阅读说明：本技术 一种巴洛沙韦中间体的制备方法 (Preparation method of Barosavir intermediate ) 是由 寇景平 王仲清 刘诗雨 廖高鸿 周自洪 巫锡伟 于 2019-11-27 设计创作，主要内容包括：本发明涉及一种巴洛沙韦中间体的制备方法,属于药物化学领域。本发明提供一种巴洛沙韦中间体式E化合物和式D化合物的制备方法。式E化合物的制备方法包括以下步骤：以式A化合物为溶剂,以碱为缚酸剂,在含钯催化剂的作用下式B化合物与一氧化碳和式A化合物在加压条件下发生反应,经过后处理,得到式E化合物。式D化合物的制备方法包括以下步骤：在催化剂的存在下,在含水和可与水互溶的有机溶剂的混合溶剂中,式E化合物发生水解反应,经过后处理,得到式D化合物。本发明制备巴洛沙韦中间体的方法具有安全、反应条件温和、易于操作等优点。(The invention relates to a preparation method of a baroxavir intermediate, belonging to the field of pharmaceutical chemistry. The invention provides a preparation method of a baloxavir intermediate compound shown as a formula E and a compound shown as a formula D. The preparation method of the compound of the formula E comprises the following steps: taking a compound in a formula A as a solvent, taking alkali as an acid-binding agent, reacting a compound in a formula B with carbon monoxide and a compound in a formula A under the action of a palladium-containing catalyst under a pressurized condition, and carrying out aftertreatment to obtain a compound in a formula E. The preparation method of the compound of the formula D comprises the following steps: in the presence of a catalyst, in a mixed solvent containing water and a water-miscible organic solvent, the compound of the formula E undergoes a hydrolysis reaction, and the compound of the formula D is obtained after post-treatment. The invention prepares the BarosavirThe intermediate method has the advantages of safety, mild reaction conditions, easy operation and the like.)

1. A process for the preparation of a compound of formula (E),

the method comprises the following steps: taking a compound of a formula (A) as a solvent, taking alkali as an acid-binding agent, reacting a compound of a formula (B) with carbon monoxide and a compound of a formula (A) under the action of a palladium-containing catalyst under a pressurized condition, and carrying out aftertreatment to obtain a compound of a formula (E), wherein R is₂Is of the general formula C_xH_yOr C_xH_yOH, x is an integer of 1 or more, y is an integer of 1 or more, R₁Selected from the group consisting of chlorine, bromine, iodine, mesylate, p-toluenesulfonate, and ethanesulfonate.

2. The method of claim 1, wherein the reaction temperature of the reaction is 65 ℃ to 105 ℃, or the reaction temperature of the reaction is 75 ℃ to 95 ℃, or the reaction temperature of the reaction is 85 ℃.

3. The method according to claim 1, wherein the compound of formula (a) is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, benzyl alcohol; the adding volume of the compound of the formula (A) is 1-100 times of the weight of the compound of the formula (B); or the adding volume of the compound of the formula (A) is 2-50 times of the weight of the compound of the formula (B); or the adding volume of the compound of the formula (A) is 5-20 times of the weight of the compound of the formula (B).

4. The process according to claim 1, wherein the base is selected from at least one of triethylamine, pyridine, piperidine, morpholine, N-diisopropylethylamine, ethanolamine, aqueous ammonia, diethylamine, N-methylmorpholine, tetrahydropyrrole, N-methyltetrahydropyrrole, N-methylpiperidine, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium oxide, magnesium oxide, calcium hydroxide, magnesium hydroxide; the feeding molar ratio of the alkali to the compound of the formula (B) is 0.1:1-10: 1; or the feeding molar ratio of the alkali to the compound of the formula (B) is 0.5:1-8: 1; or the feeding molar ratio of the alkali to the compound of the formula (B) is 1:1-5: 1.

5. The method of claim 1, wherein the palladium-containing catalyst is selected from at least one of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, dichlorodiphenylphosphinepalladium, tetratriphenylphosphinepalladium, palladium acetate, dichlorodiphenylnitrile palladium, palladium on carbon; the molar ratio of the palladium catalyst to the compound of formula (B) is 0.005:1-0.1: 1; or the feeding molar ratio of the palladium catalyst to the compound of the formula (B) is 0.01:1-0.05: 1.

