A preparation method of caronamide and its precursor caron acid

Abstract

The present invention relates to the field of pharmaceutical intermediate synthesis, and in particular to a synthetic method of caronamide. The preparation of caronamide by traditional methods will produce a large amount of waste residues and waste liquids, and the steps are cumbersome. The present invention discloses a preparation method of caronamide (6,6-dimethyl-3-azabicyclo (3.1.0) hexane-2,4-diketone), the method comprising: adding kungfu acid to water and alkaline solution, heating and dissolving, passing ozone for oxidation, using acid to adjust pH, crystallizing, filtering to obtain caron acid; then reacting with ammonia compounds, dissolving in water, cooling and crystallizing, filtering, and drying to obtain caronamide. The method of the present invention overcomes the deficiencies of the prior art, and has the advantages that: the whole process is free of organic solvents, simple to operate, safe and environmentally friendly, and has a small amount of three wastes, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical intermediate synthesis, and in particular to a method for preparing caronamide and a precursor thereof. Background Art

[0002] The first oral drug for COVID-19, Namatevir:

[0003]

[0004] For the treatment of adults and adolescents with mild to moderate COVID-19 who are at high risk of developing severe illness.

[0005] Caronamide is an important intermediate compound for the preparation of Nematevir, and its molecular formula structure is:

[0006]

[0007] The common synthesis route of caronamide mainly uses chrysanthemic acid ethyl ester, gongfu acid or isopentanol ester as raw materials, first synthesizing caronic acid, and then preparing the intermediate caronic anhydride through condensation reaction, and then preparing caronic anhydride through amination to synthesize caronamide.

[0008] For example, in patent CN114456057A, the kungfu acid is first alkalized, and then potassium permanganate, an oxidizing agent, is added to oxidize the olefin group to a carboxyl group, and finally a reducing agent is added to quench the excess potassium permanganate to prepare caronic acid. This method uses a large amount of potassium permanganate as a raw material and produces manganese residues, which is neither economical nor environmentally friendly and is not suitable for large-scale industrial production.

[0009]

[0010] Patent CN114105859A uses 6,6-dimethyl-3-oxazolylcyclo[3.1.0]hexane-2-one as the starting material, and then oxidizes it to obtain caron acid by alkaline hydrolysis. The obtained caron acid is reacted with acetic anhydride and dehydrated to obtain caron anhydride, and then caron anhydride is reacted with ammonia to obtain caronamide. This preparation method is cumbersome and complicated, with long reaction steps, and the raw materials are hard to find. The preparation method is only in the laboratory synthesis stage, and it is difficult to scale up the preparation method.

[0011]

[0012] The existing technology has already discussed the preparation routes of caronamide and its precursor caronic acid. However, considering the rapid demand for the treatment of COVID-19, how to obtain a new method for preparing caronamide that is atom-economical, environmentally friendly, and energy-saving is an urgent problem that technicians in this field need to solve. Summary of the invention

[0013] In view of the above problems, the purpose of the present invention is to provide a method for preparing caronamide and its precursor caronic acid. In the process of preparing caronic acid, the present invention replaces potassium permanganate oxidation with ozone oxidation of kung fu acid to reduce solid waste; direct crystallization in post-treatment does not use organic solvents, reduces costs, and is safe and environmentally friendly; the manufacturing cost of ozone oxidation is only 10% of that of potassium permanganate oxidation. In addition, the present invention directly reacts the obtained caronic acid with ammonia to directly obtain caronamide, and the yield can reach 90.41%, which is suitable for industrial large-scale production.

[0014] A method for preparing caronic acid comprises the following contents:

[0015]

[0016] After mixing the kung fu acid, alkali and solvent evenly, ozone is introduced and reacted at 15°C to 45°C. After the reaction is completed, acid is added to adjust the pH to 1 to 3. The reaction solution is cooled and crystallized. The crystallization temperature is preferably 0 to 20°C. Centrifugation is performed to obtain a wet product of caronic acid.

[0017] In the technical solution of the present invention, the base is an inorganic base or an organic base;

[0018] Furthermore, the inorganic base is one or more of potassium hydroxide, sodium hydroxide, and ammonia monohydrate;

[0019] Furthermore, the organic base is triethylamine.

[0020] Furthermore, the molar ratio of the base to the acid is 1.0-5.0:1.0.

[0021] In the technical solution of the present invention, the solvent is water, and the mass ratio of water to caustic soda is 5.0-10.0:1.0.

[0022] Furthermore, the reaction temperature is 20°C to 40°C.

[0023] In the technical solution of the present invention, the acid is one or more of sulfuric acid, hydrochloric acid and phosphoric acid.

[0024] Furthermore, an acid was added to adjust the pH to 1.

[0025] In the technical solution of the present invention, ozone is prepared by a GF-G10K air source ozone generator.

