Preparation method of baloxvir intermediate

Abstract

The invention relates to a preparation method of a baloxvir intermediate, and belongs to the technical field of medicine synthesis. The preparation method comprises the following steps: reacting a compound 02 with 2-fluorobenzaldehyde in the presence of an alkaline reagent, and carrying out post-treatment to obtain a compound 03. And carrying out cyclization reaction on the compound 03 in the presence of acid to obtain a compound 04. The preparation method provided by the invention is short in reaction time, mild in reaction, easy in reagent obtaining, safe to operate, high in product yield, high in product purity, capable of reducing the cost and beneficial to industrial implementation.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and specifically to a method for preparing a baloxavir intermediate. Background Technology

[0002] Baloxavir (BAL) is a novel anti-influenza drug developed by Shionogi Pharmaceutical Co., Ltd. of Japan in collaboration with Roche. It targets influenza A and B viruses, including oseltamivir-resistant strains and avian influenza strains (H7N9, H5N1). Baloxavir works by inhibiting cap-dependent endonucleases in the influenza virus. The molecular structure of baloxavir is shown below:

[0003]

[0004] Patent application JP6212678B1 discloses a method for preparing baloxavir from compound A:

[0005]

[0006] The synthetic route for compound A is as follows:

[0007]

[0008] In the synthetic route, the first step reaction uses n-butyllithium. n-butyllithium is sensitive to air and water and can react violently with them, even causing combustion or explosion. During the experimental operation, it is necessary to ensure that the entire system is anhydrous and oxygen-free. The reaction conditions are harsh and pose great safety hazards. In addition, the entire synthesis process also uses malodorous and highly toxic benzenethiophenol. This compound is a controlled substance in China and is not suitable for industrial scale-up production.

[0009] Later, several patents reported improved methods for this route. For example, Chinese patent application CN115677656A reported a three-step synthesis of 7,8-difluorodibenzo[b,e]thiaheptacyclo-11(6H)-ol from 6-bromo-2,3-difluorotoluene as a starting material. The synthetic route is as follows:

[0010]

[0011] This preparation method discloses a bromination reaction using 6-bromo-2,3-difluorotoluene as a starting material under bromine and initiator conditions to obtain 6-bromo-2,3-difluorobenzyl bromide. The 6-bromo-2,3-difluorobenzyl bromide then undergoes a substitution reaction under alkaline conditions and with 2-mercaptobenzaldehyde to obtain 3,4-difluoro-2-(((2-benzaldehyde))thio)methyl)-benzyl bromide. Finally, the 3,4-difluoro-2-(((2-benzaldehyde))thio)methyl)-benzyl bromide undergoes a nucleophilic addition reaction in the presence of an alkaline environment to achieve the baloxavir intermediate 7,8-difluorodibenzo[b,e]thiaheptacyclo-11(6H)-ol. The first two steps require reflux, resulting in high reaction temperatures and excessively long reaction times. The third step requires specific low-temperature conditions, demanding sophisticated equipment and increasing operational complexity, making it unsuitable for industrial-scale production.

[0012] Therefore, it is still necessary to study a method for preparing baloxavir intermediates to obtain a method that is simple to operate, easy to implement, has high yield, high purity, low cost, and is environmentally friendly. Summary of the Invention

[0013] To address the aforementioned technical problems, this invention provides a method for preparing a baloxavir intermediate.

[0014] In a first aspect, the present invention provides a method for preparing compound O3, comprising:

[0015]

[0016] In the presence of an alkaline reagent, compound O2 and 2-fluorobenzaldehyde undergo a coupling reaction in a solvent to give compound O3;

[0017] The alkaline reagent includes at least one of sodium hydroxide (NaOH), sodium carbonate (Na2CO3), and potassium carbonate (K2CO3).

[0018] In some embodiments, the alkaline reagent is potassium carbonate (K2CO3).

[0019] In some embodiments, the solvent in the coupling reaction includes at least one of methanol, ethanol, and N,N-dimethylformamide (DMF).

[0020] In some embodiments, the reaction temperature of the coupling reaction is 15°C to 100°C. In some embodiments, the reaction temperature of the coupling reaction is 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, or 100°C. In some preferred embodiments, the reaction temperature of the coupling reaction is 30°C to 80°C. In some more preferred embodiments, the reaction temperature of the coupling reaction is 60°C.

