Method for manufacturing pranoprofen and composition containing pranoprofen and impurities

Abstract

The present invention belongs to the field of medicine and relates to a method for manufacturing pranoprofen. The present invention also relates to a composition containing pranoprofen and impurities, a quality control method, an intermediate compound for the synthesis of pranoprofen, and a method for manufacturing the same. The method of the present invention overcomes the defects of the prior art, shortens the synthesis route, lowers requirements for process conditions, simplifies process operation, improves labor safety, is more suitable for industrial production, is environmentally friendly, and has a higher yield.

Description

Technology Field

[0001] The present invention belongs to the field of medicine and relates to a method for manufacturing pranoprofen. The present invention also relates to a composition containing pranoprofen and impurities, a quality control method, an intermediate compound for synthesizing pranoprofen, and a method for manufacturing the same. The intermediate compound is selected from the group consisting of a compound represented by Formula I or a pharmaceutically acceptable salt or ester thereof, a compound represented by Formula II or a pharmaceutically acceptable salt or ester thereof, a compound represented by Formula III or a pharmaceutically acceptable salt or ester thereof, and a compound represented by Formula IV or a pharmaceutically acceptable salt or ester thereof. Background Technology

[0002] Pranoprofen is a propionic acid-based non-steroidal anti-inflammatory drug (NSAID) developed and listed by Yoshitomiyakuhin Corporation in 1981; subsequently, it was developed in the form of eye drops by Senju Pharmaceutical Co., Ltd. and listed in Japan in 1988 under the trade name Pranopulin; it is used for the symptomatic treatment of inflammation of the external and anterior eye (blepharitis, conjunctivitis, keratitis, scleritis, superficial scleritis, iridocyclitis, and postoperative inflammation). Pranoprofen belongs to the propionic acid class of NSAIDs, and its chemical name is as follows: (2 RS)-2-(10-hydrogen-9-oxa-1-aza-anthracen-6-yl)propionic acid, and CAS registration number: 52549-17-4. The effect of pranoprofen is stronger than that of aspirin, indomethacin, and ibuprofen. Its mechanism of action is to exert pharmacological effects by blocking the function of inflammatory mediators by inhibiting the activity of cyclooxygenase, blocking the synthesis of eicosatetraene acid derivatives, and reducing the synthesis of prostaglandins.

[0003] The structural formula of pranopropene is represented by the following chemical formula 0:

[0004]

[0005] There are many reports on the synthesis of pranopropene, and the main difference is that various methods are used to establish the side chains of pranopropene, which are specifically listed as follows:

[0006] Route 1: This is based on the concept of rearrangement. Literature reporting a method for preparing 2-aryl propionic acid by the rearrangement of 2-hydroxypropylketal and sulfonyl chloride ( Bull. Chem. Soc. Jpn.There is 1987, 60, 4015-4018). Referring to Japanese patents (JP4288080, JP4288081), Jin Qingrong et al. reported in "Improvement of Synthesis Research of Pranopropene" (Fine Chemical Intermediates, 2009, 39 (3), 37-39) that using 2-chloronicotinic acid and phenol as raw materials, they obtained 5H-[1]-benzopyran[2,3-b]pyridine-5-one through nucleophilic substitution and PPA cyclization reaction, then obtained 5H-[1]-benzopyran[2,3-b]pyridine through potassium borohydride reduction and acid hydrolysis, and then obtained the core intermediate 6-(2-chloropropionyl)-10H-9-oxa-1-axanthen through an acylation reaction with 2-chloropropionyl chloride. Hydroxyketal was obtained by reacting with sodium methoxide, and then pranopropene was obtained through sulfonylation, rearrangement, and hydrolysis of the hydroxy using sulfonyl chloride.

[0007]

[0008] The disadvantages of Route 1 are that polyphosphoric acid (PPA) is used in the production process and a large amount of phosphorus-containing wastewater is generated in the post-treatment process, which does not help with environmental protection; 2-chloropropionyl chloride and sulfuryl chloride are also used in the process and have a very irritating odor, which does not help with labor protection for production personnel; and the rearrangement reaction is placed at the end, making it difficult to purify the related materials and inconvenient for quality control of the final product.

[0009] Route 2: This is based on the concept of using a side chain "2+1", using a cyanide as a carbon source to introduce a carboxyl group, and using a cyanide to extend the carbon chain. In Route 2, 2-chloronicotinic acid and p-ethylphenol are used as feedstocks, and 7-ethyl-5H-[1]-benzopyrano[2,3-b]pyridin-5-one is obtained through nucleophilic substitution and Friedel-Crafts ring closure, α-halo-5H-[1]-benzopyran[2,3-b]pyridin-7-ethane is obtained through halogenation and reduction reactions, then α-methyl-5H-[1]-benzopyran[2,3-b]pyridin-7-acetonitrile is obtained through carbon chain extension using a cyanide, and finally, pranopropene is obtained through cyanohydrolysis.

[0010]

[0011] The disadvantage of Route 2 is that highly toxic cyanide reagents are used in production, increasing safety risks and not helping with labor protection.

[0012] Route 3: This is based on the concept of using a side chain "2+1," using CO2 as a carbon source to introduce a carboxyl group, and using CO2 to extend the carbon chain. In this route, 2-chloronicotinic acid and p-ethylphenol are used as feedstocks, and through nucleophilic substitution and Friedel-Crafts ring closure, 7-ethyl-5H-[1]-benzopyrano[2,3-b]pyridine-5-one is obtained, and through halogenation and reduction reactions, α-halo-5H-[1]-benzopyran[2,3-b]pyridine-7-ethane is obtained, and this halogenated hydrocarbon reacts with magnesium to form Grignard's reagent, then carbon dioxide is supplied, and through hydrolysis under acidic conditions, pranopropene is obtained.

[0013]

[0014] The disadvantage of Route 3 is that it requires high conditions for the reaction, namely the Grignard reaction, and cryogenic conditions of -80°C, and the conditions are relatively harsh and not helpful for industrial production.

[0015] Route 4: This is based on the concept of using a "2+1" side chain and iodomethane as a carbon source to introduce a methyl group. Using 2-chloronicotinic acid and p-hydroxyphenylacetonitrile or methyl 4-hydroxyphenylacetate as starting materials, 7-R-5H-[1]-benzopyrano[2,3-b]pyridine-5-one (R=COOMe, CN) is obtained through substitution and Friedel-Crafts ring closure reactions. Subsequently, 7-R-5H-[1]-benzopyrano[2,3-b]pyridine (R=COOMe, CN) is obtained by reduction with sodium borohydride and hydrolysis with isopropanol hydrochloride. Using iodomethane, a methyl group is introduced at the α position, followed by hydrolysis of the cyano or ester group to obtain pranopropene.

[0016]

[0017] The disadvantage of Route 4 is that when methyl is introduced using iodomethane, the reaction selectivity is poor and it is difficult to purify dimethylated impurities, which does not contribute to product quality. In addition, iodomethane is a highly toxic reagent, so it does not contribute to the health of production and researchers.

[0018] Route 5: This is based on constructing a three-carbon side chain using the "1+1+1" side chain. In this route, 2-chloronicotinic acid and phenol are used as feedstocks, and a nucleophilic substitution and a phosphorus oxychloride-catalyzed Friedel-Crafts reaction are performed for ring closure to obtain 5H-[1]-benzopyrano[2,3-b]pyridine-5-one, which is then reduced with Na-Hg / ethanol and hydrolyzed with isopropanol hydrochloride to produce the tricyclic matrix 5H-[1]-benzopyrano[2,3-b]pyridine. Next, the first carbon is introduced by chloromethylation, the second carbon is introduced by cyanide, and finally the third carbon is introduced by iodomethane to obtain methyl α-methyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetate, which is finally hydrolyzed to obtain pranopropene.

[0019]

[0020] The disadvantage of Route 5 is that the reaction steps are long, affecting labor, energy consumption, and yield. In addition, highly toxic reagents such as phosphorus oxychloride, cyanide, and iodomethane are used in production, increasing safety risks and not benefiting the health of production personnel and researchers; furthermore, the introduction of iodomethane also easily generates dimethylated impurities that are difficult to separate and remove, thus affecting product quality.

[0021] In addition, regarding stability and impurities, the Japanese Pharmacopoeia stipulates that total impurities must not exceed 1.0% and single impurities must not exceed 0.5%, but there are no clear regulations regarding the structure of impurities. Since pranoprofen is not currently included in the Chinese Pharmacopoeia, there are no relevant regulations.

[0022] Generally speaking, the synthesis of pranopropene in the prior art has many flaws, which are mainly concentrated in the following aspects: long synthesis routes and lower total yields; for example, the total yield of Route 1 is 23.7%, Route 3 is 29.2%, and Route 5 is 3.7% (Routes 2 and 4 utilize many existing technologies, but their total yields are not clearly reported); the use of highly toxic chemical reagents that do not help ensure personal safety; and harsh reaction conditions that are not conducive to industrial production. There is also room for improvement in terms of impurities and impurity content. For example, the product degrades and impurities gradually increase during the batch process. Furthermore, high impurity content in the bulk drug affects the quality of the ophthalmic product. Therefore, it is necessary to improve the purity of the bulk drug and reduce the types and quantities of impurities.

[0023] Currently, it is necessary to innovate the synthesis process of pranopropene and develop process technology that is more suitable for commercial production.

[0024] Through in-depth research and creative work, the inventors obtained a new method for manufacturing pranopropene. Surprisingly, the inventors discovered that this method overcomes the shortcomings of conventional technology, shortens the synthesis route, lowers requirements for process conditions, simplifies process operations, improves labor safety, is more suitable for industrial production, is environmentally friendly, and offers a higher yield.

[0025] Accordingly, the following invention is provided:

[0026] (I)

[0027] One aspect of the present invention relates to a compound represented by Formula I or a pharmaceutically acceptable salt or ester thereof, and

[0028]

[0029] Here, R is C2-C10 It is a straight-chain or branched-chain alkyl, preferably R is a C2-C6 straight-chain or branched-chain alkyl, and more preferably R is a C2-C4 straight-chain or branched-chain alkyl such as ethyl, propyl, isopropyl, or n-butyl.

[0030] Another aspect of the present invention relates to a method for preparing a compound represented by Formula I, comprising the step of reacting a compound represented by Formula A with a compound represented by Formula B to produce a compound represented by Formula I:

[0031]

[0032] Here,

[0033] X is a halogen such as fluorine, chlorine, bromine, or iodine, preferably chlorine or bromine;

[0034] R is C2-C 10 It is a straight-chain or branched-chain alkyl, preferably R is a C2-C6 straight-chain or branched-chain alkyl, and more preferably R is a C2-C4 straight-chain or branched-chain alkyl such as ethyl, propyl, isopropyl, or n-butyl.

[0035] The structural formulas of compound A and compound B are as follows:

[0036]

[0037] Here,

[0038] X is a halogen such as fluorine, chlorine, bromine, or iodine, preferably chlorine or bromine, and

[0039]

[0040] Here, R is C2-C 10 It is a straight-chain or branched-chain alkyl, preferably R is a C2-C6 straight-chain or branched-chain alkyl, and more preferably R is a C2-C4 straight-chain or branched-chain alkyl such as ethyl, propyl, isopropyl, or n-butyl.

[0041] In some embodiments of the present invention, in a method for preparing a compound represented by Formula I, the compound represented by Formula A (2-halogenated nicotinic acid) is selected from 2-chloronicotinic acid, 2-bromonicotinic acid, and 2-iodonicotinic acid; preferably, it is 2-chloronicotinic acid or 2-bromonicotinic acid.

[0042] In some embodiments of the present invention, in a method for preparing a compound represented by Formula I, the compound represented by Formula B (a 4-hydroxyphenylketone compound) is selected from 4-hydroxypropiophenone, 4-hydroxybutyrophenone, and 4-hydroxyphenylpentylketone.

[0043] In some embodiments of the present invention, in a method for preparing a compound represented by Formula I, the reaction system temperature is 60°C to 150°C, preferably 80°C to 120°C, and more preferably 95°C to 120°C, 95°C to 110°C, 105°C to 120°C, 105°C to 115°C, 110°C to 120°C, 95°C to 105°C, 105°C to 110°C, 95°C, 100°C, 105°C, 110°C, 115°C, or 120°C.

[0044] In some embodiments of the present invention, in a method for preparing a compound represented by Formula I, the reaction time is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, 1 hour to 10 hours, 2 hours to 8 hours, 3 hours to 7 hours, 4 hours to 6 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.

[0045] In some embodiments of the present invention, in a method for preparing a compound represented by Formula I, the compound represented by Formula A and the compound represented by Formula B are reacted in an organic solvent as a reaction solvent, and preferably, the organic solvent is N,N - Dimethylformamide or dimethyl sulfoxide; more preferably, the organic solvent is N,N- It is dimethylformamide.

[0046] In some embodiments of the present invention, in a method for preparing a compound represented by Formula I, the compound represented by Formula A and the compound represented by Formula B react under the action of a catalyst, preferably, the catalyst is cuprous iodide.

[0047] In some embodiments of the present invention, in a method for preparing a compound represented by Formula I, the reaction system further comprises an acid binder such as potassium carbonate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate.

[0048] In some embodiments of the present invention, in a method for preparing a compound represented by Formula I, according to the molar ratio calculation, the compound represented by Formula A:compound represented by Formula B:catalyst:acid binder is 1:(1 to 5):(0.05 to 1):(1 to 4), and preferably 1:(1 to 3):(0.05 to 0.1):(1 to 2).

[0049] In some embodiments of the present invention, a method for preparing a compound represented by Formula I further comprises the step of separating the compound represented by Formula I from a reaction system, and preferably comprises the following steps:

[0050] Step of cooling the reaction system (e.g., to 50°C or lower), adding water, acidifying to pH 3-4, collecting the precipitated solid, adding water to disperse it, adjusting the pH to 7-7.5, filtering the solid, acidifying the filtrate to pH 3-4, collecting the precipitated solid, washing with water, and drying to obtain a compound represented by Chemical Formula I.

[0051] Although not limited by theory, the compound represented by Formula I can be produced by undergoing a direct and continuous reaction without separation to produce the compound represented by Formula II, this is not a desirable method because, without separation and purification processes, unreacted starting materials of the compound represented by Formula I participate in the second-stage reaction (the reaction to produce the compound represented by Formula II), consuming additional IBD in the second stage and generating new impurities, thereby reducing product purity and increasing the difficulty of post-processing and purification.

[0052] In some embodiments of the present invention, a method for preparing a compound represented by Formula I comprises the following steps:

[0053] A step of adding 2-halogenated nicotinic acid (compound represented by Chemical Formula A), cuprous iodide, and a reaction solvent to a reaction vessel, controlling the temperature to 60°C to 150°C, adding an acid binder and a 4-hydroxyphenyl ketone compound (compound represented by Chemical Formula B), controlling the temperature to 60°C to 150°C, and reacting for 2 to 8 hours;

[0054] Step of cooling, adding water, acidifying to pH 3-4, collecting the precipitated solid, dispersing by adding water, adjusting to pH 7-7.5 with sodium bicarbonate, filtering the solid, acidifying the filtrate to pH 3-4, collecting the precipitated solid, washing with water, and drying to obtain the intermediate 2-[4-(1-oxoalkyl)phenoxy]-3-pyridinecarboxylic acid (compound represented by Chemical Formula I).

[0055] In some embodiments of the present invention, in a method for preparing a compound represented by Formula I, the compound represented by Formula I has a yield of 50% or more, 60% or more, 70% or more, 75% or more, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 60%, 60% to 80%, 60% to 75%, 60% to 70%, 70% to 80%, 70% to 75%, 75% to 80%, or 75% to 85%.

[0056] Another aspect of the present invention relates to the use of a compound represented by Formula I or a pharmaceutically acceptable salt or ester thereof in the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen. Preferably, the compound represented by Formula I is prepared by a method for preparing a compound represented by Formula I according to any one of the items of the present invention.

[0057] Compounds represented by chemical formula I also have other uses, for example, , or It can be used as an intermediate for synthesizing various other compounds such as, etc., where R is independently C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R is a C1-C6 straight-chain or branched-chain alkyl, and more preferably R is a C1-C4 straight-chain or branched-chain alkyl such as ethyl, propyl, isopropyl, or n-butyl.

[0058] (II)

[0059] One aspect of the present invention relates to a compound represented by Formula II, or a pharmaceutically acceptable salt or ester thereof, and

[0060]

[0061] Here, R1 is C1-C 10It is a straight-chain or branched-chain alkyl, preferably R1 is a C1-C5 straight-chain or branched-chain alkyl, and more preferably R1 is a C1-C3 straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, or isopropyl.

[0062] Another aspect of the present invention relates to a method for preparing a compound represented by Formula II, comprising the step of reacting a compound represented by Formula I with a compound represented by Formula C and a compound represented by Formula D to produce a compound represented by Formula II:

[0063]

[0064] Here,

[0065] R is C2-C 10 It is a straight-chain or branched-chain alkyl, preferably R is a C2-C6 straight-chain or branched-chain alkyl, more preferably R is a C2-C4 straight-chain or branched-chain alkyl such as ethyl, propyl, isopropyl, or n-butyl;

[0066] R1 is C1-C 10 A straight-chain or branched-chain alkyl, preferably R1 is a C1-C5 straight-chain or branched-chain alkyl, more preferably R1 is a C1-C3 straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, or isopropyl;

[0067] Preferably, R has one more carbon atom than R1.

[0068] In some embodiments of the present invention, in a method for preparing a compound represented by Formula II, the compound represented by Formula I is preferably 2-[4-(1-oxopropyl)phenoxy]-3-pyridinecarboxylic acid, 2-[4-(1-oxobutyl)phenoxy]-3-pyridinecarboxylic acid or 2-[4-(1-oxopentyl)phenoxy]-3-pyridinecarboxylic acid, and more preferably 2-[4-(1-oxopropyl)phenoxy]-3-pyridinecarboxylic acid. Preferably, the compound represented by Formula I is prepared by a method for preparing a compound represented by Formula I according to any one of the items of the present invention.

[0069] In some embodiments of the present invention, a method for preparing a compound represented by Formula II further comprises the following steps:

[0070] A step in which a compound represented by chemical formula I is prepared by a method for preparing a compound represented by chemical formula I according to any one of the items of the present invention.

[0071] In some embodiments of the present invention, in a method for preparing a compound represented by Formula II, the reaction system temperature is -5°C to 30°C, preferably -5°C to 20°C, more preferably -5°C to 15°C, -5°C to 10°C, -5°C to 5°C, 5°C to 20°C, 5°C to 15°C, 5°C to 10°C, 10°C to 20°C, 10°C to 15°C, 15°C to 20°C, -5°C, 5°C, 10°C, 15°C, or 20°C.

