CN110105372B - Preparation method of R-7- (benzyloxy) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone - Google Patents
Preparation method of R-7- (benzyloxy) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone Download PDFInfo
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- CN110105372B CN110105372B CN201910488089.3A CN201910488089A CN110105372B CN 110105372 B CN110105372 B CN 110105372B CN 201910488089 A CN201910488089 A CN 201910488089A CN 110105372 B CN110105372 B CN 110105372B
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Abstract
The invention relates to a synthetic route of a preparation method of R-7- (benzyloxy) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone, which takes allyl 3-oxomorpholine-4-carboxylic ester as a raw material to synthesize the R-7- (benzyloxy) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone with high yield through five-step reactions including condensation reaction, hydroboration reduction reaction, cyclization reaction, amidation reaction and deprotection reaction. The preparation method of the Barosavir intermediate provided by the invention is a preparation method which has high yield, low cost and easy operation and is suitable for industrialization.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a preparation method of R-7- (benzyloxy) -tetrahydro-1H-oxazine-pyrido-triazine-6, 8-diketone.
Background
Influenza, a demon that does not disperse throughout the year, can bring away people with too strong resistance or low immunity every year in winter. Historically 1918 Spain has taken away a large flu far exceeding the first world war of the same period. But the means by which we can deal with this democratic is very limited at present.
The FDA in the united states announces approval of the new anti-influenza drug xofflza (baloxavir marboxil) for the treatment of non-complication acute influenza patients 12 years and older for no more than 48 hours.
R-7- (benzyloxy) -tetrahydro-1H-oxazine pyridine-triazine-6, 8-diketone is a baroxavir key intermediate, and the current synthetic method comprises two methods:
JP2018048172A discloses a method for synthesizing [1,2,4] triazine-6, 8-dione which reports that baroxavir key intermediate (R) -7- (benzyloxy) -3,4,12,12a tetrahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ], and the specific synthetic route is shown in figure 2, and has the problems that: long synthesis steps, low yield and high cost.
JP621267881 discloses that the synthetic route of [1,2,4] triazine-6, 8-diketone of Barosavir intermediate (R) -7- (benzyloxy) -3,4,12,12a tetrahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] is shown in figure 3, and has the problems of high synthetic cost, low yield, inconvenience for industrialization and the like.
Disclosure of Invention
In order to overcome the problems existing in the synthesis method, a preparation method of R-7- (benzyloxy) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone is provided.
A process for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione comprising the steps of:
the method comprises the following steps: adding allyl 3-oxomorpholine-4-carboxylate, hydrazine hydrate, alkali and a solvent into a reaction bottle, heating for reaction, concentrating after the reaction is finished, adding toluene, and distilling the solvent under reduced pressure to obtain an intermediate 1;
step two: adding the intermediate 1, sodium borohydride and a solvent into a reaction bottle, heating for reaction, distilling the solvent under reduced pressure after the reaction is finished, washing with water, and drying to obtain an intermediate 2;
step three: under the protection of nitrogen, firstly adding an intermediate A and a solvent into a reaction bottle, adding the intermediate A into a reaction bottle, then adding an intermediate 2, dropwise adding stannic chloride, stirring at low temperature, quenching the reaction by using an alkali liquor, adding dichloromethane, filtering, washing with brine, drying, distilling the solvent under reduced pressure, adding the solvent, morpholine and a catalyst, stirring at room temperature, adding methyl tert-butyl ether after the reaction is finished, filtering, and drying the solid to obtain an intermediate 3;
step four: adding the intermediate 3, (R) -tetrahydrofuran-2-carboxylic acid and a solvent into a reaction bottle, adding pyridine and propylphosphoric anhydride, stirring at room temperature, carrying out a central control reaction, filtering after the reaction is finished, pulping with ethanol, and filtering to obtain an intermediate 4;
step five: and adding the intermediate 4, the solvent and DBU into a reaction bottle, stirring at room temperature, concentrating after the reaction is finished, filtering, washing with ethyl acetate, and drying to obtain the product R-7- (benzyloxy) -tetrahydro-1H-oxazine-pyrido-triazine-6, 8-diketone.
