CN111057070A - Synthesis method of baroxavir key intermediate - Google Patents
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Abstract
The invention discloses a synthesis method of a baroxavir key intermediate, namely a synthesis method of 7- (hydroxyl substituent) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone, which synthesizes 3-methoxy morpholine through dehydration condensation reaction to obtain 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxyl substituted pyrone, synthesizes 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxyl substituted pyrone through nucleophilic substitution reaction to obtain 7- (hydroxyl substituent) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone, and prepares the baroxavir key intermediate; 3-methoxy morpholine is used as an initial raw material, and is subjected to dehydration condensation and nucleophilic substitution to synthesize an anti-influenza drug, namely a baroxavir key intermediate, reaction intermediate products are not required to be refined, the intermediate products can be directly used for the next reaction after a solvent is removed, and post-treatment is simple and convenient; the synthetic route is short, the originality is high, the cost is low, and the method is suitable for industrial production.
Description
Technical Field
The invention relates to a synthesis method of a baroxavir key intermediate.
Background
Influenza, known as influenza, is a disease caused by acute infection of respiratory tract with highly contagious influenza virus, and its symptoms include fever, myalgia, listlessness, upper respiratory symptoms, etc.
Antiviral agents are useful for the prevention and treatment of seasonal influenza, but are strictly used as adjuncts to vaccination and cannot replace vaccination. At present, medicaments such as M2 inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir) are used for chemoprevention of influenza, and the effective rate is 70-90%.
Barosavir is an innovative cap-dependent endonuclease inhibitor that is a drug developed by Nippon salt wild-type pharmaceuticals for the treatment of influenza A and influenza B. The treatment method has the advantages of less administration times and long treatment time. The chemical structural formula is as follows:
the compound shown as the following formula is a key intermediate (III) of the baroxavir:
at present, few reports are provided for the synthesis method of the compound, wherein WO2016175224 reports the synthesis method of the intermediate, but the overall yield of the route is low, the utilization rate of raw materials is not high, and the process cost is high, and the specific route is as follows:
among them, WO2017221869 reports a synthesis method of the intermediate, the urethane exchange reaction in the route needs to use excess 2- (2, 2-dimethoxyethoxy) ethylamine, the material cost is high, and the specific route is as follows:
WO2019070059 reports a synthetic method of the intermediate, the decarboxylation process adopted in the route has high cost and is not suitable for industrial production, and the specific route is as follows:
in view of the recent increase of influenza incidence year by year, anti-influenza drugs are also receiving more and more attention from scientists, so it is necessary to develop a synthetic route which is simple in process route, high in yield, low in cost and 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 baroxavir key intermediate.
The synthesis method of the baroxavir key intermediate is characterized in that the 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone shown in the formula (II) is obtained by carrying out dehydration condensation reaction on 3-methoxy morpholine shown in the formula (I); carrying out nucleophilic substitution reaction on 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone shown in formula (II) to obtain 7- (hydroxy substituent) -tetrahydro-1H-oxazine pyridotriazine-6, 8-diketone shown in formula (III), namely the baroxavir key intermediate;
in the formulas (II) and (III), R is optionally lower alkyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl, methoxymethyl, ethoxyethyl, allyl, acetyl, benzoyl and pivaloyl, and the lower alkyl is straight-chain or branched alkyl with 1-6 carbon atoms.
The synthesis method of the baroxavir key intermediate is characterized by comprising the following steps:
1) placing 3-hydroxy substituted-2-carboxyl pyrone in a solvent A, adding a condensing agent B or an acylating reagent C, reacting for 1-2h at 0-40 ℃, adding 3-methoxy morpholine shown in a formula (I) into a reaction solution, tracking by TLC until the reaction is finished, washing, drying and concentrating the reaction solution to obtain 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone shown in a formula (II);
2) placing 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone shown in formula (II) in a solvent D, adding a catalyst E and hydrazine hydrate under the protection of inert gas, reacting at 40-80 ℃ for 12-24H, tracking by TLC until the reaction is finished, washing the reaction solution with water, drying, and concentrating to obtain 7- (hydroxy substituent) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone shown in formula (III).
