CN113549088B - Preparation method of baroxavir key intermediate - Google Patents
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Abstract
The invention relates to the technical field of synthesis of medical intermediates, and provides a preparation method of a baroxavir key intermediate, which comprises the following steps: will be provided with
And
adding into a microwave reactor, and generating in a first solvent under the action of a sulfonic acid resin type solid acid catalyst and a condensing agent
Then will
Adding lithium chloride into a microwave reactor, and generating a baroxavir key intermediate in a second solvent
The preparation method of the baroxavir key intermediate provided by the invention adopts a microwave technology, so that the reaction is carried out under the microwave condition, and adopts a sulfonic acid resin type solid acid catalyst to replace traditional catalysts such as methanesulfonic acid, p-toluenesulfonic acid and the like, so that the reaction time is greatly shortened, the production efficiency is improved, and the product yield is obviously improved.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of a baroxavir key intermediate.
Background
Influenza (influenza) is an acute respiratory infectious disease caused by influenza virus, has high morbidity and mortality in the global range, is wide in spread range, and is the first of infectious diseases to cause economic loss. Human influenza viruses can be classified into three groups according to the difference in antigenicity of nucleoproteins: influenza a, influenza b, influenza c. Currently, the main measures against influenza virus infection are vaccination and drug therapy. However, the vaccine not only has certain limitation on the application range and low prevention and treatment efficiency, but also the conventional seasonal influenza vaccine can not effectively prevent and treat the continuously mutated influenza virus. Therefore, the development of the medicine for treating the influenza virus infection is very important. At present, medicaments such as M2 ion channel inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir) are used for the chemical prevention of influenza, and the effective rate is 70-90%. Barosavir (formula A) is a new drug for influenza A and B viruses, which is discovered by Japanese salt wild-sense pharmacy and developed together with Roche, is approved to be marketed in Japan in 2018, 2 and 23 months, and is approved to be marketed by the FDA in the United states in the same year 10 months. Different from other anti-influenza drugs through targeting neuraminidase, the baroxavir can selectively inhibit cap-dependent endonuclease, so that the functions of polymerase and influenza virus mRNA are prevented from being replicated, the earlier stage of the virus replication cycle can be targeted, and the effect is quicker.
The chemical structural formula of the baloxavir is as follows:
(±) -12- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e)]Sulfur complex
-11-yl) -7- (hydroxy) -3,4,12,12a tetrahydro-1H- [1,4]Oxazinyl [3,4-c ]]Pyridyl [2,1-f ]][1,2,4]The triazine-6, 8-diketone is a key intermediate for synthesizing the baroxavir, and the structure of the intermediate is shown as a formula 4.
Currently, the general method for synthesizing the baroxavir key intermediate shown in formula 4 is to synthesize 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e-]Sulfur complex
-11-ol (Compound 1) and 7- (benzyloxy) -3,4,12, 12a-tetrahydro-1H- [1,4]Oxazinyl [3,4-c ]]Pyridyl [2,1-f ]][1,2,4]Adding methanesulfonic acid or p-toluene to triazine-6, 8-dione (compound 2)Sulfonic acid is used as a catalyst, and dehydration is carried out under the action of a condensing agent to obtain the (+/-) -12- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e)]Sulfur complex
-11-yl) -7- (benzyloxy) -3,4,12,12a tetrahydro-1H- [1,4]Oxazinyl [3,4-c ]]Pyridyl group [2,1-f][1,2,4]Triazine-6, 8-diketone (compound 3), and then debenzylating the compound 3 under the action of lithium chloride to prepare a key intermediate of the baroxavir as shown in the formula 4. The synthesis method has the problems of long reaction time and low yield.
Disclosure of Invention
The invention aims to provide a preparation method of a baroxavir key intermediate shown as a formula 4, and aims to solve the technical problems of long reaction time and low yield in a method for synthesizing the baroxavir key intermediate shown as the formula 4 in the prior art.