[0072] In some embodiments of the present invention, in a method for preparing a compound represented by Formula II, the reaction time is at least 0.2 hours, at least 0.4 hours, at least 0.6 hours, at least 0.8 hours, at least 0.9 hours, at least 1 hour, 0.2 hours to 2 hours, 0.4 hours to 1.6 hours, 0.6 hours to 1.4 hours, 0.8 hours to 1.2 hours, 0.2 hours, 0.4 hours, 0.6 hours, 0.8 hours, 1 hour, 1.2 hours, 1.4 hours, 1.6 hours, 1.8 hours, or 2 hours.

[0073] In some embodiments of the present invention, in a method for preparing a compound represented by Formula II, the compound represented by Formula I reacts with a compound represented by Formula C in an organic solvent as a reaction solvent, and preferably, the organic solvent is trimethyl orthoformate. Without being limited to theory, trimethyl orthoformate is not only a reaction solvent but also a substrate participating in the reaction.

[0074] In some embodiments of the present invention, in a method for preparing a compound represented by Formula II, the compound represented by Formula I reacts with a compound represented by Formula C under the action of a catalyst, preferably the catalyst is an acid, preferably the acid is one or more selected from the group consisting of concentrated sulfuric acid, hydrochloric acid, phosphoric acid and acetic acid, and preferably concentrated sulfuric acid.

[0075] In some embodiments of the present invention, in a method for preparing a compound represented by Formula II, according to the molar ratio calculation, the compound represented by Formula I:iodobenzenediacetate:acid is 1:(1-3):(1-4), and preferably 1:(1-2):(1-3).

[0076] In some embodiments of the present invention, a method for preparing a compound represented by Formula II further comprises the step of separating the compound represented by Formula II from a reaction system, preferably comprising the following steps:

[0077] A step of neutralizing by adding an alkaline solution (e.g., an aqueous solution of sodium bicarbonate), performing extraction with an organic solvent (preferably dichloromethane), maintaining the aqueous phase, acidifying to a pH of 3-4, collecting the precipitated solid, washing with water, and drying to obtain a compound represented by Chemical Formula II.

[0078] If a compound represented by Chemical Formula III is prepared through a direct and continuous subsequent reaction without separating the compound represented by Chemical Formula II, without being limited to theory, an excess amount of trimethyl orthoformate may participate in the next step reaction, reducing the yield and generating impurities.

[0079] In some embodiments of the present invention, a method for preparing a compound represented by Formula II comprises the following steps:

[0080] A step of adding a compound represented by chemical formula I and triethyl orthoformate to a reaction vessel, slowly adding an acid solution, and controlling the reaction temperature to -5℃ to 30℃;

[0081] A step of slowly adding iodobenzene diacetate and controlling the reaction temperature to -5℃ to 30℃;

[0082] A step of slowly adding the acid solution again and controlling the reaction temperature to -5℃ to 30℃;

[0083] Step of carrying out the reaction by maintaining the temperature for 0.5 to 2 hours, neutralizing by adding an aqueous sodium bicarbonate solution, performing extraction with dichloromethane, then maintaining the aqueous phase, acidifying to a pH of 3-4, collecting the precipitated solid, washing with water, and drying to obtain the intermediate 2-[4-(2-alkoxy-1-methyl-2-oxoethyl)phenoxy]-3-pyridinecarboxylic acid (compound represented by Chemical Formula II).

[0084] Another aspect of the present invention relates to the use of a compound represented by Formula II or a pharmaceutically acceptable salt or ester thereof in the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen. Preferably, the compound represented by Formula II is prepared by a method for preparing a compound represented by Formula II according to any one of the items of the present invention.

[0085] Compounds represented by Chemical Formula II also have other uses, for example, , or It can be used as an intermediate for synthesizing various other compounds such as, etc., where R is independently C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R is a C1-C6 straight-chain or branched-chain alkyl, and more preferably R is a C1-C4 straight-chain or branched-chain alkyl such as ethyl, propyl, isopropyl, or n-butyl.

[0086] (III)

[0087] One aspect of the present invention relates to a compound represented by Formula III, or a pharmaceutically acceptable salt or ester thereof, and

[0088]

[0089] Here, R1 is C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R1 is a C1-C5 straight-chain or branched-chain alkyl, and more preferably R1 is a C1-C3 straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, or isopropyl.

[0090] Another aspect of the present invention relates to a method for preparing a compound represented by Formula III, comprising the step of preparing a compound represented by Formula III from a compound represented by Formula II:

[0091]

[0092] Here, R1 is C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R1 is a C1-C5 straight-chain or branched-chain alkyl, and more preferably R1 is a C1-C3 straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, or isopropyl.

[0093] The above reaction method includes two reactions as described below; the product in the middle bracket is not separated; and preferably, is supplied directly for a subsequent reaction.

[0094]

[0095] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, the compound represented by Formula II is preferably 2-[4-(2-methoxy-1-methyl-2-oxoethyl)phenoxy]-3-pyridinecarboxylic acid, 2-[4-(2-ethoxy-1-methyl-2-oxoethyl)phenoxy]-3-pyridinecarboxylic acid or 2-[4-(2-propoxy-1-methyl-2-oxoethyl)phenoxy]-3-pyridinecarboxylic acid; more preferably 2-[4-(2-methoxy-1-methyl-2-oxoethyl)phenoxy]-3-pyridinecarboxylic acid. Preferably, the compound represented by Formula II is prepared by a method for preparing a compound represented by Formula II according to any one of the items of the present invention.

[0096] In some embodiments of the present invention, a method for preparing a compound represented by Formula III further comprises the following steps:

[0097] A step in which a compound represented by Chemical Formula II is prepared by a method for preparing a compound represented by Chemical Formula II according to any one of the items of the present invention.

[0098] In some embodiments of the present invention, a method for preparing a compound represented by Formula III comprises the following steps:

[0099] (1) A step of obtaining a reaction product by reacting a compound represented by chemical formula II with an acylating agent,

[0100] (2) A step of producing a compound represented by the chemical formula III from the reaction product of step (1) under the action of a Lewis acid;

[0101] Preferably, it further includes the following steps:

[0102] (3) separating the compound represented by Formula III; preferably, cooling the reaction product obtained in step (2) below 20°C (e.g., quenching by adding cold water), adjusting the pH, and removing the solvent under reduced pressure to obtain the compound represented by Formula III.

[0103] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, the reaction temperature of step (1) is 10°C to 30°C, preferably 15°C to 25°C, 15°C to 20°C, or 20°C to 25°C.

[0104] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, the reaction time of step (1) is at least 0.2 hours, at least 0.4 hours, at least 0.6 hours, at least 0.8 hours, at least 0.9 hours, at least 1 hour, 0.2 hours to 2 hours, 0.4 hours to 1.6 hours, 0.6 hours to 1.4 hours, 0.8 hours to 1.2 hours, 0.2 hours, 0.4 hours, 0.6 hours, 0.8 hours, 1 hour, 1.2 hours, 1.4 hours, 1.6 hours, 1.8 hours, or 2 hours.

[0105] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, step (1) further comprises the following steps:

[0106] A step of cooling the obtained reaction product to -10℃ to 0℃.

[0107] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, the reaction temperature of step (2) is 10°C to 30°C, preferably 15°C to 25°C, 15°C to 20°C, or 20°C to 25°C.

[0108] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, the reaction time of step (2) is at least 0.2 hours, at least 0.4 hours, at least 0.6 hours, at least 0.8 hours, at least 0.9 hours, at least 1 hour, 0.2 hours to 2 hours, 0.4 hours to 1.6 hours, 0.6 hours to 1.4 hours, 0.8 hours to 1.2 hours, 1 hour to 1.5 hours, 0.2 hours, 0.4 hours, 0.6 hours, 0.8 hours, 1 hour, 1.2 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.8 hours, or 2 hours.

[0109] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, the acylating agent is one or more selected from oxalyl chloride and thionyl chloride.

[0110] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, the Lewis acid is a catalyst; preferably, the Lewis acid is one selected from aluminum anhydride and titanium tetrachloride, and preferably aluminum anhydride.

[0111] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, the reaction is carried out in an organic solvent as a reaction solvent, and preferably, the organic solvent is dichloromethane and / or N,N - It is dimethylformamide. Not limited to theory, dichloromethane is a reaction solvent, and N,N - The amount of dimethylformamide is only 0.1 equivalent, making it more suitable as a catalyst.

[0112] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, the molar ratio of the compound represented by Formula II to the acylating agent is (1:1) to (1:5), preferably 1:(1.5-3), and particularly preferably 1:2.5.

[0113] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, the molar ratio of the compound represented by Formula II to oxalyl chloride is (1:1) to (1:5), preferably 1:(1.5-3), and particularly preferably 1:2.5.

[0114] In some embodiments of the present invention, in a method for preparing a compound represented by Formula III, step (3) comprises the following operations:

[0115] Cold water is added to the reaction product of step (2) to quench the reaction, separate the organic phase, adjust the pH to 7-8 (e.g., with a sodium carbonate solution), and then separate the organic phase; the organic phase is concentrated under reduced pressure until no more distillate evaporates, and a solvent of methanol or a mixture of methanol and dichloromethane is added and the mixture is beaten for 3 to 8 hours (preferably 5 to 6 hours), and after filtration, the filtration residue is rinsed with methanol and dried to obtain a compound represented by Formula III. In some embodiments of the present invention, the volume ratio of methanol to dichloromethane is 1:(0-0.4), preferably 1:(0.1-0.2).

[0116] Without being limited to theory, the inventors have discovered that if the compound represented by Formula III is not separated, the compound represented by Formula IV cannot be produced by direct and continuous reactions because a large amount of aluminum trichloride is present in the system when producing the compound represented by Formula III. During the reaction of Step 4, it reacts with methanol, which affects the yield. Additionally, if aluminum trichloride is mixed with potassium borohydride / sodium borohydride, the methyl ester of the compound represented by Formula III can be further reduced to produce an alcohol that is not the compound represented by Formula IV.

[0117] In some embodiments of the present invention, a method for preparing a compound represented by Formula III comprises the following steps:

[0118] Compounds represented by Chemical Formula II, dichloromethane and N,N - A step of adding dimethylformamide to a first reaction vessel, mixing and stirring, adding an acylation reagent at a temperature maintained at 15°C to 25°C, carrying out the reaction by maintaining the temperature for 0.5 to 2 hours, and cooling to -10°C to 0°C and waiting;

[0119] A step of adding a Lewis acid and dichloromethane to a second reaction vessel and stirring evenly, adding the solution from the first reaction vessel at a temperature maintained at 15°C to 25°C, carrying out the reaction by maintaining the temperature for 1 hour to 1.5 hours, and quenching by slowly adding cold water at a temperature maintained below 20°C;

[0120] A step of maintaining the organic phase, adjusting the pH to 7-8 with a sodium carbonate solution, undergoing liquid separation, and then concentrating the organic phase under reduced pressure;

[0121] Step of obtaining the intermediate 2-(10-oxo-9-oxa-1-aza-anthracen-6-yl)propionate compound (compound of Formula III) by adding a mixed solvent of methanol and dichloromethane when the distillate no longer evaporates, refining for 5 to 6 hours, filtering, rinsing the solid with methanol, and drying.

[0122] The inventors also surprisingly discovered that the obtained product contains specific impurities, which are formed by passing a byproduct of a compound represented by Formula II and a compound represented by Formula II through it, and these are named Formula III compound-IMP-A, Formula III compound-IMP-B, Formula III compound-IMP-C, etc., and their structures are as follows:

[0123]

[0124] Here, R1 is C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R1 is a C1-C5 straight-chain or branched-chain alkyl, and more preferably R1 is a C1-C3 straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, or isopropyl.

[0125] The inventor speculates that if these three impurities are passed through in a subsequent reaction, they can be derivatized into the following impurities similar in structure to pranopropene:

[0126]

[0127] It is not limited to theory, and because the structures of these derivatized impurities are very similar to the structure of pranopropene, it is presumed that separation and removal from the final product will be difficult. Therefore, these impurities must be removed by prior refining, and the limits of these three impurities must be controlled. For example, each impurity must not exceed 0.1% of the total mass of the intermediate product (the maximum amount of impurities generated by the conversion of these three impurities must not exceed 0.1%), and since the quality of the final product can be controlled at the upstream stage, the final product does not need to be further inspected for derivatized impurities.

[0128] In some embodiments of the present invention, the following step is used to remove these impurities by refining:

[0129] A step of using methanol or a methanol / dichloromethane mixed solvent for pulp washing (i.e., refining) after distilling off the solvent dichloromethane. By using an optimized solvent ratio, impurities can be controlled to a desired level.

[0130] The inventor verified with experimental data from multiple batches, and when these three impurities are controlled to be below 0.1%, derivatization impurities of these three impurities are not detected in the final product, pranopropene.

[0131] Another aspect of the present invention relates to the use of a compound represented by Formula III or a pharmaceutically acceptable salt or ester thereof in the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen. Preferably, the compound represented by Formula III is prepared by a method for preparing a compound represented by Formula III according to any one of the items of the present invention.

[0132] Compounds represented by chemical formula III also have other uses, for example, , or It can be used as an intermediate for synthesizing various other compounds such as, etc., where R is independently C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R is a C1-C6 straight-chain or branched-chain alkyl, and more preferably R is a C1-C4 straight-chain or branched-chain alkyl such as ethyl, propyl, isopropyl, or n-butyl.

[0133] (IV)

[0134] One aspect of the present invention relates to a compound represented by Formula IV, or a pharmaceutically acceptable salt or ester thereof, and

[0135]

[0136] Here, R1 is C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R1 is a C1-C5 straight-chain or branched-chain alkyl, and more preferably R1 is a C1-C3 straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, or isopropyl.

[0137] Another aspect of the present invention relates to a method for preparing a compound represented by Formula IV, comprising the step of preparing a compound represented by Formula IV from a compound represented by Formula III:

[0138]

[0139] Here, R1 is C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R1 is a C1-C5 straight-chain or branched-chain alkyl, and more preferably R1 is a C1-C3 straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, or isopropyl.

[0140] In some embodiments of the present invention, in a method for preparing a compound represented by Formula IV, the compound represented by Formula III is preferably methyl 2-(10-oxo-9-oxa-1-azantracen-6-yl)propionate, ethyl 2-(10-oxo-9-oxa-1-azantracen-6-yl)propionate or propyl 2-(10-oxo-9-oxa-1-azantracen-6-yl)propionate; more preferably, methyl 2-(10-oxo-9-oxa-1-azantracen-6-yl)propionate. Preferably, the compound represented by Formula III is prepared by a method for preparing a compound represented by Formula III according to any one of the items of the present invention.

[0141] In some embodiments of the present invention, a method for preparing a compound represented by Formula IV further comprises the following steps:

[0142] A step in which a compound represented by Chemical Formula III is prepared by a method for preparing a compound represented by Chemical Formula III according to any one of the items of the present invention.

[0143] In some embodiments of the present invention, in a method for preparing a compound represented by Formula IV, the compound represented by Formula IV is prepared by reacting a compound represented by Formula III with a reducing agent. Preferably, the reducing agent is boron hydride, and more preferably, sodium borohydride.

[0144] In some embodiments of the present invention, in a method for preparing a compound represented by Formula IV, the reaction temperature is 20°C to 40°C, preferably 30°C to 40°C, 30°C to 35°C, or 35°C to 40°C.

[0145] In some embodiments of the present invention, in a method for preparing a compound represented by Formula IV, the reaction time is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, 1 hour to 100 hours, 2 hours to 50 hours, 3 hours to 40 hours, 4 hours to 30 hours, 5 hours to 25 hours, 6 hours to 20 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, or 20 hours.

[0146] In some embodiments of the present invention, in a method for preparing a compound represented by Formula IV, the reaction is carried out in an organic solvent as a reaction solvent, preferably, the organic solvent is dichloromethane and methanol (mixed solvent). Without being bound by theory, dichloromethane is the solvent, and methanol is the substrate that provides both the solvent and a hydrogen source. The molar ratio of dichloromethane to methanol is 1:(2.11-3.16), preferably 1:2.11. In some embodiments of the present invention, the mass (g) of the compound represented by Formula III : volume (mL) of the mixed solvent is 1:(5-15), preferably 1:(8-10).

[0147] In some embodiments of the present invention, in a method for preparing a compound represented by Formula IV, the molar ratio of the compound represented by Formula III to the reducing agent is (1:0.8) to (1:1.2), and preferably 1:0.9-1.1.

[0148] In some embodiments of the present invention, a method for preparing a compound represented by Formula IV further comprises the step of separating the compound represented by Formula IV from a reaction system, preferably comprising the following steps:

[0149] A step of cooling the reaction product to -10°C to 10°C and adjusting the pH to 5.5-6.5; preferably, a step of slowly adding a diluted acid solution (e.g., a 30% aqueous acetic acid solution) to a pH of 5.5-6.5 (not limited to theory, the function of the acid is to quench the excess reducing agent in the reaction, and the acid may be either a diluted inorganic acid or a diluted organic acid); the diluted acid may be an inorganic acid or an organic acid having a concentration of 30% or less;

[0150] A step of performing stirring at -10℃ to 10℃ for 5 to 30 minutes (preferably 15 minutes), adding purified water, collecting the organic phase, and sequentially washing with saturated sodium bicarbonate and purified water;

[0151] A step of obtaining a yellowish-green oil by concentrating and drying the washed organic phase at 40°C under reduced pressure;

[0152] A step of adding a crystallization solvent and stirring at 20°C to 40°C for 5 to 30 minutes (preferably 15 minutes); and

[0153] Step of slowly adding purified water dropwise, collecting the solid, washing with water, and drying in a vacuum to obtain a compound represented by chemical formula IV.

[0154] In some embodiments of the present invention, in a method for preparing a compound represented by Formula IV, preferably, the crystallization solvent may be selected from the group consisting of an aqueous methanol solution (preferably, methanol:water is 1:2), an aqueous acetone solution (preferably, acetone:water is 1:2), a mixture of methanol, acetone, and water (preferably, methanol:acetone:water is 1:1.5:5), and preferably, a mixture of methanol, acetone, and water (preferably, methanol:acetone:water is 1:1.5:5). Preferably, the mass (g) of the compound represented by Formula III : the volume (mL) of the crystallization solvent is 1:5.