[0026] The raw material of the present invention is industrial raw material Kung Fu acid (raw material for industrial production of pesticides, which is easy to buy on the market); the reaction system uses safe and environmentally friendly water as a solvent, and the post-treatment is also water crystallization, and there is no organic solvent in the whole process; ozone oxidation is relatively rare in industrialization, and the present invention uses GF-G10K air source ozone generator, which produces 10kg of ozone per hour, is safe and reliable, and the excess ozone after the reaction is discharged into the atmosphere at high altitude and quickly decomposes in the air without pollution to the environment; and water is used as a solvent, ozone oxidation is safe, and there is no danger of combustion and explosion.

[0027] The technical solution of the present invention also includes the following contents: the reaction solution after pH adjustment by acid is not cooled and crystallized, but directly extracted with an organic solvent to remove the solvent to obtain caronic acid solid.

[0028] Furthermore, the organic solvent is one or more of ethyl acetate, isopropyl acetate, dichloromethane, and methyl tert-butyl ether, preferably one or two of ethyl acetate and isopropyl acetate.

[0029] In the technical solution of the present invention, the solvent removal is to remove the organic solvent in the extract, and the methods used include but are not limited to: reduced pressure evaporation, normal pressure evaporation, drying, cooling crystallization followed by centrifugal filtration and other conventional operating means, which can be used alone or in combination.

[0030] The traditional process uses potassium permanganate for oxidation and organic solvent extraction to prepare caron acid, which is costly and produces a large amount of manganese dioxide solid waste. The caron acid prepared by the method of the present invention has a yield of up to 96.8% and a purity of up to 99.4%; the raw material cost can be controlled within 400 yuan / kg, which is 30-40% lower than the traditional process.

[0031] In addition, the present invention also provides a method for preparing caronamide from the caron acid wet product or caron acid solid prepared by the above method, comprising the following contents:

[0032]

[0033] (1) Add an aqueous solution of an ammonia compound dropwise to a wet product of caron acid or a solid product of caron acid, control the temperature to be between 0°C and 40°C, and stir until the salt is dissolved and clarified;

[0034] (2) heating the reaction solution in step (1) to evaporate the water in the system, forcing the reaction to proceed in the forward direction, maintaining the temperature at 70° C. to 180° C., and reacting for 3 to 12 hours;

[0035] (3) After the reaction is completed, water is added to dissolve the solid, and the solid is cooled and crystallized. The crystallization temperature is preferably 0° C. to 20° C., and caronamide is obtained by filtration.

[0036] Furthermore, the ammonia compound is one or more of ammonia monohydrate, ammonia gas, and ammonium salt;

[0037] In the technical solution of the present invention, when the ammonia compound used is ammonia gas, the ammonia gas can be introduced into water to prepare an ammonia solution, and then the reaction is carried out.

[0038] Further, the ammonium salt is one or more of ammonium carbonate, ammonium bicarbonate, ammonium sulfate, and ammonium bisulfate; preferably ammonium carbonate and ammonium bicarbonate;

[0039] In the technical solution of the present invention, the concentration of the ammonia compound solution is 5% to 25%.

[0040] Furthermore, the molar ratio of the amino compound to the wet product of caronic acid is 1.0-5.0:1.0.

[0041] In the technical solution of the present invention, the reaction temperature of step (2) is preferably 140° C. to 170° C., and the reaction time is preferably 5 to 10 hours.

[0042] In the methods for preparing caronamide from caron acid reported in the prior art, all of them are two-step reactions, that is, first dehydrating with acetic anhydride and sodium acetate to produce caron anhydride, and then aminating to obtain caronamide. The present invention improves the two-step reaction into a one-step reaction, and the reaction principle is to first form salts by adding ammonium compounds and carboxylic acids, remove a molecule of water, and then further react the molecular lactam and carboxylic acid to dehydrate by controlling the reaction temperature, and finally obtain lactam.

[0043] The prepared wet product of caron acid can be directly used to prepare caronamide without drying and purification in the middle. The total yield of the two reactions is above 80%, and the purity of the prepared caronamide is above 89%.

[0044] By using inorganic ammonium salt, it is safe and environmentally friendly; the traditional process has three steps of reaction, and the total raw material cost is as high as 1,200 yuan / kg; the raw and auxiliary materials of the present invention are cheap and easy to obtain, no organic solvent is discharged, and the process production cost is low, which can be reduced to 50% of the traditional process.

[0045] The present invention also provides an application of caronic acid or caronamide synthesized by the above method in the field of preparing namatevir, the main antiviral ingredient of a new oral COVID-19 drug.

[0046] The beneficial effects of the present invention are:

[0047] 1. The present invention uses ozone as an oxidant to directly oxidize kungfu acid into caronic acid, and its byproduct trifluoroacetic acid can be used as an industrial raw material. The manufacturing cost of ozone oxidation in this method is only 10% of that of potassium permanganate oxidation, which reduces solid waste and embodies atom economy.

