In view of the recent years that influenza incidence rate is rising year by year, anti-influenza drugs are receiving more and more attention from scientists, so it is necessary to develop a synthetic route which has simple process route, low cost, avoids synthesizing the compound 7 and is suitable for industrial production.

Disclosure of Invention

Aiming at the technical problems in the prior art, the invention aims to provide a synthesis method of a racemic key intermediate of baroxavir.

The embodiment of the invention provides a synthesis method of a baroxavir key intermediate, which is characterized in that diglycolamine which is cheap and easy to obtain and is shown in the following formula (I) is used for replacing 2- (2, 2-dimethoxyethoxy) ethane-1-amine which is difficult to synthesize and is shown in the formula (II) to perform amine ester exchange reaction, so that the synthesis of compounds 1-4 can be completed with high yield; the compound 1-4 is subjected to one-step cheap oxidation reaction to generate a compound 1-5; and performing Mannich reaction on the compounds 1 to 5 under acidic conditions to obtain racemic baroxavir key intermediates 1 to 6.

Compared with the traditional method, the synthesis method of the baroxavir key intermediate provided by the embodiment of the invention has the advantages of shortening the synthesis steps, higher yield, simple post-treatment, easiness in purification, reduction in material cost and contribution to industrial amplification.

According to one embodiment of the present invention, for example, the synthetic route of the synthetic method is as follows:

the synthetic route comprises the following steps:

(1) synthesis of Compounds 1-2: taking an intermediate 1-1(1 equivalent) as a starting material, adding potassium carbonate (1.2 equivalent) at room temperature, adding acetone with the volume being 10 times that of the raw material 1-1, stirring for dissolving, adding dimethyl sulfate under stirring, filtering to remove generated inorganic salt after reaction is finished, adding equal volume of ethyl acetate and water into filtrate after concentration, stirring for layering, separating out an organic phase, extracting a water phase twice with equal volume of ethyl acetate, combining the organic phases, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to remove ethyl acetate to obtain the compound 1-2.

(2) Synthesis of Compounds 1-3: taking the intermediate 1-2(1 equivalent) as a starting material, adding N, N-dimethylacetamide with 6 times of the volume of the intermediate 1-2, stirring and dissolving, adding pyridinium p-toluenesulfonate (1.5 equivalents), stirring and dissolving, heating to 70 ℃, slowly dropping tert-butyloxycarbonyl hydrazine (1.8 equivalents) at the temperature, reacting overnight, slowly dropping the reaction solution into water with the same volume, separating out a yellow solid target product, and filtering to obtain the compound 1-3.

The reaction needs to be carried out at 60-80 ℃, the reaction is slow due to the low reaction temperature, and more by-products are generated due to the high reaction temperature. The reaction is that under the acid action of pyridinium tosylate, a six-membered ring is firstly opened, and then tert-butyloxycarbonyl hydrazine is added to form a target product through ring closure, and the number of reaction active sites is large, so that the dosage of pyridinium tosylate is not too much, and about 1.5 equivalent is enough.

The tert-butyloxycarbonyl hydrazine needs to be added dropwise in about 7 hours, and the addition speed is too high, so that the tert-butyloxycarbonyl hydrazine in the reaction system cannot react with the compound 1-2, and further reacts with other active sites, and the yield is reduced.

(3) Synthesis of Compounds 1-4: taking intermediate 1-3(1 equivalent) as a starting material, adding tetrahydrofuran with 6 times volume of the intermediate 1-3, stirring and dissolving, then adding 1, 8-diazabicycloundecen-7-ene (0.2 equivalent) and diglycolamine (3 equivalent), and stirring overnight at 70 ℃ to obtain the compound 1-4. The reaction needs to be carried out at about 70 ℃, and the reaction is slow due to the excessively low temperature. The sequence of addition had little effect on the results of the reaction. The amine group of diglycolamine has a stronger nucleophile than the hydroxyl group, so that the amine group undergoes an ester exchange reaction with the ester.

(4) Synthesis of Compounds 1-5: taking 1-4(1 equivalent) of an intermediate as a starting material, adding dichloromethane with 15 times volume of the 1-4 intermediate, stirring and dissolving, then adding tetramethylpiperidine oxynitride (0.2 equivalent), stirring and dissolving, then adding aqueous solution of sodium bicarbonate (3 equivalents) and sodium bromide (2 equivalents), stirring and mixing, then slowly adding sodium hypochlorite solution (1.2 equivalents) at-5-0 ℃, and dripping off within 2 hours (the dripping speed is too high to cause the increase of peroxidation byproducts), thus obtaining the compound 1-5.