The synthesis method of the baroxavir key intermediate is characterized in that in the step 1), the solvent A is one or a mixture of two of tetrahydrofuran, dichloromethane, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxane, 1, 2-dichloroethane and acetonitrile; the condensing agent B is one or a mixture of two of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine, triethylamine, 1, 8-diazabicycloundecene-7-ene, dicyclohexylcarbodiimide, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 1-propylphosphoric anhydride, benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate and diphenyl phosphorodiazide phosphate; the acylating reagent C is one of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride and bis (trichloromethyl) carbonate.
The synthesis method of the baroxavir key intermediate is characterized in that in the step 1), the amount ratio of 3-methoxy morpholine shown in a formula (I) to a condensing agent B or an acylating agent C is 1: 0.5-2.0; the ratio of the volume of the solvent A to the amount of the substance of 3-methoxymorpholine represented by the formula (I) is 1 to 4: volume is in mL and amount of substance is in mmol.
The synthesis method of the baroxavir key intermediate is characterized in that in the step 2), the solvent D is one or a mixture of two of tetrahydrofuran, dichloromethane, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxane, 1, 2-dichloroethane and acetonitrile; the catalyst E is one of 4-dimethylamino pyridine, benzoic acid, benzenesulfonic acid, p-toluenesulfonic acid and pyridinium p-toluenesulfonic acid.
The synthesis method of the baroxavir key intermediate is characterized in that in the step 2), the mass ratio of the 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone shown in the formula (II) to the catalyst E substance is 1: 0.1-3; the mass ratio of the 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone to the hydrazine hydrate substance is 1: 1-3; the ratio of the volume of the solvent D to the amount of the substance of 2- (3-methoxy-4-carbonylmorpholine) -3-hydroxy-substituted pyrone represented by the formula (II) is 2 to 5: volume is in mL and amount of substance is in mmol.
According to the synthesis method of the baroxavir key intermediate, the solvent A in the step 1) is tetrahydrofuran, dichloromethane and N, N-dimethylacetamide; the condensing agent B is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine; and the acylating reagent C is oxalyl chloride or thionyl chloride.
According to the synthesis method of the baroxavir key intermediate, the reaction temperature in the step 1) is 0-30 ℃; the mass ratio of the 3-methoxy morpholine to the condensing agent B or the acylating agent C is 1.0-1.5.
In the synthesis method of the baroxavir key intermediate, the solvent D in the step 2) is tetrahydrofuran and acetonitrile; catalyst E is p-toluenesulfonic acid, p-pyridinium tosylate.
According to the synthesis method of the baroxavir key intermediate, the reaction temperature in the step 2) is 50-60 ℃; preferred catalysts E are p-toluenesulfonic acid, pyridinium p-toluenesulfonate; the mass ratio of the 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone to the catalyst E is 1: 0.1-0.5.
By adopting the technology, compared with the prior art, the invention has the beneficial effects that:
1) 3-methoxy morpholine shown in a formula (I) is used as an initial raw material, and a critical intermediate (III) of the anti-influenza drug Barosavir is synthesized through two steps of dehydration condensation and nucleophilic substitution;
2) in the process of synthesizing 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone shown in formula (II) and 7- (hydroxy substituent) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone shown in formula (III), reaction intermediate products do not need to be refined, the intermediate products can be directly used for the next reaction after solvent removal, and post-treatment is simple and convenient;
3) the invention has simple process route and low cost and is suitable for industrial production.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1: synthesis of 2- (3-methoxy-4-carbonyl morpholine) -3-methoxy pyrone (II)
Adding 3-methoxy-2-carboxypyranone (0.85 g, 5 mmol), tetrahydrofuran 20ml, 4-dimethylaminopyridine (0.06 g, 0.5 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol) into a 100ml three-neck flask, stirring at room temperature for reaction for 2 hours, slowly dropping a tetrahydrofuran (20 ml) solution of 3-methoxymorpholine (0.59 g, 5 mmol) shown in formula (I), continuing the reaction at 30 ℃ after the completion of the addition, tracking by TLC until the reaction is completed, wherein the reaction time is about 6 hours, adding 20-30ml of water into the reaction solution, adding ethyl acetate (20 ml) for extraction, extracting for 3 times, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove the solvent, and obtaining a colorless transparent liquid 2- (3-methoxy-4-carbonylmorpholine) -3-methoxymethylcarbodiimide Pyrone (II) 0.67g, yield 49.8%.
