WO2021248764A1

WO2021248764A1 - Method for preparing laninamivir octanoate intermediate by means of one-pot synthesis

Info

Publication number: WO2021248764A1
Application number: PCT/CN2020/120751
Authority: WO
Inventors: 袁建栋; 黄仰青; 池建文; 顾家宁; 杭文明; 林祥义; 孙鹏
Original assignee: 博瑞生物医药（苏州）股份有限公司
Priority date: 2020-06-12
Filing date: 2020-10-14
Publication date: 2021-12-16
Also published as: CN113801138A

Abstract

The present invention relates to the technical field of medicine synthesis, and specifically relates to a method for preparing a laninamivir octanoate intermediate by means of one-pot synthesis. The method for preparing a laninamivir octanoate intermediate by means of one-pot synthesis comprises: subjecting a compound as represented by formula (4) to a reaction in the presence of R1OH, NaH and (R1O)2CO to obtain a compound as represented by formula (5), wherein R1 is benzyl, substituted benzyl, or allyl. A laninamivir octanoate intermediate compound (5) is innovatively synthesized from a compound (4) by means of using one-pot synthesis; the reaction is gentle and rapid, and the next-step reaction can be carried out after simple post-treatment; energy consumption is saved, the pollution is reduced, operation is simple and the cost is low, such that the method is suitable for industrial production. The laninamivir octanoate intermediate compound (5) prepared by means of using one-pot synthesis has a yield of at least 87%.

Description

One-pot method for preparing lanimivir caprylate intermediate

Technical field

The invention relates to the technical field of drug synthesis, in particular to a one-pot method for preparing an intermediate of lanimivir octoate.

Background technique

Laninamivir caprylate is a neuraminidase inhibitor developed by Biota Pharmaceuticals and Daiichi Sankyo. It can be used to treat influenza virus infections that are resistant to oseltamivir (Tamiflu). In 2010, it was approved to be marketed in Japan under the name Inavir.

The chemical structural formula of lanimivir caprylate is as follows:

Lanimivir caprylate has good effects on H1N1, H5N1, N9 and influenza B viruses and Tamiflu-resistant viruses. Up to now, lanimivir caprylate has not been listed in the country, and there is no registered manufacturer. In order to guide the R&D and production of generic drugs and improve the availability of drugs to the public, the Center for Drug Evaluation of the State Food and Drug Administration organized a screening of foreign drugs that have expired, terminated, or become invalid and have no generic applications. Lanimivir caprylate was initially screened and included in the "List of the First Batch of Drugs with Expiration, Termination, and Invalidation without Generic Application".

At present, the preparation method of lanimivir caprylate is summarized into the following three methods:

Method 1: Patent CN101679339A discloses the synthesis of lanimivir octoate by 11-step reaction with sialic acid as the starting material. The synthesis route is as follows:

This route uses commercially supplied sialic acid as the starting material to synthesize lanimivir octoate through an 11-step reaction. The unit reaction effect is good and the overall yield is high.

Method 2: Patent CN103435582A discloses the synthesis of lanimivir octoate via a 5-step reaction with zanamivir as the starting material. The synthesis route is as follows:

Although this method has few steps, it uses zanamivir as the starting material, and the price of the raw material is too expensive to meet the demand for generic drugs;

Method 3, Ma Dawei's research group used D-isoascorbic acid as the starting material, followed by a series of oxidation, reduction, protection, deprotection and other reactions to synthesize lanimivir octoate. The synthetic route is as follows:

The synthesis route is relatively novel, the unit reaction yield is moderate, but the market supply of starting materials and catalyst ligands is small, the price is expensive, and it is not suitable for scale-up production. At the same time, the chiral purity of intermediate S-3 and intermediate S-8 is not high. , Resulting in more impurities in subsequent isomers, and the quality of the final product is difficult to control.

For the above three routes, because the raw materials of route 2 are too expensive and the reagents of route 3 are too expensive, they are not suitable for industrial production. Therefore, our research focuses on the process optimization of patent CN101679339A. We found patents in the process of repeating CN101679339A. In the process of producing compound 3, it is necessary to add concentrated sulfuric acid, the reaction conditions are relatively harsh, and the risk is high in industrial production; the reaction steps in the production process of compound 4-6 are cumbersome and require column chromatography, which is difficult to meet the requirements of industrial production, and further optimization.