Preferably, the base in the first step is triethylamine, diethylamine, diisopropylethylamine, or pyridine, and the solvent in the first step is ethanol, methanol, or isopropanol.
Preferably, the temperature rise reaction temperature in the step one is 40-60 ℃.
Preferably, the solvent in the second step is tetrahydrofuran, ethanol or methanol.
Preferably, the temperature rise reaction temperature in the second step is 20-60 ℃.
Preferably, the solvent in step three is acetonitrile, tetrahydrofuran or ethanol.
Preferably, the low temperature in the third step is-20 to-35 ℃.
Preferably, the catalyst in the third step is palladium acetate, tetrakis (triphenylphosphine) palladium and palladium chloride, and the molar equivalent of the catalyst is 0.2-0.5 mol%.
Preferably, the solvent in the fourth step is ethyl acetate, tetrahydrofuran or dichloromethane. Preferably, the solvent in the fifth step is ethanol, methanol or isopropanol.
The invention has the beneficial effects that:
(1) through the redesign of a synthesis route, a synthesis route of R-7- (benzyloxy) -tetrahydro-1H-oxazine pyrido-triazine-6, 8-diketone is developed, allyl 3-oxomorpholine-4-carboxylic ester is used as a raw material, and the (R) -7- (benzyloxy) -3,4,12,12a tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-diketone is synthesized with high yield through five-step reactions including condensation reaction, hydroboration reduction reaction, cyclization reaction, amidation reaction and deprotection reaction.
(2) The preparation method of the Barosavir intermediate provided by the invention is a preparation method which has high yield, low cost and easy operation and is suitable for industrialization.
Drawings
FIG. 1 is a process for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione of this example;
FIG. 2 is a scheme showing the synthesis of [1,2,4] triazine-6, 8-dione from the intermediate (R) -7- (benzyloxy) -3,4,12,12a tetrahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] of baroxavir in the prior art;
FIG. 3 is a scheme showing the synthesis of [1,2,4] triazine-6, 8-dione from the intermediate (R) -7- (benzyloxy) -3,4,12,12a tetrahydro-1H- [1,4] oxazino [3,4-c ] pyrido [2,1-f ] of baroxavir in the prior art;
Detailed Description
The technical solution of the present invention is clearly and completely described below with reference to the following examples. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The method comprises the following steps: adding 185g of allyl 3-oxomorpholine-4-carboxylate, 65g of hydrazine hydrate, 100ml of triethylamine and 2L of ethanol into a reaction bottle, heating to 55 ℃ for reaction, concentrating after the reaction is finished, adding toluene, and distilling the solvent under reduced pressure to obtain 159g of intermediate 1, wherein the yield is as follows: 80 percent.
Step two: adding 150g of the intermediate 1, 65g of sodium borohydride and 300ml of ethanol into a reaction bottle, heating to 40 ℃ for reaction, washing with water after the reaction is finished, drying, and distilling the solvent under reduced pressure to obtain 136g of the intermediate 2, wherein the yield is as follows: 90 percent.
Step three: under the protection of nitrogen, firstly adding 130g of intermediate A and 1L of acetonitrile into a reaction bottle, then adding 101g of intermediate 2, dropwise adding 610ml of stannic chloride, stirring for one hour at minus 25 ℃, quenching the reaction by using an aqueous solution of sodium bicarbonate, concentrating, adding 1L of dichloromethane, layering, washing by using brine, drying, distilling the solvent under reduced pressure, adding 2L of tetrahydrofuran, 280ml of morpholine and 375g of tetrakis (triphenylphosphine) palladium, stirring for 3 hours at room temperature, after the reaction is finished, adding methyl tert-butyl ether, filtering, and drying the solid to obtain 147g of intermediate 3, wherein the yield is as follows: 89 percent.