6. a process for the preparation of a compound of formula (D),

the method comprises the following steps: in the presence of a catalyst, in a mixed solvent containing water and a water-miscible organic solvent, carrying out hydrolysis reaction on the compound of the formula (E), and carrying out post-treatment to obtain the compound of the formula (D), wherein R₂Is of the general formula C_xH_yOr C_xH_yOH, x is an integer of 1 or more, and y is an integer of 1 or more.

7. The method of claim 6, wherein the catalyst is selected from at least one of hydroxides, basic carbonates, and basic oxides.

8. The method according to claim 7, wherein the hydroxide is selected from at least one of sodium hydroxide or lithium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide and magnesium hydroxide, the basic carbonate is selected from at least one of lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, and the basic oxide is selected from at least one of calcium oxide and magnesium oxide.

9. The method according to claim 6, wherein the organic solvent is at least one selected from the group consisting of methanol, tetrahydrofuran, ethanol, N-propanol, isopropanol, dioxane, N-dimethylformamide, N-methylpyrrolidone, and dimethylsulfoxide.

10. The method of claim 6, wherein the reaction temperature of the reaction is 0 ℃ to 50 ℃, or the reaction temperature of the reaction is 10 ℃ to 40 ℃, or the reaction temperature of the reaction is 20 ℃ to 30 ℃.

Technical Field

The invention relates to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a baroxavir 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 (Baloxavir marboxil) is an innovative Cap-dependent endonuclease inhibitor developed by Japan salt wild-sense pharmaceuticals (Shionogi) for the treatment of influenza A and influenza B. The treatment has the advantages of short administration time and long treatment time. The chemical structural formula is as follows:

the synthesis method of the compound is less disclosed, wherein the document Journal of medical Chemistry,2013,56(6):2218-2234 and the document Organic Process Research and Development,2015,19(7):721-734 disclose a synthesis method for preparing the baroxavir intermediate 3, 4-difluoro-2-methylbenzoic acid: the route takes a compound 1 as a substrate, and prepares 3, 4-difluoro-2-methylbenzoic acid by bromination, Grignard reagent exchange and carbon dioxide addition. The route requires the use of highly active grignard reagents, and the reaction safety is poor, limiting the industrial application thereof. The reaction scheme is as follows:

in addition, the Journal of Heterocyclic Chemistry,27(6), 1609-: reacting compound 2 as a substrate with n-butyllithium at-78 ℃, and then adding carbon dioxide. The method uses butyl lithium reagent with extremely high activity and needs a low-temperature environment of-78 ℃, the reaction safety is poor, the equipment requirement is high, and the industrial amplification is not facilitated. The reaction scheme is as follows:

in summary, the following technical problems exist in the prior art for synthesizing the baroxavir intermediate:

(1) the reaction safety is poor;

(2) the reaction conditions are harsh, the equipment requirement is high, and the industrial scale-up production is not facilitated.

Therefore, it is very necessary to develop a synthesis method of the baroxavir intermediate with high safety, mild reaction conditions and low equipment requirements.

Disclosure of Invention

In one aspect, the invention provides a preparation method of a baloxavir intermediate compound shown as a formula E, which comprises the following steps:

the preparation method comprises the following steps of taking a compound shown as a formula (A) as a solvent, taking alkali as an acid-binding agent, reacting a compound shown as a formula (B) with carbon monoxide and the compound shown as the formula (A) under the action of a palladium-containing catalyst under a pressurized condition, and carrying out aftertreatment to obtain a compound shown as a formula (E), wherein R is₂The general formula of (A) is CxHy or CxHyOH, x is an integer of more than 1, y is an integer of more than 1, and R1 is selected from chlorine, bromine, iodine, mesylate, p-toluenesulfonate and ethanesulfonate.

In some embodiments, the reaction temperature of the reaction is from 65 ℃ to 105 ℃.

In some embodiments, the reaction temperature of the reaction is from 75 ℃ to 95 ℃.

In some embodiments, the reaction temperature of the reaction is 85 ℃.

In some embodiments, the compound of formula a is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, benzyl alcohol.

In some embodiments, the compound of formula a is added in a volume 1 to 100 times the weight of the compound of formula B.

In some embodiments, the compound of formula a is added in a volume that is 2-50 times the weight of the compound of formula B.

