comprises a post-treatment step, wherein the post-treatment step comprises liquid separation to obtain an organic phase and concentration.

8. The preparation method according to claim 6, characterized in that the compound with the structure shown in formula III is subjected to chlorination reaction with a chlorinating agent to obtain the compound with the structure shown in formula IV, wherein the reaction route is as follows:

9. the method according to claim 8,

the reaction system of the chlorination reaction also contains a third organic solvent as a reaction medium, wherein the third organic solvent is one or two selected from tetrahydrofuran and N, N-dimethylformamide;

and/or the chlorinated reagent is one or more selected from phosphorus oxychloride, phosphorus pentachloride, sulfonyl chloride and thionyl chloride;

and/or the chlorination reaction temperature is 0-50 ℃;

and/or the chlorination reaction time is not more than 4 h.

10. The preparation method of claim 8, wherein the compound with the structure shown in formula II is adopted to perform Heck reaction with an aqueous solution of sodium vinylsulfonate to obtain the compound with the structure shown in formula III, and the reaction route is as follows:

11. the production method according to claim 10,

a fourth organic solvent is also adopted as a reaction medium in the reaction system of the Heck reaction, and the fourth organic solvent is selected from one or more of dimethylformamide, dimethyl sulfoxide, dioxane and acetonitrile;

and/or the concentration of the sodium vinylsulfonate aqueous solution is 20 to 30 weight percent;

and/or, the Heck reaction is carried out under the catalyst which is palladium acetate;

and/or, the Heck reaction is carried out under alkaline conditions;

and/or, the reaction system of the Heck reaction also contains a phosphine ligand, wherein the phosphine ligand is selected from one or two of triphenylphosphine and tri (o-methylphenyl) phosphorus;

and/or the Heck reaction temperature is 60-90 ℃;

and/or the Heck reaction time is not more than 12 h;

and/or, the Heck reaction also comprises a post-treatment step after the end of the Heck reaction, wherein the post-treatment step comprises extraction and concentration.

12. The preparation method of claim 10, wherein the compound of formula I and Boc anhydride are subjected to amine protection reaction to obtain a compound of formula II, wherein the reaction route is as follows:

13. the production method according to claim 12,

a fifth organic solvent is adopted as a reaction medium in a reaction system of the amino protection reaction, and the fifth organic solvent is dichloromethane;

and/or, the reaction is carried out with a catalyst of 4-dimethylaminopyridine;

and/or the post-treatment step is also included after the amino protection reaction is finished, and the post-treatment step comprises extraction and concentration.

Technical Field

The invention relates to the field of synthesis of drug intermediates, in particular to a preparation method of an intermediate compound for preparing naratriptan.

Background

Naratriptan (the english name Naratriptan, also known as amenamig), the chemical name M-methyl-3- (1 ー methyl-4-piperidinyl) -1, 4-indolino-5-ethylsulfonamide, has the following structural formula:

the synthetic route is as follows:

naratriptan is a second generation triptan anti-migraine drug developed by glatiramer Kanggong, is used for treating migraine, cluster headache, chronic paroxysmal migraine and headache caused by vascular disorder, and is used for relieving symptoms related to the migraine, and the intermediate VII has high market value.

The data published to date show that the naratriptan synthetic route is divided into two major classes. One of the main groups is ethyl sulfonamide derivatives substituted by benzene ring, and then indole ring closing and condensation with N-methyl piperidone are carried out. The method has no commercial supply of synthetic starting materials, long steps and low yield, and expensive reagents or reagents with large environmental pollution such as tin dichloride, titanium tetrachloride and the like are used in the ring closing process, so that the industrial production and the commercial production are difficult.

Another general synthetic route of naratriptan is to introduce an ethylsulfamide group on an indole ring to obtain a key intermediate 2- (1H-indol-5-yl) -N-methylethyl-1-sulfamide (VII) and then condense the key intermediate with N-methylpiperidinone. The method is the main method for industrially producing naratriptan at present.