In the synthesis reaction of the compounds 1-5, the mixing sequence of reactants cannot be changed, sodium bicarbonate solution is adopted to adjust the pH value of the system to 8.5-10, sodium hypochlorite solution is slowly added, sodium hypochlorite and sodium bromide in the system rapidly react under the action of tetramethyl piperidine nitrogen oxide to generate high-activity sodium hypobromite, so that the catalytic oxidation reaction is further carried out, the system reacts violently when the dropping speed is too high, byproducts are generated, a dichloromethane phase is separated after the reaction is finished, and the compounds 1-5 are obtained after concentration.

(5) Synthesis of racemic balosavir key intermediates 1-6: taking a compound 1-5(1 equivalent) as a starting material, adding acetonitrile with 10 times of volume, stirring to form a suspension, adding water, heating to 65 ℃, dissolving the compound 1-5 and the water into a hemiacetal mixed solution of the acetonitrile and the water, dissolving the reaction solution into the reaction solution, slowly dropping methanesulfonic acid within 1h, reacting overnight, and increasing the temperature of the reaction solution due to the fact that the dropping speed of the methanesulfonic acid is too high. And after the reaction is finished, adding 30 wt% of sodium hydroxide aqueous solution to adjust the pH of the reaction solution to 9-11, carrying out reduced pressure concentration to remove acetonitrile, separating out a product, and filtering to obtain the racemic balsalavir key intermediate 1-6.

(6) Synthesis of Compounds 1-7: using racemic baroxavir key intermediate 1-6(1 equivalent) as a starting material, adding ethyl acetate with the volume 20 times that of the intermediate 1-6, stirring, sequentially adding 1-propyl phosphate glycoside (3 equivalents), triethylamine (8 equivalents) and (R) -tetrahydrofuran-2-formic acid (2 equivalents), and heating to 65 ℃ for reaction overnight. The reaction is carried out under the condition of heating to 65 ℃, the reaction is difficult to carry out at too low temperature, the charging sequence has no influence on the reaction result, after the reaction is finished, ethyl acetate is removed by concentration, water and dichloromethane with the same volume are added for stirring and separating, after the organic phase is concentrated, ethanol with the volume of 10 times is added, the temperature is raised to 60 ℃ under stirring, then the heating is stopped, the product is separated out after the organic phase is cooled to room temperature, and the compound 1-7 is obtained by filtering.

(7) Synthesis of a baroxavir key intermediate 1-8: taking compounds 1-7(1 equivalent) as a starting material, adding ethyl acetate, stirring, then sequentially adding 1, 8-diazabicycloundecen-7-ene and methanol, wherein the influence of the feeding sequence on the reaction result is small, the compounds 1-7 have good solubility in the ethyl acetate, the products of the baroxavir key intermediates 1-8 have poor solubility in the ethyl acetate, after the reaction is finished, the products of the baroxavir key intermediates 1-8 are separated out from the reaction solution, and the baroxavir key intermediates 1-8 are obtained after filtering. Preferably, the molar ratio of compound 1-7 to 1, 8-diazabicycloundec-7-ene is 1: 0.08-1: 0.12, preferably 1: 0.1; the molar ratio of compounds 1-7 to methanol was 1: 0.8-1: 1.2, preferably 1: 1; the volume ratio of the compounds 1-7 to ethyl acetate is 1: 8-1: 12, preferably 1: 10.

Detailed Description

The following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more clearly understand the advantages and features of the present invention and to clearly define the scope of the present invention.