[0155] In some embodiments of the present invention, a method for preparing a compound represented by Formula IV comprises the following steps:

[0156] A step of adding a compound represented by Chemical Formula III, dichloromethane, and methanol to a reaction vessel and stirring to dissolve them at a temperature of 15°C to 30°C;

[0157] Steps of slowly adding boron hydride, reacting by maintaining the temperature at 20°C to 40°C for 6 to 20 hours, cooling to -10°C to 10°C, slowly adding a 30% aqueous acetic acid solution dropwise to a pH of 5.5 to 6.5, stirring for 5 to 30 minutes (preferably 15 minutes) while controlling the temperature at -10°C to 10°C, adding purified water, collecting the organic phase, washing with saturated sodium bicarbonate, and washing again with purified water;

[0158] A step of obtaining a yellowish-green oil by concentrating and drying the organic phase at 40°C under reduced pressure;

[0159] A step of adding a mixed solution of methanol / acetone and dispersing by stirring at 20°C to 40°C for 15 minutes, slowly adding purified water dropwise to crystallize for 1 to 5 hours (preferably 2 hours), collecting the solid, washing with water, and drying under vacuum to obtain an intermediate 2-(10-hydroxy-9-oxa-1-axantracene-6-yl)propionate compound (compound of Formula IV).

[0160] Without being bound by theory, the function of acetic acid is to quench excess sodium borohydride, and the pH range is controlled to ensure complete quenching.

[0161] Another aspect of the present invention relates to the use of a compound represented by Formula IV or a pharmaceutically acceptable salt or ester thereof in the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen. Preferably, the compound represented by Formula IV is prepared by a method for preparing a compound represented by Formula IV according to any one of the items of the present invention.

[0162] Compounds represented by chemical formula IV also have other uses, for example, , , , , or It can be used as an intermediate for synthesizing various other compounds such as, etc., where R and R' are each independently C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R is a C1-C6 straight-chain or branched-chain alkyl, more preferably R is a C1-C4 straight-chain or branched-chain alkyl such as ethyl, propyl, isopropyl or n-butyl; and X is a halogen such as fluorine, chlorine, bromine or iodine.

[0163] (V)

[0164] Another aspect of the present invention relates to a method for preparing pranoprofen (a compound represented by chemical formula 0) or a pharmaceutically acceptable salt or ester of pranoprofen, comprising the step of preparing the following:

[0165] A compound represented by chemical formula I or a pharmaceutically acceptable salt or ester thereof,

[0166] A compound represented by Chemical Formula II or a pharmaceutically acceptable salt or ester thereof,

[0167] A compound represented by Chemical Formula III or a pharmaceutically acceptable salt or ester thereof, and / or

[0168] A compound represented by Chemical Formula IV or a pharmaceutically acceptable salt or ester thereof;

[0169] Preferably, the compound represented by Formula I is prepared by a method for preparing the compound represented by Formula I according to any one of the items of the present invention;

[0170] Preferably, the compound represented by Formula II is prepared by a method for preparing a compound represented by Formula III according to any one of the items of the present invention;

[0171] Preferably, the compound represented by Formula III is prepared by a method for preparing the compound represented by Formula III according to any one of the items of the present invention;

[0172] Preferably, the compound represented by Formula IV is prepared by a method for preparing the compound represented by Formula IV according to any one of the items of the present invention.

[0173] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), the synthesis route is represented as follows:

[0174]

[0175] In some embodiments of the present invention, a method for preparing pranopropene (a compound represented by chemical formula 0) comprises the following steps:

[0176] (1) A step of preparing an intermediate 2-[4-(1-oxoalkyl)phenoxy]-3-pyridinecarboxylic acid (compound represented by chemical formula I) by Ullmann condensation reaction in the presence of cuprous iodide, using 2-halogenated nicotinic acid (compound represented by chemical formula A) and 4-hydroxyphenylketone compound (compound represented by chemical formula B) as starting materials;

[0177] (2) A step of preparing the intermediate 2-[4-(2-methoxy-1-methyl-2-oxoalkyl)phenoxy]-3-pyridinecarboxylic acid (a compound represented by Formula II) by a rearrangement reaction of trimethyl orthoformate under the action of acid and iodobenzene diacetate;

[0178] (3) A step of preparing an intermediate 2-(10-oxo-9-oxa-1-axanthracen-6-yl)propionate compound (a compound represented by Chemical Formula III) by intramolecular ring closure under the action of a Lewis acid after halogenation to form an acid chloride;

[0179] (4) A step of preparing an intermediate 2-(10-hydroxy-9-oxa-1-axantracen-6-yl)propionate compound (a compound represented by Chemical Formula IV) after reduction with boron hydride;

[0180] (5) Finally, a step of producing pranopropene (a compound represented by chemical formula 0) by the “one-pot method” through reduction with isopropanol and hydrogen chloride, hydrolysis with a base, and post-treatment acidification.

[0181] The structural formulas of compound A and compound B are as follows:

[0182]

[0183] Here,

[0184] X is a halogen such as fluorine, chlorine, bromine, or iodine, preferably chlorine or bromine, and

[0185]

[0186] Here, R is C2-C 10 It is a straight-chain or branched-chain alkyl, preferably R is a C2-C6 straight-chain or branched-chain alkyl, and more preferably R is a C2-C4 straight-chain or branched-chain alkyl such as ethyl, propyl, isopropyl, or n-butyl.

[0187] Another aspect of the present invention relates to a method for preparing pranopropene (a compound represented by Chemical Formula 0) or a pharmaceutically acceptable salt or ester of pranopropene, comprising the step of preparing pranopropene from a compound represented by Chemical Formula IV:

[0188]

[0189] Here, R1 is C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R1 is a C1-C5 straight-chain or branched-chain alkyl, and more preferably R1 is a C1-C3 straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, or isopropyl.

[0190] In some embodiments of the present invention, a method for preparing pranopropene (a compound represented by chemical formula 0) comprises the following steps:

[0191] (1) First, a step of preparing a compound represented by chemical formula V from a compound represented by chemical formula IV (reduction reaction);

[0192] (2) A step of preparing pranopropene (a compound represented by chemical formula 0) from a compound represented by chemical formula V (hydrolysis reaction);

[0193]

[0194] Here, R1 is C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R1 is a C1-C5 straight-chain or branched-chain alkyl, and more preferably R1 is a C1-C3 straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, or isopropyl.

[0195] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by formula 0), the compound represented by formula IV is preferably methyl 2-(10-hydroxy-9-oxa-1-azantracen-6-yl)propionate, ethyl 2-(10-hydroxy-9-oxa-1-azantracen-6-yl)propionate or propyl 2-(10-hydroxy-9-oxa-1-azantracen-6-yl)propionate; more preferably methyl 2-(10-hydroxy-9-oxa-1-azantracen-6-yl)propionate.

[0196] In some embodiments of the present invention, in a method for producing pranopropene (a compound represented by chemical formula 0), in step (1), a compound represented by chemical formula IV reacts with a reducing agent to produce a compound represented by chemical formula V.

[0197] In some embodiments of the present invention, in a method for producing pranopropene (a compound represented by chemical formula 0), in step (1), the reducing agent is one or more selected from isopropanol hydrogen chloride and isopropanol hydrochloride.

[0198] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), in step (1), the molar ratio of the compound represented by chemical formula IV to the reducing agent is 1:(1.5-3.5), preferably 1:(2.5-3.5), e.g. 1:2.5, 1:3, or 1:3.5.

[0199] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), in step (1), the reaction is carried out in an organic solvent as a reaction solvent, and preferably, the organic solvent is isopropanol.

[0200] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), in step (1), the reaction temperature is 50°C to 90°C, preferably 60°C to 80°C, 60°C to 70°C, 70°C to 80°C, or 65°C to 75°C.

[0201] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), in step (1), the reaction time is at least 0.5 hours, at least 1 hour, at least 1.5 hours, at least 2 hours, 1 hour to 10 hours, 2 hours to 8 hours, 2 hours to 6 hours, 2 hours to 4 hours, 2 hours to 3 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.

[0202] In some embodiments of the present invention, in a method for producing pranopropene (a compound represented by chemical formula 0), in step (2), a compound represented by chemical formula V is reacted with a base (hydrolysis reaction) to produce pranopropene (a compound represented by chemical formula 0).

[0203] In some embodiments of the present invention, in a method for producing pranopropene (a compound represented by chemical formula 0), in step (2), the base is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, preferably sodium hydroxide and / or potassium hydroxide.

[0204] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), in step (2), the reaction temperature is 40°C to 75°C, preferably 40°C to 55°C, 40°C to 50°C, 45°C to 55°C, 40°C to 45°C, 45°C to 50°C, or 50°C to 55°C.

[0205] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), in step (2), the reaction time is at least 0.5 hours, at least 1 hour, at least 1.5 hours, 0.5 hours to 10 hours, 1 hour to 8 hours, 1.5 hours to 6 hours, 1.5 hours to 4 hours, 1.5 hours to 3 hours, 1.5 hours to 2.5 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.

[0206] In some embodiments of the present invention, a method for producing pranopropene (a compound represented by chemical formula 0) further comprises the step of separating pranopropene (a compound represented by chemical formula 0) from a reaction system; preferably, it comprises the following step (3):

[0207] A step of adding purified water to a reaction system, followed by extracting the aqueous phase with ethyl acetate;

[0208] A step of collecting the aqueous phase, adjusting the pH to 2-7 with acid (preferably with a 20% dilute acid solution), and slowly precipitating the solid;

[0209] A step of filtering, continuously rinsing the filter cake with purified water and methanol, and drying under vacuum to obtain crude pranopropene (a compound represented by chemical formula 0); and

[0210] A step of obtaining refined pranopropene (a compound represented by chemical formula 0) by recrystallization from methanol (preferably recrystallization under reflux with 8 to 12 volumes of methanol, e.g., 10 volumes of methanol).

[0211] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), in step (3), the pH is preferably 5-7, more preferably 5.5-6.5, and particularly preferably 5.8-6.2.

[0212] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), in step (3), the acid is one or more selected from the group consisting of acetic acid, phosphoric acid, hydrochloric acid and sulfuric acid, preferably acetic acid and / or hydrochloric acid.

[0213] In some embodiments of the present invention, a method for producing pranopropene (a compound represented by chemical formula 0) does not include a step of separating a compound represented by chemical formula V.

[0214] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by formula 0), the compound represented by formula IV is preferably methyl 2-(10-hydroxyl-9-oxa-1-axanthen-6-yl)propionate, ethyl 2-(10-hydroxy-9-oxa-1-axantracen-6-yl)propionate or propyl 2-(10-hydroxy-9-oxa-1-axantren-6-yl)propionate; more preferably methyl 2-(10-hydroxy-9-oxa-1-axantracen-6-yl)propionate.

[0215] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), the compound represented by chemical formula IV is prepared by a method for preparing a compound represented by chemical formula IV according to any one of the items of the present invention.

[0216] In some embodiments of the present invention, a method for preparing pranopropene (a compound represented by chemical formula 0) further comprises the following steps:

[0217] A step in which a compound represented by chemical formula IV is prepared by a method for preparing a compound represented by chemical formula IV according to any one of the items of the present invention.

[0218] In some embodiments of the present invention, in a method for preparing pranopropene (a compound represented by chemical formula 0), the molar ratio of the compound represented by chemical formula IV to the reducing agent is (1:1) to (1:5), preferably (1:1) to (1:3) or (1:1.5) to (1:3.5), more preferably (1:2) to (1:3) or (1:2) to (1:3.5), e.g. 1:2, 1:2.5, or 1:3.

[0219] In some embodiments of the present invention, a method for preparing pranopropene (a compound represented by chemical formula 0) comprises the following steps:

[0220] A step of adding a compound represented by Chemical Formula IV, a reducing agent, and isopropanol to a reaction vessel, stirring and heating to 50°C to 90°C, maintaining the temperature for 2 to 4 hours to react, concentrating and drying under reduced pressure at 55°C, cooling to room temperature, adding methanol (using methanol as a solvent), then adding alkaline water (or adding alkaline water, then cooling to room temperature, and then adding methanol), and maintaining the temperature at 40°C to 75°C for 2 hours to react;

[0221] A step of adding purified water to the reaction solution, then extracting the aqueous phase with ethyl acetate, collecting the aqueous phase, adjusting the pH to 2-7 with a 20% dilute acid solution, and slowly precipitating the solid;

[0222] After filtration, a step of continuously rinsing the filter cake with purified water and methanol;

[0223] A step of obtaining a crude product by vacuum drying and refining by methanol recrystallization to obtain a final product of pranopropene (a compound represented by chemical formula 0).

[0224] In some embodiments of the present invention, a method for preparing pranopropene (a compound represented by chemical formula 0) comprises the process steps of Preparation Examples 1a, 2c, 3c, 4b, and 5a.

[0225] Another aspect of the present invention relates to a method for preparing a compound represented by formula V or a pharmaceutically acceptable salt or ester of a compound represented by formula V, comprising the step of preparing a compound represented by formula V from a compound represented by formula IV:

[0226]

[0227] Here, R1 is C1-C 10 It is a straight-chain or branched-chain alkyl, preferably R1 is a C1-C5 straight-chain or branched-chain alkyl, and more preferably R1 is a C1-C3 straight-chain or branched-chain alkyl such as methyl, ethyl, propyl, or isopropyl.

[0228] In some embodiments of the present invention, in a method for preparing a compound represented by formula V, the compound represented by formula V is prepared by reacting a compound represented by formula IV with a reducing agent.

[0229] In some embodiments of the present invention, in a method for preparing a compound represented by the formula V, the reducing agent is one or more selected from the group consisting of isopropanol hydrogen chloride and isopropanol hydrochloride.

[0230] In some embodiments of the present invention, in a method for preparing a compound represented by formula V, the molar ratio of the compound represented by formula IV to the reducing agent is 1:(1.5-3.5), preferably 1:(2.5-3.5), and for example, 1:2.5, 1:3, or 1:3.5.

[0231] In some embodiments of the present invention, in a method for preparing a compound represented by formula V, the reaction is carried out in an organic solvent as a reaction solvent, and preferably, the organic solvent is isopropanol.

[0232] In some embodiments of the present invention, in a method for preparing a compound represented by formula V, the reaction temperature is 50°C to 90°C, preferably 60°C to 80°C, 60°C to 70°C, 70°C to 80°C, or 65°C to 75°C.

[0233] In some embodiments of the present invention, in a method for preparing a compound represented by formula V, the reaction time is at least 0.5 hours, at least 1 hour, at least 1.5 hours, at least 2 hours, 1 hour to 10 hours, 2 hours to 8 hours, 2 hours to 6 hours, 2 hours to 4 hours, 2 hours to 3 hours, 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.

[0234] Another aspect of the present invention relates to the use of a compound represented by Formula V or a pharmaceutically acceptable salt or ester thereof in the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen. Preferably, the compound represented by Formula V is prepared by a method for preparing a compound represented by Formula V according to any one of the items of the present invention.

[0235] Some intermediate compounds related to the present invention are shown in Table A below.

[0236] Table A: Some intermediate compounds related to the present invention

[0237]

[0238]

[0239] (VI)

[0240] A composition comprising pranopropene and impurities, wherein the content of impurities in the composition, calculated as a mass percentage, is 0.5% or less, 0.4% or less, 0.3% or less, 0.25% or less, 0.24% or less, 0.23% or less, 0.22% or less, 0.21% or less, 0.20% or less, 0.19% or less, 0.18% or less, 0.17% or less, 0.16% or less, 0.15% or less, 0.14% or less, 0.13% or less, 0.12% or less, 0.11% or less, 0.10% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, 0.01% It is less than or equal to 0.005%.

[0241] In one or more embodiments of the present invention, in a composition calculated as a mass percentage, the content (purity) of pranopropene in the composition is 99% or more, 99.1% or more, 99.2% or more, 99.3% or more, 99.4% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, 99.9% or more, 99.91% or more, 99.92% or more, 99.93% or more, 99.94% or more, 99.95% or more, 99.96% or more, 99.97% or more, 99.98% or more, or 99.99% or more.

[0242] In one or more embodiments of the present invention, the impurity content in the composition is greater than 0.

[0243] In one or more embodiments of the present invention, the composition consists of pranopropene and impurities.

[0244] In one or more embodiments of the present invention, in the composition, the impurity is the sum of the impurities.

[0245] In one or more embodiments of the present invention, in the composition, the impurity is at most a single impurity.

[0246] In one or more embodiments of the present invention, the composition comprises any one, any two, any three, or any four types selected from the group consisting of impurity A, impurity C, impurity D, and impurity L.

[0247] In one or more embodiments of the present invention, the impurities in the composition consist of any one, any two, any three, or any four types selected from the group consisting of impurity A, impurity C, impurity D, and impurity L.

[0248] In one or more embodiments of the present invention, in the composition, the impurity is impurity A, impurity C, impurity D, or impurity L.

[0249] In one or more embodiments of the present invention, in the composition, the impurity is impurity A.

[0250] In one or more embodiments of the present invention, in the composition, the impurity is impurity C.

[0251] In one or more embodiments of the present invention, in the composition, the impurity is impurity D.

[0252] In one or more embodiments of the present invention, in the composition, the impurity is impurity L.

[0253] In one or more embodiments of the present invention, in the composition, the impurities are impurity A and impurity C.

[0254] In one or more embodiments of the present invention, in the composition, the impurity consists of impurity A and impurity D.

[0255] In one or more embodiments of the present invention, in the composition, the impurity consists of impurity A and impurity L.

[0256] In one or more embodiments of the present invention, in the composition, the impurity consists of impurity C and impurity D.

[0257] In one or more embodiments of the present invention, in the composition, the impurity consists of impurity C and impurity L.

[0258] In one or more embodiments of the present invention, in the composition, the impurity consists of impurity D and impurity L.

[0259] In one or more embodiments of the present invention, the impurities in the composition consist of impurity A, impurity C, and impurity D.

[0260] In one or more embodiments of the present invention, the impurities in the composition consist of impurity A, impurity C, and impurity L.

[0261] In one or more embodiments of the present invention, the impurities in the composition consist of impurity A, impurity D, and impurity L.

[0262] In one or more embodiments of the present invention, the impurities in the composition consist of impurity C, impurity D, and impurity L.

[0263] In one or more embodiments of the present invention, the impurities in the composition consist of impurity A, impurity C, impurity D, and impurity L.

[0264] In one or more embodiments of the present invention, the impurities in the composition include impurity A, impurity C, impurity D, and impurity L.

[0265] In one or more embodiments of the present invention, the total impurity content in the composition is 0.2% or less, 0.15% or less, 0.12% or less, 0.1% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, or 0.01% or less.

[0266] In one or more embodiments of the present invention, the content of impurity A in the composition is 0.2% or less, 0.15% or less, 0.12% or less, 0.1% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, or 0.01% or less.

[0267] In one or more embodiments of the present invention, the content of impurity C in the composition is 0.2% or less, 0.15% or less, 0.12% or less, 0.1% or less, 0.09% or less, 0.08%, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, 0.01% or less, or 0.005% or less.

[0268] In one or more embodiments of the present invention, the content of impurity D in the composition is 0.2% or less, 0.15% or less, 0.12% or less, 0.1% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, 0.01% or less, or 0.005% or less.

[0269] In one or more embodiments of the present invention, the content of impurity L in the composition is 0.2% or less, 0.15% or less, 0.12% or less, 0.1% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, 0.01% or less, or 0.005% or less.