Summary of the invention

The purpose of the present invention is to provide a one-pot method for preparing lanimivir octoate intermediates.

In order to achieve the above objective, the technical solution of the present invention is:

A one-pot method for preparing lanimivir octoate intermediates adopts a synthetic method including the following:

Wherein, R ₁ is a benzyl group, a substituted benzyl group, or an allyl group.

The aforementioned substituted benzyl group means that the benzene ring on the benzyl group is mono- or multiple-substituted by groups such as chlorine, bromine, iodine, nitro, alkoxy, alkyl, and aromatic.

The above-mentioned one-pot method for preparing lanimivir octoate intermediate includes the following steps: _{mixing and stirring the compound represented by formula (4) with an organic solvent and R 1} OH, and then adding NaH and stirring for 30-60 min under the protection of nitrogen. Then (R ₁ O) ₂ CO is added, and the reaction is stirred at 0-80° C. for 30 min-24 h, and then separated to obtain the compound represented by formula (5).

The crude compound of formula (5) is crystallized by toluene or methanol to obtain crystals of the compound represented by formula (5).

Preferably, the reaction temperature is 10-60°C.

More preferably, the reaction temperature is 50-55°C.

Preferably, the reaction time is 30 minutes to 5 hours.

The organic solvent is any one or more of toluene, N,N-dimethylformamide, benzyl alcohol, n-heptane, methyl tert-butyl ether, tetrahydrofuran, and 1,4-dioxane.

The mass concentration of the NaH is 60%.

Preferably, R ₁ is benzyl.

In the above method, the mass ratio of the compound represented by formula (4), R ₁ OH, NaH, and (R ₁ O) ₂ CO is 8-12:15-30:0.02-0.1:12-36. Preferably, the mass ratio of the compound represented by formula (4), R ₁ OH, NaH, and (R ₁ O) ₂ CO is 9.8:20:0.04:24.22.

The compound represented by the above formula (4) is synthesized by the following route:

Wherein, R ₁ is benzyl, substituted benzyl or allyl, X is ^{^{^{Cl -, Br -, I -}}} , MeSO 4 -, TfO -.

Step 1. In the presence of a base, the compound represented by formula (1) reacts with R ₁ X to produce the compound represented by formula (2).

The base is not particularly limited, as long as it can be neutralized with a carboxylic acid, and it may be an organic base or an inorganic base.

Preferably, the organic base such as triethylamine, diisopropylethylamine, N,N-dimethyl-4-aminopyridine or pyridine; inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide or Potassium hydroxide.

An inorganic base is preferable, and cesium carbonate or potassium carbonate is more preferable.

Step 2. In the presence of an organic base, the compound represented by formula (2) reacts with acetic anhydride to produce the compound represented by formula (3). There is no restriction on the organic base, as long as it can be neutralized with carboxylic acid.

Preferably, the organic base is any one or more of triethylamine, diisopropylethylamine, N,N-dimethyl-4-aminopyridine, and pyridine.

The reaction temperature in step 2 is -30°C to 100°C. Preferably it is 0-35 degreeC.

The reaction time of step 2 is 30min-24h. Preferably it is 10-15h.

Step 3. The compound represented by the formula (3) is catalyzed by trimethylsilyl trifluoromethanesulfonate to produce the compound represented by the formula (4).

The reaction temperature in step 3 is 0 to 70°C. Preferably it is 30 degreeC-60 degreeC.

The reaction time of step 3 is 1.0h-24h. Preferably it is 1.0-3.0h.

After step 3, triethylamine was added dropwise to quench the reaction.

A preparation method of lanimivir octoate (compound of formula I) adopts a synthetic method including the following:

Step 5 is to react the compound represented by formula (5) with dimethyl sulfate or methyl iodide in the presence of a base to produce the compound represented by formula (6).

The reaction temperature in step 5 is 0-70°C, preferably 0-30°C.

Step 5: The reaction time is 30 minutes to 24 hours, preferably 1.0 to 15 hours.

Step 6 is to react the compound represented by formula (6) with azide trimethylsilane under the catalysis of titanium isopropoxide to produce the compound represented by formula (7).

Step 6: The reaction temperature is 0 to 120°C, preferably 0 to 40°C.

Step 6: The reaction time is 3.0 to 48 hours, preferably 3.0 to 24 hours.

Step 7 is the reaction of the compound represented by formula (7) with triphenylphosphine to produce the compound represented by formula (8).