Example 2: synthesis of 2- (3-methoxy-4-carbonyl morpholine) -3-methoxy pyrone (II)
Adding 3-methoxy-2-carboxypyranone (0.85 g, 5 mmol), dichloromethane (10 ml), triethylamine (1.01 g, 10 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol) into a 100ml three-neck flask, stirring at room temperature for reaction for 2 hours, slowly dropping a dichloromethane (10 ml) solution of 3-methoxymorpholine (0.59 g, 5 mmol) shown in formula (I), continuing the reaction at 30 ℃ after the completion of the addition, tracking by TLC until the reaction is completed, wherein the reaction time is about 6 hours, tracking by TLC until the reaction is completed, adding 20-30ml of water into the reaction solution, adding dichloromethane (20 ml) for extraction for 2 times, combining organic phases, washing by saturated saline (20 ml) for 1 time, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure to remove the solvent, to obtain colorless transparent liquid 2- (3-methoxy-4-carbonyl morpholine) -3-methoxy pyrone (II) 0.76 g, yield 56.5%.
Example 3: synthesis of 2- (3-methoxy-4-carbonyl morpholine) -3-methoxy pyrone (II)
After 3-methoxy-2-carboxypyranone (0.85 g, 5 mmol), dichloromethane (10 ml), oxalyl chloride (0.83 g, 6.5 mmol) and dimethylformamide (0.02 ml) are added into a 100ml three-neck flask and stirred under ice bath for reaction for 20 minutes, a dichloromethane (10 ml) solution of 3-methoxy morpholine (0.59 g, 5 mmol) shown in formula (I) is slowly dropped, the reaction is continued at 30 ℃ after the completion of the addition, TLC tracking is carried out until the reaction is completed, the reaction time is about 6 hours, TLC tracking is carried out until the reaction is completed, 20-30ml of water is added into the reaction solution, dichloromethane (20 ml) is added for extraction for 2 times, organic phases are combined, saturated saline solution (20 ml) is washed for 1 time, anhydrous sodium sulfate is dried, filtration is carried out, the solvent is removed by concentration under reduced pressure, 0.95 g of colorless transparent liquid 2- (3-methoxy-4-carbonylmorpholine) -3-methoxypyranone (II) is obtained, the yield thereof was found to be 70.6%.
Example 4: synthesis of 2- (3-methoxy-4-carbonylmorpholine) -3-benzyloxypyrone (II)
After 3-benzyloxy-2-carboxypyranone (2.46 g, 10 mmol), N, N-dimethylacetamide (10 ml), 4-dimethylaminopyridine (0.12 g, 1 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.30 g, 12 mmol) were added to a 100ml three-necked flask, and the mixture was stirred at room temperature for 2 hours, a solution of 3-methoxymorpholine (1.18 g, 10 mmol) represented by formula (I) in N, N-dimethylacetamide (10 ml) was slowly dropped, and after completion of the addition, the reaction was continued at 30 ℃ and followed by TLC until the completion of the reaction, the reaction time was about 6 hours, after completion of the TLC following the reaction, 20 to 30ml of water was added to the reaction mixture, ethyl acetate (20 ml) was further added and extracted 3 times, the organic phases were combined, and the organic layer was washed with a saturated aqueous ammonium chloride solution (20 ml) and a saturated saline solution (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, whereby 2.14g of 2- (3-methoxy-4-carbonylmorpholine) -3-benzyloxypyrone (II) was obtained as a colorless transparent liquid in a yield of 62.0%.