In order to realize the purpose, the invention adopts the technical scheme that:
the invention provides a preparation method of a baroxavir key intermediate, which comprises the following steps:
s1, adding a compound 1 with a structure of a formula 1 and a compound 2 with a structure of a formula 2 into a microwave reactor, and generating an intermediate 3 with a structure of a formula 3 in a first solvent under the action of a sulfonic acid resin type solid acid catalyst and a condensing agent;
s2, adding the intermediate 3 and lithium chloride into a microwave reactor, and generating the baroxavir key intermediate with the structure of the formula 4 in a second solvent.
The preparation method of the baroxavir key intermediate provided by the invention adopts a microwave reactor, so that the reaction is carried out under the microwave condition, and adopts a sulfonic acid resin type solid acid catalyst to replace traditional catalysts such as methanesulfonic acid, p-toluenesulfonic acid and the like, so that the reaction time is greatly shortened, the production efficiency is improved, and the product yield is obviously improved.
The microwave is used as an electromagnetic wave, is applied to the chemical synthesis reaction of the medicine, has the advantages of high heating speed, uniform heating, no temperature gradient, no hysteresis effect and the like, and can greatly improve the reaction speed. Due to the particularity of action mechanisms such as a pyrogenicity effect, an induced catalytic effect and the like of the microwave, the microwave can promote a chemical reaction, and can reduce the use amount of solvent with high price or toxic solvent or even completely avoid the use of solvent, so that the cost and the toxicity are reduced; and the operating conditions are well controlled, which is convenient for monitoring the reaction degree by thin layer chromatography.
The invention adopts the sulfonic resin type solid acid catalyst to replace catalysts such as methanesulfonic acid, p-toluenesulfonic acid and the like, can improve the reaction rate and the product yield, is convenient to recover and can be repeatedly used, reduces the production cost and energy consumption, and is beneficial to protecting the environment. The sulfonic acid resin type solid acid catalyst may be selected from commercially available common species such as HND series resins developed by southern Kao university, amberlyst series resins from DuPont, and the like.
Further, the mass ratio of the sulfonic acid resin type solid acid catalyst to the compound 1 is 3-10:100.
further, the condensing agent is 1-propyl phosphoric anhydride.
Further, the molar ratio of the condensing agent to the compound 1 is 1.5-2.5:1.
further, the first solvent is at least one of ethyl acetate, N-Dimethylformamide (DMF), ethyl butyrate, tetrahydrofuran (THF), methyltetrahydrofuran, and chloroform.
Further, the reaction temperature of the microwave reactor in the step S1 is 145-155 ℃.
Further, in the step S1, the temperature rise time of the microwave reactor is 45 to 55min, and/or the reaction time of the microwave reactor is 25 to 35min.
Further, the second solvent is at least one of Dimethylacetamide (DMAC), N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP).
Further, the reaction temperature of the microwave reactor in the step S2 is 90-120 ℃.
Further, in the step S2, the temperature rise time of the microwave reactor is 8-15min, and/or the reaction time of the microwave reactor is 2.5-3.5h.
The invention has the beneficial effects that:
the preparation method of the baroxavir key intermediate provided by the invention adopts a microwave technology, so that the reaction is carried out under the microwave condition, and adopts a sulfonic acid resin type solid acid catalyst to replace traditional catalysts such as methanesulfonic acid, p-toluenesulfonic acid and the like, so that the reaction time is greatly shortened, the production efficiency is improved, and the product yield is obviously improved. The sulfonic acid resin type solid acid catalyst applied in the invention is convenient to use and recycle, can be reused, reduces the production cost and energy consumption, and is beneficial to environmental protection.
Drawings
Fig. 1 is a mass spectrum of a baroxavir key intermediate 4 prepared in example 1 of the present invention.
Fig. 2 is a nuclear magnetic resonance hydrogen spectrum of the baroxavir key intermediate 4 prepared in the example 1 of the present invention.
Fig. 3 is a nuclear magnetic resonance carbon spectrum of the baroxavir key intermediate 4 prepared in the example 1 of the present invention.