[0021] In some embodiments, the molar ratio of compound O2 to 2-fluorobenzaldehyde is 1.0:(1.0 to 2.0). In some embodiments, the molar ratio of compound O2 to 2-fluorobenzaldehyde is 1.0:1.0, 1.0:1.5, or 1.0:2.0.

[0022] In some embodiments, the molar ratio of compound O2 to alkaline reagent is 1.0:(0.5-2.5). In some embodiments, the molar ratio of compound O2 to alkaline reagent is 1.0:0.5, 1.0:1.0, 1.0:1.5, 1.0:2.0, or 1.0:2.5. In some preferred embodiments, the molar ratio of compound O2 to alkaline reagent is 1.0:(1.0-2.0). In some more preferred embodiments, the molar ratio of compound O2 to alkaline reagent is 1.0:1.5.

[0023] In some embodiments, the preparation method of compound 03 further includes a post-processing step after the coupling reaction is completed, the post-processing step including: vacuum drying, adding water to crystallize, filtering, and drying the filter cake.

[0024] Secondly, the present invention provides a method for preparing compound O4, comprising:

[0025]

[0026] In the presence of acid, compound 03 undergoes a cyclization reaction in a solvent to give compound 04.

[0027] In some embodiments, the acid includes at least one of trifluoroacetic acid (TFA) and trifluoromethanesulfonic acid (TfOH).

[0028] In some embodiments, the solvent for the cyclization reaction includes trifluoroacetic acid (TFA).

[0029] In some embodiments, the cyclization reaction temperature is 40°C to 80°C. In some embodiments, the cyclization reaction temperature is 40°C, 50°C, 60°C, 70°C, or 80°C.

[0030] In some embodiments, the molar ratio of compound O3 to acid is 1.0:(0.5-1.5), for example, it can be 1.0:0.5, 1.0:0.6, 1.0:0.7, 1.0:0.8, 1.0:0.9, 1.0:1.0, 1.0:1.1, 1.0:1.2, 1.0:1.3, 1.0:1.4 or 1.0:1.5.

[0031] In some embodiments, the preparation method of compound 04 further includes a post-processing step, which includes: cooling, ice-water bath crystallization and pulping, filtration, and drying.

[0032] In some embodiments, the method for preparing compound 04 further includes the preparation of compound 03: preparing compound 03 according to the preparation method described in the first aspect.

[0033] In some embodiments, the method for preparing compound 03 further includes a method for synthesizing compound 02.

[0034]

[0035] Compound 01 reacts with potassium thioacetate in a solvent under nitrogen or inert gas atmosphere to give compound 02.

[0036] In some embodiments, the molar ratio of compound O1 to potassium thioacetate is 1.0:(1.1 to 2.0). In some embodiments, the molar ratio of compound O1 to potassium thioacetate is 1.0:1.1, 1.0:1.2, 1.0:1.3, 1.0:1.4, 1.0:1.5, 1.0:1.6, 1.0:1.7, 1.0:1.8, 1.0:1.9, or 1.0:2.0.

[0037] In some embodiments, the solvent includes at least one of N,N-dimethylformamide, acetone, methanol, and ethanol.

[0038] In some embodiments, the reaction temperature of the method for synthesizing compound O2 is 15°C-35°C. In some embodiments, the reaction temperature of the method for synthesizing compound O2 is 15°C, 20°C, 25°C, 30°C, or 35°C.

[0039] In some embodiments, the synthesis method of compound O2 further includes a post-processing step, which includes: adding water and ethyl acetate, extraction, separation, washing the resulting ethyl acetate layer with a saturated sodium chloride aqueous solution, and evaporating under reduced pressure.

[0040] Thirdly, the present invention provides a compound that is a compound of Formula 03 or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

[0041]

[0042] Beneficial effects

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] (1) A new and efficient synthetic method for preparing compound O4 is provided, which reduces the multi-step reaction in the prior art to 3 steps and reduces the cost;

[0045] (2) The present invention uses compound 01 as the starting material, which avoids the use of expensive reagents, and the reaction temperature is mild and there are no highly toxic or polluting reagents, which is conducive to industrial production.

[0046] (3) The product obtained by the method provided by the present invention has high yield and high purity.