[0270] In one or more embodiments of the present invention, in the composition, the change (increase or decrease) in the content of total impurities, maximum single impurity, impurity A, impurity C, impurity D and / or impurity L during 1 month, 2 months, or 3 months compared to 0 months after an accelerated experiment does not exceed 50%, 40%, 30%, 20%, 10%, or 5%.

[0271] In one or more embodiments of the present invention, in the composition, the change (increase or decrease) in the content of total impurities, maximum single impurity, impurity A, impurity C, impurity D and / or impurity L over 6 months compared to 0 months after an accelerated experiment does not exceed 300%, 250%, 200%, 150%, 130%, 120%, 110%, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5%.

[0272] In one or more embodiments of the present invention, in the composition, after an accelerated experiment, for 1 month, 2 months, or 3 months, the content of total impurities, maximum single impurities, impurity A, impurity C, impurity D, and / or impurity L is 0.2% or less, 0.15% or less, 0.12% or less, 0.1% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, or 0.01% or less.

[0273] In one or more embodiments of the present invention, in the composition, after an accelerated experiment, the content of total impurities, maximum single impurities, impurity A, impurity C, impurity D and / or impurity L for 6 months is 0.5% or less, 0.45% or less, 0.4% or less, 0.35% or less, 0.3% or less, 0.25% or less, 0.2% or less, 0.15% or less, 0.12% or less, 0.1% or less, 0.09% or less, 0.08% or less, 0.07% or less, 0.06% or less, 0.05% or less, 0.04% or less, 0.03% or less, 0.02% or less, or 0.01% or less.

[0274] The structures of impurities A, C, D, and L are shown in Table B below.

[0275] Table B: Some impurity compounds related to the present invention

[0276]

[0277] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound according to any one of the items of the present invention described above, and one or more pharmaceutically acceptable excipients.

[0278] In the present invention, unless otherwise specified, the composition is a pranopropene product containing a dominant amount of a pranopropene compound and one or more impurities. A person skilled in the art will understand that the presence or formation of impurities is inevitable during the synthesis, purification, and / or storage of the compound.

[0279] In the present invention, unless otherwise specified, pranopropene refers to pure pranopropene.

[0280] In the present invention, unless otherwise specified, accelerated testing is performed under conditions of 40℃±2℃ and RH75%±5% in accordance with the provisions of the “Technical Guidelines for Stability Studies of Chemical Drugs”; preferably, the average value of three samples measured simultaneously is taken.

[0281] In the present invention, unless otherwise specified, the content of each impurity or total impurity is measured by high-performance liquid chromatography. Preferably, the chromatography conditions include: using octadecylsilane-linked silica gel as a filler (5 μm, 250 mm × 4.6 mm); using a 0.05 mol / L aqueous sodium perchlorate-methanol solution (90:10, pH adjusted to 3.2 by adding perchloric acid) as mobile phase A and methanol as mobile phase B according to the gradient elution of Table 10; a flow rate of 1.0 ml / min; a column temperature of 40°C; and a detection wavelength of 275 nm. The elution program is also shown in Table 10.

[0282] In the present invention, unless otherwise specified, the content of pranopropene, impurities, total impurities, maximum single impurity, impurity A, impurity C, impurity D, or impurity L refers to the content calculated according to the mass percentage in the composition.

[0283] Another aspect of the present invention relates to a method for quality inspection or quality control of a pranoprofen product, comprising the step of detecting the content of (pure) pranoprofen or the content of impurities therein; preferably, the pranoprofen product is a composition or pharmaceutical preparation according to any one of the items of the present invention. Preferably, the method is high-performance liquid chromatography. Preferably, the chromatography conditions include: using octadecylsilane-linked silica gel as a filler (5 μm, 250 mm × 4.6 mm); using a 0.05 mol / L aqueous sodium perchlorate-methanol (90:10, pH adjusted to 3.2 by adding perchloric acid) as mobile phase A and methanol as mobile phase B according to the gradient elution of Table 10; a flow rate of 1.0 ml / min; a column temperature of 40°C; and a detection wavelength of 275 nm. The elution program is also shown in Table 10.

[0284] Another aspect of the present invention relates to any one, any two, any three, or any four uses selected from the group consisting of impurities A, C, D, and L in quality inspection or quality control of a pranoprofen product; preferably, the pranoprofen product is a composition or pharmaceutical preparation described in any one of the items of the present invention described above.

[0285] Another aspect of the present invention relates to the use of the following impurities or combinations of impurities in quality inspection or quality control of a pranoprofen product; preferably, the pranoprofen product is a composition or pharmaceutical preparation described in any one of the items of the present invention described above:

[0286] Impurity L,

[0287] Impurity L and impurity A,

[0288] Impurity L and impurity C,

[0289] Impurity L and impurity D,

[0290] Impurity L, impurity A and impurity C,

[0291] Impurity L, impurity A and impurity D,

[0292] Impurity L, impurity C and impurity D,

[0293] or

[0294] Impurity L, impurity A, impurity C and impurity D.

[0295] In one or more embodiments of the present invention, in a method for producing a compound represented by Formula I, a compound represented by Formula II, a compound represented by Formula III, a compound represented by Formula IV, or pranopropene, the method does not use highly toxic chemical reagents such as potassium cyanide or iodomethane. Accordingly, the method of production of the present invention reduces risks during production and risks to workers during work.

[0296] In one or more embodiments of the present invention, in a method for preparing a compound represented by Formula I, a compound represented by Formula II, a compound represented by Formula III, a compound represented by Formula IV, or pranopropene, the method does not use phosphorus-containing chemical reagents such as polyphosphoric acid. Therefore, the method of preparation of the present invention reduces environmental pollution and is more environmentally friendly.

[0297] In the present invention, the term "C 1-10 "Alkyl" refers to a straight-chain or branched-chain alkyl having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentoxy, 2-pentoxy, isopentoxy, neo-pentoxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, etc.; C 2-10 Alkyl, C 1-6 Alkyl, C 2-6 Alkyl, C 1-3 alkyl or C 2-4 It is an alkyl, etc., and preferably, C 1-6 Alkyl, C2-6 Alkyl, C 1-3 alkyl or C 2-4 It is an alkyl.

[0298] Beneficial effects of the present invention

[0299] The present invention achieves any one or more of the following technical effects (1) to (11):

[0300] (1) The raw materials used in the present invention can be obtained more easily;

[0301] (2) It is advantageous for continuously removing impurities in the process and improving product quality;

[0302] (3) Reduce production risks and worker work risks by avoiding the use of highly toxic chemicals such as potassium cyanide and iodomethane;

[0303] (4) By avoiding the use of phosphorus-containing chemicals such as polyphosphate, environmental pollution is reduced and it is more environmentally friendly;

[0304] (5) The reaction steps are short and the process path is simplified;

[0305] (6) The reaction conditions are mild;

[0306] (7) Easy to operate;

[0307] (8) More suitable for industrial production;

[0308] (9) The yield of compounds represented by Formula 0, Formula I, Formula II, Formula III and / or Formula IV produced by the present invention is relatively high;

[0309] (10) The purity of the compound represented by Formula 0, Formula I, Formula II, Formula III and / or Formula IV produced by the present invention is relatively high;

[0310] (11) A good balance between yield and purity of compounds represented by Formula 0, Formula I, Formula II, Formula III and / or Formula IV produced by the present invention. Brief explanation of the drawing

[0311] Figure 1 shows the high-resolution mass spectrum of the sample. Figure 2a shows the infrared spectrum of a standard product. Figure 2b shows the infrared spectrum of the sample. Figure 3a shows the UV spectrum of a neutral standard product. Figure 3b shows the UV spectrum of an acidic standard product. Figure 3c shows the UV spectrum of a basic standard product. Figure 3d shows the UV spectrum of a neutral sample. Figure 3e shows the UV spectrum of an acidic sample. Figure 3f shows the UV spectrum of an alkaline sample. Specific details for implementing the invention

[0312] Embodiments of the present invention will be described in detail below in connection with examples, but those skilled in the art will understand that the following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention. Where specific conditions were not specified in the examples, they were performed under conventional conditions or conditions recommended by the manufacturer. In the case of reagents or devices for which the manufacturer was not specified, they were all commercially available conventional products.

[0313] Preparation Examples 1a to 1i: 2-[4-(1-oxopropyl)phenoxy]-3-pyridinecarboxylic acid ( compound IA ) or 2-[4-(1-oxobutyl)phenoxy]-3-pyridinecarboxylic acid ( compound IB Manufacturing of )

[0314] 1a:

[0315]

[0316] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (2.4 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (26.9 g, 2 equivalents) and 4-hydroxypropiophenone (38.1 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the mixture was filtered. The resulting filter cake was transferred to a 1L beaker, 200g of water was added and stirred evenly. The mixture was then filtered after adjusting the pH to 7-7.5 with sodium bicarbonate. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the resulting filter cake was air-dried at 60°C to yield a compound with a yield of 85.6% and a purity of 97.53%. IA 29.5g was obtained.

[0317] 1b:

[0318]

[0319] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (1.2 g, 0.05 equivalents) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (26.9 g, 2 equivalents) and 4-hydroxypropiophenone (38.1 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and maintained for 5 hours to carry out the reaction. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the mixture was filtered. The resulting filter cake was transferred to a 1L beaker, 200g of water was added and stirred evenly. The mixture was then filtered after adjusting the pH to 7-7.5 with sodium bicarbonate. The resulting filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the resulting filter cake was air-dried at 60°C to yield a compound with a yield of 85.5% and a purity of 97.36%. IA 29.4g was obtained.

[0320] 1c:

[0321]

[0322] 2-Bromonicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (1.9 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (21.0 g, 2 equivalents) and 4-hydroxypropiophenone (29.7 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the mixture was filtered. The resulting filter cake was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the mixture was filtered after adjusting the pH to 7-7.5 with sodium bicarbonate. The resulting filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the resulting filter cake was air-dried at 60°C to yield a compound with a yield of 86.0% and a purity of 97.68%. IA 23.1g was obtained.

[0323] 1d:

[0324]

[0325] 2-Bromonicotinic acid (50.0g, 1 equivalent), N,NDimethylformazine (50 ml) and cuprous iodide (4.7 g, 0.1 equivalent) were added to a 500 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (52.5 g, 2 equivalents) and 4-hydroxybutyrophenone (81.3 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 250 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the mixture was filtered. The resulting filter cake was transferred to a 2L beaker, 500g of water was added and stirred evenly. The mixture was then filtered after adjusting the pH to 7-7.5 with sodium bicarbonate. The resulting filter cake was washed with an appropriate amount of water, the filtrate was retained, and the liquid was transferred to a clean 2L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the resulting filter cake was air-dried at 60°C to yield a compound with a yield of 83.0% and a purity of 97.11%. IB 58.4g was obtained.

[0326] 1e:

[0327]

[0328] 2-Bromonicotinic acid (20.0g, 1 equivalent), N,NDimethyl formazan (20.0 g) and cuprous iodide (1.9 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, potassium carbonate (27.4 g, 2 equivalents) and 4-hydroxypropiophenone (29.7 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The obtained filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 85.0% and a purity of 97.44%. IA 22.9g was obtained.

[0329] 1f:

[0330]

[0331] 2-Bromonicotinic acid (20.0g, 1 equivalent), N,NDimethylformazan (20.0 g) and cuprous iodide (1.9 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium bicarbonate (16.6 g, 2 equivalents) and 4-hydroxypropiophenone (29.7 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 80.6% and a purity of 96.87%. IA 21.6g was obtained.

[0332] 1g:

[0333]

[0334] 2-Bromonicotinic acid (20.0g, 1 equivalent), N,NDimethylformazan (20.0 g) and cuprous iodide (1.9 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring, then heated to 75 to 80°C, potassium bicarbonate (19.8 g, 2 equivalents) and 4-hydroxypropiophenone (29.7 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 80.2% and a purity of 96.56%. IA 21.5g was obtained.

[0335] 1h:

[0336]

[0337] 2-Bromonicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (1.9 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 60 to 65°C, sodium carbonate (21.0 g, 2 equivalents) and 4-hydroxypropiophenone (29.7 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 75 to 80°C and the reaction was carried out by maintaining the temperature for 10 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 83.4% and a purity of 96.48%. IA 22.4g was obtained.

[0338] 1i:

[0339]

[0340] 2-Bromonicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (1.9 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (21.0 g, 2 equivalents) and 4-hydroxypropiophenone (29.7 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 120 to 125°C and maintained for 4 hours to carry out the reaction. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 87.0% and a purity of 96.11%. IA 23.4g was obtained.

[0341] Comparative Examples 1j to 1w

[0342] 1j:

[0343]

[0344] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (4.8 g, 0.2 equivalents) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (13.5 g, 1 equivalent) and 4-hydroxypropiophenone (19.1 g, 1 equivalent) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the resulting filter cake was air-dried at 60°C to yield a compound with a yield of 74.2% and a purity of 93.88%. IA 25.6g was obtained.

[0345] 1k:

[0346]

[0347] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (4.8 g, 0.2 equivalents) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (13.5 g, 1 equivalent) and 4-hydroxypropiophenone (38.1 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the resulting filter cake was air-dried at 60°C to yield a compound with a yield of 79.1% and a purity of 96.43%. IA 27.2g was obtained.

[0348] 1l:

[0349]

[0350] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (4.8 g, 0.2 equivalents) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (13.5 g, 1 equivalent) and 4-hydroxypropiophenone (57.2 g, 3 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and maintained for 5 hours to carry out the reaction. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 78.8% and a purity of 96.57%. IA 27.1g was obtained.

[0351] 1m:

[0352]

[0353] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (4.8 g, 0.2 equivalents) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (13.5 g, 1 equivalent) and 4-hydroxypropiophenone (76.3 g, 4 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 79.7% and a purity of 95.29%. IA 27.4g was obtained.

[0354] 1n:

[0355]

[0356] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (4.8 g, 0.2 equivalents) were added to a 250 ml reaction bottle and mixed by stirring, then heated to 75 to 80 °C. Sodium carbonate (13.5 g, 1 equivalent) and 4-hydroxypropiophenone (95.3 g, 5 equivalents) were added to the batch. After the addition was completed, the temperature was raised to 110 to 115 °C and maintained for 5 hours to carry out the reaction. The reaction mixture was cooled to 50 °C, transferred to a 500 ml beaker, 100 g of water was added, and stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 78.9% and a purity of 95.11%. IA 27.2g was obtained.

[0357] 1o:

[0358]

[0359] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (4.8 g, 0.2 equivalents) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (26.9 g, 2 equivalents) and 4-hydroxypropiophenone (38.1 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 85.9% and a purity of 95.73%. IA 29.6g was obtained.

[0360] 1p:

[0361]

[0362] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (4.8 g, 0.2 equivalents) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (40.4 g, 3 equivalents) and 4-hydroxypropiophenone (38.1 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the resulting filter cake was air-dried at 60°C to yield a compound with a yield of 71.1% and a purity of 94.53%. IA 24.5g was obtained.

[0363] 1q:

[0364]

[0365] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (4.8 g, 0.2 equivalents) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (53.8 g, 4 equivalents) and 4-hydroxypropiophenone (38.1 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 70.2% and a purity of 94.17%. IA 24.2g was obtained.

[0366] 1r:

[0367]

[0368] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (12.1 g, 0.5 equivalents) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (26.9 g, 2 equivalents) and 4-hydroxypropiophenone (38.1 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and the reaction was carried out by maintaining the temperature for 5 hours. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the resulting filter cake was air-dried at 60°C to yield a compound with a yield of 86.1% and a purity of 94.77%. IA 29.7g was obtained.

[0369] 1s:

[0370]

[0371] 2-Chloronicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (24.2 g, 1.0 equivalent) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (26.9 g, 2 equivalents) and 4-hydroxypropiophenone (38.1 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and maintained for 5 hours to carry out the reaction. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the resulting filter cake was air-dried at 60°C to yield a compound with a yield of 87.3% and a purity of 93.85%. IA 30.1g was obtained.

[0372] 1t:

[0373]

[0374] 2-Iodonicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (1.5 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (17.0 g, 2 equivalents) and 4-hydroxypropiophenone (24.1 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and maintained for 4 hours to carry out the reaction. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 89.4% and a purity of 91.98%. IA 19.5g was obtained.

[0375] 1u:

[0376]

[0377] 2-bromonicotinic acid (20.0 g, 1 equivalent), dimethyl sulfoxide (20.0 g), and cuprous iodide (1.9 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring, then heated to 75 to 80°C, sodium carbonate (21.0 g, 2 equivalents) and 4-hydroxypropiophenone (29.7 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 110 to 115°C and maintained for 5 hours to carry out the reaction. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 78.9% and a purity of 96.38%. IA 21.2g was obtained.

[0378] 1v:

[0379]

[0380] 2-Bromonicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (1.9 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (21.0 g, 2 equivalents) and 4-hydroxypropiophenone (29.7 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 130 to 135°C and maintained for 4 hours to carry out the reaction. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the obtained filter cake was air-dried at 60°C to yield a compound with a yield of 87.3% and a purity of 93.14%. IA 22.4g was obtained.

[0381] 1w:

[0382]

[0383] 2-Bromonicotinic acid (20.0g, 1 equivalent), N,NDimethylformamide (20 ml) and cuprous iodide (1.9 g, 0.1 equivalent) were added to a 250 ml reaction bottle and mixed by stirring. The mixture was heated to 75 to 80°C, sodium carbonate (21.0 g, 2 equivalents) and 4-hydroxypropiophenone (29.7 g, 2 equivalents) were added to the batch, and after the addition was completed, the temperature was raised to 140 to 150°C and maintained for 3 hours to carry out the reaction. The reaction mixture was cooled to 50°C, 100 g of water was added, and the mixture was stirred for 15 minutes. After acidifying to a pH of 3-4, the filter cake obtained by filtration was transferred to a 1L beaker, 200g of water was added and stirred evenly, and the pH was adjusted to 7-7.5 with sodium bicarbonate and filtered. The filter cake was washed with an appropriate amount of water, the filtrate was retained, and transferred to a clean 1L beaker. The resulting filtrate was acidified to a pH of 3-4 to precipitate the product. After filtration, the resulting filter cake was air-dried at 60°C to yield a compound with a yield of 86.8% and a purity of 91.32%. IA 23.3g was obtained.

[0384] Table 1

[0385]

[0386] Preparation Examples 2a to 2d: 2-[4-(2-methoxy-1-methyl-2-oxoethyl)phenoxy]-3-pyridinecarboxylic acid (compound) II-A ) and 2-[4-(2-ethoxy-1-methyl-2-oxoethyl)phenoxy]-3-pyridinecarboxylic acid (compounds II-B Manufacture of ).

