CN111925381B - 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 formulae (II) and (III), R is a lower alkyl group, preferably methyl.
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), wherein R is lower alkyl, preferably methyl.
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 20 ml, 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) after the addition, 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 20-30 ml 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, to obtain 0.67 g of colorless transparent liquid 2- (3-methoxy-4-carbonyl morpholine) -3-methoxy pyrone (II) with the yield of 49.8 percent.1H NMR (CDCl3) δ 7.72 (d, J = 8.4 Hz, 1H), 6.12 (d, J = 8.4 Hz, 1H), 5.06 (t, J = 5.1 Hz, 1H), 3.88 – 3.86 (m, 1H), 3.85 (s, 3H), 3.82 – 3.74 (m, 4H), 3.57 – 3.51 (m, 1H), 3.26 (s, 3H).
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, adding 20-30 ml of water into the reaction solution after the TLC tracking until the reaction is completed, 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, filtration and concentration under reduced pressure were carried out to remove the solvent, whereby 0.76 g of 2- (3-methoxy-4-carbonylmorpholine) -3-methoxypyranone (II) was obtained as a colorless transparent liquid with a yield of 56.5%.1H NMR (CDCl3) δ 7.72 (d, J = 8.4 Hz, 1H), 6.12 (d, J = 8.4 Hz, 1H), 5.06 (t, J = 5.1 Hz, 1H), 3.88 – 3.86 (m, 1H), 3.85 (s, 3H), 3.82 – 3.74 (m, 4H), 3.57 – 3.51 (m, 1H), 3.26 (s, 3H).
Example 3: 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), oxalyl chloride (0.83 g, 6.5 mmol) and dimethylformamide (0.02 ml) into a 100ml three-neck flask, stirring under ice bath for 20 minutes, slowly dropping a dichloromethane (10 ml) solution of 3-methoxy morpholine (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 20-30 ml water into the reaction solution, adding dichloromethane (20 ml) for extraction for 2 times, combining organic phases, washing 1 time by saturated saline (20 ml), drying by anhydrous sodium sulfate, filtering, and removing the solvent by concentration under reduced pressure to obtain a colorless transparent liquid of 0.95.95% of 2- (3-methoxy-4-carbonylmorpholine) -3-methoxypyranone (II) g, yield 70.6%.1H NMR (CDCl3) δ 7.72 (d, J = 8.4 Hz, 1H), 6.12 (d, J = 8.4 Hz, 1H), 5.06 (t, J = 5.1 Hz, 1H), 3.88 – 3.86 (m, 1H), 3.85 (s, 3H), 3.82 – 3.74 (m, 4H), 3.57 – 3.51 (m, 1H), 3.26 (s, 3H).
Example 4: 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, 11 mmol, 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 2.03 g of a product of 7- (methoxy) -tetrahydro-1H-oxazino-pyrido-triazine-6, 8-dione (iii) in a yield of 80.9%.1H NMR (CDCl3) δ 10.09 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.17 (s, 1H), 7.87 – 7.78 (m, 2H), 7.74 (d, J = 7.7 Hz, 1H), 1.92 – 1.49 (m, 4H), 1.25 (s, 3H).
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, 11 mmol, 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 1.67 g of a product of 7- (methoxy) -tetrahydro-1H-oxazino-pyrido-triazine-6, 8-dione (III), with a yield of 66.5%.1H NMR (CDCl3) δ 10.09 (s, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.17 (s, 1H), 7.87 – 7.78 (m, 2H), 7.74 (d, J = 7.7 Hz, 1H), 1.92 – 1.49 (m, 4H), 1.25 (s, 3H).
The contents described in the present specification are merely examples of the implementation forms of the inventive concept, and the scope of the present invention should not be considered to be limited to the specific forms described in the examples, for example, the same technical effects can be obtained by using a linear or branched alkyl group having 1 to 6 carbon atoms, a trimethylsilyl group, a t-butyldimethylsilyl group, a triisopropylsilyl group, a benzyl group, a p-methoxybenzyl group, a methoxymethyl group, an ethoxyethyl group, an allyl group, an acetyl group, a benzoyl group, and a pivaloyl group as the substituent R in place of the methyl group of the present invention.
Claims (6)
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 lower alkyl, and the method specifically comprises the following steps:
1) putting 3-hydroxy-substituted-2-carboxyl pyrone into 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 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 formula (II), wherein the solvent A is one or a mixture 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, and the amount ratio of the 3-methoxy morpholine shown in the formula (I) to the condensing agent B or the acylating reagent 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: 1, volume is in mL, amount of substance is in mmol;
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); in the formulae (II) and (III), R is lower alkyl;
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 amount 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.
2. The method for synthesizing the baroxavir key intermediate as claimed in claim 1, wherein in the step 2), R is methyl.
3. The synthesis method of a baroxavir key intermediate as claimed in claim 1, 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.
4. The synthesis method of a baroxavir key intermediate as claimed in claim 1, 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.
5. The synthesis method of a baroxavir key intermediate as claimed in claim 1, wherein the solvent D in the step 2) is tetrahydrofuran, acetonitrile; catalyst E is p-toluenesulfonic acid, p-pyridinium tosylate.
6. The synthesis method of a baroxavir key intermediate as claimed in claim 1, wherein the reaction temperature in step 2) is 50-60 ℃; the catalyst E of (2) is p-toluenesulfonic acid or 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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| CN107709321A (en) * | 2015-04-28 | 2018-02-16 | 盐野义制药株式会社 | The polycyclic Pyridione derivatives and its prodrug being substituted |
| CN109912624A (en) * | 2019-04-11 | 2019-06-21 | 杭州科巢生物科技有限公司 | A kind of synthetic method of Ba Luoshawei ester key parent nucleus intermediate |
| CN110105372A (en) * | 2019-06-05 | 2019-08-09 | 南京焕然生物科技有限公司 | A kind of R-7- (benzyloxy)-tetrahydro -1H- oxazines and pyrido-triazine -6,8- diketone preparation method |
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