2-[4-(1-oxoalkyl)phenoxy]-3-pyridinecarboxylic acid, preparation method and use thereof

Abstract

The present invention belongs to the field of medicine and relates to 2-[4-(1-oxoalkyl)phenoxy]-3-picolinic acid, a preparation method and use thereof. The present invention overcomes the deficiencies of the prior art, shortens the synthesis route, reduces process conditions, simplifies process operations, improves labor safety, is more suitable for industrial production, is more environmentally friendly, and has a higher yield.

Description

Technical Field

[0001] The invention belongs to the field of medicine and relates to 2-[4-(1-oxoalkyl)phenoxy]-3-pyridinecarboxylic acid, a preparation method and use thereof. Background Art

[0002] Pranoprofen is a propionic acid non-steroidal anti-inflammatory analgesic developed and marketed by Yoshitomi Pharmaceutical Co., Ltd. in 1981. It was later developed into eye drops by Senju Pharmaceutical Co., Ltd. and marketed in Japan in 1988 under the trade name Pranopulin. It is used for the symptomatic treatment of external eye and anterior eye inflammation (blepharitis, conjunctivitis, keratitis, scleritis, superficial scleritis, iridocyclitis, postoperative inflammation). Pranoprofen belongs to the propionic acid non-steroidal anti-inflammatory drug, chemical name: (2RS)-2-(10-hydrogen-9-oxa-1-azaanthrene-6-yl) propionic acid, CAS registration number 52549-17-4. Its effect is stronger than aspirin, indomethacin, and ibuprofen. Its mechanism of action is to inhibit the activity of cyclooxygenase, block the synthesis of eicosatetraenoic acid derivatives, reduce the synthesis of prostaglandins, thereby blocking the action of inflammatory mediators and exerting its efficacy.

[0003] The structural formula of pranoprofen is shown below:

[0004]

[0005] There are many reports on the synthesis of pranoprofen, the main difference is that different methods are used to establish the side chain, as follows:

[0006] Route 1: Use the rearrangement approach. A document (Bull. Chem. Soc. Jpn. 1987, 60, 4015-4018) reported a method for preparing 2-arylpropionic acid by rearrangement reaction of 2-hydroxypropanal and sulfonyl chloride. Jin Qingrong et al. referred to some Japanese patents (JP4288080, JP4288081) in "Study and Improvement of Synthesis of Pranoprofen" (Fine Chemical Intermediates 2009, 39 (3), 37-39). 2-Chloronicotinic acid and phenol were used as raw materials, and 5H-[1]-benzopyrano[2,3-b]pyridine-5-one was obtained by nucleophilic substitution and PPA cyclization reaction. 5H-[1]-benzopyrano[2,3-b]pyridine was obtained by potassium borohydride reduction and acidic hydrolysis. 5H-[1]-benzopyrano[2,3-b]pyridine was obtained, and then acylated with 2-chloropropionyl chloride to obtain the key intermediate 6-(2-chloropropionyl)-10H-9-oxa-1-azaanthracene. It reacts with sodium methoxide to obtain hydroxy ketal, and then the hydroxyl group is sulfonylated with sulfonyl chloride and rearranged and hydrolyzed to obtain pranoprofen.

[0007]

[0008] The disadvantages of route 1 are that polyphosphoric acid (PPA) is used in the production process, which will produce a large amount of phosphorus-containing wastewater during the post-treatment process, which is not conducive to environmental protection; 2-chloropropionyl chloride and sulfonyl chloride are also used in the process, which have a strong odor and are not conducive to the labor protection of production personnel; the rearrangement reaction is placed at the end, making it difficult to purify the relevant substances and inconvenient for finished product quality control.

[0009] Route 2: Use the side chain "2+1" to introduce the carboxyl group with cyanide as the carbon source, and use cyanide to extend the carbon chain. This route uses 2-chloronicotinic acid and p-ethylphenol as raw materials, and obtains 7-ethyl-5H-[1]-benzopyrano[2,3-b]pyridine-5-one through nucleophilic substitution and Friedel-Crafts reaction ring closure. After halogenation and reduction reactions, α-halogenated-5H-[1]-benzopyrano[2,3-b]pyridine-7-ethane is obtained, and then the carbon chain is extended with cyanide to obtain α-methyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetonitrile. Finally, the cyanide is hydrolyzed to obtain pranoprofen.

[0010]

[0011] The disadvantage of route 2 is that the highly toxic reagent cyanide is used in production, which increases safety risks and is not conducive to labor protection.

[0012] Route 3: Use the side chain "2+1" to introduce the carboxyl group with CO2 as the carbon source, and use CO2 to grow the carbon chain. This route uses 2-chloronicotinic acid and p-ethylphenol as raw materials, and obtains 7-ethyl-5H-[1]-benzopyrano[2,3-b]pyridine-5-one through nucleophilic substitution and Friedel-Crafts reaction ring closure, and obtains α-halogenated-5H-[1]-benzopyrano[2,3-b]pyridine-7-ethane through halogenation and reduction. The halogenated hydrocarbon is reacted with magnesium to form a Grignard reagent, and then carbon dioxide is introduced to obtain pranoprofen under acidic hydrolysis conditions.

[0013]

[0014] The disadvantage of route three is that the reaction conditions are demanding, a Grignard reaction is required, and deep freezing conditions of -80°C are required, which are relatively harsh and not conducive to industrial production.

[0015] Route 4: Use the side chain "2+1" and use iodomethane as the 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 reaction and Friedel-Crafts reaction ring closure. Then, 7-R-5H-[1]-benzopyrano[2,3-b]pyridine (R=COOMe, CN) is obtained through sodium borohydride reduction and hydrolysis with isopropanol hydrochloride. Methyl is introduced at the α position with iodomethane, and then the cyano group or ester group is hydrolyzed to obtain pranoprofen.

[0016]

[0017] The disadvantage of route 4 is that when methyl iodide is used to introduce methyl groups, the reaction selectivity is poor, the dimethylated impurities are difficult to purify, and the product quality is not good. In addition, methyl iodide is a highly toxic reagent, which is not good for production and the health of researchers.

[0018] Route 5: Use the side chain "1+1+1" idea to construct a three-carbon side chain. This route uses 2-chloronicotinic acid and phenol as raw materials, and obtains 5H-[1]-benzopyrano[2,3-b]pyridine-5-one through nucleophilic substitution and phosphorus oxychloride-catalyzed Friedel-Crafts reaction ring closure, and then constructs the tricyclic parent 5H-[1]-benzopyrano[2,3-b]pyridine through Na-Hg / ethanol reduction and hydrochloric acid isopropanol hydrolysis. The first carbon is then introduced by chloromethylation, the second carbon is introduced by cyanation reaction, and finally iodomethane is introduced into the third carbon to obtain α-methyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetic acid methyl ester, which is finally hydrolyzed to obtain pranoprofen.

[0019]

[0020] The disadvantage of route 5 is that the reaction steps are lengthy, which affects labor, energy consumption and yield. In addition, highly toxic reagents such as phosphorus oxychloride, cyanide and methyl iodide are used in the production, which increases the safety risk and is not conducive to the health of production and researchers. The introduction of methyl groups by methyl iodide also easily produces dimethylated impurities that are difficult to separate and remove, affecting product quality.

[0021] In addition, regarding stability and impurities, the Japanese Pharmacopoeia stipulates that the total impurities should not exceed 1.0% and the single impurities should not exceed 0.5%, but does not clearly define the structure of the impurities. The Chinese Pharmacopoeia does not currently include pranoprofen, so there are no relevant regulations.

[0022] In general, the existing technology for synthesizing pranoprofen has many defects, mainly concentrated in the lengthy synthesis route and low total yield; for example, the total yield of route 1 is 23.7%, the total yield of route 3 is 29.2%, and the total yield of route 5 is 3.7% (route 2 and route 4 are a combination of multiple prior arts, and there is no clear total yield report); the use of highly toxic chemical reagents is not conducive to personnel safety protection; the reaction conditions are harsh, which is not conducive to industrial production, etc.; there is also room for improvement in impurities and impurity content, for example: the product will degrade during the storage process, and the impurities will gradually increase. In addition, if the impurity content of the raw material is high, it will affect the quality level of the eye drop product. Therefore, it is necessary to improve the purity of the raw material and reduce the types and quantities of impurities.

[0023] At present, it is necessary to innovate the synthesis process of pranoprofen and develop a process technology that is more suitable for commercial production. Summary of the invention

[0024] The inventors have obtained a new method for preparing pranoprofen through in-depth research and creative work. The inventors surprisingly found that the method overcomes the deficiencies of the prior art, shortens the synthesis route, reduces process conditions, refines process operation, improves labor safety, is more suitable for industrial production, is more environmentally friendly, and has a higher yield.

[0025] This provides the following invention: (one)

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

[0028]

[0029] Where R is C2-C 10 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, for example, ethyl, propyl, isopropyl or n-butyl.

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

[0031]

[0032] in,

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

[0034] R is C2-C 10 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, for example, ethyl, propyl, isopropyl or n-butyl.

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

[0036]

[0037] in,

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

[0039]

[0040] Where R is C2-C 10Straight 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, for example, ethyl, propyl, isopropyl or n-butyl.

[0041] In some embodiments of the present invention, the method for preparing a compound of formula I, wherein the compound of formula A (2-halonicotinic acid) is selected from 2-chloronicotinic acid, 2-bromonicotinic acid and 2-iodonicotinic acid; preferably 2-chloronicotinic acid or 2-bromonicotinic acid.

[0042] In some embodiments of the present invention, in the method for preparing a compound of formula I, the compound of formula B (4-hydroxybenzophenone compound) is selected from 4-hydroxypropiophenone, 4-hydroxybutyrophenone and 4-hydroxyvalerophenone.