[0048] 2. In the preparation process of caron acid, both the wet caron acid product prepared by crystallization and the solid caron acid obtained by extraction can be directly used in the next step of reaction to prepare caronamide. When the wet caron acid product is directly used to prepare caronamide, the entire preparation process does not require the use of organic solvents, which reduces costs and is safe and environmentally friendly.

[0049] 3. The reaction steps for preparing caronamide from caron acid are shortened, and the two-step reaction is reduced to a one-step reaction.

[0050] 4. The total yield of the entire process route is over 80%, and the cost is reduced by 50%. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 HPLC spectrum of caronic acid prepared by the method of the present invention

[0052] Figure 2 The NMR spectrum of caronamide prepared by the method of the present invention is DETAILED DESCRIPTION

[0053] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in the art or the product instructions are used. The reagents or instruments used without specifying the manufacturer are all conventional products that can be obtained commercially.

[0054] Example 1 Preparation of Caronic Acid

[0055] Add 242.6 kg of gongfu acid and 1000 kg of water to the reactor, add 120 kg of sodium hydroxide under stirring, heat to 20°C to 40°C, continuously introduce ozone through an ozone generator, control the dissolution rate according to the temperature, keep the reaction warm for 5 to 10 hours, take a sample for TLC (developing solvent: ethyl acetate: petroleum ether = 20:1) detection, the residue is ≤0.5%, stop introducing ozone after passing the test, add concentrated hydrochloric acid dropwise to adjust pH = 1, add 1000 kg of ethyl acetate × 4 to extract four times, combine the organic layers and recover ethyl acetate under reduced pressure (apply extraction), concentrate to about 500 L, stop distillation, cool to 0°C to 20°C, filter, dry below 60°C for 5 hours, and obtain 154.5 kg of white powdery solid caron acid with a yield of 97.6%. HPLC purity: 99.6% (such as Figure 1 As shown), the titration content is 98.3%. For details, see the attached Figure 1 .

[0056] Example 2-9 Preparation of Caronic Acid

[0057] As described in Example 1, 243 g of Kung Fu acid was added, and the contents of other reagents were adjusted accordingly according to the content of Kung Fu acid. Different bases and acids were selected. The results are shown in the following table:

[0058]

[0059]

[0060] Example 10 Preparation of Caronamide

[0061] 200 kg of wet caron acid (containing 12% water, to be dried, wherein the wet caron acid is obtained by the preparation method in Example 1, except that, after the reaction, no extraction is required, and the caron acid is directly cooled and crystallized, and centrifuged to obtain the obtained product), 300 kg of water is added, stirring is started, 45 kg of ammonia is introduced from the bottom of the kettle, the temperature is controlled below 40° C., stirring and dissolving, then the temperature is increased to evaporate the water in the system, the temperature is raised to 160° C., and the reaction is performed for 5 to 10 hours. The sample is taken for control, and the residue is ≤0.5%. After the sample is qualified, 1100 kg of water is added, the mixture is cooled to 0° C. to 20° C., centrifuged and filtered, and dried at 60° C. to obtain 159.1 kg of caronamide (its nuclear magnetic spectrum is shown as follows: Figure 2 The yield was 90.41% and the HPLC purity was 99.6%.

[0062] Example 11-13 Preparation method of caronamide

[0063] As described in Example 10, 176 g of caronic acid (dry basis) was used, and different ammonium salts were selected. The results are shown in the following table:

[0064] serial number Alkali Dosage Solution concentration Yield purity Embodiment 11 Ammonium bicarbonate 200g 18％ 88.5％ 98.2％ Example 12 Ammonium carbonate 120g 10％ 87.5％ 97.5％ Embodiment 13 ammonia 180g 7％ 92.4％ 99.4％

[0065] The present invention has been described in detail above, including its preferred embodiments. However, it should be understood that, considering the disclosure of the present invention, those skilled in the art may make changes and / or improvements to the present invention within the spirit of the claims, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing caronamide, characterized in that: Includes the following: (1) adding an aqueous solution of an ammonia compound to caronic acid, controlling the temperature to 10°C to 40°C, stirring to dissolve the salt and clarify; (2) heating the reaction solution in step (1) to evaporate the water in the system, and reacting at 140° C. to 170° C. for 3 to 12 hours; (3) After the reaction is completed, water is added to dissolve the solid, and the solid is cooled and crystallized at a temperature of 0°C to 20°C to obtain caronamide.

2. The preparation method according to claim 1, characterized in that: The ammonia compound is one or more of ammonia monohydrate, ammonia gas, and ammonium salt.

3. The preparation method according to claim 2, characterized in that: The ammonium salt is one or more of ammonium carbonate, ammonium bicarbonate, ammonium sulfate and ammonium bisulfate.

4. The preparation method according to claim 3, characterized in that: The ammonium salt is ammonium carbonate or ammonium bicarbonate.

5. The preparation method according to claim 1, characterized in that: The concentration of the ammonia compound solution is 5% to 25%.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the amino compound to caronic acid is 1.0-5.0:1.0.

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