[0387] 2a:

[0388]

[0389] compound IA(20.0 g, 1 equivalent) and trimethyl orthoformate (60 g) were added to a 250 ml reaction bottle and stirred to mix evenly, and then the reaction solution was cooled to 0°C. Concentrated sulfuric acid (11.1 g, 1.5 equivalents) was slowly added dropwise at a temperature controlled below 10°C, and after adding, the reaction solution was stirred for 15 minutes, and then iodobenzene diacetate (47.5 g, 2 equivalents) was slowly added within about 10 to 15 minutes at a temperature controlled between 15°C and 20°C; after adding, the reaction solution was stirred for 15 minutes at 15°C to 20°C. The temperature was lowered to 0°C, and concentrated sulfuric acid (11.1 g, 1.5 equivalents) was slowly added dropwise at a temperature controlled below 10°C. After adding concentrated sulfuric acid dropwise, the temperature was slowly returned to between 10°C and 20°C and maintained for 1 hour to carry out the reaction. The mixture was neutralized by adding an aqueous sodium bicarbonate solution, extracted with dichloromethane, and the aqueous phase was maintained. The solution was acidified to a pH of 3-4, filtered, and the filter cake was washed with water until the filtrate became nearly neutral. The mixture was then air-dried at 60°C to a constant weight to produce a yellowish-white compound with a yield of 76.0% and a purity of 97.34%. II-A 16.9g was obtained.

[0390] 2b:

[0391]

[0392] compound IA(20.0 g, 1 equivalent) and trimethyl orthoformate (60 g) were added to a 250 ml reaction bottle and stirred to mix evenly, and then the reaction solution was cooled to 0°C. Concentrated sulfuric acid (11.1 g, 1.5 equivalents) was slowly added dropwise at a controlled temperature below 5°C, and after adding, the reaction solution was stirred for 15 minutes, and iodobenzene diacetate (47.5 g, 2 equivalents) was slowly added within about 10 to 15 minutes at a controlled temperature between 5°C and 10°C, and after the addition was completed, the reaction solution was stirred at 5°C to 10°C for 15 minutes. The temperature was lowered to 0°C, and concentrated sulfuric acid (11.1 g, 1.5 equivalents) was slowly added dropwise at a temperature controlled below 10°C. After adding the concentrated sulfuric acid, the temperature was controlled to between 5°C and 10°C and maintained for 1 hour to carry out the reaction. The mixture was neutralized by adding an aqueous sodium bicarbonate solution, extracted with dichloromethane, and the aqueous phase was maintained. The solution was acidified to a pH of 3-4, filtered, and the filter cake was washed with water until the filtrate became nearly neutral. The mixture was then air-dried at 60°C to a constant weight to produce a yellowish-white compound with a yield of 72.4% and a purity of 96.28%. II-A 16.1g was obtained.

[0393] 2c:

[0394]

[0395] compound IA(20.0 g, 1 equivalent) and trimethyl orthoformate (60 g) were added to a 250 ml reaction bottle and stirred to mix well, and then the reaction solution was cooled to -5°C. Concentrated sulfuric acid (11.1 g, 1.5 equivalents) was slowly added dropwise at a temperature controlled below -5°C, and after adding, the reaction solution was stirred for 15 minutes, and iodobenzene diacetate (47.5 g, 2 equivalents) was slowly added within about 10 to 15 minutes at a temperature controlled between -5°C and 0°C, and after adding, the reaction solution was stirred for 15 minutes at -5°C to 0°C. The temperature was lowered to -5°C, concentrated sulfuric acid (11.1 g, 1.5 equivalents) was slowly added dropwise at a temperature controlled below -5°C, and after adding the concentrated sulfuric acid, the temperature was controlled between -5°C and 0°C and maintained for 1 hour to carry out the reaction. Neutralized by adding an aqueous sodium bicarbonate solution, extracted with dichloromethane, maintained the aqueous phase, acidified to a pH of 3-4, filtered, washed the filter cake with water until the filtrate became nearly neutral, and air-dried at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 71.6% and a purity of 95.61%. II-A 15.9g was obtained.

[0396] 2d:

[0397]

[0398] compound IB(50.0 g, 1 equivalent) and trimethyl orthoformate (150 g) were added to a 500 ml reaction bottle and stirred to mix evenly, and then the reaction solution was cooled to 0°C. Concentrated sulfuric acid (26.4 g, 1.5 equivalents) was slowly added dropwise at a controlled temperature below 10°C, and after adding, the reaction solution was stirred for 15 minutes. Iodobenzene diacetate (113.3 g, 2 equivalents) was slowly added within about 10 to 15 minutes at a controlled temperature between 10°C and 20°C, and after adding, the reaction solution was stirred for 15 minutes at 10°C to 20°C. The temperature was lowered to 0°C, and concentrated sulfuric acid (26.4 g, 1.5 equivalents) was slowly added dropwise at a controlled temperature below 10°C. After adding concentrated sulfuric acid dropwise, the temperature was slowly returned to between 10°C and 20°C and maintained for 1 hour to carry out the reaction. The mixture was neutralized by adding an aqueous sodium bicarbonate solution, extracted with dichloromethane, and the aqueous phase was maintained. The solution was acidified to a pH of 3-4, filtered, and the filter cake was washed with water until the filtrate became nearly neutral. The mixture was then air-dried at 60°C to a constant weight to produce a yellowish-white compound with a yield of 75.4% and a purity of 96.98%. II-B 41.5g was obtained.

[0399] Comparative Examples 2e to 2p

[0400] 2e:

[0401]

[0402] compound IA(20.0g, 1 equivalent) and trimethyl orthoformate (200g) were added to a 500ml reaction bottle and mixed well by stirring. Then, concentrated sulfuric acid (3.7g, 0.5 equivalents) was slowly added dropwise, and after adding, the reaction solution was stirred for 5 minutes. Then, iodobenzene diacetate (23.7g, 1 equivalent) was slowly added, and after adding, the reaction solution was stirred for 15 minutes. Concentrated sulfuric acid (3.7g, 0.5 equivalents) was slowly added dropwise, and after adding the concentrated sulfuric acid, the temperature was raised to 105℃ and refluxed, and the reaction was carried out by maintaining the temperature for 1 hour. After cooling to room temperature, neutralize by adding an aqueous sodium bicarbonate solution, extract with dichloromethane to maintain the aqueous phase, acidify to a pH of 3-4, filter, wash the filter cake with water until the filtrate becomes nearly neutral, and air-dry at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 74.5% and a purity of 89.73%. II-A 16.5 g was obtained.

[0403] 2f:

[0404]

[0405] compound IA(20.0g, 1 equivalent) and trimethyl orthoformate (100g) were added to a 250ml reaction bottle and mixed well by stirring. Then, concentrated sulfuric acid (3.7g, 0.5 equivalents) was slowly added dropwise, and after adding, the reaction solution was stirred for 5 minutes. Then, iodobenzene diacetate (23.7g, 1 equivalent) was slowly added and stirred for 15 minutes after addition. After adding concentrated sulfuric acid (3.7g, 0.5 equivalents), the mixture was heated to 70°C to 75°C and maintained at that temperature for 1 hour to allow the reaction to proceed. After cooling to room temperature, neutralize by adding an aqueous sodium bicarbonate solution, extract with dichloromethane to maintain the aqueous phase, acidify to pH 3-4, filter, wash the filter cake with water until the filtrate becomes nearly neutral, and air-dry at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 72.4% and a purity of 92.86%. II-A 16.1 g was obtained.

[0406] 2g:

[0407]

[0408] compound IA(20.0g, 1 equivalent) and trimethyl orthoformate (100g) were added to a 250ml reaction bottle and mixed well by stirring. Then, concentrated sulfuric acid (3.7g, 0.5 equivalents) was slowly added dropwise, and after addition, the reaction solution was stirred for 5 minutes. Then, iodobenzene diacetate (23.7g, 1 equivalent) was added and stirred for 15 minutes after addition. Concentrated sulfuric acid (3.7g, 0.5 equivalents) was slowly added dropwise, and after the addition of concentrated sulfuric acid, the mixture was heated to 45°C to 50°C and the temperature was maintained for 1 hour to allow the reaction to proceed. After cooling to room temperature, neutralize by adding an aqueous sodium bicarbonate solution, extract with dichloromethane to maintain the aqueous phase, acidify to pH 3-4, filter, wash the filter cake with water until the filtrate becomes nearly neutral, and air-dry at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 70.8% and a purity of 93.16%. II-A 15.7 g was obtained.

[0409] 2h:

[0410]

[0411] compound IA(20.0g, 1 equivalent) and trimethyl orthoformate (100g) were added to a 250ml reaction bottle and mixed well by stirring. Then, concentrated sulfuric acid (3.7g, 0.5 equivalents) was slowly added dropwise, and after adding, the reaction solution was stirred for 5 minutes. Then, iodobenzene diacetate (47.5g, 2 equivalents) was slowly added and stirred for 15 minutes after addition. After adding concentrated sulfuric acid (3.7g, 0.5 equivalents), the mixture was heated to 45°C to 50°C and maintained at that temperature for 1 hour to allow the reaction to proceed. After cooling to room temperature, neutralize by adding an aqueous sodium bicarbonate solution, extract with dichloromethane to maintain the aqueous phase, acidify to pH 3-4, filter, wash the filter cake with water until the filtrate becomes nearly neutral, and air-dry at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 71.9% and a purity of 93.68%. II-A 16.0 g was obtained.

[0412] 2i:

[0413]

[0414] compound IA(20.0g, 1 equivalent) and trimethyl orthoformate (100g) were added to a 250ml reaction bottle and mixed well by stirring. Then, concentrated sulfuric acid (3.7g, 0.5 equivalents) was slowly added, and after the dropwise addition, the reaction solution was stirred for 5 minutes. Then, iodobenzene diacetate (71.2g, 2 equivalents) was slowly added and stirred for 15 minutes after addition. Concentrated sulfuric acid (3.7g, 0.5 equivalents) was slowly added, and after the dropwise addition of concentrated sulfuric acid, the mixture was heated to 45°C to 50°C and the temperature was maintained for 1 hour to allow the reaction to proceed. After cooling to room temperature, neutralize by adding an aqueous sodium bicarbonate solution, extract with dichloromethane to maintain the aqueous phase, acidify to pH 3-4, filter, wash the filter cake with water until the filtrate becomes nearly neutral, and air-dry at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 71.7% and a purity of 93.01%. II-A 15.9 g was obtained.

[0415] 2j:

[0416]

[0417] compound IA (20.0g, 1 equivalent) and trimethyl orthoformate (100g) were added to a 250ml reaction bottle and mixed well by stirring. Then, concentrated sulfuric acid (7.4g, 1 equivalent) was slowly added, and after the dropwise addition, the reaction solution was stirred for 5 minutes. Then, iodobenzene diacetate (47.5g, 2 equivalents) was slowly added and stirred for 15 minutes after addition. Concentrated sulfuric acid (7.4g, 1 equivalent) was slowly added, and after the dropwise addition of concentrated sulfuric acid, the mixture was heated to 45°C to 50°C and the temperature was maintained for 1 hour to allow the reaction to proceed. After cooling to room temperature, neutralize by adding an aqueous sodium bicarbonate solution, extract with dichloromethane to maintain the aqueous phase, acidify to pH 3-4, filter, wash the filter cake with water until the filtrate becomes nearly neutral, and air-dry at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 72.3% and a purity of 94.28%. II-A 16.1 g was obtained.

[0418] 2k:

[0419]

[0420] compound IA (20.0g, 1 equivalent) and trimethyl orthoformate (100g) were added to a 250ml reaction bottle and mixed well by stirring. Then, concentrated sulfuric acid (11.1g, 1.5 equivalents) was slowly added, and after the dropwise addition, the reaction solution was stirred for 5 minutes. Then, iodobenzene diacetate (47.5g, 2 equivalents) was slowly added and stirred for 15 minutes after addition. Concentrated sulfuric acid (11.1g, 1.5 equivalents) was slowly added, and after the dropwise addition of concentrated sulfuric acid, the mixture was heated to 45°C to 50°C and the temperature was maintained for 1 hour to allow the reaction to proceed. After cooling to room temperature, neutralize by adding an aqueous sodium bicarbonate solution, extract with dichloromethane to maintain the aqueous phase, acidify to pH 3-4, filter, wash the filter cake with water until the filtrate becomes nearly neutral, and air-dry at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 72.9% and a purity of 94.64%. II-A 16.2 g was obtained.

[0421] 2l:

[0422]

[0423] compound IA(20.0g, 1 equivalent) and trimethyl orthoformate (100g) were added to a 250ml reaction bottle and mixed well by stirring. Then, concentrated sulfuric acid (14.8g, 2 equivalents) was slowly added, and after adding, the reaction solution was stirred for 5 minutes. Then, iodobenzene diacetate (47.5g, 2 equivalents) was slowly added and stirred for 15 minutes after addition. Concentrated sulfuric acid (14.8g, 2 equivalents) was slowly added, and after adding the concentrated sulfuric acid, the mixture was heated to 45°C to 50°C and the temperature was maintained for 1 hour to allow the reaction to proceed. After cooling to room temperature, neutralize by adding an aqueous sodium bicarbonate solution, extract with dichloromethane to maintain the aqueous phase, acidify to a pH of 3-4, filter, wash the filter cake with water until the filtrate becomes nearly neutral, and air-dry at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 72.3% and a purity of 93.45%. II-A 16.1 g was obtained.

[0424] 2m:

[0425]

[0426] compound IA (20.0g, 1 equivalent) and trimethyl orthoformate (60.0g) were added to a 250ml reaction bottle and stirred to mix evenly. Then, hydrochloric acid (30.1g, 1.5 equivalents) was slowly added, and after the dropwise addition, the reaction solution was stirred for 15 minutes. Then, iodobenzene diacetate (47.5g, 2 equivalents) was slowly added and stirred for 15 minutes after addition. Hydrochloric acid (30.1g, 1.5 equivalents) was slowly added, and after the addition of hydrochloric acid, the mixture was heated to 45°C to 50°C and maintained at that temperature for 1 hour to allow the reaction to proceed. Neutralized by adding an aqueous sodium bicarbonate solution, extracted with dichloromethane, maintained the aqueous phase, acidified to a pH of 3-4, filtered, the filter cake washed with water until the filtrate became nearly neutral, and air-dried at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 67.1% and a purity of 93.33%. II-A14.9g was obtained.

[0427] 2n:

[0428]

[0429] compound IA (20.0g, 1 equivalent) and trimethyl orthoformate (60.0g) were added to a 250ml reaction bottle and stirred to mix evenly. Then, 85% phosphoric acid (12.8g, 1.5 equivalents) was slowly added dropwise, and after adding, the reaction solution was stirred for 15 minutes. Then, iodobenzene diacetate (47.5g, 2 equivalents) was slowly added and stirred for 15 minutes after addition. After adding, 85% phosphoric acid (12.8g, 1.5 equivalents) was slowly added dropwise, and the mixture was heated to 45°C to 50°C and the temperature was maintained for 1 hour to allow the reaction to proceed. Neutralized by adding an aqueous sodium bicarbonate solution, extracted with dichloromethane, maintained the aqueous phase, acidified to a pH of 3-4, filtered, the filter cake washed with water until the filtrate became nearly neutral, and air-dried at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 64.5% and a purity of 91.79%. II-A 14.3g was obtained.

[0430] 2o:

[0431]

[0432] compound IA(20.0g, 1 equivalent) and trimethyl orthoformate (60.0g) were added to a 250ml reaction bottle and stirred to mix evenly. Then, acetic acid (10.8g, 1.5 equivalents) was slowly added, and after adding, the reaction solution was stirred for 15 minutes. Then, iodobenzenediacetate (47.5g, 2 equivalents) was slowly added and stirred for 15 minutes after addition. Acetic acid (10.8g, 1.5 equivalents) was slowly added, and after adding, the mixture was heated to 45°C to 50°C and the temperature was maintained for 1 hour to allow the reaction to proceed. Neutralized by adding an aqueous sodium bicarbonate solution, extracted with dichloromethane, maintained the aqueous phase, acidified to a pH of 3-4, filtered, the filter cake washed with water until the filtrate became nearly neutral, and air-dried at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 55.7% and a purity of 88.67%. II-A 12.4g was obtained.

[0433] 2p:

[0434]

[0435] compound IA(20.0 g, 1 equivalent) and trimethyl orthoformate (60 g) were added to a 250 ml reaction bottle and stirred to mix evenly, and then the reaction solution was cooled to 0°C to 10°C. Concentrated sulfuric acid (11.1 g, 1.5 equivalents) was slowly added dropwise at a temperature controlled below 10°C, and after adding, the reaction solution was stirred for 15 minutes, and iodobenzene diacetate (47.5 g, 2 equivalents) was slowly added within about 10 to 15 minutes at a temperature controlled below 20°C, and after adding, the reaction solution was stirred for 15 minutes. After cooling to 0°C to 10°C, concentrated sulfuric acid (11.1 g, 1.5 equivalents) was slowly added dropwise at a temperature controlled below 10°C, and after adding the concentrated sulfuric acid, the mixture was heated to 25°C to 30°C and the temperature was maintained for 1 hour to allow the reaction to proceed. Neutralized by adding an aqueous sodium bicarbonate solution, extracted with dichloromethane, maintained the aqueous phase, acidified to a pH of 3-4, filtered, the filter cake washed with water until the filtrate became nearly neutral, and air-dried at 60°C to a constant weight to obtain a yellowish-white compound with a yield of 73.1% and a purity of 94.96%. II-A 16.2g was obtained.

[0436] Table 2

[0437]

[0438] Preparation Examples 3a to 3g: Methyl 2-(10-oxo-9-oxa-1-axantracen-6-yl)propionate ( compound III-A ) and ethyl 2-(10-oxo-9-oxa-1-axantracen-6-yl)propionate ( compound III-B Manufacturing of )

[0439] 3a:

[0440]

[0441] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to reaction bottle A (250 ml) and mixed by stirring. Then, oxalyl chloride (12.6 g, 1.5 equivalents) was added dropwise at a temperature controlled to 15 to 25°C, and the temperature was maintained for 1 hour after addition. Additionally, anhydrous aluminum trichloride (17.7 g, 2 equivalents) and dichloromethane (100 ml) were added to reaction bottle B (500 ml) and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours; after the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution was stirred for 15 to 30 minutes, separated into layers, and the dichloromethane phase was retained. The aqueous phase was extracted with dichloromethane (40 ml), separated into layers, and then the dichloromethane phase was combined. The pH was adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, and the dichloromethane layer was washed once with purified water (100 ml). The dichloromethane was recovered by concentrating under reduced pressure; after the distillate no longer evaporated, methanol (100 ml) was added and the mixture was refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake was rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 86.8% and a purity of 99.55%. III-A 16.3g was obtained.