The process of patent US4997841 is a Heck reaction of N-methylvinylsulfonamide (1) with 5-bromoindole (2) followed by a hydro-reduction to introduce the ethanesulfonamide group, the synthetic route being as follows:

one of the starting materials for the Heck reaction in this route, compound (1), is not commercially available, is easily polymerized, and is difficult to prepare, thereby making it difficult to industrially and commercially produce.

The method of patent CN200410093115 introduces ethanesulfonamide group by condensing group-protected N-methylmethanesulfonamide (3) and 5-formaldehyde indole (4) under alkaline condition, then deprotecting agent, hydrogenation reducing, and synthesizing the following route:

the method has the defects that strong base butyl lithium, LDA and the like are needed to be used for ultralow temperature reaction, and the requirement on reaction equipment is high; the cyano reduction step requires microwave reaction, which is not suitable for industrial mass production.

Disclosure of Invention

In view of the disadvantages of the prior art, the invention aims to provide a preparation method of an intermediate compound for preparing naratriptan, which is used for solving the problems of harsh reaction conditions, high cost and unsuitability for large-scale production in the synthesis of important intermediate compounds of naratriptan in the prior art.

To achieve the above objects and other related objects, the present invention includes the following technical solutions.

The invention discloses a preparation method of an intermediate compound for preparing naratriptan, which comprises the following steps of carrying out hydrogenation reaction on a compound with a structure shown as a formula VI and hydrogen to obtain an intermediate compound with a structure shown as a formula VII, wherein the reaction route is as follows:

according to the above-mentioned preparation method of the intermediate compound, the hydrogenation reaction system further comprises a reaction medium, and the reaction medium is a first organic solvent. More preferably, the first organic solvent is one or more selected from tetrahydrofuran, ethanol and methanol. More preferably, the first organic solvent is tetrahydrofuran.

According to the above-described process for producing an intermediate compound, the hydrogenation reaction is carried out in the presence of a catalyst. More preferably, the catalyst is palladium on carbon or raney nickel. More preferably, the catalyst is palladium on carbon.

According to the above-mentioned method for producing an intermediate compound, the hydrogenation reaction is carried out in a hydrogen atmosphere at a hydrogen pressure of 0.1MPa to 1 MPa. The reaction can be normally carried out under the hydrogen pressure of 0.1MPa, but the reaction speed is slow, and the reaction speed is increased along with the increase of the hydrogen pressure, and after the hydrogen pressure is higher than 1MPa, the double bond of the indole ring generates impurities. More preferably, the hydrogen pressure in the reaction system is 0.1MPa to 0.2 MPa.

According to the preparation method of the intermediate compound, the hydrogenation reaction temperature is 20-60 ℃. More preferably, the reaction temperature is 20 to 40 ℃.

According to the preparation method of the intermediate compound, after the hydrogenation reaction is finished, the method further comprises a post-treatment step, wherein the post-treatment step comprises suction filtration, concentration, pulping and suction filtration. Preferably, suction filtration means to extract the reaction solution. Concentrating refers to concentrating to dryness. Preferably, a mixed solvent of ethyl acetate and petroleum ether is added for beating. More preferably, the volume of the ethyl acetate is 0.5 to 5 times of the volume of the compound of formula VI. More preferably, the volume of the petroleum ether is 3 to 10 times of the volume of the compound of formula VI. More preferably, the final product is suction filtered.

The invention also discloses a compound with the structure shown in the formula V, which is obtained by deprotection reaction under an acidic condition, wherein the reaction route is as follows:

according to the preparation method, for the reaction of obtaining the intermediate compound with the structural formula shown in the formula VI, the reaction system of the deprotection reaction also contains a reaction medium, and the reaction medium is a second organic solvent. More preferably, the second organic solvent is one or two selected from dichloromethane and methanol. More preferably, the second organic solvent is dichloromethane.

According to the preparation method, the Boc removing condition needs acid or alkali, and for the reaction for obtaining the intermediate compound with the structural formula shown in formula VI, the reaction system also contains one or more selected from hydrochloric acid and trifluoroacetic acid. More preferably, the Boc removal conditions are acidic conditions, and more preferably, the acid is trifluoroacetic acid.