The reaction temperature in step 7 is -10 to 80°C, preferably 0 to 60°C.

Step 7: The reaction time is 10 minutes to 48 hours, preferably 10 minutes to 5 hours.

Step 8 is the reaction of the compound represented by formula (8) with a base to produce the compound represented by formula (9).

Regarding the base, inorganic bases are preferred, and lithium hydroxide, sodium hydroxide, and potassium hydroxide are more preferred.

The reaction temperature in step 8 is preferably -10 to 100°C, more preferably 0 to 50°C.

Step 8: The reaction time is preferably 10 minutes to 48 hours, more preferably 0.5 hours to 6 hours.

Step 9 is the reaction of the compound represented by formula (9) with the compound represented by formula (10) to produce the compound represented by formula (11).

The step 9 reaction solvent is preferably purified water.

The reaction temperature in Step 9 is 0-100°C, and preferably 5-50°C.

Step 9: The reaction time is 24h to 72h, and preferably 24 to 60h.

Step 10 is the reaction of the compound represented by formula (11) in the presence of trifluoroacetic acid to produce the compound represented by formula (12).

The reaction temperature in step 10 is -20 to 100°C, and preferably 0 to 45°C.

The reaction time of step 10 is 0.5 to 24 hours, and preferably 0.5 to 8 hours.

Step 11 is to react the compound represented by formula (12) with compound 13 or compound 14 in the presence of an acid, and then react with water to produce the compound represented by formula (I) or a pharmacologically acceptable salt thereof.

The acid in step 11 is preferably an inorganic acid, and more preferably hydrochloric acid.

The reaction temperature in step 11 is preferably -10 to 70°C, and preferably 0 to 50°C.

The step 11 reaction time is preferably 10 minutes to 24 hours, and more preferably 10 minutes to 5 hours.

Compound 13 and compound 14 can be prepared by the preparation methods in the prior art; they can also be prepared by the following route:

The beneficial effects of the present invention:

The use of CN101679339A to prepare compound 3 requires the addition of concentrated sulfuric acid, which is not suitable for industrial production. Researchers have found that the use of TMSOTf can react better, and the post-treatment is easy, and industrial pollution will not occur.

The present invention innovatively adopts a one-pot method to synthesize lanimivir octoate intermediate compound (5) from compound (4). The reaction is mild and fast, and the product does not require column chromatography, and simple post-treatment can proceed to the next reaction, saving energy Consumption, pollution reduction, simple operation, low cost, suitable for industrial production.

The lanimivir octoate intermediate compound (5) prepared by the one-pot method in the present invention has a yield of more than 87%, and the yield of lanimivir octoate prepared by using the intermediate is more than 85%. However, the product of the CN101679339A method has many impurities and requires column chromatography, and the yield of the two-step method is only 76.9%.

Description of the drawings

Figure 1 is a hydrogen spectrum of compound (2);

Figure 2 is a hydrogen spectrum of compound (3);

Figure 3 is a hydrogen spectrum of compound (4);

Figure 4 is a hydrogen spectrum of compound (5);

Figure 5 is a hydrogen spectrum of compound (6);

Figure 6 is a hydrogen spectrum of compound (12);

Figure 7 is a hydrogen spectrum of compound (13).

detailed description

The one-pot method for preparing the lanimivir caprylate intermediate of the present invention adopts the following synthetic methods:

Preferably, the reaction temperature is 10-60°C.

More preferably, the reaction temperature is 50-55°C.

Preferably, the reaction time is 30 minutes to 5 hours.

The mass concentration of the NaH is 60%.

Preferably, R ₁ is benzyl.

Preferably, the organic base such as triethylamine, diisopropylethylamine, N,N-dimethyl-4-aminopyridine or pyridine; inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, sodium hydroxide, Potassium hydroxide.

Step 2. In the presence of an organic base, the compound represented by formula (2) reacts with acetic anhydride to produce the compound represented by formula (3). There is no restriction on the organic base, as long as it can be neutralized with a carboxylic acid.

The reaction time of step 2 is 30min-24h. Preferably it is 10-15h.

Step 3. The compound represented by formula (3) is catalyzed by trimethylsilyl trifluoromethanesulfonate to produce the compound represented by formula (4).

The reaction time of step 3 is 1.0h-24h. Preferably it is 1.0-3.0h.

After step 3, triethylamine was added dropwise to quench the reaction.