FIG. 4 is a high performance liquid chromatogram of a Barosavir key intermediate 4 prepared in example 1 of the present invention
FIG. 5 is a mass spectrum of racemic Barosavir prepared in example 1 of the present invention.
FIG. 6 is a NMR chart of racemic Balosavir prepared in example 1 of the present invention.
FIG. 7 is a NMR C-spectrum of racemic Balosanwei prepared in example 1 of the present invention.
FIG. 8 is a high performance liquid chromatogram of racemic Barosavir prepared in example 1 of the present invention.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present invention more apparent, the present invention is further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present patent and do not limit the scope of the invention in any way.
The preparation method of the baroxavir key intermediate provided by the invention comprises the following steps:
s1, adding a compound 1 with a structure of a formula 1 and a compound 2 with a structure of a formula 2 into a microwave reactor, and generating an intermediate 3 with a structure of a formula 3 in a first solvent under the action of a sulfonic acid resin type solid acid catalyst and a condensing agent;
s2, adding the intermediate 3 and lithium chloride into a microwave reactor, and generating the baroxavir key intermediate with the structure of the formula 4 in a second solvent.
Wherein the mass ratio of the sulfonic acid resin type solid acid catalyst to the compound 1 is 3-10:100. for example, 3: 100. 5: 100. 7: 100. 10:100, etc.
The condensing agent is 1-propyl phosphoric anhydride.
The molar ratio of the condensing agent to the compound 1 is 1.5-2.5:1. for example, it may be 1.5: 1. 1.8: 1. 2: 1. 2.4: 1. 2.5:1, etc.
The first solvent is at least one of ethyl acetate, N-Dimethylformamide (DMF), ethyl butyrate, tetrahydrofuran (THF), methyltetrahydrofuran and chloroform.
In step S1, the reaction temperature of the microwave reactor is 145-155 ℃. For example, 145 ℃, 148 ℃, 150 ℃, 153 ℃, 155 ℃ and the like can be used.
In step S1, the temperature rise time of the microwave reactor is 45-55min. For example, 45min, 46min, 49min, 50min, 53min, 55min, etc. may be mentioned.
In the step S1, the reaction time of the microwave reactor is 25-35min. For example, the concentration may be 25min, 27min, 30min, 31min, 33min, 35min, or the like.
The second solvent is at least one of Dimethylacetamide (DMAC), N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and N-methylpyrrolidone (NMP).
In step S2, the reaction temperature of the microwave reactor is 90-120 ℃. For example, the temperature may be 90 ℃, 95 ℃, 100 ℃, 108 ℃, 110 ℃, 120 ℃ or the like.
In step S2, the temperature rise time of the microwave reactor is 8-15min. For example, the time period may be 8min, 9min, 10min, 12min, 13min, 15min, or the like.
In the step S2, the reaction time of the microwave reactor is 2.5-3.5h. For example, it may be 2.5h, 2.7h, 3.0h, 3.1h, 3.3h, 3.5h, etc.