EXAMPLE 1 preparation of Compounds 1-2

Compound 1-1(30g,122mmol) and potassium carbonate (20.8g,150.5mmol) were added to a 500mL three-necked flask equipped with a magnetic stirrer, followed by addition of 300mL of acetone, and the mixture was stirred at room temperature, whereupon the reaction solution became yellow turbid. A mixed solution of dimethyl sulfate (17g,134.8mmol) and 30mL of acetone is slowly added dropwise at room temperature, and the dropwise addition is finished within 0.5-1 h. After the dropwise addition, the temperature was gradually raised to an internal temperature of 55 ℃ for 1 hour. Sampling was monitored by Thin Layer Chromatography (TLC). The compound 1-1 is completely consumed, and the target product compound 1-2 is generated. Developing with developing agent (dichloromethane: methanol volume ratio is 15:1) under 254nm ultraviolet lamp. After the reaction is finished, after the reaction liquid is cooled to room temperature, off-white precipitate is filtered out, the filtrate is concentrated on rotary evaporation to remove acetone to obtain brown oily matter, water (90.00mL) and ethyl acetate (300.00mL) are added, the mixture is stirred for 0.5h at room temperature, standing and layering are carried out, after an aqueous phase is separated out, ethyl acetate (100mL) is added to wash the aqueous phase twice, standing and layering are carried out, organic phases are separated out and combined, water is used for washing once, standing and layering are carried out, an organic phase is separated out, anhydrous sodium sulfate is used for drying, then reduced pressure concentration is carried out until the organic phase is dried, the product compound 1-2 is obtained, standing is carried out until the room temperature is.

The above-mentioned optimal reaction conditions are the optimal reaction conditions obtained by the inventors after screening a series of different reaction conditions, and the conditions tried to be optimized are as follows:

1. the dosage of the solvent is as follows: in an attempt to reduce the amount of acetone used as a solvent, when 5 volumes of acetone were used, the other reaction conditions remained unchanged and the yield of the desired product after work-up was 85%.

2. Reaction temperature: the inventors also tried the effect of different reaction temperatures on this reaction, and tried 45 ℃ and 65 ℃ respectively and the reaction yields 89% and 80% respectively, while keeping the other reaction conditions unchanged. The optimum reaction temperature was thus finally determined to be 55 ℃.

3. Dropping speed of dimethyl sulfate: the inventors tried the influence of the dropping speed on the reaction yield. The effect of dropping dimethyl sulfate at 15min, 30min and 1 hour on the reaction was tried. It was found that different dropping rates did not have a great influence on the yield of the reaction, and the product yield was maintained between 96% and 98%.

EXAMPLE 2 preparation of Compounds 1-3

A1L three-necked reaction flask was charged with 1-2(50g, 192mmol) of the compound, 300mL of N, N-dimethylacetamide (DMAc) was added, p-toluenesulfonate (72.4g, 288mmol) was added and dissolved by stirring, and the reaction mixture was slowly heated to an internal temperature of 65 ℃ to 70 ℃. Then, a DMAc solution (400mL) of tert-butyl carbazate (46g, 346mmol) was slowly added dropwise (after 7 hours) over the above temperature range, and dropwise addition was completed over 6-7 hours. The reaction was carried out at 65 ℃ to 70 ℃ overnight. Consumption of starting compound 1-2 was monitored by TLC. Developing with developing agent (dichloromethane: methanol volume ratio is 20:1), developing with 254nm ultraviolet lamp, and developing with tert-butyl carbazate only with iodine. And (3) finishing the reaction, cooling to 20-30 ℃, slowly dripping the reaction solution into 1L of water, stirring while dripping, separating out yellow solid when dripping, and continuing stirring at room temperature for two hours after finishing dripping, wherein a large amount of solid is separated out. After filtration, a crude product of the compound 1 to 3 was obtained, and the crude product was further slurried with 600mL of a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate volume ratio: 5:1) to remove most of impurities, and the solvent and water were filtered off to obtain the target compound 1 to 346.7 g in a yield of 65%.

The above-mentioned optimum reaction conditions are the optimum reaction conditions determined by the inventors of the present invention after conducting a series of different reaction condition screens, and the conditions tried to be optimized are as follows:

1. reaction temperature: the optimum reaction temperature was determined to be 65 ℃ to 70 ℃. Two different reaction temperatures of 55 ℃ to 60 ℃ and 75 ℃ to 80 ℃ were tried with other conditions controlled unchanged. The final yield of the reaction is 51 percent and 44 percent respectively, and when the temperature is too low, the reaction rate is slowed down, so that the yield is lowered; when the temperature is too high, the reaction system is complicated, resulting in a decrease in yield.

2. Dropping speed of tert-butyl carbazate: under the optimal reaction conditions, the inventors used a DMAc solution of tert-butyl carbazate added dropwise over 7 hours. The condition of adding dropwise in 1h is tried, the reaction system is complicated, and the yield after treatment is only 33 percent. The condition of dripping after 4 hours is tried, the yield is improved, and the product yield after treatment is 45 percent. Also, an attempt was made to extend the dropping time to 11h, and it was found that the product yield did not continue to increase to 63%. The final dropping time was thus determined to be 7 h.