[0047] Terminology Explanation

[0048] In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0049] The term “room temperature” refers to ambient temperature, which is between approximately 10°C and approximately 30°C, or approximately 20°C and 30°C, or approximately 25°C.

[0050] In the description of this invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this invention, "a plurality of" means two or more, unless otherwise explicitly specified.

[0051] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0052] In the following content, all figures disclosed herein, whether or not they use words such as "approximately" or "about," are approximate values. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%, etc. Whenever a figure with a value of N is disclosed, any figure with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% will be explicitly disclosed, where "+ / -" indicates addition or subtraction. Detailed Implementation

[0053] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0054] All reagents used in this invention can be purchased from the market, prepared by existing technology or conventional means, or prepared by the methods described in this invention.

[0055] DMF stands for N,N-dimethylformamide. EA stands for ethyl acetate. TFA stands for trifluoroacetic acid. TfOH stands for trifluoromethanesulfonic acid. TLC stands for thin-layer chromatography.

[0056] Example 1: Synthesis of Compound O2

[0057]

[0058] 30.0 g of 2,3-difluorobenzyl bromide, 24.7 g of potassium thioacetate, and 90 mL of DMF were mixed and reacted at room temperature under nitrogen protection with stirring. The reaction was monitored by TLC until the reactants were completely reacted. 450 mL of water was added, followed by extraction with 450 mL of ethyl acetate (EA). The EA layer was washed once with saturated NaCl solution, and then evaporated under reduced pressure to obtain 29.3 g of a yellow oily substance, with a yield of 100% and a purity of 98.74%. LC-MS: m / z (ESI): 203.1 (M+H) + . 1 H NMR (599MHz, DMSO) δ7.32(dtd,J=9.9,8.1,1.7Hz,1H),7.22(dd,J=7.7,6.4Hz,1H),7.19–7.12(m,1H),4.18(d,J=0.9Hz,2H),2.36(s,3H).

[0059] Example 2: Synthesis of Compound 03

[0060]

[0061] 29.3 g of 2,3-difluorobenzyl thioacetate, 21.6 g of o-fluorobenzaldehyde, 30.0 g of potassium carbonate, and 300 mL of methanol were mixed and heated to 60 °C. The reaction was monitored by TLC until the reactants had completely reacted. The mixture was cooled to room temperature, and the MeOH was evaporated under reduced pressure. 300 mL of water was added dropwise to the system, and crystals were precipitated at room temperature. The crystals were filtered, washed with water, and dried under vacuum at 50 °C to give 35.61 g of an off-white solid, with a yield of 93.0% and a purity of 99.33%. LC-MS: m / z (ESI): 265.1 (M+H) + .

[0062] 1 H NMR (599MHz, DMSO) δ10.13(s,1H),7.90(dd,J=7.6,1.5Hz,1H),7.69–7.63(m,1H),7.61(d,J=7.5Hz,1H),7.44( td,J=7.5,1.0Hz,1H),7.35(dtd,J=9.7,8.1,1.5Hz,1H),7.23(t,J=7.1Hz,1H),7.18–7.12(m,1H),4.33(s,2H).

[0063] Example 3: Synthesis of Compound 03

[0064]

[0065] 5.0 g of 2,3-difluorobenzyl thioethyl acetate, 3.7 g of o-fluorobenzaldehyde, 5.1 g of potassium carbonate, and 50 mL of ethanol were mixed and heated to 60 °C. The reaction was monitored by TLC until the reactants were completely reacted. The mixture was then cooled to room temperature, and EtOH was evaporated under reduced pressure. 50 mL of water was added dropwise to the system, and crystals were precipitated at room temperature. The crystals were filtered, washed with water, and dried under vacuum at 50 °C to give 5.98 g of an off-white solid, with a yield of 91.5% and a purity of 99.1%.

[0066] Example 4: Synthesis of Compound 03

[0067]

[0068] 5.0 g of 2,3-difluorobenzyl thioacetate, 3.7 g of o-fluorobenzaldehyde, 5.1 g of potassium carbonate, and 25 mL of LDM were mixed and heated to 60 °C. The reaction was monitored by TLC until the reactants were completely reacted. The mixture was then cooled to room temperature, and 120 mL of water was added dropwise. The mixture was cooled to 10 °C to induce crystallization. After filtration and rinsing with water, the crystals were dried under vacuum at 50 °C to obtain 5.26 g of an off-white solid, with a yield of 80.5% and a purity of 99.5%.