Step four: 140g of intermediate 3, 55g of (R) -tetrahydrofuran-2-carboxylic acid and 700ml of ethyl acetate were added to a reaction flask, 150ml of pyridine and 50% ethyl propyl phosphate acetate solution were added, and stirred at room temperature for 10 hours, concentrated, filtered, slurried with ethanol, filtered to obtain 176g of intermediate 4, yield: 97 percent.
Step five: 100g of the intermediate 4a, 2L of ethanol and 70ml of DBU are added into a reaction bottle, stirred for 40 minutes at room temperature, concentrated, filtered, washed by ethyl acetate and dried to obtain 70g of the product R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, yield: 91 percent.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the technical scope of the present invention, so that the technical solutions formed by equivalent substitutions or equivalent changes are all within the protection scope of the present invention.
Claims (10)
1. A process for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, comprising the steps of:
the method comprises the following steps: adding allyl 3-oxomorpholine-4-carboxylate, hydrazine hydrate, alkali and a solvent into a reaction bottle, heating for reaction, concentrating after the reaction is finished, adding toluene, and distilling the solvent under reduced pressure to obtain an intermediate 1;
step two: adding the intermediate 1, sodium borohydride and a solvent into a reaction bottle, heating for reaction, distilling the solvent under reduced pressure after the reaction is finished, washing with water, and drying to obtain an intermediate 2;
step three: under the protection of nitrogen, firstly adding an intermediate A and a solvent into a reaction bottle, adding the intermediate A into a reaction bottle, then adding an intermediate 2, dropwise adding stannic chloride, stirring at low temperature, quenching the reaction by using an alkali liquor, adding dichloromethane, filtering, washing with brine, drying, distilling the solvent under reduced pressure, adding the solvent, morpholine and a catalyst, stirring at room temperature, adding methyl tert-butyl ether after the reaction is finished, filtering, and drying the solid to obtain an intermediate 3;
step four: adding the intermediate 3, (R) -tetrahydrofuran-2-carboxylic acid and a solvent into a reaction bottle, adding pyridine and propylphosphoric anhydride, stirring at room temperature, carrying out a central control reaction, filtering after the reaction is finished, pulping with ethanol, and filtering to obtain an intermediate 4;
step five: and adding the intermediate 4, the solvent and DBU into a reaction bottle, stirring at room temperature, concentrating after the reaction is finished, filtering, washing with ethyl acetate, and drying to obtain the product R-7- (benzyloxy) -tetrahydro-1H-oxazine-pyrido-triazine-6, 8-diketone.
2. The process according to claim 1 for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, characterized in that: the base in the first step is triethylamine, diethylamine, diisopropylethylamine and pyridine, and the solvent in the first step is ethanol, methanol and isopropanol.
3. The process according to claim 1 for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, characterized in that: the temperature rise reaction temperature in the first step is 40-60 ℃.
4. The process according to claim 1 for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, characterized in that: the solvent in the second step is tetrahydrofuran, ethanol and methanol.
5. The process according to claim 1 for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, characterized in that: and the temperature rise reaction temperature in the second step is 20-60 ℃.
6. The process according to claim 1 for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, characterized in that: the solvent in the third step is acetonitrile, tetrahydrofuran and ethanol.
7. The process according to claim 1 for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, characterized in that: the low temperature in the third step is-20 to-35 ℃.
8. The process according to claim 1 for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, characterized in that: the catalyst in the third step is palladium acetate, tetrakis (triphenylphosphine) palladium and palladium chloride, and the molar equivalent of the catalyst is 0.2-0.5 mol%.
9. The process according to claim 1 for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, characterized in that: the solvent in the fourth step is ethyl acetate, tetrahydrofuran and dichloromethane.
10. The process according to claim 1 for the preparation of R-7- (benzyloxy) -tetrahydro-1H-oxazinopyridino-triazine-6, 8-dione, characterized in that: and the solvent in the step five is ethanol, methanol and isopropanol.
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