In some embodiments, the compound of formula a is added in a volume 5 to 20 times the weight of the compound of formula B.

In some embodiments, the base is selected from at least one of triethylamine, pyridine, piperidine, morpholine, N-diisopropylethylamine, ethanolamine, ammonia, diethylamine, N-methylmorpholine, tetrahydropyrrole, N-methyltetrahydropyrrole, N-methylpiperidine, lithium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium oxide, magnesium oxide, calcium hydroxide, magnesium hydroxide.

In some embodiments, the base to compound of formula B is charged in a molar ratio of 0.1:1 to 10: 1.

In some embodiments, the base to compound of formula B is charged in a molar ratio of 0.5:1 to 8: 1.

In some embodiments, the base is dosed at a molar ratio to the compound of formula B of 1:1 to 5: 1.

In some embodiments, the palladium-containing catalyst is selected from at least one of [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, dichlorobistriphenylphosphine palladium, tetratriphenylphosphine palladium, palladium acetate, dichlorodiphenylnitrile palladium, palladium on carbon hydroxide.

In some embodiments, the molar ratio of the palladium catalyst to the compound of formula B charged is from 0.005:1 to 0.1: 1.

In some embodiments, the molar ratio of the palladium catalyst to the compound of formula B charged is from 0.01:1 to 0.05: 1.

In some embodiments, the reaction pressure of the reaction is between 0.5Mpa and 5 Mpa.

In some embodiments, the reaction pressure of the reaction is between 1Mpa and 4 Mpa.

In some embodiments, the reaction pressure of the reaction is between 2Mpa and 3 Mpa.

In some embodiments, the post-treatment comprises spin-drying the solvent, extraction, purification.

In another aspect, the invention also provides a preparation method of the baroxavir intermediate compound shown in the formula D, which comprises the following steps:

the preparation method comprises the following steps: in the presence of a catalyst, in a mixed solvent containing water and a water-miscible organic solvent, carrying out hydrolysis reaction on the compound of the formula E, and carrying out post-treatment to obtain a compound of a formula D, wherein R is₂The general formula of (A) is CxHy or CxHyOH, x is an integer of more than 1, and y is an integer of more than 1.

In some embodiments, the catalyst is selected from at least one of hydroxides, basic carbonates, basic oxides.

In some embodiments, the hydroxide is selected from at least one of sodium or lithium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide.

In some embodiments, the molar ratio of the hydroxide to the compound of formula E charged is from 0.5:1 to 6: 1.

In some embodiments, the molar feed ratio of the hydroxide to the compound of formula E is from 1:1 to 5: 1.

In some embodiments, the feed molar ratio of the hydroxide to the compound of formula E is from 1.5:1 to 3: 1.

In some embodiments, the water is added in a volume of 0.5 to 40 times the weight of the compound of formula E.

In some embodiments, the water is added in a volume 1 to 20 times the weight of the compound of formula E.

In some embodiments, the water is added in a volume of 2 to 10 times the weight of the compound of formula E.

In some embodiments, the water is added in a volume 4 to 8 times the weight of the compound of formula E.

In some embodiments, the basic carbonate is selected from at least one of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate.

In some embodiments, the basic oxide is selected from at least one of calcium oxide, magnesium oxide.

In some embodiments, the organic solvent is selected from at least one of methanol, tetrahydrofuran, ethanol, N-propanol, isopropanol, dioxane, N-dimethylformamide, N-methylpyrrolidone, and dimethylsulfoxide.

In some embodiments, the organic solvent is added in a volume of 0.5 to 40 times the weight of the compound of formula E.

In some embodiments, the organic solvent is added in a volume 1 to 20 times the weight of the compound of formula E.

In some embodiments, the organic solvent is added in a volume of 2 to 10 times the weight of the compound of formula E.

In some embodiments, the organic solvent is added in a volume 4 to 8 times the weight of the compound of formula E.

In some embodiments, the reaction temperature of the reaction is from 0 ℃ to 50 ℃.

In some embodiments, the reaction temperature of the reaction is from 10 ℃ to 40 ℃.

In some embodiments, the reaction temperature of the reaction is from 20 ℃ to 30 ℃.