The invention is described in more detail by referring to a part of the tests, which are carried out in sequence, and the following detailed description is given by combining specific examples:
unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments, equipment, etc. used in the following examples are either commercially available or available by existing methods; the dosage of the reagent is the dosage of the reagent in the conventional experiment operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
Example 1
A preparation method of a baroxavir key intermediate with a structure shown in a formula 4 comprises the following steps:
compound 1 (2.64g, 10mmol), compound 2 (3.27g, 10mmol) and a solid acid catalyst HND-580 (0.132 g) were charged into a 100mL microwave reaction vessel, and 12mL of a 50wt% solution of 1-propylphosphoric anhydride in ethyl acetate (12 mL of the solution contained 20.18mmol of 1-propylphosphoric anhydride); putting the reaction kettle into a microwave reactor (XH-800 SP model Nanocube multifunctional microwave hydrothermal parallel synthesizer), setting the reaction temperature to be 150 ℃, the maximum power to be 300w, the heating time to be 50min and the reaction time to be 30min, clicking a start button and starting stirring after setting; after the reaction is finished, pouring the reaction liquid into ice water, and filtering to recover the catalyst; extracting the filtrate with dichloromethane, combining organic phases, washing with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution in sequence, and drying with anhydrous sodium sulfate to obtain a yellow oily compound which is a crude compound 3; adding the crude product of the compound 3 into a 100mL microwave reaction kettle, adding 20mL Dimethylacetamide (DMAC) and 2.53g anhydrous lithium chloride, putting the reaction kettle into a microwave reactor, setting the reaction temperature to be 100 ℃, the maximum power to be 300w, the heating time to be 10min and the reaction time to be 3h, clicking a start button and starting stirring after the setting is finished; after the reaction is finished, adding water into the reaction solution, and adjusting the pH of the reaction solution to about 6 by using 1M dilute hydrochloric acid; filtering, washing a filter cake with water, and drying the filter cake to obtain a light yellow solid; it was dissolved in chloroform, and isopropyl ether was added to precipitate a solid, which was filtered to give 3.48g of the baroxavir key intermediate (compound 4) as a pale yellow solid in 72.0% yield and 92% purity, melting point 230 ℃ (decomposition).
The identification of the yellowish solid obtained is carried out:
the mass spectrum of the yellowish solid is shown in FIG. 1, and ESI-MS (m/z) of the obtained yellowish solid is 484.1142[ M + H ]] + Consistent with the molecular weight of the baroxavir key intermediate having the structure of formula 4 (483.1064).
The NMR spectra and the carbon spectrum of the pale yellow solid are shown in FIG. 2 and FIG. 3, respectively.
1 H NMR(400MHz,CDCl 3 )δ7.14–7.06(m,3H),7.06–7.00(m,2H),6.84(m,1H),6.68(m,1H),5.77(m,1H),5.28(m,2H),4.66(m,1H),4.58(m,1H),4.06(m,1H),3.95(m,1H),3.80(m,1H),3.63(m,1H),3.48(m,1H),3.00(m,1H).
13 C NMR(100MHz,CDCl 3 )δ171.99,161.75,154.14,138.33,135.72,132.88,131.42,130.37,128.79,128.04,125.83,125.45,124.15,124.02,116.84,116.66,114.61,111.54,77.20,75.77,70.34,69.49,66.61,45.88,23.27.
The purity of the light yellow solid is detected by adopting a high performance liquid chromatography, and the detection method comprises the following steps:
a ZORBAX SB-Phenyl C18 column (4.6X 250mm,5 μm) was used, the detection wavelength was 210nm, the column temperature was 30 ℃, the sample volume was 10 μ L, the flow rate was 1.0mL/min, and the mobile phase A:0.1% phosphoric acid solution (pH = 4.0), mobile phase B: methanol, gradient elution according to the following table:
the chromatographic detection result is shown in FIG. 4, the retention time is 25.655min, and the purity is 92%.
Racemic balosavir was prepared using compound 4 prepared in this example, following the procedure and results:
adding 0.5g of chloromethyl methyl carbonate, 0.6g of potassium carbonate and 0.4g of potassium iodide into 10mL of DMAC, adding 0.63g (1.3 mmol) of compound 4, heating to 50 ℃, adding 1M hydrochloric acid and water after the reaction is finished, extracting with ethyl acetate, combining organic phases, washing with water and a saturated sodium chloride solution respectively, and drying with anhydrous sodium sulfate; the mixture was then concentrated and passed through a silica gel column (DCM: CH) 3 OH =20: 1) The above chromatographic purification gave 0.57g of rac-baroxavir in 76.8% yield, 94% purity, mp 253 ℃.
The obtained racemic balosavir was identified:
the mass spectrum is shown in FIG. 5, and ESI-MS (m/z) of the obtained product is 572.1282[ m ] +H] + And the molecular weight of the racemic baroxavir is consistent with the molecular weight (571.1225) of the racemic baroxavir.
The hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are respectively shown in FIG. 6 and FIG. 7.
1 H NMR(400MHz,CDCl 3 )δ7.13-7.02(m,4H),7.00(m,1H),6.88–6.80(m,2H),5.88(m,2H),5.32–5.25(m,2H),4.63(m 1H),4.50(m,1H),4.06(m,1H),3.91(m,1H),3.84(s,3H),3.73(m,1H),3.54(m,1H),3.43(m,1H),2.92–3.00(m,2H).
13 C NMR(100MHz,CDCl 3 )δ173.89,155.12,154.80,149.85,140.10,135.70,133.47,130.23,128.61,127.92,127.80,125.89,125.60,124.25,124.12,116.75,116.58,114.92,90.51,77.20,75.65,69.82,69.32,66.57,54.90,46.25,23.26.
The purity detection is carried out according to the high performance liquid chromatography condition which is the same as the purity of the detection compound 4, the detection result is shown in figure 8, the retention time is 28.398min, and the purity is 94%.
Example 2
A preparation method of a baroxavir key intermediate with a structure shown in a formula 4 comprises the following steps:
compound 1 (2.64g, 10mmol), compound 2 (3.27g, 10mmol) and a solid acid catalyst HND-586 (0.132 g) were added to a 100mL microwave reaction vessel, and 12mL of a 50wt% solution of 1-propylphosphoric anhydride in ethyl acetate was added; putting the reaction kettle into a microwave reactor (XH-800 SP model Nanocube multifunctional microwave hydrothermal parallel synthesizer), setting the reaction temperature to be 150 ℃, the maximum power to be 300w, the heating time to be 50min and the reaction time to be 30min, clicking a start button and starting stirring after setting; after the reaction is finished, pouring the reaction liquid into ice water, and filtering to recover the catalyst; extracting the filtrate with dichloromethane, combining organic phases, washing with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution in sequence, and drying with anhydrous sodium sulfate to obtain a yellow oily compound which is a crude compound 3; adding the crude product of the compound 3 into a 100mL microwave reaction kettle, adding 20mL Dimethylacetamide (DMAC) and 2.53g anhydrous lithium chloride, putting the reaction kettle into a microwave reactor, setting the reaction temperature to be 100 ℃, the maximum power to be 300w, the heating time to be 10min and the reaction time to be 3h, clicking a start button and starting stirring after the setting is finished; after the reaction is finished, adding water into the reaction solution, and adjusting the pH of the reaction solution to about 6 by using 1M dilute hydrochloric acid; filtering, washing a filter cake with water, and drying the filter cake to obtain a light yellow solid; it was dissolved in chloroform and isopropyl ether was added to precipitate a solid which was filtered to give 3.18g of the baroxavir key intermediate (compound 4) as a pale yellow solid in 65.8% yield and 91% purity.
Example 3
A preparation method of a baroxavir key intermediate with a structure shown in a formula 4 comprises the following steps:
compound 1 (2.64g, 10mmol), compound 2 (3.27g, 10mmol) and the solid acid catalyst Amberlyst35 (0.132 g) were added to a 100mL microwave reaction kettle, and 12mL of a 50wt% solution of 1-propylphosphoric anhydride in ethyl acetate was added; putting the reaction kettle into a microwave reactor (XH-800 SP model Nanocube multifunctional microwave hydrothermal parallel synthesizer), setting the reaction temperature to be 150 ℃, the maximum power to be 300w, the heating time to be 50min and the reaction time to be 30min, clicking a start button and starting stirring after setting; after the reaction is finished, pouring the reaction liquid into ice water, and filtering to recover the catalyst; extracting the filtrate with dichloromethane, combining organic phases, washing with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution in sequence, and drying with anhydrous sodium sulfate to obtain a yellow oily compound which is a crude compound 3; adding the crude product of the compound 3 into a 100mL microwave reaction kettle, adding 20mL Dimethylacetamide (DMAC) and 2.53g anhydrous lithium chloride, putting the reaction kettle into a microwave reactor, setting the reaction temperature to be 100 ℃, the maximum power to be 300w, the heating time to be 10min and the reaction time to be 3h, clicking a start button and starting stirring after the setting is finished; after the reaction is finished, adding water into the reaction solution, and adjusting the pH of the reaction solution to about 6 by using 1M dilute hydrochloric acid; filtering, washing a filter cake with water, and drying the filter cake to obtain a light yellow solid; it was dissolved in chloroform and isopropyl ether was added to precipitate a solid which was filtered to give 3.50g of the baroxavir key intermediate (compound 4) as a pale yellow solid in 72.4% yield and 92% purity.