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

[0044] In some embodiments of the present invention, the method for preparing a compound of formula I, wherein the reaction time is at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, 1-10 hours, 2-8 hours, 3-7 hours, 4-6 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, the method for preparing a compound of formula I, wherein the compound of formula A reacts with the compound of formula B in an organic solvent as a reaction solvent, preferably, the organic solvent is N,N-dimethylformamide or dimethyl sulfoxide; more preferably, the organic solvent is N,N-dimethylformamide.

[0046] In some embodiments of the present invention, in the method for preparing the compound of formula I, the compound of formula A reacts with the compound of formula B in the presence of a catalyst, preferably, the catalyst is cuprous iodide.

[0047] In some embodiments of the present invention, in the method for preparing the compound of formula I, the reaction system further contains an acid binding agent, such as potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.

[0048] In some embodiments of the present invention, the method for preparing the compound of formula I, wherein the molar ratio of compound of formula A: compound of formula B: catalyst: acid binding agent is 1: (1-5): (0.05-1): (1-4), preferably 1: (1-3): (0.05-0.1): (1-2).

[0049] In some embodiments of the present invention, the method for preparing the compound of formula I further comprises the step of separating the compound of formula I from the reaction system, preferably comprising the following steps:

[0050] After cooling the reaction system (for example, to 50° C. or lower), water is added to acidify to pH 3-4, the precipitated solid is collected, dispersed with water, the pH is adjusted to 7-7.5, the solid is filtered out, the filtrate is acidified to pH 3-4, the precipitated solid is collected, washed with water and dried to obtain the compound of formula I.

[0051] Without being bound by theory, the compound of formula I may be prepared by direct continuous reaction without separation of the compound of formula I, but this is not a preferred solution because if there is no separation and purification process, the unreacted starting materials for preparing the compound of formula I will also participate in the second step reaction (the reaction for preparing the compound of formula II), which will not only consume the IBD of the second step, but also generate new impurities, reduce the purity of the product, and increase the difficulty of post-processing and purification.

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

[0053] Put 2-halonicotinic acid (compound of formula A), cuprous iodide and reaction solvent into a reaction vessel, control the temperature to 60°C-150°C, add acid binding agent and 4-hydroxybenzophenone compound (compound of formula B) in batches, control the temperature to 60°C-150°C, and keep the temperature to react for 2-8 hours;

[0054] After cooling, water is added to acidify to pH 3-4, the precipitated solid is collected, dispersed with water, and the pH is adjusted to 7-7.5 with sodium bicarbonate. The solid is filtered out, the filtrate is acidified to pH 3-4, the precipitated solid is collected, washed with water and dried to obtain the intermediate 2-[4-(1-oxoalkyl)phenoxy]-3-pyridinecarboxylic acid (compound of Formula I).

[0055] In some embodiments of the present invention, the method for preparing a compound of formula I, wherein the yield of the compound of formula I is greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 75%, 50%-80%, 50%-75%, 50%-70%, 50%-60%, 60%-80%, 60%-75%, 60%-70%, 70%-80%, 70%-75%, 75%-80% or 75%-85%.

[0056] Another aspect of the present invention relates to the use of a compound of 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 of formula I is prepared according to any method for preparing a compound of formula I described in the present invention.

[0057] The compounds of formula I also have other uses, for example, they can be used as intermediates to synthesize several other compounds, such as etc., wherein R is independently C1-C 10 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, for example, ethyl, propyl, isopropyl or n-butyl. (two)

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

[0060]

[0061] Where R1 is C1-C 10 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.

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

[0063]

[0064] in,

[0065] R is C2-C 10 Straight or branched alkyl, preferably, R is a C2-C6 straight or branched alkyl, more preferably, R is a C2-C4 straight or branched alkyl, for example, ethyl, propyl, isopropyl or n-butyl;

[0066] R1 is C1-C 10 Straight or branched alkyl, preferably, R1 is a C1-C5 straight or branched alkyl, more preferably, R1 is a C1-C3 straight or branched alkyl, for example, methyl, ethyl, propyl or isopropyl;

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

[0068] In some embodiments of the present invention, the method for preparing a compound of formula II, wherein the compound of 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, more preferably 2-[4-(1-oxopropyl)phenoxy]-3-pyridinecarboxylic acid. Preferably, the compound of formula I is prepared according to the method for preparing a compound of formula I described in any one of the present invention.

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

[0070] The compound of formula I is prepared according to any one of the methods for preparing the compound of formula I of the present invention.

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

[0072] In some embodiments of the present invention, the method for preparing a compound of formula II, wherein 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, 0.2-2 hours, 0.4-1.6 hours, 0.6-1.4 hours, 0.8-1.2 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, the method for preparing the compound of formula II, wherein the compound of formula I reacts with the compound of formula C in an organic solvent as a reaction solvent, preferably, the organic solvent is trimethyl orthoformate. Without being limited by theory, trimethyl orthoformate is both a reaction solvent and a substrate, and participates in the reaction.

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

[0075] In some embodiments of the present invention, the method for preparing the compound of formula II, wherein the molar ratio of the compound of formula I: iodobenzene diacetate: acid is 1:(1-3):(1-4), preferably 1:(1-2):(1-3).

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

[0077] Add an alkaline solution (such as sodium bicarbonate aqueous solution) for neutralization, extract with an organic solvent (preferably dichloromethane), retain the aqueous phase, acidify to pH 3-4, collect the precipitated solid, wash with water and dry to obtain the compound of formula II.

[0078] Without being limited by theory, if the compound of formula II is not separated and the subsequent compound of formula III is directly reacted continuously to prepare the compound, the excess trimethyl orthoformate may participate in the next reaction, reduce the yield, and produce impurities.

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

[0080] Put the compound of formula I and trimethyl orthoformate into a reaction container, slowly add acid solution, and control the reaction temperature at -5°C to 30°C;

[0081] Slowly add iodobenzene diacetate and control the reaction temperature between -5°C and 30°C;

[0082] Then slowly add acid solution and control the reaction temperature between -5°C and 30°C;

[0083] The reaction was kept warm for 0.5-2 hours, and an aqueous sodium bicarbonate solution was added for neutralization. The aqueous phase was retained after extraction with dichloromethane and acidified to pH 3-4. The precipitated solid was collected, washed with water and dried to obtain the intermediate 2-[4-(2-alkoxy-1-methyl-2-oxoethyl)phenoxy]-3-pyridinecarboxylic acid (compound of formula II).

[0084] Another aspect of the present invention relates to the use of a compound of 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 of formula II is prepared according to the method for preparing a compound of formula I described in any one of the present invention.

[0085] The compound of formula II has other uses, for example, it can be used as an intermediate to synthesize several other compounds, such as etc., wherein R is independently C1-C 10Straight 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, for example, ethyl, propyl, isopropyl or n-butyl. (three)

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

[0088]

[0089] Where R1 is C1-C 10 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.

[0090] Another aspect of the present invention relates to a method for preparing a compound of formula III, comprising the steps of preparing a compound of formula III from a compound of formula II:

[0091]

[0092] Where R1 is C1-C 10 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.

[0093] The above reaction formula includes two reactions, as shown below; the product in the middle bracket is not separated; preferably, the material is directly added for subsequent reaction.

[0094]

[0095] In some embodiments of the present invention, the method for preparing a compound of formula III, wherein the compound of 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 of formula II is prepared according to the method for preparing a compound of formula II described in any one of the present invention.

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

[0097] The compound of formula II can be prepared according to any one of the methods for preparing the compound of formula II of the present invention.

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

[0099] (1) reacting the compound of formula II with an acylating agent to obtain a reaction product,

[0100] (2) treating the reaction product in step (1) with a Lewis acid to generate a compound of formula III;

[0101] Preferably, the method further comprises the following steps:

[0102] (3) isolating the compound of formula III; preferably, the reaction product obtained in step (2) is cooled to below 20° C. (e.g., quenched by adding cold water), the pH is adjusted, and the solvent is removed under reduced pressure to obtain the compound of formula III.

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

[0104] In some embodiments of the present invention, the method for preparing the compound of formula III, wherein, in step (1), the reaction time is at least 0.2 hour, at least 0.4 hour, at least 0.6 hour, at least 0.8 hour, at least 0.9 hour, at least 1 hour, 0.2-2 hours, 0.4-1.6 hours, 0.6-1.4 hours, 0.8-1.2 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, the method for preparing the compound of formula III, wherein step (1) further comprises the following steps:

[0106] The obtained reaction product was cooled to -10°C to 0°C.

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

[0108] In some embodiments of the present invention, the method for preparing the compound of formula III, wherein, in step (2), the reaction time is at least 0.2 hour, at least 0.4 hour, at least 0.6 hour, at least 0.8 hour, at least 0.9 hour, at least 1 hour, 0.2-2 hours, 0.4-1.6 hours, 0.6-1.4 hours, 0.8-1.2 hours, 1-1.5 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 the method for preparing the compound of 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 the method for preparing the compound of formula III, the Lewis acid is a catalyst; preferably, the Lewis acid is selected from one or more of anhydrous aluminum chloride and titanium tetrachloride, preferably anhydrous aluminum chloride.

[0111] In some embodiments of the present invention, the method for preparing the compound of formula III, wherein the reaction is carried out in an organic solvent as a reaction solvent, preferably, the organic solvent is dichloromethane and / or N,N-dimethylformamide. Without being bound by theory, dichloromethane is the reaction solvent, and the amount of N,N-dimethylformamide is only 0.1 equivalents, which is more suitable as a catalyst.