[0442] 3b:

[0443]

[0444] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to reaction bottle A (250 ml) and mixed by stirring. Then, oxalyl chloride (12.6 g, 1.5 equivalents) was added dropwise at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after adding. Additionally, anhydrous aluminum trichloride (26.6 g, 3 equivalents) and dichloromethane (100 ml) were added to reaction bottle B (500 ml) and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours after adding. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution was stirred for 15 to 30 minutes, separated into layers, and the dichloromethane phase was retained. The aqueous phase was extracted with dichloromethane (40 ml), separated into layers, and the dichloromethane phase was combined. The pH was adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, and the dichloromethane layer was washed once with purified water (100 ml). Subsequently, the solution was concentrated under reduced pressure to recover the dichloromethane. When the distillate no longer evaporated, methanol (100 ml) was added and the solution was refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake was washed with methanol and air-dried at 45°C to obtain a compound with a yield of 84.1% and a purity of 99.59%. III-A 15.8g was obtained.

[0445] 3c:

[0446]

[0447] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to reaction bottle A (250 ml) and mixed by stirring. Then, oxalyl chloride (12.6 g, 1.5 equivalents) was added dropwise at a temperature controlled to 15 to 25°C, and after adding, the temperature was maintained at 15 to 25°C for 1 hour. Additionally, anhydrous aluminum trichloride (35.4 g, 4 equivalents) and dichloromethane (100 ml) were added to reaction bottle B (500 ml) and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is maintained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, methanol (100 ml) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 84.3% and a purity of 99.54%. III-A 15.9g was obtained.

[0448] 3d:

[0449]

[0450] compound II-B (40.0g, 1 equivalent), dichloromethane (200ml), N,N- Dimethylformamide (0.9 g) was added to reaction bottle A in 500 ml and mixed by stirring. Then, oxalyl chloride (24.2 g, 1.5 equivalents) was added dropwise at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after adding. Additionally, anhydrous aluminum trichloride (33.9 g, 2 equivalents) and dichloromethane (200 ml) were added to reaction bottle B in 1000 ml and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is maintained, the aqueous phase is extracted with dichloromethane (80 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (200 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, methanol (200 ml) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 85.7% and a purity of 99.26%. III-B 32.2g was obtained.

[0451] 3e:

[0452]

[0453] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to 250 ml of reaction bottle A and mixed by stirring. Then, thionyl chloride (11.8 g, 1.5 equivalents) was added at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after dropwise addition. Additionally, anhydrous aluminum trichloride (17.7 g, 2 equivalents) and dichloromethane (100 ml) were added to 500 ml of reaction bottle B and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is maintained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, methanol (100 ml) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 87.1% and a purity of 99.67%. III-A 16.4g was obtained.

[0454] 3f:

[0455]

[0456] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to 250 ml of reaction bottle A and mixed by stirring. Then, thionyl chloride (11.8 g, 1.5 equivalents) was added at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after dropwise addition. Additionally, anhydrous aluminum trichloride (17.7 g, 2 equivalents) and dichloromethane (100 ml) were added to 500 ml of reaction bottle B and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is retained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, a methanol / dichloromethane mixed solvent (100 ml, solvent ratio 1:0.1) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 85.6% and a purity of 99.71%. III-A 16.1g was obtained.

[0457] 3g:

[0458]

[0459] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to 250 ml of reaction bottle A and mixed by stirring. Then, thionyl chloride (11.8 g, 1.5 equivalents) was added at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after dropwise addition. Additionally, anhydrous aluminum trichloride (17.7 g, 2 equivalents) and dichloromethane (100 ml) were added to 500 ml of reaction bottle B and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, and the dichloromethane phase is retained. The aqueous phase is extracted with dichloromethane (40 ml), separated into layers, and the dichloromethane phase is combined. The pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, and the dichloromethane layer is washed once with purified water (100 ml). The solution is concentrated under reduced pressure to recover the dichloromethane. When the distillate no longer evaporates, a methanol / dichloromethane mixed solvent (100 ml, solvent ratio 1:0.2) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 83.5% and a purity of 99.73%. III-A 15.7g was obtained.

[0460] Comparative Examples 3h to 3p

[0461] 3h:

[0462]

[0463] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to reaction bottle A (250 ml) and mixed by stirring. Then, oxalyl chloride (9.3 g, 1.1 equivalents) was added dropwise at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after adding. Additionally, anhydrous aluminum trichloride (9.7 g, 1.1 equivalents) and dichloromethane (100 ml) were added to reaction bottle B (500 ml) and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is maintained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, methanol (100 ml) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 76.8% and a purity of 91.26%. III-A 14.4g was obtained.

[0464] 3i:

[0465]

[0466] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to reaction bottle A (250 ml) and mixed by stirring. Then, oxalyl chloride (12.6 g, 1.5 equivalents) was added dropwise at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after adding. Additionally, anhydrous aluminum trichloride (9.7 g, 1.1 equivalents) and dichloromethane (100 ml) were added to reaction bottle B (500 ml) and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is maintained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, methanol (100 ml) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 79.2% and a purity of 94.07%. III-A 14.9g was obtained.

[0467] 3j:

[0468]

[0469] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to reaction bottle A (250 ml) and mixed by stirring. Then, oxalyl chloride (16.9 g, 2 equivalents) was added dropwise at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after adding. Additionally, anhydrous aluminum trichloride (9.7 g, 1.1 equivalents) and dichloromethane (100 ml) were added to reaction bottle B (500 ml) and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is maintained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, methanol (100 ml) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 78.7% and a purity of 94.11%. III-A 14.8g was obtained.

[0470] 3k:

[0471]

[0472] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to reaction bottle A (250 ml) and mixed by stirring. Then, oxalyl chloride (25.3 g, 3 equivalents) was added dropwise at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after adding. Additionally, anhydrous aluminum trichloride (9.7 g, 1.1 equivalents) and dichloromethane (100 ml) were added to reaction bottle B (500 ml) and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is maintained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, methanol (100 ml) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 78.2% and a purity of 93.84%. III-A 14.7g was obtained.

[0473] 3l:

[0474]

[0475] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to reaction bottle A (250 ml) and mixed by stirring. Then, oxalyl chloride (12.6 g, 1.5 equivalents) was added dropwise at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after adding. Additionally, anhydrous aluminum trichloride (13.3 g, 1.5 equivalents) and dichloromethane (100 ml) were added to reaction bottle B (500 ml) and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is maintained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, methanol (100 ml) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 81.8% and a purity of 98.57%. III-A 15.4g was obtained.

[0476] 3m:

[0477]

[0478] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to reaction bottle A (250 ml) and mixed by stirring. Oxalyl chloride (12.6 g, 1.5 equivalents) was added dropwise at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after adding. Additionally, anhydrous aluminum trichloride (44.3 g, 5 equivalents) and dichloromethane (100 ml) were added to reaction bottle B (500 ml) and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is maintained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, methanol (100 ml) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 85.1% and a purity of 98.71%. III-A 16.0g was obtained.

[0479] 3n:

[0480]

[0481] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to reaction bottle A (250 ml) and mixed by stirring. Then, thionyl chloride (11.8 g, 1.5 equivalents) was added at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after dropwise addition. Additionally, titanium tetrachloride (25.2 g, 2 equivalents) and dichloromethane (100 ml) were added to reaction bottle B (500 ml) and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is maintained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, methanol (100 ml) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 72.4% and a purity of 95.43%. III-A 13.6g was obtained.

[0482] 3o:

[0483]

[0484] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to 250 ml of reaction bottle A and mixed by stirring. Then, thionyl chloride (11.8 g, 1.5 equivalents) was added at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after dropwise addition. Additionally, anhydrous aluminum trichloride (17.7 g, 2 equivalents) and dichloromethane (100 ml) were added to 500 ml of reaction bottle B and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. After addition, the reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is retained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, a methanol / dichloromethane mixed solvent (100 ml, solvent ratio 1:0.3) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 79.9% and a purity of 99.78%. III-A 15.0g was obtained.

[0485] 3p:

[0486]

[0487] compound II-A (20.0g, 1 equivalent), dichloromethane (100ml), N,N- Dimethylformamide (0.5 g) was added to 250 ml of reaction bottle A and mixed by stirring. Then, thionyl chloride (11.8 g, 1.5 equivalents) was added at a temperature controlled to 15 to 25°C, and the temperature was maintained at 15 to 25°C for 1 hour after dropwise addition. Additionally, anhydrous aluminum trichloride (17.7 g, 2 equivalents) and dichloromethane (100 ml) were added to 500 ml of reaction bottle B and mixed by stirring. The acyl chloride solution from reaction bottle A was transferred dropwise to reaction bottle B at a temperature controlled to 15 to 25°C, and the reaction was carried out by maintaining the temperature for 1 to 1.5 hours. After the reaction was completed, the reaction solution was cooled to -10°C. The reaction solution was slowly transferred to cold water and quenched at a temperature controlled to below 20°C. The reaction solution is stirred for 15 to 30 minutes, separated into layers, the dichloromethane phase is retained, the aqueous phase is extracted with dichloromethane (40 ml), separated into layers, the dichloromethane phase is combined, the pH is adjusted to 7-8 with a sodium bicarbonate solution, separated into layers, the dichloromethane layer is washed once with purified water (100 ml), and the dichloromethane is recovered by concentrating under reduced pressure. When the distillate no longer evaporates, a methanol / dichloromethane mixed solvent (100 ml, solvent ratio 1:0.4) is added and the mixture is refined at 20 to 25°C for 5 to 6 hours. After filtration, the filter cake is rinsed with methanol and air-dried at 45°C to obtain a compound with a yield of 77.0% and a purity of 99.81%. III-A 14.5g was obtained.

[0488] Table 3

[0489]

[0490] Preparation Examples 4a to 4c: Methyl 2-(10-hydroxyl-9-oxa-1-axantracen-6-yl)propionate (compound IV-A ) and ethyl 2-(10-hydroxyl-9-oxo-1-axantracen-6-yl)propionate (compounds IV-B Manufacturing of )

[0491] 4a:

[0492]

[0493] compound III-A (20.0g, 1 equivalent), dichloromethane (80ml), and methanol (80ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution, sodium borohydride (2.7g, 1 equivalent) is slowly added within about 30 minutes, the temperature is maintained at 25°C to 30°C for 8 hours, then lowered to -5°C to 5°C, and a 30% aqueous acetic acid solution is slowly added dropwise to a pH of 5.5 to 6.5, and after adding, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (120ml) is added and stirred to separate into layers, and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (40 ml), the dichloromethane phase was combined, washed once with saturated aqueous sodium bicarbonate (20 ml), and washed again with purified water (40 ml). The resulting dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (20.0 g), which was added to a methanol / acetone mixed solution (50 ml / 50 ml) and dissolved and dispersed under stirring for 15 minutes at 25°C to 30°C to obtain a clear yellowish-green solution. Purified water (200 ml) was added dropwise to crystallize for 2 hours, and after suction filtration, the filter cake was washed with purified water and vacuum dried in the dark at 40°C to obtain a compound with a yield of 81.5% and a purity of 96.72%. IV-A 16.4g was obtained.

[0494] 4b:

[0495]

[0496] compound III-A(20.0g, 1 equivalent), dichloromethane (80ml), and methanol (80ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution, sodium borohydride (2.7g, 1 equivalent) is slowly added within about 30 minutes, and after addition, the temperature is maintained at 35°C to 40°C for 6 hours, then lowered to -5°C to 5°C, and a 30% aqueous acetic acid solution is slowly added dropwise to a pH of 5.5 to 6.5, and after addition, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (120ml) is added and stirred to separate into layers, and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (40 ml), the dichloromethane phase was combined, washed once with saturated aqueous sodium bicarbonate (20 ml), and washed again with purified water (40 ml). The resulting dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (20.0 g), which was added to a methanol / acetone mixed solution (50 ml / 50 ml) and dissolved and dispersed under stirring for 15 minutes at 25°C to 30°C to obtain a clear yellowish-green solution. Purified water (200 ml) was added dropwise to crystallize for 2 hours, and after suction filtration, the filter cake was washed with purified water and vacuum dried in the dark at 40°C to obtain a compound with a yield of 82.5% and a purity of 98.46%. IV-A 16.6g was obtained.

[0497] 4c:

[0498]

[0499] compound III-B(30.0g, 1 equivalent), dichloromethane (120ml), and methanol (120ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution; sodium borohydride (3.8g, 1 equivalent) is slowly added within about 30 minutes, and after addition, the temperature is maintained at 35°C to 40°C for 6 hours, then lowered to -5°C to 5°C, the reaction solution is transferred to a 1L beaker, and a 30% aqueous acetic acid solution is slowly added dropwise to reach a pH of 5.5-6.5; after addition, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (180ml) is added, and the mixture is stirred to separate into layers and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (60 ml), the dichloromethane phase was combined, washed once with a saturated aqueous sodium bicarbonate solution (30 ml), and washed again once with purified water (60 ml). The obtained dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (30.0 g), which was added to a methanol / acetone mixed solution (75 ml / 75 ml) and dissolved and dispersed under stirring for 15 minutes at 20°C to 30°C to obtain a clear yellowish-green solution. Purified water (300 ml) was slowly added dropwise to crystallize for 2 hours, and after suction filtration, the filter cake was washed with purified water and vacuum dried in the dark at 40°C to obtain a compound with a yield of 79.8% and a purity of 98.77%. IV-B 24.1g was obtained.

[0500] Comparative Examples 4d to 4l

[0501] 4d:

[0502]

[0503] compound III-A(20.0g, 1 equivalent), dichloromethane (80ml), and methanol (80ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution, sodium borohydride (1.3g, 0.5 equivalents) is slowly added within about 30 minutes, and after addition, the temperature is maintained at 15°C to 20°C for 12 hours, then lowered to -5°C to 5°C, and a 30% aqueous acetic acid solution is slowly added dropwise to a pH of 5.5 to 6.5, and after addition, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (120ml) is added and stirred to separate into layers, and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (40 ml), the dichloromethane phase was combined, and washed once with saturated aqueous sodium bicarbonate (20 ml); and washed again once with purified water (40 ml). The resulting dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (20.0 g), which was added to acetone (100 ml) and dissolved and dispersed under stirring for 15 minutes at 25°C to 30°C to obtain a transparent yellowish-green solution. Purified water (200 ml) was added dropwise and crystallized for 2 hours; after suction filtration, the filter cake was washed with purified water and vacuum dried in a dark place at 40°C to obtain a compound with a yield of 74.7% and a purity of 89.86%. IV-A 15.0g was obtained.

[0504] 4e:

[0505]

[0506] compound III-A(20.0g, 1 equivalent), dichloromethane (80ml), and methanol (80ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution, sodium borohydride (1.6g, 0.6 equivalents) is slowly added within about 30 minutes, and after addition, the temperature is maintained at 15°C to 20°C for 12 hours, then lowered to -5°C to 5°C, and a 30% aqueous acetic acid solution is slowly added dropwise to a pH of 5.5 to 6.5, and after addition, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (120ml) is added and stirred to separate into layers, and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (40 ml), the dichloromethane phase was combined, and washed once with saturated aqueous sodium bicarbonate (20 ml); and washed again once with purified water (40 ml). The resulting dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (20.0 g), which was added to acetone (100 ml) and dissolved and dispersed under stirring for 15 minutes at 25°C to 30°C to obtain a transparent yellowish-green solution. Purified water (200 ml) was added dropwise and crystallized for 2 hours; after suction filtration, the filter cake was washed with purified water and vacuum dried in a dark place at 40°C to obtain a compound with a yield of 76.4% and a purity of 92.58%. IV-A 15.4g was obtained.

[0507] 4f:

[0508]

[0509] compound III-A(20.0g, 1 equivalent), dichloromethane (80ml), and methanol (80ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution, sodium borohydride (2.7g, 1 equivalent) is slowly added within about 30 minutes, and after addition, the temperature is maintained at 15°C to 20°C for 10 hours, then lowered to -5°C to 5°C, and a 30% aqueous acetic acid solution is slowly added dropwise to a pH of 5.5 to 6.5, and after addition, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (120ml) is added and stirred to separate into layers, and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (40 ml), the dichloromethane phase was combined, washed once with saturated aqueous sodium bicarbonate (20 ml), and washed again with purified water (40 ml). The resulting dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (20.0 g), which was added to acetone (100 ml) and dissolved and dispersed under stirring for 15 minutes at 25°C to 30°C to obtain a clear yellowish-green solution. Purified water (200 ml) was added dropwise and crystallized for 2 hours; after suction filtration, the filter cake was washed with purified water and vacuum dried in the dark at 40°C to obtain a compound with a yield of 81.4% and a purity of 94.86%. IV-A 16.4g was obtained.

[0510] 4g:

[0511]

[0512] compound III-A(20.0g, 1 equivalent), dichloromethane (80ml), and methanol (80ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution, sodium borohydride (2.7g, 1 equivalent) is slowly added within about 30 minutes, and after addition, the temperature is maintained at 15°C to 20°C for 10 hours, then lowered to -5°C to 5°C, and a 30% aqueous acetic acid solution is slowly added dropwise to a pH of 5.5 to 6.5, and after addition, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (120ml) is added and stirred to separate into layers, and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (40 ml), the dichloromethane phase was combined, washed once with saturated aqueous sodium bicarbonate (20 ml), and washed again with purified water (40 ml). The obtained dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (20.0 g), which was added to methanol (100 ml) and dissolved and dispersed under stirring for 15 minutes at 25°C to 30°C to obtain a yellowish-green transparent solution. Purified water (200 ml) was added dropwise and crystallized for 2 hours; after suction filtration, the filter cake was washed with purified water and vacuum dried in a dark place at 40°C to obtain a compound with a yield of 83.5% and a purity of 93.97%. IV-A 17.8g was obtained.

[0513] 4h:

[0514]

[0515] compound III-A(20.0g, 1 equivalent), dichloromethane (80ml), and methanol (80ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution, sodium borohydride (2.7g, 1 equivalent) is slowly added within about 30 minutes, and after addition, the temperature is maintained at 15°C to 20°C for 10 hours, then lowered to -5°C to 5°C, and a 30% aqueous acetic acid solution is slowly added dropwise to a pH of 5.5 to 6.5, and after addition, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (120ml) is added and stirred to separate into layers, and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (40 ml), the dichloromethane phase was combined, washed once with saturated aqueous sodium bicarbonate (20 ml), and washed again with purified water (40 ml). The obtained dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (20.0 g), which was added to a methanol / acetone mixed solution (50 ml / 50 ml) and dissolved and dispersed under stirring for 15 minutes at 25°C to 30°C to obtain a clear yellowish-green solution. Purified water (200 ml) was added dropwise to crystallize for 2 hours, and after suction filtration, the filter cake was washed with purified water and vacuum dried in the dark at 40°C to obtain a compound with a yield of 81.0% and a purity of 95.23%. IV-A 16.3g was obtained.