Example 4
A preparation method of a baroxavir key intermediate with a structure shown in a formula 4 comprises the following steps:
compound 1 (2.64g, 10mmol), compound 2 (3.27g, 10mmol) and the solid acid catalyst Amberlyst36 (0.132 g) were charged into a 100mL microwave reaction vessel, and 12mL of a 50wt% solution of 1-propylphosphoric anhydride in ethyl acetate was added; putting the reaction kettle into a microwave reactor (XH-800 SP model Nanocube multifunctional microwave hydrothermal parallel synthesizer), setting the reaction temperature to be 150 ℃, the maximum power to be 300w, the heating time to be 50min and the reaction time to be 30min, clicking a start button and starting stirring after setting; after the reaction is finished, pouring the reaction liquid into ice water, and filtering to recover the catalyst; extracting the filtrate with dichloromethane, combining organic phases, washing with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution in sequence, and drying with anhydrous sodium sulfate to obtain a yellow oily compound which is a crude product of the compound 3; adding the crude product of the compound 3 into a 100mL microwave reaction kettle, adding 20mL Dimethylacetamide (DMAC) and 2.53g anhydrous lithium chloride, putting the reaction kettle into a microwave reactor, setting the reaction temperature to be 100 ℃, the maximum power to be 300w, the temperature rise time to be 10min and the reaction time to be 3h, clicking a start button and starting stirring after the setting is finished; after the reaction is finished, adding water into the reaction solution, and adjusting the pH of the reaction solution to about 6 by using 1M dilute hydrochloric acid; filtering, washing a filter cake with water, and drying the filter cake to obtain a light yellow solid; it was dissolved in chloroform and isopropyl ether was added to precipitate a solid which was filtered to give 3.26g of the baroxavir key intermediate (compound 4) as a pale yellow solid in 67.5% yield and 90% purity.
Example 5
A preparation method of a baroxavir key intermediate with a structure shown in a formula 4 comprises the following steps:
compound 1 (2.64g, 10mmol), compound 2 (3.27g, 10mmol) and a solid acid catalyst HND-580 (0.212 g) were added to a 100mL microwave reaction vessel, and 12mL of a 50wt% solution of 1-propylphosphoric anhydride in ethyl acetate was added; putting the reaction kettle into a microwave reactor (XH-800 SP model Nanocube multifunctional microwave hydrothermal parallel synthesizer), setting the reaction temperature to be 150 ℃, the maximum power to be 300w, the heating time to be 50min and the reaction time to be 30min, clicking a start button and starting stirring after setting; after the reaction is finished, pouring the reaction liquid into ice water, and filtering to recover the catalyst; extracting the filtrate with dichloromethane, combining organic phases, washing with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution in sequence, and drying with anhydrous sodium sulfate to obtain a yellow oily compound which is a crude compound 3; adding the crude product of the compound 3 into a 100mL microwave reaction kettle, adding 20mL Dimethylacetamide (DMAC) and 2.53g anhydrous lithium chloride, putting the reaction kettle into a microwave reactor, setting the reaction temperature to be 100 ℃, the maximum power to be 300w, the heating time to be 10min and the reaction time to be 3h, clicking a start button and starting stirring after the setting is finished; after the reaction is finished, adding water into the reaction solution, and adjusting the pH of the reaction solution to about 6 by using 1M dilute hydrochloric acid; filtering, washing a filter cake with water, and drying the filter cake to obtain a light yellow solid; it was dissolved in chloroform and isopropyl ether was added to precipitate a solid which was filtered to give 3.54g of the baroxavir key intermediate (compound 4) as a pale yellow solid in 73.2% yield and 90% purity.