EXAMPLE 3 preparation of Compounds 1-4

Adding compound 1-3(50g, 133.7mmol) into a 500mL round-bottom flask reaction bottle, adding 300mL tetrahydrofuran, stirring to dissolve, then adding 1, 8-diazabicyclo [5.4.0] undec-7-ene (3.1mL, 20.1mmol) and diglycolamine (40.2mL, 401.1mmol) respectively, mixing and stirring, gradually heating to 70-75 ℃ for reaction, and reacting at the temperature for 24h to substantially finish the reaction. Consumption of starting compounds 1-3 was monitored by TLC. Developing with developing agent (dichloromethane: methanol volume ratio is 20:1), developing raw materials and products under 254nm ultraviolet lamp, and developing with iodine only with diglycolamine. And (3) finishing the reaction, cooling to 20-30 ℃, slowly adding acetic acid under stirring to adjust the reaction liquid to be weakly acidic (pH is 4-5), concentrating under reduced pressure to remove tetrahydrofuran in the reaction liquid, then sequentially adding ethyl acetate (200mL) and water (200mL), stirring, mixing, separating liquid, extracting the water phase twice with ethyl acetate (120mL), combining organic phases, washing the organic phases once with water (300mL), drying with anhydrous sodium sulfate, concentrating, and draining to obtain the product compound 1-4, wherein the product yield is 93%.

The inventors of the present invention determined the above-mentioned optimal reaction conditions after conducting a series of different reaction condition screens, and attempted optimization conditions were as follows:

1. reaction temperature: the reaction under the conditions of 60-65 ℃ and 80-85 ℃ is respectively tried, and the reaction rate is reduced when the reaction temperature is controlled to be 60-65 ℃, the raw materials are completely consumed after 48 hours of reaction, and the yield of the product is slightly reduced to 88%. When the reaction is carried out by heating to 80-85 ℃, the reaction rate is accelerated, the raw materials are completely consumed within 12 hours, but the reaction system becomes complex, and the yield is only 75 percent.

2.1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) in an amount: the inventors also tried to change the amount of DBU. Because diglycolamine also has alkalinity, the inventor tries to ensure that DBU is not used in the reaction and the reaction can be smoothly carried out, but the reaction rate is greatly reduced, and a large amount of raw materials are not completely consumed after the reaction is carried out for 72 hours at the temperature of 70-75 ℃. An attempt was made to increase the reaction rate by 0.05 equivalents of DBU, which was complete in 48 hours, but the yield was only 70% lower. It was also tried to use 0.3 equivalent of DBU, the reaction yield was 92% which is not much different from the optimum condition, and the inventors decided to use 0.15 equivalent of DBU as the optimum condition after comprehensively considering the material cost.

3. The dosage of diglycolamine: the inventors have also tried to change the amount of diglycolamine. When 2 equivalents of diglycolamine were used, the reaction yield decreased to 80%, and when 4 equivalents of diglycolamine were used, the reaction yield did not significantly differ from the optimum conditions.

Example 4 preparation of Compounds 1-5

Adding 1-4(15g, 33.6mmol) of a compound into a 500mL three-mouth reaction bottle, lapping a constant-pressure dropping funnel, adding 220mL of dichloromethane under the protection of nitrogen, stirring and dissolving, placing the reaction bottle in a low-temperature reactor, controlling the reaction internal temperature to be-5-0 ℃, stirring for 5min, adding 1.05g, 67mmol of 2,2,6, 6-tetramethylpiperidine oxide (TEMPO), and stirring and dissolving. Sodium bromide (6.91g, 67.12mmol) and sodium bicarbonate (8.46g, 100.68mmol) were weighed into a beaker, 130mL of purified water was added at room temperature and dissolved with stirring, and then the aqueous solution of sodium bromide and sodium bicarbonate was added to the above three-neck reaction flask and stirred rapidly until the internal temperature of the reaction flask became-5 ℃ to 0 ℃ again. Weighing a newly purchased sodium hypochlorite aqueous solution (42mL) which is just refrigerated and taken out from a refrigerator, pouring the sodium hypochlorite aqueous solution into the constant-pressure dropping funnel, controlling the temperature in the reaction to be between 5 ℃ below zero and 0 ℃, slowly dropping the sodium hypochlorite aqueous solution into the reaction bottle, and finishing dropping within 20min to 30 min. And continuing to react for 30min-1h after the sodium hypochlorite solution is dripped, and finishing the consumption of the raw materials. Consumption of starting compounds 1-4 was monitored by TLC. Developing agent (dichloromethane: methanol volume ratio is 20:1), raw material and product under 254nm ultraviolet lamp. And (3) finishing the reaction, transferring the reaction liquid into a separating funnel, standing and layering to separate a lower organic phase, extracting an aqueous phase twice with dichloromethane (150mL), combining the organic phases, washing the organic phase once with 200mL saturated salt, drying with anhydrous sodium sulfate, and concentrating to obtain 14g of a crude product of the compound 1-5. The product yield was 75%.