[0112] In some embodiments of the present invention, in the method for preparing the compound of formula III, the molar ratio of the compound of 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 the method for preparing the compound of formula III, the molar ratio of the compound of 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, the method for preparing the compound of formula III, wherein step (3) comprises the following operations:

[0115] Add cold water to the reaction product of step (2) to quench the reaction, separate the organic phase, adjust the pH to 7-8 (for example, with sodium carbonate solution), and separate the organic phase again; concentrate the organic phase under reduced pressure, add methanol or a mixed solvent of methanol and dichloromethane to slurry for 3-8 hours (preferably 5-6 hours) when the fraction no longer evaporates, filter, rinse the filter residue with methanol, and dry to obtain a compound of 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 bound by theory, the present inventors have found that it is not possible to directly and continuously react to prepare the subsequent compound of formula IV without isolating the compound of formula III, because a large amount of aluminum chloride is present in the system when preparing the compound of formula III, which will react with methanol during the fourth step reaction, affecting the yield. The mixing of aluminum chloride with potassium borohydride / sodium borohydride may also reduce the methyl ester of the compound of formula III to alcohol without generating the compound of formula IV.

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

[0118] Add the compound of formula II, dichloromethane and N,N-dimethylformamide into the first reaction container, mix and stir, add the acylating agent at a temperature of 15°C-25°C, keep the temperature for reaction for 0.5-2 hours, and cool to -10°C to 0°C for standby use;

[0119] Add Lewis acid and dichloromethane to the second reaction vessel, stir evenly, control the temperature at 15°C-25°C, add the solution in the first reaction vessel, keep the temperature to react for 1-1.5h, control the temperature below 20°C and slowly add cold water to quench;

[0120] The organic phase was retained, and the pH was adjusted to 7-8 with sodium carbonate solution, and the liquids were separated, and the organic phase was concentrated under reduced pressure;

[0121] When the fraction no longer evaporates, a mixed solvent of methanol and dichloromethane is added to slurry for 5-6 hours, filtered, rinsed with methanol, and dried to obtain an intermediate 2-(10-oxo-9-oxa-1-azaanthracen-6-yl)propionic acid ester compound (compound of formula III).

[0122] The inventors also surprisingly found that the specific impurities contained in the obtained product include the compound of formula II and the impurities generated by the by-product of the compound of formula II, which are respectively named as the compound of formula III-IMP-A, the compound of formula III-IMP-B, the compound of formula III-IMP-C, etc., and the structures are as follows:

[0123]

[0124] Compound of formula III-IMP-A Compound of formula III-IMP-B Compound of formula III-IMP-C

[0125] Where R1 is C1-C 10 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.

[0126] The inventors speculate that if these three impurities are transferred backward, they may be derived into impurities with a similar structure to pranoprofen in subsequent reactions, as follows:

[0127]

[0128] Without being bound by theory, since the structures of these derived impurities are very similar to that of pranoprofen, it is presumed that they are difficult to separate and remove from the finished product. Therefore, these impurities are refined and removed in advance, and the limits of these three impurities are controlled. For example, it is required that each impurity shall not exceed 0.1% of the total mass of the intermediate product (the maximum impurities generated by the conversion of these three impurities will not exceed 0.1%), so that the quality of the finished product can be controlled upstream; therefore, the finished product does not need to be additionally tested for derived impurities.

[0129] In some embodiments of the present invention, the following steps are used to refine and remove these impurities:

[0130] After the solvent dichloromethane is distilled off, methanol or a methanol / dichloromethane mixed solvent is used for pulp washing (i.e., pulping). Impurities can be controlled at a desired level through a preferred solvent ratio.

[0131] The inventors have verified through multiple batches of experimental data that when the three impurities are controlled below 0.1%, no derivative impurities of the three impurities are detected in the finished product pranoprofen.

[0132] Another aspect of the present invention relates to the use of a compound of 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 of formula III is prepared according to any method for preparing a compound of formula III described in the present invention.

[0133] The compound of formula III has other uses, for example, it can be used as an intermediate to synthesize several other compounds, such as etc., wherein R is independently C1-C 10 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, for example, ethyl, propyl, isopropyl or n-butyl. (Four)

[0135] One aspect of the present invention relates to a compound of formula IV, or a pharmaceutically acceptable salt or ester thereof,

[0136]

[0137] Where R1 is C1-C 10 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.

[0138] Another aspect of the present invention relates to a method for preparing a compound of formula IV, comprising the step of preparing a compound of formula IV from a compound of formula III:

[0139]

[0140] Where R1 is C1-C 10 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.

[0141] In some embodiments of the present invention, the method for preparing the compound of formula IV, wherein the compound of formula III is preferably methyl 2-(10-oxo-9-oxa-1-azaanthen-6-yl) propionate, ethyl 2-(10-oxo-9-oxa-1-azaanthen-6-yl) propionate or propyl 2-(10-oxo-9-oxa-1-azaanthen-6-yl) propionate; more preferably methyl 2-(10-oxo-9-oxa-1-azaanthen-6-yl) propionate. Preferably, the compound of formula III is prepared according to the method for preparing the compound of formula III described in any one of the present invention.

[0142] In some embodiments of the present invention, the method for preparing the compound of formula IV further comprises the following steps:

[0143] The compound of formula III can be prepared according to any one of the methods for preparing the compound of formula III of the present invention.

[0144] In some embodiments of the present invention, the method for preparing the compound of formula IV, wherein the compound of formula III is reacted with a reducing agent to obtain the compound of formula IV. Preferably, the reducing agent is a borohydride, more preferably sodium borohydride.

[0145] In some embodiments of the present invention, in the method for preparing the compound of formula IV, the reaction temperature is 20°C-40°C, preferably 30°C-40°C, 30°C-35°C or 35°C-40°C.

[0146] In some embodiments of the present invention, the method for preparing the compound of formula IV, wherein 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, 1-100 hours, 2-50 hours, 3-40 hours, 4-30 hours, 5-25 hours, 6-20 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.

[0147] In some embodiments of the present invention, the method for preparing the compound of formula IV, wherein 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 limited by theory, dichloromethane is a solvent, and methanol is both a solvent and a substrate, providing 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 of formula III: the volume (mL) of the mixed solvent is 1: (5-15), preferably 1: (8-10).

[0148] In some embodiments of the present invention, in the method for preparing the compound of formula IV, the molar ratio of the compound of formula III to the reducing agent is (1:0.8) to (1:1.2), preferably 1:0.9-1.1.

[0149] In some embodiments of the present invention, the method for preparing the compound of formula IV further comprises the step of separating the compound of formula IV from the reaction system; preferably, the method comprises the following steps:

[0150] Cooling the reaction product to -10°C to 10°C, adjusting the pH to 5.5-6.5; preferably, slowly dropping a dilute acid solution (e.g., 30% acetic acid aqueous solution) to a pH of 5.5-6.5 (without being limited by theory, the role of the acid is to quench the excess reducing agent in the reaction, and a dilute inorganic acid or a dilute organic acid may be used); the dilute acid may be an inorganic acid or an organic acid having a concentration of less than or equal to 30%;

[0151] Control the temperature at -10°C to 10°C and stir for 5-30 minutes (preferably 15 minutes), add purified water, collect the organic phase, and wash with saturated sodium bicarbonate and purified water in sequence;

[0152] The washed organic phase was concentrated to dryness under reduced pressure at 40°C to obtain a yellow-green oil;

[0153] Add a crystallization solvent and stir at 20°C-40°C for 5-30 minutes (preferably 15 minutes); and

[0154] Purified water was slowly added dropwise, and the solid was collected, washed with water, and dried in vacuo to obtain a compound of formula IV.

[0155] In some embodiments of the present invention, the method for preparing the compound of formula IV, wherein, preferably, the crystallization solvent can be selected from methanol aqueous solution (preferably methanol: water is 1:2), acetone aqueous solution (preferably acetone: water is 1:2), a mixture of methanol, acetone and water (preferably methanol: acetone: water is 1:1.5:5), preferably a mixture of methanol, acetone and water (preferably methanol: acetone: water is 1:1.5:5). Preferably, the mass (g) of the compound of formula III: the volume (mL) of the crystallization solvent is 1:5.

[0156] In some embodiments of the present invention, the method for preparing the compound of formula IV comprises the following steps:

[0157] Add the compound of formula III, dichloromethane and methanol into a reaction vessel, control the temperature at 15°C-30°C, and stir to dissolve;

[0158] Slowly add borohydride, control the temperature at 20°C-40°C to react for 6-20h, cool to -10°C to 10°C, slowly add 30% acetic acid aqueous solution to pH 5.5-6.5, control the temperature at -10°C to 10°C and stir for 5-30min (preferably 15min), add purified water, collect the organic phase, wash with saturated sodium bicarbonate, and wash again with purified water;

[0159] The organic phase was concentrated to dryness under reduced pressure at 40°C to obtain a yellow-green oil;

[0160] Add methanol / acetone mixed solution and stir and disperse at 20°C-40°C for 15 minutes. Slowly add purified water dropwise for crystallization for 1-5 hours (preferably 2 hours), collect the solid, wash with water, and vacuum dry to obtain the intermediate 2-(10-hydroxy-9-oxa-1-azaanthracen-6-yl) propionate compound (compound of formula IV).

[0161] Without being limited by theory, the role of acetic acid is to quench excess sodium borohydride, and the pH range is controlled to ensure complete quenching.

[0162] Another aspect of the present invention relates to the use of a compound of 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 of formula IV is prepared according to any method for preparing a compound of formula IV described in the present invention.