In some embodiments, the post-treatment comprises spin-drying the solvent under reduced pressure, adding acid dropwise to adjust the pH to precipitate the product, cooling, stirring, crystallizing, filtering, washing the filter cake with water, and drying the filter cake.

The beneficial technical effects of the invention comprise:

(1) active organic metal reagents (n-butyllithium, Grignard reagents and the like) are avoided, and the reaction condition is relatively mild, safe and easy to operate.

(2) The route does not use a high-activity Grignard reagent, the reaction is safer, and a sulfuric acid-dibromo hydantoin bromination system is used in the first step, so that a large amount of metal salts generated in the post-treatment process by using Lewis acid are avoided; and the damage of a large amount of bromine steam to people during operation is avoided by improving the bromine source.

(3) The use of active reagents such as butyl lithium and the like is avoided, the safety of the process is improved, and the extreme reaction condition of ultralow temperature of-78 ℃ is avoided, so that the industrial amplification feasibility of the method is greatly improved.

Description of terms:

"the volume of the compound of the formula (A) added is 1 to 100 times the weight of the compound of the formula (B)", which means that 1ml to 100ml of the compound of the formula (A) is added per gram of the compound of the formula (B), and other times the volume is defined as the same. g means g, mg means mg, DEG C means centigrade, h means h, mL means mL, min means min, HPLC means high performance liquid chromatography, pH means pH, Mpa means MPa, CO means carbon monoxide, Pd (dppf) Cl₂Represents [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, MeOH for methanol, TEA for triethylamine, DIPEA for N, N-diisopropylethylamine, H₂O represents water, THF represents tetrahydrofuran, KOH represents potassium hydroxide, and LiOH represents lithium hydroxide.

In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

In the present invention, the expression "compound a" and "compound represented by formula a" means the same compound.

Detailed Description

EXAMPLE 1 preparation of a Compound of formula G

10.00g of the compound of formula F, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride 0.70g, methanol 100ml, triethylamine 9.77g and carbon monoxide are added into an autoclave at room temperature to replace the air in the autoclave for 3 times, the pressure is increased to 1.0Mpa, the internal temperature is 85 ℃, and the reaction is stirred until no raw material is detected by HPLC. Cooling the autoclave to room temperature, discharging carbon monoxide, spin-drying to recover the solvent, adding 50ml of water into the spin-dried product, extracting the water layer with toluene for 20ml times and 3 times, combining the organic layers, and distilling and purifying the product under reduced pressure to obtain 7.93G of the compound shown in the formula G, wherein the yield is 88.2 percent, and the purity is 97.1 percent. MS: [ M +1] ═ 187.1, 1H NMR (400MHz, DMSO-d6): delta 7.66(M,1H),7.22(M,1H),3.85(s,3H),2.43(s,3H).

EXAMPLE 2 preparation of the Compound of formula G

10.00g of the compound of the formula F, 0.67g of palladium tetratriphenylphosphine, 100ml of methanol, 12.48g of DIPEA and carbon monoxide are added into an autoclave at room temperature to replace air in the autoclave for 3 times, the pressure is increased to 1.0Mpa, and the reaction is stirred at the internal temperature of 85 ℃ until no raw material is detected by HPLC. Cooling the autoclave to room temperature, discharging carbon monoxide, spin-drying to recover the solvent, adding 50ml of water into the spin-dried product, extracting the water layer by 20ml × 3 times by toluene, combining the organic layers, and distilling under reduced pressure to purify the product. 57.69G of the compound of formula G is obtained with 85.5% yield and 95.3% purity.

EXAMPLE 3 preparation of a Compound of formula G

10.00g of the compound of the formula F, 0.37g of palladium dichlorodicyanide, 80ml of methanol, 9.77g of N-methylmorpholine and carbon monoxide are added into an autoclave at room temperature, the air in the autoclave is replaced by the carbon monoxide for 3 times, the pressure is increased to 1.0MPa, the internal temperature is 85 ℃, and the mixture is stirred and reacted until no raw material is detected by HPLC. Cooling the autoclave to room temperature, discharging carbon monoxide, spin-drying to recover the solvent, adding 50ml of water into the spin-dried product, extracting the water layer by 20ml × 3 times by toluene, combining the organic layers, and distilling under reduced pressure to purify the product. 5.91G of the compound shown in the formula G is obtained, the yield is 65.7%, and the purity is 92.2%.