The inventors have determined the above optimal reaction conditions after a series of different reaction condition screens, and the conditions for trying to optimize are as follows:

1. screening water in the reaction: when the reaction was carried out using tap water, the reaction yield was only 50% under the same conditions, and it was presumed that hypochlorous acid used for disinfection in the tap water affected the progress of the reaction.

2. Use of sodium hypochlorite solution: the inventors also tried to use stock sodium hypochlorite solution for this reaction, and the reaction yield was only 23% under the same conditions. Probably because the content of available chlorine in the sodium hypochlorite solution stored for a long time is greatly reduced, the reaction is not carried out.

3. Screening the proportion of the reaction solvent: the inventors tried dichloromethane: the water volume ratio is 1:1, the reaction system is complicated, the yield of the reaction product is only 56%, and the acid as the peroxidation product is generated in the water phase.

4. Dropping speed of sodium hypochlorite solution: the inventor tries to dropwise add the sodium hypochlorite solution within 15min, and finds that the reaction system is faster in temperature rise, the temperature is not well controlled, the reaction system is more complex, and the yield is 44%. When the dropping speed is controlled to be 1h, the reaction yield is not obviously improved compared with the optimal condition.

EXAMPLE 5 preparation of Compounds 1-6

Adding pure compounds 1-5(14g, 31.5mmol) into a 500mL three-mouth reaction bottle, overlapping a reflux condenser tube, adding 150mL of acetonitrile under the protection of nitrogen, stirring and dissolving to obtain a compound 1-5 with poor solubility in acetonitrile, wherein the reaction solution is a white turbid solution, adding 40mL of water, mixing, and continuing stirring. At this time, the reaction solution was still a white turbid solution. Then, the temperature was gradually raised to an internal temperature of 65 ℃ and the compounds 1 to 5 were gradually dissolved with the rise of the reaction temperature, and the reaction mixture was changed to a clear solution. Then a solution of methanesulfonic acid (6.12mL, 94.4mmol) in acetonitrile (10mL) was added slowly (15min complete dropwise) at 65 ℃. After the dropwise addition was completed for about 15min, the reaction was allowed to react at 65 ℃ for 16 h. The reaction was monitored by TLC. Developing agent (dichloromethane: methanol volume ratio is 20:1), raw material and product under 254nm ultraviolet lamp. After the reaction, the reaction solution was cooled to room temperature, and an aqueous sodium hydroxide solution (30 wt%) was slowly added (15min was completed) to make the reaction solution alkaline, followed by concentration to remove most of the acetonitrile solution, whereupon a large amount of yellow solid product precipitated, and the reaction solution was filtered and washed with water once to obtain 8.74g of the objective product with a yield of 85%.

1. screening of reaction solvent: the inventors tried to use pure acetonitrile as the reaction solvent, and compounds 1 to 5 were not well soluble in acetonitrile and remained cloudy at elevated temperatures up to 65 ℃. Slowly dripping methanesulfonic acid, gradually dissolving the reaction solution to be clear, reacting for 16 hours, finishing the reaction, and generating a target product and two byproducts. The yield of the target product was 51%.

2. Screening of reaction temperature: the reaction at 55 ℃ and 75 ℃ was attempted, respectively, and the product yield was reduced to 74% and 77%, respectively.

3. Screening the amount of the methanesulfonic acid: attempting to use 2 equivalents of methanesulfonic acid, the reaction rate decreased and the reaction yield decreased to 66%.

4. Screening of the regulating alkaline reagent: after the reaction is complete, different attempts have been made to adjust the effect of the basic reagent on the product yield. The organic base triethylamine was tried to neutralize the excess methanesulfonic acid in the reaction system and the product was filtered off after work-up in 65% yield.