The preparation method of lanimivir octoate (compound of formula I) of the present invention adopts a synthetic method including the following:

The reaction temperature in step 5 is 0-70°C, preferably 0-30°C.

Step 6 is to react the compound represented by formula (6) with azidotrimethylsilane under the catalysis of titanium isopropoxide to produce the compound represented by formula (7).

Step 6: The reaction temperature is 0 to 120°C, preferably 0 to 40°C.

Step 6: The reaction time is 3.0 to 48 hours, preferably 3.0 to 24 hours.

The reaction temperature in step 7 is -10 to 80°C, preferably 0 to 60°C.

The step 9 reaction solvent is preferably purified water.

The reaction temperature in Step 9 is 0-100°C, and preferably 5-50°C.

Step 9: The reaction time is 24h to 72h, and preferably 24 to 60h.

The reaction time of step 10 is 0.5 to 24 hours, and preferably 0.5 to 8 hours.

Example 1

The preparation of compound (2) includes the following steps:

At room temperature, add 30.93g of N-acetylneuraminic acid (compound 1), Cs ₂ CO ₃ 16.30g, 125ml DMF, and BrBn 26.70g to a 500ml reaction flask, and react with magnetic stirring for 24h. After the reaction is over, filter and concentrate the mother liquor. To dryness, add 300ml isopropanol, heat to 70°C, heat to filter out the insoluble matter, stir the filtrate at room temperature for 3-4h, filter, rinse the filter cake with isopropanol, dry the filter cake under reduced pressure to obtain compound (2) White powder 18.50g, yield 46.25%. The hydrogen spectrum of compound (2) is shown in Figure 1.

In other embodiments, in the preparation process of compound (2), after adding 300 ml of isopropanol, the temperature can be increased to 80°C or 75°C, and then the insoluble matter can be filtered out by hot filtration.

Example 2

The preparation of compound (3) includes the following steps:

At room temperature, in a 250ml reaction flask, add about 70ml of pyridine, 18.50g of compound (2), add 37.50g of acetic anhydride, and then add 4-dimethylaminopyridine (DMAP ) About 0.2g, maintain at 20～25℃, stir and react overnight, pour the reaction solution into 350ml purified water and 1850ml ethyl acetate mixture, after the addition, let stand for layering, and the organic layer shall be 200ml*2 5.0% HCl aqueous solution in turn After extraction and washing with 200ml*2 saturated sodium bicarbonate aqueous solution, the organic layer was dried with anhydrous sodium sulfate, filtered, rinsed, and concentrated under reduced pressure to dryness to obtain 30.02 g of a colorless oil with a yield of 106.4%. Purify by column chromatography (n-heptane～n-heptane/ethyl acetate=1/2), collect the target components (developing solvent: ethyl acetate), and concentrate to dryness under reduced pressure to obtain 14.50g of white powder of compound (3) . The hydrogen spectrum of compound (3) is shown in Figure 2.

Example 3

The preparation of compound (4) includes the following steps:

At room temperature, N ₂ protection, to a 1000ml reaction flask were added the compound (3) 13.20g, 265ml of ethyl acetate, clarified and stirred to dissolve, temperature 15 ~ 25 ℃, dropwise TMSOTf 14.46g, dropping, temperature control In the range of 50～55℃, stir and react for 2h, then control the temperature at 0～5℃, add 11.0g of triethylamine dropwise, then add 100ml of ice water, stir for 10min, stand for separation, and then use 100ml+50ml purified water for the organic layer Extract and wash twice, dry the organic layer with anhydrous sodium sulfate, filter, rinse, and concentrate under reduced pressure to dryness to obtain a colorless oil. Purification by column chromatography (n-heptane ~ n-heptane/ethyl acetate = 1/1 ~ ethyl acetate) to collect the target components, and concentrate under reduced pressure to dryness to obtain 9.14 g of compound (4) as a colorless oily substance. The hydrogen spectrum of compound (4) is shown in Figure 3.