[0163] The compound of formula IV has other uses, for example, it can be used as an intermediate to synthesize several other compounds, such as etc., wherein R and R' are independently C1-C 10 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; X is a halogen, such as fluorine, chlorine, bromine or iodine. (five)

[0165] Another aspect of the present invention relates to a method for preparing pranoprofen (compound of formula 0) or a pharmaceutically acceptable salt or ester of pranoprofen, comprising preparing:

[0166] A compound of formula I or a pharmaceutically acceptable salt or ester thereof,

[0167] A compound of formula II or a pharmaceutically acceptable salt or ester thereof,

[0168] A compound of formula III or a pharmaceutically acceptable salt or ester thereof, and / or

[0169] The compound of formula IV or a pharmaceutically acceptable salt or ester thereof

[0170] Steps;

[0171] Preferably, the compound of formula I is prepared according to any one of the methods for preparing a compound of formula I described in the present invention;

[0172] Preferably, the compound of formula II is prepared according to the method for preparing the compound of formula III described in any one of the present invention;

[0173] Preferably, the compound of formula III is prepared according to the method for preparing the compound of formula III described in any one of the present invention;

[0174] Preferably, the compound of formula IV is prepared according to any one of the methods for preparing the compound of formula IV described in the present invention.

[0175] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein the synthesis route is shown as follows:

[0176]

[0177] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0) comprises the following steps:

[0178] (1) using 2-halonicotinic acid (compound of formula A) and 4-hydroxybenzophenone compound (compound of formula B) as starting materials, and carrying out Ullmann condensation reaction in the presence of cuprous iodide to obtain the intermediate 2-[4-(1-oxoalkyl)phenoxy]-3-pyridinecarboxylic acid (compound of formula I);

[0179] (2) Rearrangement reaction is carried out in trimethyl orthoformate under the action of acid and iodophenyl diacetic acid to obtain the intermediate 2-[4-(2-methoxy-1-methyl-2-oxoalkyl)phenoxy]-3-pyridinecarboxylic acid (compound of formula II);

[0180] (3) after halogenation to form an acyl chloride, the cyclization is closed intramolecularly under the action of Lewis acid to obtain an intermediate 2-(10-oxo-9-oxa-1-azaanthracen-6-yl) propionate compound (compound of formula III);

[0181] (4) reducing with borohydride to obtain an intermediate 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl)propionic acid ester compound (compound of formula IV);

[0182] (5) Finally, the one-pot method is carried out by reduction with hydrogen chloride isopropanol and alkaline hydrolysis, followed by post-treatment and acidification to obtain pranoprofen (compound of formula 0).

[0183] The structural formulas of the compound of formula A and the compound of formula B are as follows:

[0184]

[0185] in,

[0186] X is halogen, such as fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.

[0187]

[0188] Where R is C2-C 10 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, for example, ethyl, propyl, isopropyl or n-butyl.

[0189] Another aspect of the present invention relates to a method for preparing pranoprofen (compound of formula O) or a pharmaceutically acceptable salt or ester of pranoprofen, comprising the step of preparing pranoprofen from a compound of formula IV:

[0190]

[0191] Where R1 is C1-C 10 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.

[0192] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0) comprises the following steps:

[0193] (1) first preparing a compound of formula V from a compound of formula IV (reduction reaction);

[0194] (2) preparing pranoprofen (compound of formula 0) from the compound of formula V (hydrolysis reaction);

[0195]

[0196] Where R1 is C1-C 10 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.

[0197] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula O), wherein the compound of formula IV is preferably methyl 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl) propionate, ethyl 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl) propionate or propyl 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl) propionate; more preferably methyl 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl) propionate.

[0198] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein in step (1), the compound of formula IV is reacted with a reducing agent to obtain the compound of formula V.

[0199] In some embodiments of the present invention, in the method for preparing pranoprofen (compound of formula 0), in step (1), the reducing agent is selected from one or more of isopropyl hydrochloride and isopropyl hydrochloride.

[0200] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein in step (1), the molar ratio of the compound of formula IV to the reducing agent is 1:(1.5-3.5), preferably 1:(2.5-3.5), for example 1:2.5, 1:3 or 1:3.5.

[0201] In some embodiments of the present invention, in the method for preparing pranoprofen (compound of formula 0), wherein in step (1), the reaction is carried out in an organic solvent as a reaction solvent, preferably, the organic solvent is isopropanol.

[0202] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein in step (1), the reaction temperature is 50°C-90°C, preferably 60°C-80°C, 60°C-70°C, 70°C-80°C or 65°C-75°C.

[0203] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein in step (1), the reaction time is at least 0.5 hour, at least 1 hour, at least 1.5 hours, at least 2 hours, 1-10 hours, 2-8 hours, 2-6 hours, 2-4 hours, 2-3 hours, 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours.

[0204] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein in step (2), the compound of formula V is reacted with a base (hydrolysis reaction) to obtain pranoprofen (compound of formula 0).

[0205] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein in step (2), the base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, preferably sodium hydroxide and / or potassium hydroxide.

[0206] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein in step (2), the reaction temperature is 40°C-75°C, preferably 40°C-55°C, 40°C-50°C, 45°C-55°C, 40°C-45°C, 45°C-50°C or 50°C-55°C.

[0207] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein in step (2), the reaction time is at least 0.5 hour, at least 1 hour, at least 1.5 hours, 0.5-10 hours, 1-8 hours, 1.5-6 hours, 1.5-4 hours, 1.5-3 hours, 1.5-2.5 hours, 0.5 hour, 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.

[0208] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0) further comprises the step of separating pranoprofen (compound of formula 0) from the reaction system; preferably, the method comprises the following step (3):

[0209] Purified water was added to the reaction system, and then the aqueous phase was extracted with ethyl acetate;

[0210] Collect the aqueous phase and adjust the pH to 2-7 with acid (preferably with 20% dilute acid solution), and gradually precipitate solid;

[0211] Filtering, washing the filter cake with purified water and methanol in sequence, and vacuum drying to obtain crude pranoprofen (compound of formula 0); and

[0212] Recrystallize from methanol (preferably using 8-12 times the volume, such as 10 times the volume, of methanol for reflux recrystallization) to obtain refined pranoprofen (compound of formula 0);.

[0213] In some embodiments of the present invention, in the method for preparing pranoprofen (compound of formula 0), in step (3), the pH is preferably 5-7, more preferably 5.5-6.5, and particularly preferably 5.8-6.2.

[0214] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein in step (3), the acid is one or more selected from acetic acid, phosphoric acid, hydrochloric acid and sulfuric acid, preferably acetic acid and / or hydrochloric acid.

[0215] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0) does not include the step of isolating the compound of formula V.

[0216] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein the compound of formula IV is preferably methyl 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl) propionate, ethyl 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl) propionate or propyl 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl) propionate; more preferably methyl 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl) propionate.

[0217] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein the compound of formula IV is prepared according to any one of the methods for preparing the compound of formula IV of the present invention.

[0218] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0) further comprises the following steps:

[0219] The compound of formula IV can be prepared according to any one of the methods for preparing the compound of formula IV of the present invention.

[0220] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0), wherein the molar ratio of the compound of 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), for example 1:2, 1:2.5 or 1:3.

[0221] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0) comprises the following steps:

[0222] Add the compound of formula IV, a reducing agent and isopropanol to a reaction vessel, stir and heat to 50°C-90°C, keep the temperature for reaction for 2-4h, concentrate to dryness at 55°C under reduced pressure, cool to room temperature, add methanol (methanol as solvent) and then add alkaline water (or add alkaline water, cool to room temperature and then add methanol), keep the temperature for reaction at 40°C-75°C for 2h;

[0223] Purified water was added to the reaction solution, and then the aqueous phase was extracted with ethyl acetate. The aqueous phase was collected and adjusted to pH 2-7 with 20% dilute acid solution to gradually precipitate solids;

[0224] Filter, and rinse the filter cake with purified water and methanol in sequence;

[0225] The crude product was dried in vacuo and then refined by recrystallization from methanol to obtain the finished product of pranoprofen (compound of formula 0).

[0226] In some embodiments of the present invention, the method for preparing pranoprofen (compound of formula 0) comprises the process steps of Preparation Examples 1a, 2c, 3c, 4b, and 5a.

[0227] Another aspect of the present invention relates to a method for preparing a compound of formula V or a pharmaceutically acceptable salt or ester of the compound of formula V, comprising the step of preparing the compound of formula V from a compound of formula IV:

[0228]

[0229] Where R1 is C1-C 10 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.

[0230] In some embodiments of the present invention, the method for preparing the compound of formula V comprises reacting the compound of formula IV with a reducing agent to obtain the compound of formula V.

[0231] In some embodiments of the present invention, in the method for preparing the compound of formula V, the reducing agent is selected from one or more of isopropyl hydrogen chloride and isopropyl hydrochloride.

[0232] In some embodiments of the present invention, in the method for preparing the compound of formula V, the molar ratio of the compound of formula IV to the reducing agent is 1:(1.5-3.5), preferably 1:(2.5-3.5), for example 1:2.5, 1:3 or 1:3.5.

[0233] In some embodiments of the present invention, in the method for preparing the compound of formula V, the reaction is carried out in an organic solvent as a reaction solvent, preferably, the organic solvent is isopropanol.

[0234] In some embodiments of the present invention, in the method for preparing the compound of formula V, the reaction temperature is 50°C-90°C, preferably 60°C-80°C, 60°C-70°C, 70°C-80°C or 65°C-75°C.

[0235] In some embodiments of the present invention, the method for preparing the compound of formula V, wherein the reaction time is at least 0.5 hour, at least 1 hour, at least 1.5 hours, at least 2 hours, 1-10 hours, 2-8 hours, 2-6 hours, 2-4 hours, 2-3 hours, 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours.