Example 5: synthesis of 2- (3-methoxy-4-carbonylmorpholine) -3-hexyloxypyranone (II)
After 3-hexyloxy-2-carboxypyranone (2.40 g, 10 mmol), N, N-dimethylacetamide (10 ml), 4-dimethylaminopyridine (0.12 g, 1 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.30 g, 12 mmol) were added to a 100ml three-necked flask, and stirred at room temperature for 2 hours, a solution of 3-methoxymorpholine (1.18 g, 10 mmol) represented by formula (I) in N, N-dimethylacetamide (10 ml) was slowly dropped, and after completion of the addition, the reaction was continued at 30 ℃ and followed by TLC until completion of the reaction, the reaction time was about 6 hours, after completion of the TLC following the reaction, 20 to 30ml of water was added to the reaction mixture, ethyl acetate (20 ml) was further added thereto and extracted 3 times, the organic phases were combined, and the organic layer was washed with a saturated aqueous ammonium chloride solution (20 ml) and a saturated saline solution (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, whereby 2.16g of 2- (3-methoxy-4-carbonylmorpholine) -3-hexyloxypyranone (II) was obtained as a colorless transparent liquid with a yield of 63.7%.
Example 6: synthesis of 7- (methoxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione (III)
2- (3-methoxy-4-carbonylmorpholine) -3-methoxypyranone (II) (2.69 g, 10 mmol) and tetrahydrofuran (20 ml) were charged in a 100ml three-necked flask, p-toluenesulfonic acid monohydrate (0.38 g, 2 mmol) was added, hydrazine hydrate (0.69 g, 11mmol, 80%) was slowly added, and after stirring well, heating was carried out to 60 ℃ for 14 hours. After the reaction, the mixture was slowly cooled to room temperature, 5% sodium bicarbonate solution (30 ml) was added thereto and stirred, the aqueous phase was extracted with ethyl acetate (20 ml) 3 times, the organic phases were combined, washed with saturated brine (20 ml) 1 time, dried over anhydrous sodium sulfate, filtered, concentrated, slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered, and dried to obtain 2.03g of a product of 7- (methoxy) -tetrahydro-1H-oxazino-pyrido-triazine-6, 8-dione (iii) in a yield of 80.9%.
Example 7: synthesis of 7- (methoxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione (III)
2- (3-methoxy-4-carbonylmorpholine) -3-methoxypyranone (2.69 g, 10 mmol) of the formula (II) and acetonitrile (20 ml) were charged in a 100ml three-necked flask, p-toluenesulfonic acid monohydrate (0.38 g, 2 mmol) was added, hydrazine hydrate (0.69 g, 11mmol, 80%) was slowly added, and after stirring, the mixture was heated to 45 ℃ to react for 22 hours. After the reaction, the mixture was slowly cooled to room temperature, 5% sodium bicarbonate solution (30 ml) was added thereto and stirred, the aqueous phase was extracted 3 times with ethyl acetate (20 ml), the organic phases were combined, washed 1 time with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, concentrated, slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered, and dried to obtain 1.67g of a product of 7- (methoxy) -tetrahydro-1H-oxazino-pyrido-triazine-6, 8-dione (III), with a yield of 66.5%.
Example 8: synthesis of 7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione (III)
2- (3-methoxy-4-carbonylmorpholine) -3-benzyloxypyrone (1.72 g, 5 mmol) represented by the formula (II) and tetrahydrofuran (10 ml) were charged in a 100ml three-necked flask, pyridinium p-toluenesulfonate (0.25 g, 1 mmol) was added, hydrazine hydrate (0.38 g, 6mmol, 80%) was slowly added, and after stirring, the mixture was heated to 65 ℃ for reaction for 15 hours. After the reaction, the mixture was slowly cooled to room temperature, 5% sodium bicarbonate solution (15 ml) was added thereto and stirred, the aqueous phase was extracted 3 times with ethyl acetate (10 ml), the organic phases were combined, washed 1 time with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated, slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered, and dried to obtain 1.21g of 7- (benzyloxy) -tetrahydro-1H-oxazino-pyrido-triazine-6, 8-dione (III) as a product in a yield of 77.6%.