[0069] Example 4: Synthesis of Compound 04

[0070]

[0071] 20 g of 2-((2,3-difluorobenzyl)thio)benzaldehyde was mixed with 120 mL of TFA and 120 g of TfOH in an ice-water bath. The mixture was heated to 50-60 °C and stirred. The mixture was spotted by TLC. After the reaction was complete, the mixture was cooled to room temperature and poured into an ice-water bath to crystallize. The crystals were filtered and dried under vacuum at 50 °C to obtain 17.2 g of a yellowish-brown solid, with a yield of 86.0% and a purity of 99.7%. LC-MS: m / z (ESI): 287.0 (M+Na) + .

[0072] 1 H NMR (599MHz, CDCl3) δ7.53–7.44(m,1H),7.26–7.18(m,2H),7.18–7.11(m,2H),7.09–6.99(m, 1H), 6.11 (d, J = 3.1Hz, 1H), 4.69 (d, J = 14.5Hz, 1H), 4.28–4.16 (m, 1H), 2.83 (d, J = 3.5Hz, 1H).

[0073] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for preparing compound O3, characterized in that, include: In the presence of an alkaline reagent, compound O2 and 2-fluorobenzaldehyde undergo a coupling reaction in a solvent to yield compound O3; wherein the alkaline reagent includes at least one of sodium hydroxide, sodium carbonate, and potassium carbonate.

2. The preparation method according to claim 1, wherein the alkaline reagent is potassium carbonate.

3. The preparation method according to any one of claims 1-2, wherein the solvent in the coupling reaction comprises at least one of methanol, ethanol, and N,N-dimethylformamide; Optionally, the reaction temperature of the coupling reaction is 15°C to 100°C, preferably 30°C to 80°C, and more preferably 60°C.

4. The preparation method according to any one of claims 1-3, wherein the molar ratio of compound O2 to 2-fluorobenzaldehyde is 1.0:(1.0-2.0); Optionally, the molar ratio of compound O2 to alkaline reagent is 1.0:(0.5-2.5), preferably 1.0:(1.0-2.0), and more preferably 1.0:1.

5.

5. The preparation method according to claim 1, wherein the preparation method of compound O3 further includes a post-processing step after the coupling reaction is completed, the post-processing step including: Reduced pressure evaporation, water addition for crystallization, filtration, and drying of the filter cake.

6. A method for preparing compound O4, characterized in that, include: In the presence of acid, compound 03 undergoes a cyclization reaction in a solvent to give compound 04.

7. The preparation method according to claim 6, wherein the acid comprises at least one of trifluoroacetic acid and trifluoromethanesulfonic acid; Optionally, the solvent for the cyclization reaction includes trifluoroacetic acid; Optionally, the reaction temperature of the cyclization reaction is 40°C to 80°C; Optionally, the molar ratio of compound O3 to the acid is 1.0:(0.5-1.5); Optionally, the method for preparing compound 04 further includes a post-processing step, the post-processing step comprising: Cool down, crystallize and pulp in an ice-water bath, filter, and dry.

8. The method for preparing compound 04 according to any one of claims 6-7 further includes the preparation of compound 03: compound 03 is prepared according to the method according to any one of claims 1-5.

9. The preparation method according to any one of claims 1-8, wherein the preparation method of compound 03 further includes a method for synthesizing compound 02. Under a nitrogen or inert gas atmosphere, compound 01 reacts with potassium thioacetate in a solvent to give compound 02; optionally, the molar ratio of compound 01 to potassium thioacetate is 1.0:(1.1 to 2.0). Optionally, the solvent includes at least one selected from N,N-dimethylformamide, acetone, methanol, and ethanol, preferably N,N-dimethylformamide. Dimethylformamide; Optionally, the reaction temperature of the method for synthesizing compound O2 is 15°C-35°C; Optionally, the method for synthesizing compound O2 further includes a post-processing step, the post-processing comprising: Add water and ethyl acetate, extract, separate the layers, wash the resulting ethyl acetate layer with sodium chloride aqueous solution, and evaporate to dryness under reduced pressure.

10. A compound that is a compound of Formula 03 or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof.

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