[0236] Another aspect of the present invention relates to the use of a compound of 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 of formula V is prepared according to any method for preparing a compound of formula V described in the present invention.

[0237] Some of the intermediate compounds involved in the present invention are shown in Table A below.

[0238]

[0239] (six)

[0241] A composition comprising pranoprofen and impurities, wherein, calculated by mass percentage, the content of the impurities in the composition is less than or equal to 0.5%, less than or equal to 0.4%, less than or equal to 0.3%, less than or equal to 0.25%, less than or equal to 0.24%, less than or equal to 0.23%, less than or equal to 0.22%, less than or equal to 0.21%, less than or equal to 0.20%, less than or equal to 0.19%, less than or equal to 0.18%, less than or equal to 0.17%, less than or equal to 0.16 %, less than or equal to 0.15%, less than or equal to 0.14%, less than or equal to 0.13%, less than or equal to 0.12%, less than or equal to 0.11%, less than or equal to 0.10%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.05%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, less than or equal to 0.01%, or less than or equal to 0.005%.

[0242] In one or more embodiments of the present invention, the composition, wherein, calculated by mass percentage, the content (purity) of pranoprofen in the composition is greater than or equal to 99%, greater than or equal to 99.1%, greater than or equal to 99.2%, greater than or equal to 99.3%, greater than or equal to 99.4%, greater than or equal to 99.5%, greater than or equal to 99.6%, greater than or equal to 99.7%, greater than or equal to 99.8%, greater than or equal to 99.9%, greater than or equal to 99.91%, greater than or equal to 99.92%, greater than or equal to 99.93%, greater than or equal to 99.94%, greater than or equal to 99.95%, greater than or equal to 99.96%, greater than or equal to 99.98% or greater than or equal to 99.99%.

[0243] In one or more embodiments of the present invention, the composition, wherein the content of impurities is greater than zero.

[0244] In one or more embodiments of the present invention, the composition consists of pranoprofen and impurities.

[0245] In one or more embodiments of the present invention, the composition, wherein the impurities are total impurities.

[0246] In one or more embodiments of the present invention, the composition, wherein the impurity is a largest single impurity.

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

[0248] In one or more embodiments of the present invention, the composition, wherein the impurities are any one, any two, any three or any four selected from impurity A, impurity C, impurity D and impurity L.

[0249] In one or more embodiments of the present invention, the composition, wherein the impurity is impurity A, impurity C, impurity D or impurity L.

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

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

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

[0253] In one or more embodiments of the present invention, the composition, wherein the impurity is impurity L.

[0254] In one or more embodiments of the present invention, the composition, wherein the impurities are impurity A and impurity C.

[0255] In one or more embodiments of the present invention, the composition, wherein the impurities are impurity A and impurity D.

[0256] In one or more embodiments of the present invention, the composition, wherein the impurities are impurity A and impurity L.

[0257] In one or more embodiments of the present invention, the composition, wherein the impurities are impurity C and impurity D.

[0258] In one or more embodiments of the present invention, the composition, wherein the impurities are impurity C and impurity L.

[0259] In one or more embodiments of the present invention, the composition, wherein the impurities are impurity D and impurity L.

[0260] In one or more embodiments of the present invention, the composition, wherein the impurities are impurity A, impurity C and impurity D.

[0261] In one or more embodiments of the present invention, the composition, wherein the impurities are impurity A, impurity C and impurity L.

[0262] In one or more embodiments of the present invention, the composition, wherein the impurities are impurity A, impurity D and impurity L.

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

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

[0265] In one or more embodiments of the present invention, the composition, wherein the impurities include impurity A, impurity C, impurity D and impurity L.

[0266] In one or more embodiments of the present invention, the composition, wherein the content of total impurities is less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, or less than or equal to 0.01%.

[0267] In one or more embodiments of the present invention, the composition, wherein the content of impurity A is less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, or less than or equal to 0.01%.

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

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

[0270] In one or more embodiments of the present invention, the composition, wherein the content of impurity L is less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, less than or equal to 0.01%, or less than or equal to 0.005%.

[0271] In one or more embodiments of the present invention, the composition, wherein, after 1 month, 2 months or 3 months of accelerated experiment, compared with 0 month, the change (increase or decrease) in the content of total impurities, maximum single impurity, impurity A, impurity C, impurity D and / or impurity L does not exceed 50%, 40%, 30%, 20%, 10% or 5%.

[0272] In one or more embodiments of the present invention, the composition, wherein, after 6 months of accelerated testing, compared with 0 month, the change (increase or decrease) in the content of total impurities, maximum single impurity, impurity A, impurity C, impurity D and / or impurity L does not exceed 300%, 250%, 200%, 150%, 130%, 120%, 110%, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10% or 5%.

[0273] In one or more embodiments of the present invention, the composition, wherein, after 1 month, 2 months or 3 months of accelerated testing, the content of total impurities, maximum single impurities, impurity A, impurity C, impurity D and / or impurity L is less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, or less than or equal to 0.01%.

[0274] In one or more embodiments of the present invention, the composition, wherein, after 6 months of accelerated testing, the content of total impurities, maximum single impurities, impurity A, impurity C, impurity D and / or impurity L is less than or equal to 0.5%, less than or equal to 0.45%, less than or equal to 0.4%, less than or equal to 0.35%, less than or equal to 0.3%, less than or equal to 0.25%, less than or equal to 0.2%, less than or equal to 0.15%, less than or equal to 0.12%, less than or equal to 0.1%, less than or equal to 0.09%, less than or equal to 0.08%, less than or equal to 0.07%, less than or equal to 0.06%, less than or equal to 0.06%, less than or equal to 0.04%, less than or equal to 0.03%, less than or equal to 0.02%, or less than or equal to 0.01%.

[0275] The structures of impurity A, impurity C, impurity D, and impurity L are shown in Table B below.

[0276]

[0277] Another aspect of the present invention relates to a pharmaceutical preparation, which comprises the composition described in any one of the above inventions, and one or more pharmaceutically acceptable excipients.

[0278] In the present invention, unless otherwise specified, the composition is a pranoprofen product, which contains an absolute amount of pranoprofen compound and one or more impurities. It will be understood by those skilled in the art that the presence or generation of impurities is difficult to avoid during the synthesis, purification and / or storage of the compound.

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

[0280] In the present invention, unless otherwise specified, the accelerated experiment refers to the experiment carried out at 40°C ± 2°C and RH 75% ± 5% in accordance with the provisions of the Technical Guidelines for Stability Studies of Chemical Drugs; preferably, three samples are measured in parallel and the average value is taken.

[0281] In the present invention, if not otherwise specified, the content of each impurity or total impurity is measured by high performance liquid chromatography. Preferably, the chromatographic conditions are: octadecylsilane bonded silica gel is used as a filler (5 μm, 250 mm×4.6 mm); 0.05 mol / L sodium perchlorate aqueous solution-methanol = (90:10, add perchloric acid to adjust the pH to 3.2) is used as mobile phase A, methanol is used as mobile phase B, and the gradient elution in Table 10 is performed at 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 also shown in Table 10.

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

[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 as described in any one of the present invention. Preferably, the method is a high performance liquid chromatography. Preferably, the chromatographic conditions are: using octadecylsilane bonded silica gel as a filler (5 μm, 250 mm×4.6 mm); using 0.05 mol / L sodium perchlorate aqueous solution-methanol = (90:10, adding perchloric acid to adjust the pH to 3.2) as mobile phase A, methanol as mobile phase B, according to the gradient elution in Table 10, flow rate 1.0 ml / min, column temperature 40°C, detection wavelength 275 nm. The elution procedure is also shown in Table 10.

[0284] Another aspect of the present invention relates to the use of any one, any two, any three or any four selected from impurity A, impurity C, impurity D and impurity L for quality inspection or quality control of pranoprofen products; preferably, the pranoprofen product is a composition or pharmaceutical preparation as described in any one of the present invention.

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

[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, the method for preparing the compound of formula I, the compound of formula II, the compound of formula III, the compound of formula IV or pranoprofen, wherein the preparation method does not use highly toxic chemical reagents such as potassium cyanide and methyl iodide. Therefore, the preparation method of the present invention reduces production hazards and worker operation risks.

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

[0297] In the present invention,

[0298] The term "C 1-10 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, etc.; C 2-10 Alkyl, C 1-6 Alkyl, C 2-6 Alkyl, C 1-3 Alkyl or C 2-4 Alkyl can also be understood similarly. 1-6 Alkyl, C 2-6 Alkyl, C 1-3 Alkyl or C 2-4 alkyl.

[0299] Advantageous Effects of the Invention

[0300] The present invention achieves any one or more of the following technical effects (1)-(11):

[0301] (1) The raw materials used in the present invention are more readily available;

[0302] (2) It is conducive to the continuous purification of impurities during the process and improve product quality;

[0303] (3) Avoid the use of highly toxic chemicals such as potassium cyanide and methyl iodide, reducing production hazards and worker operation risks;

[0304] (4) Avoid the use of phosphorus-containing chemicals such as polyphosphoric acid, reduce environmental pollution, and be more environmentally friendly;

[0305] (5) Short reaction steps and simplified process route;

[0306] (6) Mild reaction conditions;

[0307] (7) Easy to operate;

[0308] (8) More suitable for industrial production;

[0309] (9) The yield of the compound of formula (0), formula (I), formula (II), formula (III) and / or formula (IV) prepared by the present invention is relatively high;

[0310] (10) The purity of the compound of formula 0, formula I, formula II, formula III and / or formula IV prepared by the present invention is relatively high;

[0311] (11) The present invention prepares the compounds of formula (0), formula (1), formula (II), formula (III) and / or formula (IV) with a good balance between yield and purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0312] Figure 1 : High-resolution mass spectrum of the sample.