[0516] 4i:

[0517]

[0518] compound III-A(20.0g, 1 equivalent), dichloromethane (80ml), and methanol (80ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution, potassium borohydride (3.8g, 1 equivalent) is slowly added within about 30 minutes, and after addition, the temperature is maintained at 15°C to 20°C for 10 hours, then lowered to -5°C to 5°C, and a 30% aqueous acetic acid solution is slowly added dropwise to a pH of 5.5 to 6.5, and after addition, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (120ml) is added and stirred to separate into layers, and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (40 ml), the combined dichloromethane phase was combined, washed once with saturated aqueous sodium bicarbonate (20 ml), and washed again with purified water (40 ml). The obtained dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (20.0 g), which was added to a methanol / acetone mixed solution (50 ml / 50 ml) and dissolved and dispersed under stirring for 15 minutes at 25°C to 30°C to obtain a clear yellowish-green solution. Purified water (200 ml) was slowly added dropwise to crystallize for 2 hours, and after suction filtration, the filter cake was washed with purified water and vacuum dried in the dark at 40°C to obtain a compound with a yield of 80.0% and a purity of 95.28%. IV-A 16.1g was obtained.

[0519] 4j:

[0520]

[0521] compound III-A(20.0g, 1 equivalent), dichloromethane (80ml), and methanol (80ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution, lithium borohydride (3.8g, 1 equivalent) is slowly added within about 30 minutes, and after addition, the temperature is maintained at 15°C to 20°C for 10 hours, then lowered to -5°C to 5°C, and a 30% aqueous acetic acid solution is slowly added dropwise to a pH of 5.5 to 6.5, and after addition, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (120ml) is added and stirred to separate into layers, and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (40 ml), the dichloromethane phase was combined, washed once with saturated aqueous sodium bicarbonate (20 ml), and washed again with purified water (40 ml). The obtained dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (20.0 g), which was added to a methanol / acetone mixed solution (50 ml / 50 ml) and dissolved and dispersed under stirring for 15 minutes at 25°C to 30°C to obtain a clear yellowish-green solution. Purified water (200 ml) was added dropwise to crystallize for 2 hours, and after suction filtration, the filter cake was washed with purified water and vacuum dried in the dark at 40°C to obtain a compound with a yield of 78.7% and a purity of 94.03%. IV-A 15.9g was obtained.

[0522] 4k:

[0523]

[0524] compound III-A(20.0g, 1 equivalent), dichloromethane (80ml), and methanol (80ml) are added to a 500ml reaction flask and stirred at 15°C to 30°C for 5 to 10 minutes to dissolve and obtain a clear solution, sodium borohydride (3.8g, 1 equivalent) is slowly added within about 30 minutes, and after addition, the temperature is maintained at 20°C to 25°C for 8 hours, then lowered to -5°C to 5°C, and a 30% aqueous acetic acid solution is slowly added dropwise to a pH of 5.5 to 6.5, and after addition, the reaction solution is stirred at -5°C to 5°C for 15 minutes, purified water (120ml) is added and stirred to separate into layers, and the organic phase is separated; The aqueous phase was extracted once with dichloromethane (40 ml), the dichloromethane phase was combined, washed once with saturated aqueous sodium bicarbonate (20 ml), and washed again with purified water (40 ml). The obtained dichloromethane solution was concentrated and dried (-0.09 MPa) at 35°C under reduced pressure to obtain a yellowish-green oil (20.0 g), which was added to a methanol / acetone mixed solution (50 ml / 50 ml) and dissolved and dispersed under stirring for 15 minutes at 25°C to 30°C to obtain a clear yellowish-green solution. Purified water (200 ml) was added dropwise to crystallize for 2 hours, and after suction filtration, the filter cake was washed with purified water and vacuum dried in a dark place at 40°C to obtain a compound with a yield of 81.5% and a purity of 95.86%. IV-A 16.4g was obtained.

[0525] Table 4

[0526]

[0527] Preparation Examples 5a to 5g: Preparation of Pranoprofen

[0528] 5a:

[0529]

[0530] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added and reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500 ml beaker, purified water (300 ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100 ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 14.3 g of crude pranopropene with a yield of approximately 79.9% and a purity of 99.62%. The crude product of pranopropene was recrystallized with methanol to obtain a final pranopropene product with a purity exceeding 99.9% and a single impurity content of less than 0.05%.

[0531] 5b:

[0532]

[0533] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 60°C to 65°C and reacted for 2.5 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added, and reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500 ml beaker, purified water (300 ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100 ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 14.4 g of crude pranopropene with a yield of approximately 80.5% and a purity of 99.27%. The crude product of pranopropene was recrystallized with methanol to obtain a final pranopropene product with a purity of over 99.9% and a single impurity content of less than 0.05%.

[0534] 5c:

[0535]

[0536] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 70°C to 75°C and reacted for 2.5 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added, and reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500 ml beaker, purified water (300 ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100 ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 14.3 g of crude pranopropene with a yield of approximately 79.9% and a purity of 99.48%. The crude product of pranopropene was recrystallized with methanol to obtain a final pranopropene product with a purity exceeding 99.9% and a single impurity content of less than 0.05%.

[0537] 5d:

[0538]

[0539] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a potassium hydroxide solution prepared with potassium hydroxide (15.7g, 4 equivalents) and purified water (40ml) was added, and reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500 ml beaker, purified water (300 ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100 ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 14.2 g of crude pranopropene with a yield of approximately 79.4% and a purity of 99.63%. The crude product of pranopropene was recrystallized with methanol to obtain a final pranopropene product with a purity of over 99.9% and a single impurity content of less than 0.05%.

[0540] 5e:

[0541]

[0542] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added and reacted at 40°C to 45°C for 2 hours. The reaction solution was transferred to a 500 ml beaker, purified water (300 ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100 ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 14.6 g of crude pranopropene with a yield of approximately 81.6% and a purity of 99.68%. The crude product of pranopropene was recrystallized with methanol to obtain a final pranopropene product with a purity of over 99.9% and a single impurity content of less than 0.05%.

[0543] 5f:

[0544]

[0545] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added and reacted at 40°C to 45°C for 2 hours. The reaction solution was transferred to a 500 ml beaker, purified water (300 ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100 ml). After separating the aqueous phase, the pH was adjusted to 5-6 with 10% dilute hydrochloric acid, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 14.6 g of crude pranopropene with a yield of approximately 81.6% and a purity of 99.67%. The crude product of pranopropene was recrystallized with methanol to obtain a final pranopropene product with a purity of over 99.9% and a single impurity content of less than 0.05%.

[0546] 5g:

[0547]

[0548] compound IV-B(20.0g, 1 equivalent), hydrochloric acid (23.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask and stirred to dissolve. The mixture was heated to 80°C to 85°C and reacted under reflux for 2 hours. The mixture was then concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve. Subsequently, a sodium hydroxide solution prepared with sodium hydroxide (10.7g, 4 equivalents) and purified water (40ml) was added and reacted at 40°C to 45°C for 2 hours. The reaction solution was transferred to a 500 ml beaker, purified water (300 ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100 ml). After separating the aqueous phase, the pH was adjusted to 5-6 with 10% dilute hydrochloric acid, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.6 g of crude pranopropene with a yield of approximately 79.5% and a purity of 99.62%. The crude product of pranopropene was recrystallized with methanol to obtain a final pranopropene product with a purity of over 99.9% and a single impurity content of less than 0.05%.

[0549] Comparative Examples 5h to 5t

[0550] 5h:

[0551]

[0552] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (10.6g, 1.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask and stirred to dissolve, heated to 50°C to 55°C and reacted for 4 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added and reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.1g of zopranopropene with a yield of approximately 73.2% and a purity of 97.76%.

[0553] 5i:

[0554]

[0555] compound IV-A(20.0g, 1 equivalent), isopropanol, hydrogen chloride (29.0g, 13.2wt.%, 1.5 equivalents), and isopropanol (208ml) were added to a 250ml reaction flask and stirred to dissolve. The mixture was heated to 50°C to 55°C and reacted for 4 hours. At 55°C, the mixture was concentrated under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve. Subsequently, a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added, and the mixture was reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.1g of zopranopropene with a yield of approximately 73.2% and a purity of 97.78%.

[0556] 5j:

[0557]

[0558] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (14.2g, 2 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask and stirred to dissolve, heated to 50°C to 55°C and reacted for 4 hours, and then concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, and then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added and reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.3g of zopranopropene with a yield of approximately 74.3% and a purity of 98.12%.

[0559] 5k:

[0560]

[0561] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (17.7g, 2.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 50°C to 55°C and reacted for 4 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added, and reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.6g of zopranopropene with a yield of approximately 76.0% and a purity of 98.63%.

[0562] 5l:

[0563]

[0564] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 50°C to 55°C and reacted for 4 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added, and reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.7g of zopranopropene with a yield of approximately 76.6% and a purity of 98.77%.

[0565] 5m:

[0566]

[0567] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium carbonate solution prepared with sodium carbonate (29.7g, 4 equivalents) and purified water (40ml) was added and reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.9g of zopranopropene with a yield of approximately 77.7% and a purity of 98.79%.

[0568] 5n:

[0569]

[0570] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a potassium carbonate solution prepared with potassium carbonate (38.8g, 4 equivalents) and purified water (40ml) was added, and reacted at 50°C to 55°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.8g of zopranopropene with a yield of approximately 77.1% and a purity of 98.92%.

[0571] 5o:

[0572]

[0573] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added, and reacted at 60°C to 65°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 5-6 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 14.0g of zopranopropene with a yield of approximately 78.2% and a purity of 98.86%.

[0574] 5p:

[0575]

[0576] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added and reacted at 40°C to 45°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 5-6 with 10% dilute sulfuric acid, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.7g of zopranopropene with a yield of approximately 76.6% and a purity of 98.81%.

[0577] 5q:

[0578]

[0579] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added and reacted at 40°C to 45°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 5-6 with 10% dilute phosphoric acid, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.9g of zopranopropene with a yield of approximately 77.7% and a purity of 98.64%.

[0580] 5r:

[0581]

[0582] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added and reacted at 40°C to 45°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 4-5 with 10% dilute hydrochloric acid, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 14.7g of zopranopropene with a yield of approximately 82.1% and a purity of 98.74%.

[0583] 5s:

[0584]

[0585] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added and reacted at 40°C to 45°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 6-7 with 10% dilute hydrochloric acid, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 13.3g of zopranopropene with a yield of approximately 74.3% and a purity of 99.77%.

[0586] 5t:

[0587]

[0588] compound IV-A(20.0g, 1 equivalent), hydrochloric acid (24.8g, 3.5 equivalents), and isopropanol (240ml) were added to a 250ml reaction flask, stirred to dissolve, heated to 80°C to 85°C and reacted under reflux for 2 hours, and concentrated at 55°C under reduced pressure until no distillate was removed by distillation to obtain foaming oil (24g). After cooling to room temperature, methanol (10ml) was added and stirred to dissolve, then a sodium hydroxide solution prepared with sodium hydroxide (11.2g, 4 equivalents) and purified water (40ml) was added and reacted at 40°C to 45°C for 2 hours. The reaction solution was transferred to a 500ml beaker, purified water (300ml) was added, and the aqueous phase was extracted four times with ethyl acetate (100ml). After separating the aqueous phase, the pH was adjusted to 3-4 with 10% dilute hydrochloric acid, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain 15.0g of zopranopropene with a yield of approximately 83.8% and a purity of 98.53%.

[0589] Table 5

[0590]

[0591] Experimental Example 1: Structural Characterization

[0592] Pranoprofen samples were synthesized according to the process described above in the present invention, and the synthesis process of this sample batch was carried out according to the manufacturing conditions of 1a, 2c, 3c, 4b, and 5a. Standard products of pranoprofen were purchased directly from the Chinese National Institute for Food and Drug Control.

[0593] Structural verification was performed.

[0594] Elemental composition of compounds:

[0595] (1) High-resolution mass spectrometry (HRMS)

[0596] Device Model: Bruker SolariX 7.0T (FT-ICR MS).

[0597] Test conditions: ESI ionization mode.

[0598] Test results: As shown in Fig. 1. The test results show that the quasimolecular ion peak m / z 254.081876 in the high-resolution mass spectrum is [MH] - It was a peak, and the elemental composition was C 15 H 12 Since it is NO3, the elemental composition of the sample is C 15 H 13 It was NO3, which indicated that it matched the elemental composition of the molecule's free base moiety.

[0599] (2) Infrared spectrum (IR)

[0600] Device Model: Bruker IFS-55 Infrared Photometer (Revised in accordance with General Regulations 0402 of the Chinese Pharmacopoeia 2015).

[0601] Experimental method: KBr tablet method.

[0602] Experimental Results: The measured data are shown in Table 6 below. The standard infrared spectrum is shown in Fig. 2a. The infrared spectrum of the sample is shown in Fig. 2b.

[0603] Table 6: Infrared spectrum determination data of the sample

[0604]

[0605] analyze:

[0606] a. 3427.6cm -1 The absorption peak at is the -OH stretching vibration peak, indicating that a carboxyl group may be present in the molecule.

[0607] b. 2968.2cm -1 , 2943.1cm -1 , 2881.9cm -1 and 1465cm -1 to 1376cm -1The absorption peak at is the CH stretching and bending vibration peak, indicating that methyl and methylene groups may be present in the molecule.

[0608] c. 1706.7cm -1 The absorption peak at is the C=O stretching vibration peak, indicating that a carbonyl group may be present in the molecule.

[0609] d. 1608.6cm -1 , 1584.3cm -1 , and 1499.5cm -1 The absorption peak at is the C=C stretching vibration peak of the benzene ring, and at 767.8 cm⁻¹ -1 is the CH bending vibration peak of the benzene ring, and 804.0 cm⁻¹ -1 This is the C=C bending vibration peak of the benzene ring, indicating the presence of a benzene ring in the molecule.

[0610] Conclusion: The position, peak shape, and intensity of the absorption peak of the functional group in the infrared spectrum of the sample were consistent with the molecular structure of pranopropene; the infrared spectrum of the sample was consistent with the infrared spectrum of the reference substance and the corresponding spectrum of the Japanese Pharmacopoeia JP17 version.

[0611] (3) Ultraviolet spectrum (UV)

[0612] Device Model: Agilent Cary-60 UV Spectrometer

[0613] Solution preparation: Take 0.02g of this sample, dissolve it in a 1 mol / L hydrochloric acid solution, and dilute it to 100ml to make the mother liquor; take 10ml of the mother liquor, add water to dilute it to 100ml to make the neutral test sample.

[0614] 10 ml of the above mother liquor was collected and diluted to 100 ml by adding a 1 mol / L hydrochloric acid solution to prepare an acidic test sample; 10 ml of the above mother liquor was collected and diluted to 100 ml by adding a 1 mol / L sodium hydroxide solution to prepare an alkaline test sample. The test results are shown in Table 7 and Figures 3a to 3f below.

[0615] Table 7: UV measurement results of samples and standard products

[0616]

[0617] Analysis: In the UV spectrum of the sample, the peak shape and maximum absorption wavelength of the sample matched the peak shape and maximum absorption wavelength of the reference material.

[0618] Conclusion: The UV absorption of the sample was consistent with the molecular structure of pranopropene; the UV spectrum of the sample was consistent with the UV spectrum of the reference substance.

[0619] (4) Nuclear magnetic resonance (NMR)

[0620] 1 H-NMR

[0621] Device Model: Bruker AV-600 Nuclear Magnetic Resonance Device.

[0622] Test conditions: Solvent DMSO-d6, TMS internal standard.

[0623] The test data is shown in Table 8 below.

[0624]

[0625] Table 8: Analysis of NMR H spectrum data of the samples

[0626]

[0627] analyze:

[0628] The single peak at δ12.34 ppm was a carboxyl hydrogen.

[0629] The 1H of δ7.09 ppm was a hydrogen at the 8-position of the benzene ring.

[0630] The 1H of δ7.16 ppm was a hydrogen at the 7th position of the benzene ring.

[0631] The 1H of δ7.18 was a hydrogen at the 5-position of the benzene ring.

[0632] The 1H of δ7.15 ppm was a hydrogen at the 3-position of the pyridine ring.

[0633] The 1H of δ7.72 ppm was a hydrogen at the 4-position of the pyridine ring.

[0634] The 1H of δ8.13 ppm was a hydrogen on the pyridine ring at the 2-position.

[0635] The 2H singlet at δ4.11 ppm was a hydrogen on the methylene phase at the 10-position.

[0636] The 1H quartet at δ3.66 ppm was an isopropyl hydrogen at the 15-position, which was bonded to a methyl hydrogen at the 17-position and was a quartet resulting from cleavage.

[0637] The 3H doublet at δ1.36 ppm was a methyl hydrogen at the 17th position, which was bonded to an isopropyl hydrogen at the 15th position and was a doublet resulting from cleavage.

[0638] Conclusion: of the sample 1 The H-NMR spectrum data matched the structure of pranopropene, and the spectrum of the sample matched the spectrum of the reference substance.

[0639] 13 C-NMR

[0640] Device Model: Bruker AV-600 Nuclear Magnetic Resonance Imaging System.

[0641] Test conditions: Solvent DMSO-d6, TMS internal standard.

[0642] The test data is shown in Table 9 below.

[0643] Table 9: Analysis of NMR C spectrum data of the samples

[0644]

[0645] analyze:

[0646] The pranopropene molecule contains 15 carbon atoms, including 1 primary carbon, 1 secondary carbon, 7 tertiary carbons, and 6 quaternary carbons; it contains 13 hydrogen atoms, and the analysis results are as follows:

[0647] 1. The carbon at δ175.39 ppm was a quaternary carbon atom, which was associated with hydrogen atoms on the carbons at positions 15 and 17 in the HMBC spectrum and could be identified as the carboxyl carbon at position 16.

[0648] 2. The carbon at δ157.83 ppm was a quaternary carbon atom, which was associated with hydrogen atoms in the pyridine ring at positions 2 and 4 and hydrogen atoms in the methylene at position 10 in the HMBC spectrum, and could be identified as an oxygen-bonded pyridine ring carbon at position 11.

[0649] 3. The carbon at δ150.03 ppm was a quaternary carbon atom, which was associated with hydrogen atoms on the benzene ring at positions 5, 7, and 8 and hydrogen atoms on the methylene carbon at position 10 in the HMBC spectrum, and could be identified as an oxygen-bonded benzene ring carbon at position 14.

[0650] 4. The carbon at δ136.71 ppm was a quaternary carbon atom, which was associated with the hydrogen on the benzene ring carbon at position 7, the hydrogen on the isopropyl carbon at position 15, and the hydrogen on the methyl carbon at position 17 in the HMBC spectrum, and could be identified as the benzene ring carbon at position 6.

[0651] 5. The carbon at δ120.00 ppm was a quaternary carbon atom, which was associated with the hydrogen on the 8-position benzene ring carbon and the hydrogen on the 10-position methylene carbon in the HMBC spectrum, and could be identified as the 14-position benzene ring carbon.