Example 9: synthesis of 7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione (III)
2- (3-methoxy-4-carbonylmorpholine) -3-benzyloxypyrone (1.72 g, 5 mmol) represented by the formula (II) and acetonitrile (10 ml) were charged in a 100ml three-necked flask, p-toluenesulfonic acid monohydrate (0.19 g, 1 mmol) was added, hydrazine hydrate (0.38 g, 6mmol, 80%) was slowly added, and after stirring, the mixture was heated to 75 ℃ to react for 12 hours. After the reaction, the mixture was slowly cooled to room temperature, 5% sodium bicarbonate solution (15 ml) was added thereto and stirred, the aqueous phase was extracted 3 times with ethyl acetate (10 ml), the organic phases were combined, washed 1 time with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated, slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered, and dried to obtain 1.12g of 7- (benzyloxy) -tetrahydro-1H-oxazino-pyrido-triazine-6, 8-dione (III) as a product, with a yield of 71.8%.
Example 10: synthesis of 7- (hexyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione (III)
2- (3-methoxy-4-carbonylmorpholine) -3-hexyloxypyranone (1.70 g, 5 mmol) represented by the formula (II) and tetrahydrofuran (10 ml) were charged in a 100ml three-necked flask, pyridinium p-toluenesulfonate (0.25 g, 1 mmol) was added, hydrazine hydrate (0.38 g, 6mmol, 80%) was slowly added, and after stirring, the mixture was heated to 80 ℃ for 12 hours. After the reaction, the mixture was slowly cooled to room temperature, 5% sodium bicarbonate solution (15 ml) was added thereto and stirred, the aqueous phase was extracted with ethyl acetate (10 ml) 3 times, the organic phases were combined, washed with saturated brine (10 ml) 1 time, dried over anhydrous sodium sulfate, filtered, concentrated, slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered, and dried to obtain 1.16g of a product of 7- (hexyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione (III), with a yield of 75.8%.
Example 11: synthesis of 7- (hexyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione (III)
2- (3-methoxy-4-carbonylmorpholine) -3-hexyloxypyranone (1.70 g, 5 mmol) represented by the formula (II) and acetonitrile (10 ml) were charged in a 100ml three-necked flask, p-toluenesulfonic acid monohydrate (0.19 g, 1 mmol) was added, hydrazine hydrate (0.38 g, 6mmol, 80%) was slowly added, and after stirring, the mixture was heated to 65 ℃ for 16 hours. After the reaction, the mixture was slowly cooled to room temperature, 5% sodium bicarbonate solution (15 ml) was added thereto and stirred, the aqueous phase was extracted with ethyl acetate (10 ml) 3 times, the organic phases were combined, washed with saturated brine (10 ml) 1 time, dried over anhydrous sodium sulfate, filtered, concentrated, slurried with a mixed solvent of ethyl acetate and petroleum ether, filtered, and dried to obtain 1.09g of 7- (hexyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione (III) as a product in 71.2% yield.
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (10)
1. A synthesis method of a baroxavir key intermediate is characterized in that 3-methoxy morpholine shown in a formula (I) is subjected to dehydration condensation reaction to obtain 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone shown in a formula (II); carrying out nucleophilic substitution reaction on 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone shown in formula (II) to obtain 7- (hydroxy substituent) -tetrahydro-1H-oxazine pyridotriazine-6, 8-diketone shown in formula (III), namely the baroxavir key intermediate;
in the formulas (II) and (III), R is optionally lower alkyl, trimethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl, methoxymethyl, ethoxyethyl, allyl, acetyl, benzoyl and pivaloyl, and the lower alkyl is straight-chain or branched alkyl with 1-6 carbon atoms.
2. The synthesis method of a baroxavir key intermediate as claimed in claim 1, characterized by comprising the following steps:
placing 3-hydroxy substituted-2-carboxyl pyrone in a solvent A, adding a condensing agent B or an acylating reagent C, reacting for 1-2h at 0-40 ℃, adding 3-methoxy morpholine shown in a formula (I) into a reaction solution, tracking by TLC until the reaction is finished, washing, drying and concentrating the reaction solution to obtain 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone shown in a formula (II);
placing 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone shown in formula (II) in a solvent D, adding a catalyst E and hydrazine hydrate under the protection of inert gas, reacting at 40-80 ℃ for 12-24H, tracking by TLC until the reaction is finished, washing the reaction solution with water, drying, and concentrating to obtain 7- (hydroxy substituent) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone shown in formula (III).