According to the preparation method, for the reaction of obtaining the intermediate compound with the structural formula shown in formula VI, the reaction temperature of the deprotection reaction is 20-60 ℃. More preferably, the reaction temperature is 30 to 40 ℃.

According to the preparation method of the intermediate compound F, for the reaction of obtaining the intermediate compound with the structural formula shown in the formula VI, the reaction time of the deprotection reaction is 15-20 h.

According to the preparation method, for the reaction for obtaining the intermediate compound with the structural formula shown in the formula VI, the method also comprises a post-treatment step after the reaction for removing the protecting group is finished, wherein the post-treatment step comprises cooling and suction filtration. More preferably, the reaction after the completion of the reaction is also cooled and then filtered with suction.

The invention also discloses a condensation reaction of a compound with a structure shown in the formula IV and a tetrahydrofuran solution of methylamine to obtain a compound with a structure shown in the formula V, wherein the reaction route is as follows:

according to the preparation method, the compound with the structure shown in the formula IV is dropped into tetrahydrofuran solution of methylamine or the tetrahydrofuran solution of methylamine is dropped into the compound with the structure shown in the formula IV for condensation reaction. More preferably, the compound having the structure of formula IV is added dropwise to a solution of methylamine in tetrahydrofuran.

According to the preparation method, the condensation reaction temperature of the reaction for obtaining the compound with the structure shown in the formula V is-20-10 ℃. More preferably, the condensation reaction temperature is 0-10 ℃.

According to the preparation method, the condensation reaction time of the reaction for obtaining the compound with the structure shown in the formula V is not more than 1 h. Preferably, the condensation reaction time is 0.1-1 h.

According to the preparation method, for the reaction for obtaining the compound with the structure shown in the formula V, after the condensation reaction is finished, the post-treatment step is also included, and the post-treatment step comprises liquid separation and concentration. More preferably, separating refers to separating the organic phase. Preferably, the concentration is distillation of the organic phase under reduced pressure.

The invention also discloses a method for preparing the compound shown in the formula IV by chlorination reaction of the compound shown in the formula III and a chlorinated reagent, wherein the reaction route is as follows:

according to the preparation method, for the reaction of obtaining the compound with the structure shown in the formula IV, the reaction system of the chlorination reaction also contains a reaction medium, and the reaction medium is a third organic solvent. More preferably, the third organic solvent is one or two selected from tetrahydrofuran and N, N-dimethylformamide.

According to the preparation method, for the reaction of obtaining the intermediate compound with the structure shown in the formula IV, the chlorinated reagent is one or more selected from phosphorus oxychloride, phosphorus pentachloride, sulfuryl chloride and thionyl chloride. More preferably, the chlorinating reagent is thionyl chloride.

According to the preparation method, the reaction temperature of chlorination reaction is 0-50 ℃ for the reaction of obtaining the intermediate compound with the structure shown in the formula IV. More preferably, the reaction temperature of the chlorination reaction is 40-50 ℃.

According to the preparation method, the chlorination reaction time is not more than 4h for the reaction of obtaining the intermediate compound with the structure shown in the formula IV. Preferably, the chlorination reaction time is 0.5-4 h.

According to the preparation method, for the reaction for obtaining the intermediate compound with the structure shown in the formula IV, after chlorination reaction, no post-treatment is needed, and the reaction liquid is directly fed to the next step.

The invention also discloses a method for preparing the compound shown in the formula III by using the compound shown in the formula II and the sodium vinylsulfonate aqueous solution to carry out Heck reaction, wherein the reaction route is as follows:

according to the preparation method, for the reaction of obtaining the compound with the structural formula shown in the formula III, a fourth organic solvent is also adopted as a reaction medium in a Heck reaction system. More preferably, the fourth organic solvent is selected from one or more of dimethylformamide (abbreviated as DMF), dimethylsulfoxide (abbreviated as DMSO), dioxane and acetonitrile. More preferably, the organic solvent is acetonitrile.