Example 4

The preparation of compound (5) includes the following steps:

At room temperature, the reaction flask was added successively the compound (4) 9.80g, toluene 40ml, benzyl alcohol (i.e. R ₁ taken benzyl) 20.0 mL, addition was completed, stirring at room temperature, nitrogen, after which was added 60% NaH 0.04g, stirring 30min, dibenzyl carbonate (i.e., R ₁ taken benzyl) 24.22 g, IH reaction was stirred at 50 deg.] C, 0.032mol glacial acetic acid was added to quench the reaction, the wet column, rinsing small polar impurities with dichloromethane, dichloro Methane/methanol=40/1, scrub the target components, and concentrate to dry under reduced pressure to obtain compound (5) as a white solid, 6.85 g, with a yield of 87.96%. The yield is much higher than the yield (76.9%) of compound (5) obtained by the two-step method in CN101679339A. The hydrogen spectrum of compound (5) is shown in Fig. 4.

In the preparation example of other compound (5), after adding dibenzyl carbonate, the reaction was stirred at 55° C. for 2 h. In other embodiments, the stirring reaction temperature can also be 10°C, 52°C, 60°C, or 80°C. The stirring reaction time can be adjusted within 30min-24h. Changing the above reaction temperature or time, the yield of compound (5) is basically the same as that of Example 4.

In the preparation examples of other compounds (5), the toluene solvent can also be replaced with N,N-dimethylformamide, benzyl alcohol, n-heptane, methyl tert-butyl ether, tetrahydrofuran, 1,4-di Any one or more of oxane.

In other preparation examples of compound (5), _{the mass ratio of the compound represented by formula (4), R 1} OH, NaH, and (R ₁ O) ₂ CO is 8:30:0.02:36.

In other preparation examples of compound (5), _{the mass ratio of the compound represented by formula (4), R 1} OH, NaH, and (R ₁ O) ₂ CO is 12:15:0.1:12.

In other embodiments, R1 can also be benzyl substituted by chlorine, bromine, iodine, nitro, alkoxy, alkyl or aromatic; even R1 can also be allyl.

Example 5

The preparation of compound (6) includes the following steps:

Under the protection of N ₂ , add 6.85g of compound (5), 28ml of THF, and 7ml of DMF to a 250ml reaction flask in sequence. After the addition, stir until the dissolution is clear. The temperature is controlled within the range of 0-5℃, and 60% NaH is added in batches. 0.91g, after addition, maintain the temperature at 0-5°C, stir for 30min, add 2.88g of dimethyl sulfate, keep the temperature for the reaction overnight, then add 100ml of toluene and 1.06g of glacial acetic acid to quench the reaction. Use 40ml*2 5.0% for the reaction solution Extract and wash with NaHCO ₃ aqueous solution twice, and wash the water layer with 70ml*2 toluene twice, combine all the toluene layers and dry with anhydrous sodium sulfate, filter, rinse, concentrate to near dryness, and purify by column chromatography (dichloromethane→dichloro Methane/methanol 20/1) to obtain 8.0 g of compound (6) as a colorless oil. The hydrogen spectrum of compound (6) is shown in Figure 5.

Example 6

The preparation of compound (7) includes the following steps:

Under the protection of N ₂ and at room temperature, in a 100ml reaction flask, add compound (6) 7.10g, toluene 21ml, tert-butanol 7ml, after the addition, stir until the dissolution is clear, add TMSN ₃ 4.10g, titanium isopropoxide 1.55g , The reaction was stirred at 20-25°C for 24h, then filtered, the filtrate was drained, 10ml methanol was rinsed, and the oil pump had a dry filter cake to obtain 5.76g off-white solid of compound (7), yield: 72.6%.

Example 7

The preparation of compound (8) includes the following steps:

At room temperature, add 5.00g of compound (7) and 20ml of tetrahydrofuran to a 100ml reaction flask, stir until it is clear, add 3.24g of triphenylphosphine, heat up to 40～50℃ after addition, stir and react for 10min, TLC (DCM/ME = 10/1), the raw materials disappeared, and the temperature was reduced to room temperature to obtain the compound (8) reaction solution.

Example 8

The preparation of compound (9) includes the following steps:

In the reaction solution of compound (8) in Example 7, 12.5g of purified water and 5.40g of 25% NaOH aqueous solution were added, the temperature was controlled at 40～45℃, and the reaction was stirred for 2h. TLC (DCM/ME=10/1), raw material Disappear, drop to room temperature, stand for liquid separation, add 6ml THF to the water layer to extract and wash once, add about 4ml concentrated hydrochloric acid dropwise to the water layer, adjust PH=2～3, and then adjust pH=9～10 with 25% NaOH aqueous solution. Compound (9) reaction solution.