[0313] Figure 2A : Infrared spectrum of standard product.

[0314] Figure 2B : Infrared spectrum of samples.

[0315] Figure 3A : UV spectrum of neutral standard.

[0316] Figure 3B : UV spectrum of acid standard.

[0317] Figure 3C : UV spectrum of alkaline standard.

[0318] Figure 3D : UV spectrum of neutral sample.

[0319] Figure 3E : UV spectrum of acidic sample.

[0320] Figure 3F : UV spectra of alkaline samples. DETAILED DESCRIPTION

[0321] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0322] Preparation Example 1a-1i: Preparation of 2-[4-(1-oxopropyl)phenoxy]-3-pyridinecarboxylic acid (Compound IA) or 2-[4- (1-Oxobutyl)phenoxy]-3-pyridinecarboxylic acid (Compound IB)

[0323] 1a:

[0324]

[0325] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (2.4 g, 0.1 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (26.9 g, 2 equiv.) and 4-hydroxypropiophenone (38.1 g, 2 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 1 L beaker, added 200 g of water, stirred evenly, adjusted the pH to 7-7.5 with sodium bicarbonate, filtered, washed the filter cake with an appropriate amount of water, retained the filtrate, and transferred to a clean 1 L beaker. The filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 29.5 g, a yield of 85.6%, and a purity of 97.53%.

[0326] 1b:

[0327]

[0328] Put 2-chloronicotinic acid (20.0g, 1equiv.), N,N-dimethylformamide (20ml), cuprous iodide (1.2g, 0.05equiv.) into a 250ml reaction bottle, stir and mix, heat to 75℃-80℃, add sodium carbonate (26.9g, 2equiv.) and 4-hydroxypropiophenone (38.1g, 2equiv.) in batches, heat to 110℃-115℃, and keep warm for 5h. Cool the reaction solution to 50℃, add 100g water, and stir for 15min. Acidify to pH 3-4, filter the filter cake, transfer it to a 1L beaker, add 200g water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with appropriate amount of water, retain the filtrate, and transfer it to a clean 1L beaker. The filtrate obtained is acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 29.4 g, a yield of 85.5%, and a purity of 97.36%.

[0329] 1c:

[0330]

[0331] Put 2-bromonicotinic acid (20.0g, 1equiv.), N,N-dimethylformamide (20ml), cuprous iodide (1.9g, 0.1equiv.) into a 250mL reaction bottle, stir and mix, heat to 75℃-80℃, add sodium carbonate (21.0g, 2equiv.) and 4-hydroxypropiophenone (29.7g, 2equiv.) in batches, heat to 110℃-115℃, and keep warm for 5h. Cool the reaction solution to 50℃, add 100g water, and stir for 15min. Acidify to pH 3-4, filter the filter cake, transfer it to a 1L beaker, add 200g water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with appropriate amount of water, retain the filtrate, and transfer it to a clean 1L beaker. The filtrate obtained is acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 23.1 g, a yield of 86.0%, and a purity of 97.68%.

[0332] 1d:

[0333]

[0334] 2-bromonicotinic acid (50.0 g, 1 equiv.), N,N-dimethylformamide (50 ml), and cuprous iodide (4.7 g, 0.1 equiv.) were added to a 500 ml reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (52.5 g, 2 equiv.) and 4-hydroxybutyrophenone (81.3 g, 2 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 250 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 2L beaker, added 500 g of water, stirred evenly, adjusted the pH to 7-7.5 with sodium bicarbonate, filtered, washed the filter cake with an appropriate amount of water, retained the filtrate, and transferred to a clean 2L beaker. The obtained filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IB with a weight of 58.4 g, a yield of 83.0%, and a purity of 97.11%.

[0335] 1e:

[0336]

[0337] Add 2-bromonicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20.0 g), and cuprous iodide (1.9 g, 0.1 equiv.) into a 250 ml reaction bottle, stir and mix, heat to 75°C-80°C, add potassium carbonate (27.4 g, 2 equiv.) and 4-hydroxypropiophenone (29.7 g, 2 equiv.) in batches, heat to 110°C-115°C, and keep warm for 5 hours. Cool the reaction solution to 50°C, add 100 g of water, and stir for 15 minutes. Acidify to pH 3-4, filter the filter cake, transfer it to a 1L beaker, add 200 g of water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with an appropriate amount of water, retain the filtrate, and transfer it to a clean 1L beaker. The filtrate obtained is acidified and adjusted to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 22.9 g, a yield of 85.0%, and a purity of 97.44%.

[0338] 1f:

[0339]

[0340] Add 2-bromonicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20.0 g), and cuprous iodide (1.9 g, 0.1 equiv.) into a 250 ml reaction bottle, stir and mix, heat to 75°C-80°C, add sodium bicarbonate (16.6 g, 2 equiv.) and 4-hydroxypropiophenone (29.7 g, 2 equiv.) in batches, heat to 110°C-115°C, and keep warm for 5 hours. Cool the reaction solution to 50°C, add 100 g of water, and stir for 15 minutes. Acidify to pH 3-4, filter the filter cake, transfer it to a 1L beaker, add 200 g of water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with an appropriate amount of water, retain the filtrate, and transfer it to a clean 1L beaker. The filtrate obtained is acidified and adjusted to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 21.6 g, a yield of 80.6%, and a purity of 96.87%.

[0341] 1g:

[0342]

[0343] Add 2-bromonicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20.0 g), and cuprous iodide (1.9 g, 0.1 equiv.) into a 250 ml reaction bottle, stir and mix, heat to 75°C-80°C, add potassium bicarbonate (19.8 g, 2 equiv.) and 4-hydroxypropiophenone (29.7 g, 2 equiv.) in batches, heat to 110°C-115°C, and keep warm for 5 hours. Cool the reaction solution to 50°C, add 100 g of water, and stir for 15 minutes. Acidify to pH 3-4, filter the filter cake, transfer it to a 1L beaker, add 200 g of water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with an appropriate amount of water, retain the filtrate, and transfer it to a clean 1L beaker. The filtrate obtained is acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 21.5 g, a yield of 80.2%, and a purity of 96.56%.

[0344] 1h:

[0345]

[0346] Add 2-bromonicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (1.9 g, 0.1 equiv.) into a 250 mL reaction bottle, stir and mix, heat to 60°C-65°C, add sodium carbonate (21.0 g, 2 equiv.) and 4-hydroxypropiophenone (29.7 g, 2 equiv.) in batches, heat to 75°C-80°C, and keep warm for 10 hours. Cool the reaction solution to 50°C, add 100 g of water, and stir for 15 minutes. Acidify to pH 3-4, filter the filter cake, transfer it to a 1 L beaker, add 200 g of water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with an appropriate amount of water, retain the filtrate, and transfer it to a clean 1 L beaker. The filtrate obtained is acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 22.4 g, a yield of 83.4%, and a purity of 96.48%.

[0347] 1i:

[0348]

[0349] Add 2-bromonicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (1.9 g, 0.1 equiv.) into a 250 mL reaction bottle, stir and mix, heat to 75°C-80°C, add sodium carbonate (21.0 g, 2 equiv.) and 4-hydroxypropiophenone (29.7 g, 2 equiv.) in batches, heat to 120°C-125°C, and keep warm for 4 hours. Cool the reaction solution to 50°C, add 100 g of water, and stir for 15 minutes. Acidify to pH 3-4, filter the filter cake, transfer it to a 1 L beaker, add 200 g of water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with an appropriate amount of water, retain the filtrate, and transfer it to a clean 1 L beaker. The filtrate obtained is acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 23.4 g, a yield of 87.0%, and a purity of 96.11%.

[0350] Comparative Examples 1j-1w

[0351] 1j:

[0352]

[0353] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (4.8 g, 0.2 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (13.5 g, 1 equiv.) and 4-hydroxypropiophenone (19.1 g, 1 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 1 L beaker, added 200 g of water, stirred evenly, adjusted the pH to 7-7.5 with sodium bicarbonate, filtered, washed the filter cake with an appropriate amount of water, retained the filtrate, and transferred to a clean 1 L beaker. The obtained filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 25.6 g, a yield of 74.2%, and a purity of 93.88%.

[0354] 1k:

[0355]

[0356] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (4.8 g, 0.2 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (13.5 g, 1 equiv.) and 4-hydroxypropiophenone (38.1 g, 2 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 1 L beaker, added 200 g of water, stirred evenly, adjusted the pH to 7-7.5 with sodium bicarbonate, filtered, washed the filter cake with an appropriate amount of water, retained the filtrate, and transferred to a clean 1 L beaker. The filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 27.2 g, a yield of 79.1%, and a purity of 96.43%.

[0357] 1l:

[0358]

[0359] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (4.8 g, 0.2 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (13.5 g, 1 equiv.) and 4-hydroxypropiophenone (57.2 g, 3 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 1 L beaker, added 200 g of water, stirred evenly, adjusted the pH to 7-7.5 with sodium bicarbonate, filtered, washed the filter cake with an appropriate amount of water, retained the filtrate, and transferred to a clean 1 L beaker. The filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 27.1 g, a yield of 78.8%, and a purity of 96.57%.

[0360] 1m:

[0361]

[0362] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (4.8 g, 0.2 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (13.5 g, 1 equiv.) and 4-hydroxypropiophenone (76.3 g, 4 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 1 L beaker, added 200 g of water, stirred evenly, adjusted the pH to 7-7.5 with sodium bicarbonate, filtered, washed the filter cake with an appropriate amount of water, retained the filtrate, and transferred to a clean 1 L beaker. The obtained filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 27.4 g, a yield of 79.7%, and a purity of 95.29%.