According to the preparation method, for the reaction of obtaining the compound with the structural formula shown in the formula III, the concentration of the sodium vinylsulfonate aqueous solution is 20-30 wt%, and the preferred concentration is 25 wt%.

According to the preparation method, the Heck reaction is carried out in the presence of a catalyst for the reaction of obtaining the compound with the structural formula shown in the formula III. More preferably, the catalyst is palladium acetate.

According to the preparation method, the Heck reaction is carried out under the alkaline condition for the reaction of obtaining the compound with the structure shown in the formula III. More preferably, the basic condition is one or more of potassium carbonate, sodium acetate and triethylamine added to the reaction system. More preferably, the base is triethylamine. The basic conditions are used to neutralize the acid produced in the reaction.

According to the preparation method, for the reaction of obtaining the compound with the structural formula shown in the formula III, a reaction system of the Heck reaction also contains a phosphine ligand. More preferably, the phosphine ligand is selected from one or both of triphenylphosphine and tris (o-methylphenyl) phosphorus. More preferably, the phosphine ligand is triphenylphosphine.

According to the preparation method, the Heck reaction temperature for the reaction of obtaining the compound with the structural formula shown in the formula III is 60-90 ℃. More preferably, the Heck reaction temperature is 70-80 ℃.

According to the preparation method, the Heck reaction time for the reaction of obtaining the compound with the structural formula shown in the formula III is not more than 12 h. Preferably, the Heck reaction time is 0.5h to 12 h.

According to the preparation method, for the reaction of obtaining the compound with the structure shown in the formula III, the method also comprises a post-treatment step after the Heck reaction is finished, wherein the post-treatment step comprises extraction and concentration. More preferably, the extraction is to add water and ethyl acetate into the system after the reaction is finished for layering to obtain a water phase, acidify the water phase until the pH value is 2-3, and extract with dichloromethane to obtain an organic phase, namely the compound with the structure shown in the formula III. More preferably, the acidification is to add a hydrochloric acid aqueous solution into the water phase to adjust the pH value to 2-3; the concentration of the hydrochloric acid aqueous solution can be 0.5-5 mol/L. In the extraction process, impurities are extracted under an alkaline condition, and then the compound with the structure shown in the formula III is obtained through acid regulation and extraction, and the compound can play a role in purifying products in a post-treatment process. More preferably, the volume of water used in the extraction is at least 12L, such as 13L, 14L, 15L, etc., based on 1kg of the compound having the structure shown in formula II. More preferably, the volume of the ethyl acetate and the dichloromethane is at least 10L based on 1kg of the compound with the structure shown in the formula II in the extraction. Preferably, the concentration is distillation of the organic phase under reduced pressure.

The invention also discloses a method for carrying out amino protection reaction on a compound with a structural formula shown as a formula I and Boc anhydride to obtain a compound with a structural formula shown as a formula II, wherein the reaction route is as follows:

according to the preparation method, for the reaction of obtaining the compound with the structural formula shown in the formula II, a reaction medium is adopted in a reaction system of the amino protection reaction, and the reaction medium is a fifth organic solvent. More preferably, the fifth organic solvent is selected from dichloromethane.

According to the preparation method, the amino protection reaction is carried out in the presence of a catalyst for the reaction of obtaining the compound with the structural formula shown in the formula II. More preferably, the catalyst is 4-dimethylaminopyridine (abbreviated DMAP).

According to the preparation method, for the reaction of obtaining the compound with the structural formula shown in the formula II, the method also comprises a post-treatment step after the amino protection reaction is finished, wherein the post-treatment step comprises extraction and concentration. More preferably, the extraction is to add dilute hydrochloric acid aqueous solution into the system after the reaction is finished and to stratify to obtain an organic phase, and then to add saturated sodium bicarbonate aqueous solution into the organic phase and to stratify to obtain the organic phase. More preferably, the volumes of the dilute aqueous hydrochloric acid and the saturated aqueous sodium bicarbonate solution are each at least 2 times the volume of the compound of formula I. More preferably, the concentration of the dilute hydrochloric acid aqueous solution is 0.5-3 mol/L. Preferably, the concentration is distillation of the organic phase under reduced pressure.