Example 9

The preparation of compound (11) includes the following steps:

At room temperature, add 30ml of methanol and 3.82g of N,N'-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (compound 10) to the reaction solution of compound (9) of Example 8, maintaining 20～ Stir the reaction at 25°C for 48h, adjust pH=8.5～8.8, concentrate the reaction solution to dryness, add 100ml ethyl acetate and concentrate under reduced pressure to remove methanol. The concentrated solution is extracted and washed with 50ml*3 ethyl acetate for 3 times, and the water layer is washed with about 1.3g concentrated hydrochloric acid adjusted PH=2~3, the water layer was extracted with 50ml*3 ethyl acetate, and the combined organic layers were concentrated to dryness to obtain 5.20g of white solid (compound 11) with a yield of 85.1%.

Example 10

The preparation of compound (12) includes the following steps:

The compound (11) of Example 9 was added to 50ml of dichloromethane, 5g of trifluoroacetic acid was added to react at room temperature for 3h, concentrated under reduced pressure to dryness, 25ml of purified water was added, and the pH was adjusted to pH=6-8 with a 10% aqueous sodium hydroxide solution. Add 50 ml of methanol, stir and crystallize at room temperature, filter, rinse the filter cake with methanol, and dry under reduced pressure at 40°C to obtain 2.74 g of compound (12) as a white powder with a yield of 70.62%. The hydrogen spectrum of compound (12) is shown in Fig. 7.

Example 11

At room temperature, under N _2, with 100ml reaction flask, were added the compound (12) 2.00g, methanol 10ml, 3.54g compound 13, and finally methanol was added 10.5ml HCl (1N methanolic hydrogen chloride solution), the addition, to clarify the system, Keep at 20-25℃, stir and react for 1h, concentrate under reduced pressure to nearly dryness, add 20ml purified water, extract and wash with 20ml*3 ethyl acetate three times, adjust the pH to 7 with saturated sodium carbonate, stir for 1h, and then saturate it with Adjust pH=8.5～9.0 with sodium carbonate, stir for 3h, adjust pH=5～6 with 6N hydrochloric acid, stir for 30min, filter, filter cake purified water rinse, filter cake 35℃, dry under reduced pressure to constant weight to obtain compound (I ) White powder 2.34g, yield 85.6%, HPLC 99.84%.

Compound 13 in this example can be replaced with compound 14, and other conditions remain unchanged.

Comparative example 1

This comparative example is different from Example 4 only in that dibenzyl carbonate is replaced with carbonyl diimidazole. The product has many impurities and requires column chromatography, and the final yield of compound (5) is only 20%.

Comparative example 2

This comparative example is different from Example 4 only in that dibenzyl carbonate is replaced with benzyl chloroformate. There are many impurities and column chromatography is required. The final yield of compound (5) is only 25%.

For those skilled in the art, various other corresponding changes and deformations can be made based on the technical solutions and concepts described above, and all these changes and deformations should fall within the protection scope of the claims of the present invention.

Claims

A one-pot method for preparing lanimivir octoate intermediates, which is characterized in that a synthesis method including the following is adopted:

Wherein, R 1 is a benzyl group, a substituted benzyl group, or an allyl group.
The method according to claim 1, characterized in that it comprises the following steps: mixing and stirring the compound represented by formula (4) with an organic solvent and R 1 OH, and then under the protection of nitrogen, adding NaH and stirring for 30-60 min, and then adding (R 1 O) 2 CO, stirred and reacted at 0～80°C for 30min～24h, and then separated to obtain the compound represented by formula (5).
The method according to claim 2, wherein the reaction temperature is 10-60°C.
The method of claim 3, wherein the reaction temperature is 50-55°C.
The method according to claim 2, wherein the reaction time is 30 minutes to 5 hours.
The method according to claim 2, wherein the organic solvent is toluene, N,N-dimethylformamide, benzyl alcohol, n-heptane, methyl tert-butyl ether, tetrahydrofuran, 1,4- Any one or more of dioxane.
The method according to claim 1, wherein the mass concentration of the NaH is 60%.
The method according to any one of claims 1-7, wherein R 1 is benzyl.
The method according to claim 1, wherein the mass ratio of the compound represented by formula (4), R 1 OH, NaH, and (R 1 O) 2 CO is 8-12: 15-30: 0.02-0.1: 12-36.
The method according to claim 9, wherein the mass ratio of the compound represented by formula (4), R 1 OH, NaH, and (R 1 O) 2 CO is 9.8:20:0.04:24.22.