[0363] 1n:

[0364]

[0365] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (4.8 g, 0.2 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (13.5 g, 1 equiv.) and 4-hydroxypropiophenone (95.3 g, 5 equiv.) were added in batches. After the addition was completed, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, transferred to a 500 ml beaker, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 1 L beaker, 200 g of water was added, and stirred evenly. The pH was adjusted to 7-7.5 with sodium bicarbonate, filtered, and the filter cake was washed with an appropriate amount of water. The filtrate was retained and transferred to a clean 1 L beaker. The obtained filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 27.2 g, a yield of 78.9%, and a purity of 95.11%.

[0366] 1o:

[0367]

[0368] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (4.8 g, 0.2 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (26.9 g, 2 equiv.) and 4-hydroxypropiophenone (38.1 g, 2 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 1 L beaker, added 200 g of water, stirred evenly, adjusted the pH to 7-7.5 with sodium bicarbonate, filtered, washed the filter cake with an appropriate amount of water, retained the filtrate, and transferred to a clean 1 L beaker. The obtained filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 29.6 g, a yield of 85.9%, and a purity of 95.73%.

[0369] 1p:

[0370]

[0371] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (4.8 g, 0.2 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (40.4 g, 3 equiv.) and 4-hydroxypropiophenone (38.1 g, 2 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, the filter cake obtained by filtering was transferred to a 1 L beaker, 200 g of water was added, and stirred evenly. The pH was adjusted to 7-7.5 with sodium bicarbonate, and then filtered. The filter cake was washed with an appropriate amount of water, and the filtrate was retained and transferred to a clean 1 L beaker. The obtained filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 24.5 g, a yield of 71.1%, and a purity of 94.53%.

[0372] 1q:

[0373]

[0374] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (4.8 g, 0.2 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (53.8 g, 4 equiv.) and 4-hydroxypropiophenone (38.1 g, 2 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 1 L beaker, added 200 g of water, stirred evenly, adjusted the pH to 7-7.5 with sodium bicarbonate, filtered, washed the filter cake with an appropriate amount of water, retained the filtrate, and transferred to a clean 1 L beaker. The obtained filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 24.2 g, a yield of 70.2%, and a purity of 94.17%.

[0375] 1r:

[0376]

[0377] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (12.1 g, 0.5 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (26.9 g, 2 equiv.) and 4-hydroxypropiophenone (38.1 g, 2 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 1 L beaker, added 200 g of water, stirred evenly, adjusted the pH to 7-7.5 with sodium bicarbonate, filtered, washed the filter cake with an appropriate amount of water, retained the filtrate, and transferred to a clean 1 L beaker. The filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 29.7 g, a yield of 86.1%, and a purity of 94.77%.

[0378] 1s:

[0379]

[0380] 2-Chloronicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (24.2, 1.0 equiv.) were added to a 250 mL reaction bottle, stirred and mixed, heated to 75°C-80°C, and sodium carbonate (26.9 g, 2 equiv.) and 4-hydroxypropiophenone (38.1 g, 2 equiv.) were added in batches. After addition, the temperature was raised to 110°C-115°C, and the reaction was kept warm for 5 hours. The reaction solution was cooled to 50°C, 100 g of water was added, and stirred for 15 minutes. Acidified to pH 3-4, filtered the filter cake, transferred to a 1 L beaker, added 200 g of water, stirred evenly, adjusted the pH to 7-7.5 with sodium bicarbonate, filtered, washed the filter cake with an appropriate amount of water, retained the filtrate, and transferred to a clean 1 L beaker. The obtained filtrate was acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 30.1 g, a yield of 87.3%, and a purity of 93.85%.

[0381] 1t:

[0382]

[0383] Add 2-iodonicotinic acid (20.0 g, 1 equiv.), N,N-dimethylformamide (20 ml), and cuprous iodide (1.5 g, 0.1 equiv.) into a 250 ml reaction bottle, stir and mix, heat to 75°C-80°C, add sodium carbonate (17.0 g, 2 equiv.) and 4-hydroxypropiophenone (24.1 g, 2 equiv.) in batches, heat to 110°C-115°C, and keep warm for 4 hours. Cool the reaction solution to 50°C, add 100 g of water, and stir for 15 minutes. Acidify to pH 3-4, filter the filter cake, transfer it to a 1L beaker, add 200 g of water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with an appropriate amount of water, retain the filtrate, and transfer it to a clean 1L beaker. The filtrate obtained is acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 19.5 g, a yield of 89.4%, and a purity of 91.98%.

[0384] 1u:

[0385]

[0386] Add 2-bromonicotinic acid (20.0 g, 1 equiv.), dimethyl sulfoxide (20.0 g), and cuprous iodide (1.9 g, 0.1 equiv.) into a 250 ml reaction bottle, stir and mix, heat to 75°C-80°C, add sodium carbonate (21.0 g, 2 equiv.) and 4-hydroxypropiophenone (29.7 g, 2 equiv.) in batches, heat to 110°C-115°C, and keep warm for 5 hours. Cool the reaction solution to 50°C, add 100 g of water, and stir for 15 minutes. Acidify to pH 3-4, filter the filter cake, transfer it to a 1 L beaker, add 200 g of water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with an appropriate amount of water, retain the filtrate, and transfer it to a clean 1 L beaker. The filtrate obtained is acidified and adjusted to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 21.2 g, a yield of 78.9%, and a purity of 96.38%.

[0387] 1v:

[0388]

[0389] Put 2-bromonicotinic acid (20.0g, 1equiv.), N,N-dimethylformamide (20ml), cuprous iodide (1.9g, 0.1equiv.) into a 250mL reaction bottle, stir and mix, heat to 75℃-80℃, add sodium carbonate (21.0g, 2equiv.) and 4-hydroxypropiophenone (29.7g, 2equiv.) in batches, heat to 130℃-135℃, and keep warm for 4h. Cool the reaction solution to 50℃, add 100g water, and stir for 15min. Acidify to pH 3-4, filter the filter cake, transfer it to a 1L beaker, add 200g water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with appropriate amount of water, retain the filtrate, and transfer it to a clean 1L beaker. The filtrate obtained is acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 22.4 g, a yield of 87.3%, and a purity of 93.14%.

[0390] 1w:

[0391]

[0392] Put 2-bromonicotinic acid (20.0g, 1equiv.), N,N-dimethylformamide (20ml), cuprous iodide (1.9g, 0.1equiv.) into a 250mL reaction bottle, stir and mix, heat to 75℃-80℃, add sodium carbonate (21.0g, 2equiv.) and 4-hydroxypropiophenone (29.7g, 2equiv.) in batches, heat to 140℃-150℃, and keep warm for 3h. Cool the reaction solution to 50℃, add 100g water, and stir for 15min. Acidify to pH 3-4, filter the filter cake, transfer it to a 1L beaker, add 200g water, stir evenly, adjust the pH to 7-7.5 with sodium bicarbonate, filter, wash the filter cake with appropriate amount of water, retain the filtrate, and transfer it to a clean 1L beaker. The filtrate obtained is acidified to pH 3-4 to precipitate the product. The filter cake was filtered and dried at 60°C to obtain compound IA with a weight of 23.3 g, a yield of 86.8%, and a purity of 91.32%.

[0393]

[0394]

[0395] Preparation Examples 2a-2d: Preparation of 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 (Compound II-B)

[0396] 2a:

[0397]

[0398] Add compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (60 g) to a 250 ml reaction bottle, stir and mix well, and then cool the reaction solution to 0°C. Slowly add concentrated sulfuric acid (11.1 g, 1.5 equiv.), control the temperature below 10°C, and after the addition, stir for 15 min, then slowly add iodobenzene diacetate (47.5 g, 2 equiv.), control the temperature at 15°C-20°C, for about 10-15 min, and stir at 15°C-20°C for 15 min after the addition. Cool down to 0°C, slowly add concentrated sulfuric acid (11.1 g, 1.5 equiv.), control the temperature below 10°C. After the addition of concentrated sulfuric acid, slowly return to 10°C-20°C and keep the temperature for 1 h. Sodium bicarbonate aqueous solution was added for neutralization, and the aqueous phase was retained after extraction with dichloromethane, acidified to pH 3-4, and the filter cake was filtered and washed with water until the filtrate was nearly neutral, and dried at 60° C. to constant weight to obtain an off-white compound II-A weighing 16.9 g, with a yield of 76.0% and a purity of 97.34%.

[0399] 2b:

[0400]

[0401] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (60 g) were added to a 250 ml reaction bottle, stirred and mixed evenly, and then the reaction solution was cooled to 0°C. Concentrated sulfuric acid (11.1 g, 1.5 equiv.) was slowly added dropwise, and the temperature was controlled below 5°C. After the addition was completed, iodobenzene diacetate (47.5 g, 2 equiv.) was slowly added, and the temperature was controlled at 5°C to 10°C for about 10-15 minutes. After the addition was completed, the temperature 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 equiv.) was slowly added dropwise, and the temperature was controlled below 10°C. After the addition of concentrated sulfuric acid, the temperature was controlled at 5°C to 10°C, and the reaction was kept warm for 1 hour. Sodium bicarbonate aqueous solution was added for neutralization, and the aqueous phase was retained after extraction with dichloromethane, acidified to pH 3-4, and the filter cake was filtered and washed with water until the filtrate was nearly neutral, and dried at 60° C. to constant weight to obtain an off-white compound II-A weighing 16.1 g, with a yield of 72.4% and a purity of 96.28%.