The preparation method provided by the invention can obtain a high-quality intermediate compound for preparing naratriptan, and the synthesis route in the application takes 5-bromo-1H-indole as an initial raw material and obtains a target product through Boc protection, Heck reaction, chlorination, condensation, Boc removal and hydrogenation; the 5-bromo-1H-indole and the sodium vinylsulfonate are all commercial raw materials which are simple and easy to obtain and have relatively low cost, the reaction conditions are conventional operations, the ultralow temperature reaction conditions are avoided, the intermediates obtained in each step do not need to be separated and purified by using a silica gel column, the complex post-treatment operation is also not needed, the complex separation and purification steps are avoided, the waste of the raw materials is avoided, the reaction yield is over 80 percent, and the total yield reaches 40 percent. Solves the problems of difficult obtainment of raw materials, rigorous reaction conditions, high cost and unsuitability for large-scale production in the synthesis of important intermediate compounds of naratriptan in the prior art, reduces the production cost and is more suitable for industrial production.

Drawings

FIG. 1 is a scheme for the preparation of the compounds shown as intermediate compound II in the examples

FIG. 2 is a preparation scheme of a compound of formula III in the examples

FIG. 3 is a preparation scheme of a compound of formula IV in the examples

FIG. 4 is a preparation scheme of a compound having the structure shown in formula V in the examples

FIG. 5 is a preparation scheme of the compound of formula VI in the examples

FIG. 6 is a preparation scheme of compounds of formula VII in the examples

FIG. 7 is H of a compound of formula II prepared in the examples¹NMR spectra

FIG. 8 is an HPLC chromatogram of the compound of formula II prepared in the example

FIG. 9 is H of a compound of formula V prepared in the examples¹NMR spectra

FIG. 10 is an HPLC chromatogram of the compound of formula V prepared in the example

FIG. 11 is H of a compound of formula VI prepared in the examples¹NMR spectra

FIG. 12 is an HPLC chromatogram of the compound of formula VI prepared in the example

FIG. 13 is H of a compound of formula VII prepared in the examples¹NMR spectra

FIG. 14 is an HPLC chromatogram of the compound of formula VII prepared in the examples

Detailed Description

The following description of the embodiments of the present invention is provided for illustrative purposes, and other advantages and effects of the present invention will become apparent to those skilled in the art from the present disclosure.

Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Test methods in which specific conditions are not specified in the following examples are generally carried out under conventional conditions or under conditions recommended by the respective manufacturers.

When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.

The analytical method of HPLC in the examples of this application is as follows:

the instrument comprises the following steps: HPLC, LC-20A, with UV detector

Reagent: acetonitrile (chromatographic grade); phosphoric acid (AR grade); 'Wahaha' pure water

Preparing a sample solution: an appropriate amount of sample was weighed and dissolved in 20% acetonitrile/water to a sample concentration of about 0.5 mg/ml.

Mobile phase configuration: phase A: 0.01% H₃PO₄/H₂And O, adding 600mL of water into a 1L volumetric flask, transferring 0.1mL of phosphoric acid into the volumetric flask, adding water to dilute to a constant volume, and fully and uniformly mixing. Phase B: acetonitrile

The chromatographic conditions are as follows

Example 1

This example is a synthetic route as shown in figure 1: and (3) preparing an intermediate compound II.

A mechanically stirred 100L reactor was charged with Compound I (12kg, 61.2mol), dichloromethane (60L), triethylamine (7.4kg, 73.5mol), and Boc anhydride (16kg, 73.5mol) was added dropwise at room temperature and reacted at room temperature for 12 h. Diluted hydrochloric acid (1M, 24L) is dropped into the reaction liquid, saturated sodium bicarbonate solution (24L) is added into the organic phase after liquid separation, the organic phase is separated after stirring for 10min, and the organic phase is concentrated in vacuum, so that 17.2kg of brown crystals are obtained, and the yield is 95%. FIG. 7 shows H for the compound of formula II prepared in this example¹-NMR spectrum.