Example 6 preparation of Compounds 1-7

Adding pure compounds 1-6(14g, 42.7mmol) into a 1L three-mouth reaction bottle, overlapping a reflux condenser tube, adding 420mL of ethyl acetate under the protection of nitrogen, stirring and dissolving, wherein the compounds 1-6 have poor solubility in the ethyl acetate, the reaction liquid is a white turbid liquid, adding 1-propyl phosphate glycoside (82g, 128.4mmol, 50% ethyl acetate solution), mixing, continuing stirring, and gradually heating to 60-65 ℃. At this time, the reaction solution gradually became clear, but a small amount of white solid remained and was not completely dissolved. At the temperature of 60-65 ℃, triethylamine (34.5g, 342.4mmol) is slowly dripped within 10-15 min, and at the moment, a large amount of white solid is gradually separated out from the reaction solution to form a white turbid solution. Then slowly dripping 8.75g of (R) -tetrahydrofuran-2-formic acid (75.3 mmol) at the temperature of 60-65 ℃, finishing dripping within 10-15 min, gradually dissolving the reaction liquid into light yellow along with the dripping of the (R) -tetrahydrofuran-2-formic acid, and gradually deepening the color of the reaction liquid along with the progress of the reaction. The reaction was monitored by TLC. Since the developing solvent (dichloromethane: methanol in a volume ratio of 20:1) develops color of the starting material and the product under an ultraviolet lamp of 254nm, the product compound 1-7 is unstable and easily hydrolyzed back to the starting material compound 1-6, and thus the target product compound 1-7 and the compound 1-7b are formed when the progress of the reaction is checked by TLC, but the starting material compound 1-6 is always present. Therefore, a liquid phase mass spectrometer is needed for monitoring the reaction process. When the reaction progress is monitored, two drops of reaction liquid are taken, ethyl acetate is added for dilution, the reaction liquid is directly sent to LCMS, the reaction is stopped after the peak of the compound 1-6 on the LCMS is completely disappeared, and the LCMS shows that the content of the compound 1-6 is 2 percent and the content of the compound 1-7 is 98 percent after the reaction is carried out for 20 hours. After the reaction is finished, the reaction solution is cooled to room temperature, most of ethyl acetate is removed through rotary evaporation concentration, 300mL of dichloromethane is added for dilution, then 300mL of water is added for stirring and liquid separation, an organic phase is separated out, an aqueous phase is extracted twice with 200mL of dichloromethane, the organic phase is combined, anhydrous sodium sulfate is dried, concentration and pumping are carried out to obtain 18g of a non-corresponding isomer mixture of the target product compounds 1-7, 270mL (15 times volume) of ethanol is added for recrystallization, 8.3g of pure target product compounds 1-7 is obtained, and the yield is 46%.

1. reaction temperature: reactions at 50-55 ℃ and 70-75 ℃ were attempted, respectively. When the reaction is carried out at the temperature of 50-55 ℃, the reaction rate is slow, the conversion rate of the raw materials is 80% after 24 hours of reaction, and the conversion rate of the raw materials is not improved along with the continuous extension of the reaction time. When the reaction is carried out at 70-75 ℃, the reaction speed is not obviously improved, and the conversion rate of the raw materials is the same as that under the condition of 60-65 ℃ in the same time.

2.1-Propylphosphoside used: in an attempt to reduce the amount of 1-propylphosphate, when 1.5 equivalents of 1-propylphosphate were used, the reaction rate was greatly reduced and the conversion of the starting material was only 65% under the same conditions and for the same time.

3. Optimization of chiral resolution conditions: when slurried with 15 volumes of ethanol at room temperature overnight, the chiral resolution yield was very low, only 23%. When 10 volumes of ethanol were used for the thermal recrystallization, the product yield was only 33%. After heating for recrystallization using 20 volumes of ethanol, the product yield was 25%.

Example 7 preparation of Compounds 1-8

A250 mL single-neck reaction flask was charged with pure compound 1-7(7.5g, 17.6mmol), 40mL of ethyl acetate was added and stirred, at this time, the reaction solution was a white turbid solution, and the compound 1-7 could not be completely dissolved, then 1, 8-diazabicyclo [5.4.0] undec-7-ene (0.8g, 5.3mmol) was added, and then a mixed solution of 1mL of methanol and 10mL of ethyl acetate was slowly added dropwise and stirred at room temperature overnight, and a large amount of white solid was precipitated from the reaction solution. The filtrate was filtered to obtain 4.8g of the target product, yield 83%, and optical purity 99.9%.