[0652] 6. The carbon at δ115.62 ppm was a quaternary carbon atom, which was associated with the hydrogen on the 4-position pyridine ring carbon and the hydrogen on the 10-position methylene carbon in the HMBC spectrum and could be identified as the 12-position pyridine ring carbon.

[0653] 7. The carbon at δ146.26 ppm was a tertiary carbon atom, which was associated with a hydrogen on the 2nd-position pyridine ring carbon in the HSQC spectrum and with a hydrogen atom on the 3rd-position and 4th-position pyridine ring carbon atoms in the HMBC spectrum, and could be identified as the 2nd-position pyridine ring carbon.

[0654] 8. The carbon at δ138.89 ppm was a tertiary carbon atom, which was associated with a hydrogen on the 4th-position pyridine ring carbon in the HSQC spectrum, and with a hydrogen on the 2nd-position pyridine ring carbon and a hydrogen on the 10th-position methylene carbon in the HMBC spectrum, and could be identified as a 4th-position pyridine ring carbon.

[0655] 9. The carbon at δ127.79 ppm was a tertiary carbon atom, which was associated with a hydrogen on the 5-position benzene ring carbon in the HSQC spectrum, and with a 10-position methylene hydrogen and a 15-position isopropyl hydrogen in the HMBC spectrum, and could be identified as the 5-position benzene ring carbon.

[0656] 10. The carbon at δ127.01 ppm was a tertiary carbon atom, which was associated with a hydrogen on the 7th-position benzene ring carbon in the HSQC spectrum, and with a hydrogen on the 5th-position benzene ring carbon and a 15th-position isopropyl hydrogen in the HMBC spectrum, and could be identified as the 7th-position benzene ring carbon.

[0657] 11. The carbon at δ120.27 ppm was a tertiary carbon atom, which was associated with a hydrogen on the pyridine ring carbon at position 3 in the HSQC spectrum and with a methylene hydrogen at position 10 in the HMBC spectrum, and could be identified as the pyridine ring carbon at position 3.

[0658] 12. The carbon at δ116.41 ppm was a tertiary carbon atom, which was associated with a hydrogen on the 8th-position benzene ring carbon in the HSQC spectrum and with the absence of hydrogen in the HMBC spectrum, and could be identified as the 8th-position benzene ring carbon.

[0659] 13. The carbon at δ27.19 ppm was a tertiary carbon atom, which was associated with a hydrogen on the isopropyl carbon at position 15 in the HSQC spectrum and with a hydrogen atom on the benzene ring carbon at positions 5 and 7 in the HMBC spectrum, and could be identified as the isopropyl carbon at position 15.

[0660] 14. The carbon at δ43.94 ppm was a secondary carbon atom, which was associated with a 10-position methylene hydrogen in the HSQC spectrum and could be identified as a 10-position methylene carbon.

[0661] 15. The carbon at δ18.54 ppm was a primary carbon atom, which was associated with a hydrogen on the methyl carbon at position 17 in the HSQC spectrum, associated with an isopropyl hydrogen at position 15 in the HMBC spectrum, and could be identified as the methyl carbon at position 17.

[0662] Conclusion: of the sample 13 The C-NMR spectral data matched the structure of pranopropene, and the spectrum of the sample matched the spectrum of the reference substance.

[0663] summation:

[0664] (1) The IR, UV, NMR, and MS measurements of this sample were consistent with the measurements of the reference material, and thus they were compounds with the same structure and the same crystal form, that is, this sample was pranopropene.

[0665] (2) Sample m / z 295.201619 measured by high-resolution mass spectrometry is [MH] - It was a peak, and the elemental composition was C 15 H 12 Since it is NO3, the elemental composition of the sample is C 15 H 13 It was NO3, which matched the structure of the molecule's organic base moiety.

[0666] (3) The UV spectrum showed a strong absorption peak at 260 nm to 270 nm, and the IR spectrum was 1591.9 cm⁻¹ -1 , 1521.1cm -1 , 804.0cm -1 and 767.8cm -1 It showed an absorption peak at, 1 The H-NMR spectrum showed absorption peaks at δ 7.30 ppm, δ 7.25 ppm, and δ 6.87 ppm, and 13 The C-NMR spectrum showed absorption peaks at δ118.14 ppm, δ113.35 ppm, and δ109.91 ppm, indicating the presence of three substituted benzene ring structure fragments.

[0667] (4) 1706.7 cm of the IR spectrum -1 The absorption peak at and 13 The absorption peak at δ175.39 ppm in the C-NMR spectrum indicated the presence of a carbonyl structural fragment.

[0668] In summary, the molecular structure of the sample matched the molecular structure of pranopropene.

[0669] Experimental Example 2: Stability Study

[0670] 1. Experimental Sample

[0671] According to the process of the present invention, three kilogram-scale scale-up batches were prepared under optimal experimental conditions and named 20190101, 20190201, and 20190202, respectively. The three batches are products prepared in independent batches, and the synthesis process was carried out according to the preparation conditions of 1a, 2c, 3c, 4b, and 5a, and they were obtained by refining and purifying with methanol (i.e., methanol recrystallization). The purity of the products of the three batches was 99.91%, 99.90%, and 99.95%, respectively.

[0672] 2. Experimental Method

[0673] In accordance with the relevant regulations of the "Technical Guidelines on Stability Studies of Chemicals," samples from the three batches above were collected and tested for 6 months under conditions of 40°C ± 2°C and RH 75% ± 5%. Samples were also collected for indicator detection at the end of months 0, 1, 2, 3, and 6 of the experiment.

[0674] Chromatography conditions:

[0675] The experiment was performed according to high-performance liquid chromatography (Chinese Pharmacopoeia General Regulation 0512, 2015 edition), using octadecylsilane-bound silica gel as the filler (5 µm, 250 mm × 4.6 mm); using 0.05 mol / L sodium perchlorate aqueous solution-methanol (90:10, pH adjusted to 3.2 by adding perchloric acid) as mobile phase A and methanol as mobile phase B; gradient elution was performed according to the table below, with a flow rate of 1.0 ml / min, a column temperature of 40°C, and a detection wavelength of 275 nm. The elution procedure is shown in Table 10 below.

[0676] Table 10: Dissolution Procedure

[0677]

[0678] 10 μl of the test solution was precisely drawn and injected into a liquid chromatograph. If there are impurity peaks in the chromatogram of the test solution, the single impurity must not exceed 0.1%, and the total impurity must not exceed 0.5%.

[0679] The impurities to be detected are total impurities, impurity A, impurity C, impurity D, impurity L, and maximum single impurity; the detection conditions are the same as above.

[0680] Method for preparing impurity A: Add purified water (140 ml) and sodium hydroxide (14.8 g) to a 1000 ml three-necked flask, stir to dissolve, and then the compound III-A (35g) and anhydrous methanol (20ml) were added, heated to 45°C and reacted for 2 hours, then cooled to 20°C to 30°C, diluted by adding 70ml of purified water, extracted with 105ml of ethyl acetate, and the aqueous phase was collected. The aqueous phase was adjusted to pH 5-6 with a 20% aqueous phosphoric acid solution to precipitate a white solid, stirred for 30 minutes, filtered by suction, the filter cake was washed with 105ml of water, and air-dried at 50°C to obtain the desired product.

[0681] Method for preparing impurity C: 2-chloronicotinic acid (30 g, 0.19 mol), 4-ethylphenol (69.6 g, 0.57 mol) and anhydrous potassium carbonate (52.5 g, 0.38 mol), cuprous iodide (1.8 g, 0.01 mol) and N,N- Dimethylformil (30 ml) was added to a 500 ml three-necked flask, heated to 100 to 110°C and reacted for 6 hours, cooled to 30 to 35°C, then diluted by adding 120 ml of water, transferred to a 2 L plastic beaker, adjusted to pH 3-4 with 30% phosphoric acid, filtered by suction, and the filter cake was rinsed with petroleum ether. The filter cake was added to 100 ml of water, adjusted to pH 7-8 with a saturated sodium bicarbonate aqueous solution, filtered by suction, the filtrate was collected, adjusted to pH 3-4 with 30% phosphoric acid, filtered by suction, and the filter cake was dried.

[0682] 37g of solid was taken and added to a 1000ml three-necked flask, 125g of polyphosphoric acid was added, heated to 120℃ to 130℃ and reacted for 4 hours, then cooled to 20℃ to 30℃, 600ml of water was added, and after suction filtration, the filter cake was washed with 200ml of water, and the obtained filter cake was air-dried at 60℃ to obtain the desired product.

[0683] Method of preparing impurity D: Pranopropene (15g), N,NDimethylformamide (4.5 ml) and anhydrous methanol (90 ml) were added to a 250 ml three-neck flask, and the system was suspended. Thionyl chloride solution (8.4 g) in dichloromethane (20 ml) was added dropwise, and the reaction was carried out at 20 to 30°C for 4 hours after the dropwise reaction. After the reaction was complete, the system was transferred to a 500 ml single-neck bottle and concentrated under reduced pressure in a water bath at 55°C until no obvious distillate was removed by distillation. The resulting concentrate was diluted with 150 ml of dichloromethane, adjusted to pH 7-8 with a saturated sodium bicarbonate aqueous solution, stirred for 10 minutes, and left to stand to allow liquid separation. The organic phase was washed with 100 ml of a saturated sodium bicarbonate aqueous solution and 100 ml of saturated brine, respectively. The organic phase was concentrated under reduced pressure in a water bath at 45°C until no obvious distillate was removed by distillation to obtain a white solid, 100 ml of n-hexane was added to this and stirred for 30 minutes, filtered by suction, and the filter cake was vacuum dried at 40°C to obtain the desired product.

[0684] Method for preparing impurity L: THF (150 ml) and compound IV-A(25g) was added to a 500ml single-neck bottle and dissolved until clear, then acetone (30.7g) was added and stirred to obtain a colorless solution. Aluminum trichloride (23.5g) was added to the batch, and after the addition was completed, a pale yellow solution was obtained, which was reacted for 4 hours, concentrated under pressure at 45°C until no clear distillate was removed by distillation, then the concentrate was diluted with 100ml of water, adjusted to pH 2-3 with a saturated sodium bicarbonate aqueous solution, extracted twice with 100ml of DCM, combined the organic phase, washed with 50ml of water, collected the organic phase, concentrated under reduced pressure at 45°C until no clear distillate was removed by distillation, and the product was obtained by column chromatography. The obtained product (25g), methanol (125ml), water (12.5ml), and sodium hydroxide (9.2g) were stirred and reacted for 1 hour. The reaction solution was transferred to a 500ml beaker, purified water (300g) was added, and the aqueous phase was extracted four times with ethyl acetate (90g). After separating the aqueous phase, the pH was adjusted to approximately 5.8 with a 20% aqueous acetic acid solution, and a white powder solid was slowly precipitated. After filtration, the filter cake was rinsed sequentially with purified water and cold methanol, and vacuum dried at 40°C to obtain the desired product.

[0685] Preparation of test solution: 50 mg of this product was taken, dissolved in a solvent (acetonitrile-water = 1:1), and diluted to 50 ml to obtain a test solution.

[0686] Control stock solution of mixed impurities: 10.0 mg of each impurity A, C, D, and L is weighed and added to each 10.0 ml volumetric flask, then methanol is added to dissolve and dilute, and labeled; 1.0 ml of each of the above solutions is taken and added to a 100.0 ml volumetric flask, then a solvent is added to dilute and labeled to obtain a control stock solution of impurities.

[0687] Control solution of mixed impurities: Accurately take 1.0 ml of the test solution and dilute it to 100.0 ml by adding solvent; accurately take 1.0 ml of the above solution, add 1.0 ml of the control stock solution of mixed impurities, and add solvent to make 10.0 ml to obtain the control solution of mixed impurities.

[0688] Preparation of system-compatible solution: Accurately take 1.0 ml of the control stock solution of mixed impurities, add the test solution, and dilute to 10 ml to obtain the system-compatible solution.

[0689] Preparation of control solution: Take 1.0 ml of the test solution, add a solvent to dilute it to 10.0 ml, take 1.0 ml of the solution, add a solvent to dilute it to 100.0 ml to obtain a control solution.

[0690] 3. Experimental Results

[0691] The experimental results are shown in Table 11 below.

[0692] Table 11

[0693]

[0694] Note: The maximum single impurity generally refers to an unannounced maximum single impurity, while announced impurities are expressed directly by impurity codes.

[0695] The results indicated that the quality of the products of the three batches produced by the present invention is stable and reliable.

[0696] Although specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and substitutions may be made to these details based on all the teachings disclosed, and that all such changes are within the scope of the present invention. The full scope of the present invention is provided by the appended claims and any equivalents thereof.

Claims

Claim 1 A method for preparing pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen, comprising the following steps: a first step of reacting a compound represented by formula A with a compound represented by formula B to produce a compound represented by formula I; Step 2: Preparing a compound represented by Chemical Formula II from a compound represented by Chemical Formula I: Step 3: Preparing a compound represented by Chemical Formula III from a compound represented by Chemical Formula II: Step 4: Preparing a compound represented by Chemical Formula IV from a compound represented by Chemical Formula III: Step 5 for preparing pranopropene from a compound represented by Chemical Formula IV: Here, X is a halogen, and R is C2-C 10 It is a straight-chain or branched-chain alkyl, and R1 is C1-C 10 It is a straight-chain or branched-chain alkyl. Claim 2 A method of manufacturing according to claim 1, wherein X is fluorine, chlorine, bromine, or iodine. Claim 3 A method of manufacturing according to claim 1, wherein R is ethyl, propyl, isopropyl, or n-butyl, and R1 is methyl, ethyl, propyl, or isopropyl. Claim 4 A method of manufacturing according to any one of claims 1 to 3, comprising the following steps: ① using a compound represented by formula A and a compound represented by formula B as starting materials, and performing a Ullmann condensation reaction in the presence of cuprous iodide to produce a compound represented by formula I; ② performing a rearrangement reaction in trimethyl orthoformate under the action of an acid and iodobenzene diacetate to obtain a compound represented by formula II; ③ forming an acyl chloride through halogenation, followed by performing intramolecular ring closure under the action of a Lewis acid to obtain a compound represented by formula III; ④ obtaining a compound represented by formula IV through boron hydride reduction; ⑤ finally, obtaining pranopropene through isopropanol hydrochloride reduction, alkali hydrolysis, and post-treatment acidification via a "one-pot method". Claim 5 A method of manufacturing according to any one of claims 1 to 3, comprising the following steps: (1) preparing a compound represented by formula V from a compound represented by formula IV; (2) preparing pranopropene from a compound represented by formula V; . Claim 6 A method of preparation according to claim 5, wherein the compound represented by the chemical formula IV is methyl 2-(10-hydroxy-9-oxa-1-azantracen-6-yl)propionate, ethyl 2-(10-hydroxy-9-oxa-1-azantracen-6-yl)propionate, or propyl 2-(10-hydroxy-9-oxa-1-azantracen-6-yl)propionate. Claim 7 A method of manufacturing according to claim 5, wherein in step (1), the compound represented by formula IV reacts with a reducing agent to obtain the compound represented by formula V. Claim 8 A method of manufacturing according to claim 7, wherein the reducing agent is one or more selected from the group consisting of isopropanol hydrogen chloride and isopropanol hydrochloride. Claim 9 A method of preparation according to claim 7, wherein the molar ratio of the compound represented by chemical formula IV to the reducing agent is 1:(1.5-3.5). Claim 10 A method of claim 5, wherein in step (1); the reaction is carried out in an organic solvent as a reaction solvent, and the organic solvent is isopropanol; the temperature of the reaction is 50°C to 90°C; and the time of the reaction is at least 0.5 hours. Claim 11 A method of manufacturing according to claim 5, wherein in step (2), the compound represented by the formula V reacts with a base to produce pranopropene, and the base is one or more selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate. Claim 12 A method of manufacturing according to claim 5, wherein in step (2); the temperature of the reaction is 40°C to 75°C; and the time of the reaction is at least 0.5 hours. Claim 13 A manufacturing method according to claim 5, further comprising the following steps: (3) separating pranopropene (a compound represented by chemical formula 0) from the reaction. Claim 14 A method of manufacturing according to claim 13, wherein step (3) comprises adding purified water to the reaction and then extracting the aqueous phase with ethyl acetate; collecting the aqueous phase and adjusting the pH to 2-7 with acid and slowly precipitating the solid; after filtration, washing the filter cake sequentially with purified water and methanol and drying under vacuum to obtain crude pranopropene; and obtaining the refined pranopropene by recrystallizing it from methanol. Claim 15 A method of manufacturing according to claim 14, wherein in step (3); the pH is 5 to 7; and the acid is one or more selected from the group consisting of acetic acid, phosphoric acid, hydrochloric acid and sulfuric acid. Claim 16 A manufacturing method according to claim 5, which does not include the step of separating a compound represented by the chemical formula V. Claim 17 A method of manufacturing according to claim 5, comprising the following steps: adding a compound represented by Formula IV, a reducing agent, and isopropanol to a reaction vessel, stirring and heating to 50°C to 90°C, maintaining the temperature for 2 to 4 hours to react, concentrating and drying under reduced pressure at 55°C, cooling to room temperature and adding methanol used as a solvent, then adding alkaline water, or adding alkaline water, then cooling to room temperature and adding methanol, and reacting at 40°C to 75°C for 2 hours; adding purified water to the solution of the reaction, then extracting the aqueous phase with ethyl acetate, collecting the aqueous phase, adjusting the pH to 2-7 with a 20% dilute acid solution, and slowly precipitating the solid; after filtration, washing the filter cake sequentially with purified water and methanol; performing vacuum drying to obtain a crude product, and refining the product by methanol recrystallization to obtain pranopropene. Step. Claim 18 A method of preparation according to any one of claims 1 to 3, wherein the compound represented by formula A is selected from the group consisting of 2-chloronicotinic acid, 2-bromonicotinic acid, and 2-iodonicotinic acid; and the compound represented by formula B is selected from the group consisting of 4-hydroxypropiophenone, 4-hydroxybutyrophenone, and 4-hydroxyvalerophenone. Claim 19 A method according to any one of claims 1 to 3, comprising the step of reacting a compound represented by chemical formula I with a compound represented by chemical formula C and a compound represented by chemical formula D to produce a compound represented by chemical formula II: Here, R is ethyl; R1 is methyl. Claim 20 A method of preparation according to claim 1, wherein the compound represented by the chemical formula I is 2-[4-(1-oxopropyl)phenoxy]-3-pyridinecarboxylic acid, 2-[4-(1-oxobutyl)phenoxy]-3-pyridinecarboxylic acid, or 2-[4-(1-oxopentyl)phenoxy]-3-pyridinecarboxylic acid. 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