FIG. 8 is an HPLC chromatogram of the compound of formula II prepared in the examples.

Example 2

This example is a synthetic route as shown in fig. 2: preparation of a compound with a structural formula shown in formula III.

Adding a compound II (8kg, 27mol), a sodium vinylsulfonate aqueous solution (14.8kg, 28.4mol), triethylamine (4.1kg, 40.5mol), triphenylphosphine (629g, 2.4mol), acetonitrile (64L), palladium acetate (48.5g, 0.22mol) into a mechanically-stirred 100L reaction kettle, reacting for 12 hours at 70-80 ℃ under the protection of argon, cooling to room temperature, adding water (96L) into the reaction solution, washing twice with 80L x 2 ethyl acetate, retaining a water phase, acidifying the water phase to pH 3 by using 1mol/L hydrochloric acid, extracting with 80L x 4 dichloromethane, combining the dichloromethane, and carrying out vacuum concentration to obtain the compound shown in the formula III, wherein the compound is directly put into the reaction kettle without further purification.

Example 3

This example is a synthetic route as shown in fig. 3: preparation of a compound with a structural formula shown in formula IV.

Adding a compound III (2.39kg, 7.4mol) and tetrahydrofuran (8L) into a mechanically-stirred 20L reaction kettle, adding thionyl chloride (1.1kg, 8.9mol) at 10-20 ℃, dropwise heating to 40-50 ℃ for reaction for 3 hours, and cooling the reaction solution to room temperature for directly feeding to the next step.

Example 4

This example is a synthetic route as shown in fig. 4: preparation of a compound with a structural formula shown as a formula V.

Adding a tetrahydrofuran solution (15L, 44.6mol) of (3M/L) methylamine into a mechanically-stirred 100L reaction kettle, controlling the temperature to be 0-10 ℃, dropwise adding the reaction solution (3), stirring for 15min, separating liquid, carrying out vacuum concentration on an organic phase, and carrying out oil pump drying to obtain 2kg of a viscous product, wherein the yield of the product is 1.6kg, and the yield of the two steps is 65%; the product was directly subjected to the next reaction without further purification.

FIG. 9 shows H for the compound of formula V prepared in this example¹NMR spectra

FIG. 10 is an HPLC chromatogram of the compound of formula V prepared in this example

Example 5

This example is a synthetic route as shown in fig. 5: preparation of a compound with a structural formula shown in formula VI.

Adding a compound V (2kg, 5.9mol), dichloromethane (10L) and trifluoroacetic acid (2L, 1vol) into a mechanically-stirred 20L reaction kettle, heating to 35 ℃ for reaction for 12h, cooling to 10 ℃, stirring for 2h, performing suction filtration, and drying to obtain 1.1kg of white solid with the yield of 80%.

FIG. 11 is a H1-NMR spectrum of the compound of formula VI prepared in this example.

FIG. 12 is an HPLC chromatogram of the compound of formula VI prepared in this example.

Example 6

This example is a synthetic route as shown in fig. 6: preparation of the final product of formula VII.

Adding a compound VI (2kg, 8.5mol), tetrahydrofuran (10L) and palladium-carbon (100g) into a mechanically-stirred 20L hydrogenation kettle, adding hydrogen to 0.2MPa under room temperature for reaction for 12h, carrying out vacuum concentration on the filtered clear liquid, adding ethyl acetate (2L) into the product, pulping with petroleum ether (10L) for 2h, and carrying out suction filtration and drying to obtain a white solid 1.6kg with the yield of 80%.

FIG. 13 shows H for the compound of formula VII prepared in this example¹-NMR spectrum.

FIG. 14 is an HPLC chromatogram of the compound of structure formula VII prepared in this example.

The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.