Example 6
A preparation method of a baroxavir key intermediate with a structure shown in a formula 4 comprises the following steps:
compound 1 (2.64g, 10mmol), compound 2 (3.27g, 10mmol) and a solid acid catalyst HND-580 (0.264 g) were added to a 100mL microwave reaction kettle, and 12mL of a 50wt% solution of 1-propylphosphoric anhydride in ethyl acetate was added; putting the reaction kettle into a microwave reactor (XH-800 SP model Nanocube multifunctional microwave hydrothermal parallel synthesizer), setting the reaction temperature to be 150 ℃, the maximum power to be 300w, the temperature rise time to be 50min and the reaction time to be 30min, clicking a start button and starting stirring after the setting is finished; after the reaction is finished, pouring the reaction liquid into ice water, and filtering to recover the catalyst; extracting the filtrate with dichloromethane, combining organic phases, washing with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride solution in sequence, and drying with anhydrous sodium sulfate to obtain a yellow oily compound which is a crude compound 3; adding the crude product of the compound 3 into a 100mL microwave reaction kettle, adding 20mL Dimethylacetamide (DMAC) and 2.53g anhydrous lithium chloride, putting the reaction kettle into a microwave reactor, setting the reaction temperature to be 100 ℃, the maximum power to be 300w, the heating time to be 10min and the reaction time to be 3h, clicking a start button and starting stirring after the setting is finished; after the reaction is finished, adding water into the reaction solution, and adjusting the pH of the reaction solution to about 6 by using 1M dilute hydrochloric acid; filtering, washing a filter cake with water, and drying the filter cake to obtain a light yellow solid; it was dissolved in chloroform and isopropyl ether was added to precipitate a solid which was filtered to give 3.77g of the baroxavir key intermediate (compound 4) as a pale yellow solid in 78.0% yield and 92% purity.
Comparative example 1
A preparation method of a baroxavir key intermediate with a structure shown as a formula 4 is different from that in example 1: the dosage of the solid acid catalyst HND-580 is 0.026g.
The preparation yielded 0.88g of baroxavir key intermediate (compound 4), 18.2% yield, 89% purity.
Comparative example 2
A preparation method of a baroxavir key intermediate with a structure shown in a formula 4 is different from that of an example 1: the amount of the solid acid catalyst HND-580 was 0.053g.
The preparation method obtains 1.49g of the baroxavir key intermediate (compound 4), the yield is 30.8%, and the purity is 90%.
Comparative example 3
A preparation method of a baroxavir key intermediate with a structure shown as a formula 4 is different from that in example 1: the solid acid catalyst HND-580 was replaced with methanesulfonic acid.
The preparation method obtains 1.92g of the baroxavir key intermediate (compound 4), the yield is 39.7%, and the purity is 90%.
Comparative example 4
A preparation method of a baroxavir key intermediate with a structure shown as a formula 4 is different from that in example 1: the solid acid catalyst HND-580 was replaced with p-toluenesulfonic acid.
The preparation yielded 2.17g of baroxavir key intermediate (compound 4), 44.9% yield, 90% purity.
Comparative example 5
A preparation method of a baroxavir key intermediate with a structure shown as a formula 4 is different from that in example 1: in the process of reacting the compound 1 with the compound 2 to generate the compound 3, the temperature of the microwave reaction is 140 ℃.
The preparation method obtains 1.03g of the baroxavir key intermediate (compound 4), the yield is 21.3%, and the purity is 88%.