Claims

1. A synthesis method of a baroxavir key intermediate, wherein the structure of the baroxavir key intermediate is shown as the following formulas 1-6, and the synthesis method comprises the following steps: a step of subjecting diglycolamine, a compound represented by the following formula I, to an amine transesterification reaction to obtain a compound represented by the following formulae 1 to 4; a step of preparing a compound represented by the following formula 1-5 by a one-step oxidation reaction of a compound represented by the following formula 1-4; carrying out Mannich reaction on compounds shown in the following formulas 1-5 under acidic conditions to obtain the baroxavir key intermediates 1-6; wherein, in the amine transesterification, a compound 2- (2, 2-dimethoxyethoxy) ethane-1-amine represented by the following formula II is not used,

2. the synthetic method according to claim 1, comprising the synthetic route shown below:

。

3. the synthetic method according to claim 1, comprising the synthetic route shown below:

。

4. the synthesis method according to claim 2, characterized in that it comprises the following steps:

(1) synthesis of Compounds 1-2: taking a compound 1-1 as a starting material, adding potassium carbonate at room temperature, adding acetone, stirring for dissolving, adding dimethyl sulfate under stirring, filtering to remove generated inorganic salt after reaction is finished, adding equal volume of ethyl acetate and water after filtrate is concentrated, stirring for layering, separating out an organic phase, extracting a water phase with equal volume of ethyl acetate, combining the organic phases, drying, and concentrating under reduced pressure to remove ethyl acetate to obtain the compound 1-2;

preferably, the molar ratio of compound 1-1 to potassium carbonate is 1: 1.1-1: 1.3, preferably 1: 1.2; the volume ratio of the compound 1-1 to acetone is 1: 8-1: 12, preferably 1: 10; the drying is carried out by adopting anhydrous sodium sulfate;

(2) synthesis of Compounds 1-3: taking a compound 1-2 as a starting material, adding N, N-dimethylacetamide, stirring and dissolving, adding pyridinium p-toluenesulfonate, stirring and dissolving, heating to 60-80 ℃ (preferably 70 ℃), slowly dropping tert-butoxycarbonylhydrazine at the temperature, reacting overnight, slowly dropping a reaction solution into water with the same volume, separating out a yellow solid target product, and filtering to obtain a compound 1-3;

preferably, the molar ratio of the compound 1-2 to the pyridinium p-toluenesulfonate is 1: 1.2-1: 1.8, preferably 1: 1.5; the molar ratio of the compound 1-2 to the tert-butyloxycarbonyl hydrazine is 1: 1.6-1: 2.0, preferably 1: 1.8; the volume ratio of the compound 1-2 to the N, N-dimethylacetamide is 1: 4-8, preferably 1: 6; preferably, the slowly dropping of the tert-butoxycarbonylhydrazine comprises: slowly dripping tert-butyloxycarbonyl hydrazine, and finishing dripping within 6-8 hours, preferably 7 hours;

(3) synthesis of Compounds 1-4: taking a compound 1-3 as a starting material, adding tetrahydrofuran, stirring for dissolving, then adding 1, 8-diazabicycloundecen-7-ene and diglycolamine, and stirring at 60-80 ℃ (preferably 70 ℃) overnight to obtain a compound 1-4;

preferably, the molar ratio of compound 1-3 to 1, 8-diazabicycloundec-7-ene is 1: 0.1-1: 0.3, preferably 1: 0.2; preferably, the molar ratio of the compounds 1 to 3 to diglycolamine is 1: 2-1: 4, preferably 1: 3; preferably, the volume ratio of the compounds 1 to 3 to tetrahydrofuran is 1: 4-1: 8, preferably 1: 6;