EXAMPLE 4 preparation of the Compound of formula H

10.00g of the compound of the formula F, 1.12g of palladium tetratriphenylphosphine, 100ml of ethanol, 9.70g of N-methylpiperidine and carbon monoxide are added into an autoclave at room temperature to replace the air in the autoclave for 3 times, the pressure is increased to 1.0MPa, and the reaction is stirred at the internal temperature of 85 ℃ until no raw material is detected by HPLC. Cooling the autoclave to room temperature, discharging carbon monoxide, spin-drying to recover the solvent, adding 50ml of water into the spin-dried product, extracting the water layer by 20ml × 3 times by toluene, combining the organic layers, and distilling under reduced pressure to purify the product. 8.12g of the compound shown in the formula H is obtained, the yield is 83.9 percent, and the purity is 94.2 percent.

EXAMPLE 5 preparation of the Compound of formula D

Adding 4.30G of sodium hydroxide, 30ml of water and 30ml of methanol into a reaction bottle at room temperature, stirring and dissolving for 10min at room temperature, adding 10.00G of the compound G into the reaction solution, and stirring and reacting at room temperature until no raw material exists by HPLC detection. And (3) decompressing and removing the methanol, dropwise adding an HCl solution with the concentration of 2mol/L into the water while stirring to adjust the pH value to be 3, wherein the reaction solution is turbid, the product is separated out, stirring and crystallizing for 2 hours at 10 ℃, performing suction filtration, washing the filter cake for 10ml multiplied by 2 times, and drying the filter cake to obtain the product, namely the compound of the formula D, 9.03g, the yield is 97.7 percent, and the purity is 98.5 percent. MS: [ M-1] ═ 171.0, nuclear magnetic 1H NMR (400MHz, DMSO-d6): δ 13.3(s,1H),7.71(M,1H),7.35(M,1H),2.48(s,3H).

EXAMPLE 6 preparation of the Compound of formula D

Adding 4.30G of sodium hydroxide, 30ml of water and 30ml of THF into a reaction bottle at room temperature, stirring and dissolving for 10min at room temperature, adding 10.00G of the compound of the formula G into the reaction liquid, and stirring and reacting at room temperature until no raw material exists in HPLC detection. And (3) reducing pressure, removing THF, dropwise adding 2mol/L HCl solution into water while stirring to adjust the pH value to be 3, wherein the reaction solution is turbid, precipitating a product, stirring at 10 ℃ for crystallization for 2 hours, carrying out suction filtration, washing a filter cake by 10ml × 2 times, and drying the filter cake. 8.84g of the compound of the formula D is obtained, the yield is 95.6%, and the purity is 98.2%.

EXAMPLE 7 preparation of the Compound of formula D

Adding 6.03G of potassium hydroxide, 30ml of water and 30ml of ethanol into a reaction bottle at room temperature, stirring and dissolving for 10min at room temperature, adding 10.00G of the compound G into the reaction solution, and stirring and reacting at room temperature until no raw material exists by HPLC detection. And (3) reducing the pressure, removing the ethanol by rotation, dropwise adding 2mol/L HCl solution into the water while stirring to adjust the pH value to be 3, wherein the reaction solution is turbid, precipitating the product, stirring at 10 ℃ for crystallization for 2 hours, carrying out suction filtration, washing the filter cake by 10ml × 2 times, and drying the filter cake. 8.88g of the compound shown in the formula D is obtained, the yield is 96.1%, and the purity is 96.7%.

EXAMPLE 8 preparation of the Compound of formula D

2.60G of lithium hydroxide, 30ml of water and 30ml of dioxane are added into a reaction bottle at room temperature, stirred and dissolved for 10min at room temperature, and then 10.00G of the compound of the formula G is added into the reaction liquid, stirred and reacted at room temperature until no raw material is detected by HPLC. And (3) reducing pressure, removing ethanol, dropwise adding 2mol/L HCl solution into water while stirring to adjust the pH value to be 3, wherein the reaction solution is turbid, separating out a product, stirring at 10 ℃ for crystallization for 2 hours, carrying out suction filtration, washing a filter cake for 10ml 2 times, and drying the filter cake. 8.55g of the compound shown in the formula D is obtained, the yield is 92.5%, and the purity is 97.4%.

While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.