Comparative example 6
A preparation method of a baroxavir key intermediate with a structure shown as a formula 4 is different from that in example 1: in the process of reacting the compound 1 with the compound 2 to generate the compound 3, the temperature of the microwave reaction is 160 ℃.
The preparation method provided 2.21g of the baroxavir key intermediate (compound 4), the yield was 45.7%, and the purity was 90%.
Comparative example 7
A preparation method of a baroxavir key intermediate with a structure shown as a formula 4 is different from that in example 1: in the process of reacting the compound 1 with the compound 2 to generate the compound 3, the temperature rise time of the microwave reaction is 40min.
The preparation method obtains 2.69g of the baroxavir key intermediate (compound 4), the yield is 55.7%, and the purity is 89%.
Comparative example 8
A preparation method of a baroxavir key intermediate with a structure shown as a formula 4 is different from that in example 1: in the process of reacting the compound 1 and the compound 2 to generate the compound 3, the reaction time of the microwave reactor is 20min. The reaction was not fully carried out as monitored by TLC.
Comparative example 9
A preparation method of a baroxavir key intermediate with a structure shown in a formula 4 comprises the following steps:
compound 1 (160mg, 0.6 mmol), compound 2 (196mg, 0.6 mmol) and solid acid catalyst HND-580 (8 mg) were charged into a 100mL microwave reaction vessel, and 20mL of a 50% by weight solution of 1-propylphosphoric anhydride in ethyl acetate (20 mL of a solution containing 33.63mmol of 1-propylphosphoric anhydride) was added; putting the reaction kettle into a microwave reactor (XH-800 SP model Nanocube multifunctional microwave hydrothermal parallel synthesizer), setting the reaction temperature to be 150 ℃, the maximum power to be 300w, the heating time to be 50min and the reaction time to be 30min, clicking a start button and starting stirring after setting; after the reaction is finished, pouring the reaction liquid into ice water, and filtering to recover the catalyst; the filtrate was extracted with dichloromethane, and the organic phases were combined, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate to give a yellow viscous oily compound. The yellow viscous oily compound is complex in composition by TLC detection, and the content of the compound 3 is low, so that the purification and the subsequent debenzylation reaction are difficult.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (8)
1. A method for preparing a baroxavir key intermediate having a structure shown in formula 4, which comprises the following steps:
s1, adding a compound 1 with a structure of a formula 1 and a compound 2 with a structure of a formula 2 into a microwave reactor, and generating an intermediate 3 with a structure of a formula 3 in a first solvent under the action of a sulfonic acid resin type solid acid catalyst and a condensing agent, wherein the sulfonic acid resin type solid acid catalyst is HND-580, HND-586, amberlyst35 or Amberlyst36;
s2, adding the intermediate 3 and lithium chloride into a microwave reactor, and generating a baroxavir key intermediate with a structure shown in a formula 4 in a second solvent;
the mass ratio of the sulfonic acid resin type solid acid catalyst to the compound 1 is 5-10: 100, respectively; the reaction temperature of the microwave reactor in the step S1 is 150 ℃;
in the step S1, the temperature rise time of the microwave reactor is 50min.
2. The method according to claim 1, wherein the condensing agent is 1-propylphosphoric anhydride.
3. The method according to claim 2, wherein the molar ratio of the condensing agent to the compound 1 is 1.5 to 2.5:1.
4. the method according to claim 1, wherein the first solvent is at least one selected from the group consisting of ethyl acetate, N-dimethylformamide, ethyl butyrate, tetrahydrofuran, methyltetrahydrofuran, and chloroform.
5. The method according to claim 1, wherein in the step S1, the reaction time of the microwave reactor is 25-35min.
6. The method according to claim 1, wherein the second solvent is at least one of dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidone.
7. The method according to claim 1, wherein the reaction temperature of the microwave reactor in the step S2 is 90 to 120 ℃.
8. The method according to claim 1, wherein in step S2, the microwave reactor is heated for 8-15min, and/or the microwave reactor is heated for 2.5-3.5h.
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