(4) synthesis of Compounds 1-5: taking the compound 1-4 as a starting material, adding dichloromethane, stirring for dissolving, then adding tetramethylpiperidine nitrogen oxide, stirring for dissolving, then adding an aqueous solution of sodium bicarbonate and sodium bromide, stirring for mixing, then slowly adding a sodium hypochlorite solution at the temperature of-5-0 ℃, and slowly adding dropwise to obtain a compound 1-5;

preferably, the molar ratio of the compound 1-4 to the tetramethylpiperidine nitroxide is 1: 0.1-1: 0.3, preferably 1: 0.2; preferably, the molar ratio of the compounds 1 to 4 to the sodium bicarbonate is 1: 2-1: 4, preferably 1: 3; preferably, the molar ratio of compounds 1-4 to sodium bromide is 1: 1-1: 3, preferably 1: 2; preferably, the molar ratio of compounds 1-4 to sodium hypochlorite is 1: 1-1: 1.4, preferably 1: 1.2; preferably, the slow dripping is finished, namely the dripping time is 1-2 hours; preferably, the volume ratio of the compounds 1 to 4 to dichloromethane is 1: 10-1: 20, preferably 1: 15; preferably, after adding sodium bicarbonate, the pH of the system is between 8.5 and 10;

(5) synthesis of racemic balosavir key intermediates 1-6: taking a compound 1-5 as a starting material, adding acetonitrile, stirring to form a suspension, adding water, heating to 65 ℃, dissolving the compound 1-5 and the water into a hemiacetal, dissolving the hemiacetal in a mixed solution of the acetonitrile and the water, slowly dropping methanesulfonic acid, reacting overnight, increasing the temperature of a reaction solution due to the fact that the dropping speed of the methanesulfonic acid is too high, adding a 30 wt% sodium hydroxide aqueous solution to adjust the pH of the reaction solution to 9-11 after the reaction is finished, concentrating under reduced pressure to remove the acetonitrile, separating out a product, and filtering to obtain a racemic balsalavir key intermediate 1-6;

preferably, the volume ratio of the compounds 1 to 5 to acetonitrile is 1: 8-1: 12, preferably 1: 10; preferably, the slow dropping of the methanesulfonic acid means that the dropping is completed within 0.5h to 1 h.

5. The method of synthesis of claim 4, further comprising the steps of:

(6) synthesis of Compounds 1-7: taking racemic baroxavir key intermediate 1-6 as a starting material, adding ethyl acetate, stirring, sequentially adding 1-propylphosphate, triethylamine and (R) -tetrahydrofuran-2-formic acid, heating to 60-70 ℃ (preferably 65 ℃) to react overnight, and after the reaction is finished, separating and purifying to obtain a compound 1-7;

preferably, the volume ratio of the racemic baroxavir key intermediate 1-6 to the ethyl acetate is 1: 15-1: 25, preferably 1: 20; preferably, the molar ratio of the racemic baroxavir key intermediate 1-6 to the 1-propylphosphate glycoside is 1: 2-1: 4, preferably 1: 3; preferably, the mole ratio of the racemic baroxavir key intermediate 1-6 to the triethylamine is 1: 6-1: 10, preferably 1: 8; the molar ratio of racemic baroxavir key intermediate 1-6 to (R) -tetrahydrofuran-2-carboxylic acid is 1: 1-1: 3, preferably 1: 2; preferably, the separation and purification comprises: concentrating the reaction mixture to remove ethyl acetate, adding water and dichloromethane with the same volume, stirring, separating, concentrating the organic phase, adding ethanol with the volume of 10 times, heating to 55-65 ℃ under stirring (preferably 60 ℃), stopping heating, cooling to room temperature, separating out a product, and filtering to obtain the compounds 1-7;

(7) synthesis of a baroxavir key intermediate 1-8: taking compounds 1-7 as starting materials, adding ethyl acetate, stirring, then sequentially adding 1, 8-diazabicycloundecen-7-ene and methanol, wherein the influence of the charging sequence on the reaction result is small, the compounds 1-7 have good solubility in the ethyl acetate, the products of the baroxavir key intermediates 1-8 have poor solubility in the ethyl acetate, after the reaction is finished, the products of the baroxavir key intermediates 1-8 are separated out from the reaction solution, and filtering is carried out to obtain the baroxavir key intermediates 1-8;

preferably, the molar ratio of compound 1-7 to 1, 8-diazabicycloundec-7-ene is 1: 0.08-1: 0.12, preferably 1: 0.1; the molar ratio of compounds 1-7 to methanol was 1: 0.8-1: 1.2, preferably 1: 1; the volume ratio of the compounds 1-7 to ethyl acetate is 1: 8-1: 12, preferably 1: 10.

6. The synthetic method according to claim 1, comprising the synthetic route shown below:

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