3. The method for synthesizing the baroxavir key intermediate as claimed in claim 2, wherein in the step 1), the solvent A is one or two mixtures of tetrahydrofuran, dichloromethane, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxane, 1, 2-dichloroethane and acetonitrile; the condensing agent B is one or a mixture of two of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine, triethylamine, 1, 8-diazabicycloundecene-7-ene, dicyclohexylcarbodiimide, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 1-propylphosphoric anhydride, benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate and diphenyl phosphorodiazide phosphate; the acylating reagent C is one of thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride and bis (trichloromethyl) carbonate.
4. The synthesis method of a baroxavir key intermediate as claimed in claim 2, wherein in step 1), the ratio of the amount of the 3-methoxy morpholine shown in formula (I) to the amount of the substance of the condensing agent B or the acylating agent C is 1: 0.5-2.0; the ratio of the volume of the solvent A to the amount of the substance of 3-methoxymorpholine represented by the formula (I) is 1 to 4: volume is in mL and amount of substance is in mmol.
5. The method for synthesizing the baroxavir key intermediate as claimed in claim 2, wherein in the step 2), the solvent D is one or two mixtures of tetrahydrofuran, dichloromethane, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, toluene, ethanol, methanol, 1, 4-dioxane, 1, 2-dichloroethane and acetonitrile; the catalyst E is one of 4-dimethylamino pyridine, benzoic acid, benzenesulfonic acid, p-toluenesulfonic acid and pyridinium p-toluenesulfonic acid.
6. The synthesis method of the baroxavir key intermediate as claimed in claim 2, wherein in the step 2), the amount ratio of the 2- (3-methoxy-4-carbonylmorpholine) -3-hydroxy substituted pyrone shown as the formula (II) to the catalyst E substance is 1: 0.1-3; the mass ratio of the 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone to the hydrazine hydrate substance is 1: 1-3; the ratio of the volume of the solvent D to the amount of the substance of 2- (3-methoxy-4-carbonylmorpholine) -3-hydroxy-substituted pyrone represented by the formula (II) is 2 to 5: volume is in mL and amount of substance is in mmol.
7. The synthesis method of a baroxavir key intermediate as claimed in claim 2, wherein the solvent A in step 1) is tetrahydrofuran, dichloromethane, N-dimethylacetamide; the condensing agent B is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine; and the acylating reagent C is oxalyl chloride or thionyl chloride.
8. The synthesis method of a baroxavir key intermediate as claimed in claim 2, wherein the reaction temperature in step 1) is 0-30 ℃; the mass ratio of the 3-methoxy morpholine to the condensing agent B or the acylating agent C is 1.0-1.5.
9. The synthesis method of a baroxavir key intermediate as claimed in claim 2, wherein the solvent D in the step 2) is tetrahydrofuran, acetonitrile; catalyst E is p-toluenesulfonic acid, p-pyridinium tosylate.
10. The synthesis method of a baroxavir key intermediate as claimed in claim 2, wherein the reaction temperature in step 2) is 50-60 ℃; preferred catalysts E are p-toluenesulfonic acid, pyridinium p-toluenesulfonate; the mass ratio of the 2- (3-methoxy-4-carbonyl morpholine) -3-hydroxy substituted pyrone to the catalyst E is 1: 0.1-0.5.
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| CN201911046848.7A CN111057070A (en) | 2019-10-30 | 2019-10-30 | Synthesis method of baroxavir key intermediate |
| CN202010958584.9A CN111925381B (en) | 2019-10-30 | 2020-09-14 | Synthesis method of baroxavir key intermediate |
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| CN112679519B (en) * | 2020-12-31 | 2022-01-04 | 重庆医科大学 | Polycyclic carbamoylpyridone analogs, their preparation and use |
| CN113549088B (en) * | 2021-08-25 | 2022-10-04 | 北京理工大学 | Preparation method of baroxavir key intermediate |
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