[0402] 2c:

[0403]

[0404] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (60 g) were added to a 250 ml reaction bottle, stirred and mixed evenly, and then the reaction solution was cooled to -5°C. Concentrated sulfuric acid (11.1 g, 1.5 equiv.) was slowly added dropwise, and the temperature was controlled below -5°C. After the addition was completed, iodobenzene diacetate (47.5 g, 2 equiv.) was slowly added, and the temperature was controlled at -5°C-0°C for about 10-15 minutes. After the addition was completed, the temperature was stirred at -5°C-0°C for 15 minutes. The temperature was lowered to -5°C, and concentrated sulfuric acid (11.1 g, 1.5 equiv.) was slowly added dropwise, and the temperature was controlled below -5°C. After the addition of concentrated sulfuric acid, the temperature was controlled at -5°C-0°C, and the reaction was kept warm for 1 hour. Sodium bicarbonate aqueous solution was added for neutralization, and the aqueous phase was retained after extraction with dichloromethane, acidified to pH 3-4, and the filter cake was filtered and washed with water until the filtrate was nearly neutral, and dried at 60° C. to constant weight to obtain an off-white compound II-A weighing 15.9 g, with a yield of 71.6% and a purity of 95.61%.

[0405] 2d:

[0406]

[0407] Add compound IB (50.0 g, 1 equiv.) and trimethyl orthoformate (150 g) to a 500 ml reaction bottle, stir and mix well, and then cool the reaction solution to 0°C. Slowly add concentrated sulfuric acid (26.4 g, 1.5 equiv.), control the temperature below 10°C, after the addition, stir for 15 min, then slowly add iodobenzene diacetate (113.3 g, 2 equiv.), control the temperature at 10°C-20°C, for about 10-15 min, after the addition, stir at 10°C-20°C for 15 min. Cool down to 0°C, slowly add concentrated sulfuric acid (26.4 g, 1.5 equiv.), control the temperature below 10°C. After the addition of concentrated sulfuric acid, slowly return to 10°C-20°C, and keep the temperature for 1 h. Sodium bicarbonate aqueous solution was added for neutralization, and the aqueous phase was retained after extraction with dichloromethane, acidified to pH 3-4, and the filter cake was filtered and washed with water until the filtrate was nearly neutral, and dried at 60° C. to constant weight to obtain an off-white compound II-B weighing 41.5 g, with a yield of 75.4% and a purity of 96.98%.

[0408] Comparative Examples 2e-2p

[0409] 2e:

[0410]

[0411] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (200 g) were added to a 500 ml reaction bottle, and concentrated sulfuric acid (3.7 g, 0.5 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (23.7 g, 1 equiv.) was slowly added after stirring for 5 min. After the addition was completed, the mixture was stirred for 15 min. Concentrated sulfuric acid (3.7 g, 0.5 equiv.) was slowly added dropwise. After the addition of concentrated sulfuric acid, the mixture was heated to 105 ° C and refluxed. The reaction was kept warm for 1 h. The mixture was cooled to room temperature, and a sodium bicarbonate aqueous solution was added to neutralize the mixture. After extraction with dichloromethane, the aqueous phase was retained and acidified to pH 3-4. The filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60 ° C until constant weight was obtained to obtain an off-white compound II-A weighing 16.5 g, with a yield of 74.5% and a purity of 89.73%.

[0412] 2f:

[0413]

[0414] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (100 g) were added to a 250 ml reaction bottle, and concentrated sulfuric acid (3.7 g, 0.5 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (23.7 g, 1 equiv.) was slowly added after stirring for 5 min. After the addition was completed, the mixture was stirred for 15 min. Concentrated sulfuric acid (3.7 g, 0.5 equiv.) was slowly added dropwise. After the addition of concentrated sulfuric acid, the mixture was heated to 70°C-75°C and kept for 1 h. The mixture was cooled to room temperature, and an aqueous sodium bicarbonate solution was added for neutralization. After extraction with dichloromethane, the aqueous phase was retained and acidified to pH 3-4. The filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60°C with air blast to constant weight to obtain an off-white compound II-A weighing 16.1 g, with a yield of 72.4% and a purity of 92.86%.

[0415] 2g:

[0416]

[0417] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (100 g) were added to a 250 ml reaction bottle, and concentrated sulfuric acid (3.7 g, 0.5 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (23.7 g, 1 equiv.) was slowly added after stirring for 5 min. After the addition was completed, the mixture was stirred for 15 min. Concentrated sulfuric acid (3.7 g, 0.5 equiv.) was slowly added dropwise. After the addition of concentrated sulfuric acid, the mixture was heated to 45°C-50°C and kept warm for 1 h. The mixture was cooled to room temperature, and an aqueous sodium bicarbonate solution was added for neutralization. After extraction with dichloromethane, the aqueous phase was retained and acidified to pH 3-4. The filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60°C with air blast to constant weight to obtain an off-white compound II-A weighing 15.7 g, with a yield of 70.8% and a purity of 93.16%.

[0418] 2h:

[0419]

[0420] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (100 g) were added to a 250 ml reaction bottle, and concentrated sulfuric acid (3.7 g, 0.5 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (47.5 g, 2 equiv.) was slowly added after stirring for 5 min. After the addition was completed, the mixture was stirred for 15 min. Concentrated sulfuric acid (3.7 g, 0.5 equiv.) was slowly added dropwise. After the addition of concentrated sulfuric acid, the mixture was heated to 45°C-50°C and kept warm for 1 h. The mixture was cooled to room temperature, and an aqueous sodium bicarbonate solution was added for neutralization. After extraction with dichloromethane, the aqueous phase was retained and acidified to pH 3-4. The filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60°C with air blast to constant weight to obtain an off-white compound II-A weighing 16.0 g, with a yield of 71.9% and a purity of 93.68%.

[0421] 2i:

[0422]

[0423] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (100 g) were added to a 250 ml reaction bottle, and concentrated sulfuric acid (3.7 g, 0.5 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (71.2 g, 2 equiv.) was slowly added after stirring for 5 min. After the addition was completed, the mixture was stirred for 15 min. Concentrated sulfuric acid (3.7 g, 0.5 equiv.) was slowly added dropwise. After the addition of concentrated sulfuric acid, the mixture was heated to 45°C-50°C and kept warm for 1 h. The mixture was cooled to room temperature, and an aqueous sodium bicarbonate solution was added for neutralization. After extraction with dichloromethane, the aqueous phase was retained and acidified to pH 3-4. The filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60°C with air blast to constant weight to obtain an off-white compound II-A weighing 15.9 g, with a yield of 71.7% and a purity of 93.01%.

[0424] 2j:

[0425]

[0426] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (100 g) were added to a 250 ml reaction bottle, and concentrated sulfuric acid (7.4 g, 1 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (47.5 g, 2 equiv.) was slowly added after stirring for 5 min. After the addition was completed, the mixture was stirred for 15 min. Concentrated sulfuric acid (7.4 g, 1 equiv.) was slowly added dropwise. After the addition of concentrated sulfuric acid, the mixture was heated to 45°C-50°C and kept warm for 1 h. The mixture was cooled to room temperature, and an aqueous sodium bicarbonate solution was added for neutralization. After extraction with dichloromethane, the aqueous phase was retained and acidified to pH 3-4. The filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60°C with air blast to constant weight to obtain an off-white compound II-A weighing 16.1 g, with a yield of 72.3% and a purity of 94.28%.

[0427] 2k:

[0428]

[0429] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (100 g) were added to a 250 ml reaction bottle, and concentrated sulfuric acid (11.1 g, 1.5 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (47.5 g, 2 equiv.) was slowly added after stirring for 5 min. After the addition was completed, the mixture was stirred for 15 min. Concentrated sulfuric acid (11.1 g, 1.5 equiv.) was slowly added dropwise. After the addition of concentrated sulfuric acid, the mixture was heated to 45°C-50°C and kept warm for 1 h. The mixture was cooled to room temperature, and an aqueous sodium bicarbonate solution was added for neutralization. After extraction with dichloromethane, the aqueous phase was retained and acidified to pH 3-4. The filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60°C with air blast to constant weight to obtain an off-white compound II-A weighing 16.2 g, with a yield of 72.9% and a purity of 94.64%.

[0430] 2l:

[0431]

[0432] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (100 g) were added to a 250 ml reaction bottle, and concentrated sulfuric acid (14.8 g, 2 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (47.5 g, 2 equiv.) was slowly added after stirring for 5 min. After the addition was completed, the mixture was stirred for 15 min. Concentrated sulfuric acid (14.8 g, 2 equiv.) was slowly added dropwise. After the addition of concentrated sulfuric acid, the mixture was heated to 45°C-50°C and kept warm for 1 h. The mixture was cooled to room temperature, and an aqueous sodium bicarbonate solution was added to neutralize the mixture. The aqueous phase was retained after extraction with dichloromethane and acidified to pH 3-4. The filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60°C with air blast to constant weight to obtain an off-white compound II-A weighing 16.1 g, with a yield of 72.3% and a purity of 93.45%.

[0433] 2m:

[0434]

[0435] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (60.0 g) were added to a 250 ml reaction bottle, and hydrochloric acid (30.1 g, 1.5 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (47.5 g, 2 equiv.) was slowly added after stirring for 15 min. After the addition was completed, the mixture was heated to 45°C-50°C and kept warm for 1 h. Sodium bicarbonate aqueous solution was added for neutralization, and the aqueous phase was retained after extraction with dichloromethane, acidified to pH 3-4, and the filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60°C with air blast to constant weight to obtain an off-white compound II-A weighing 14.9 g, with a yield of 67.1% and a purity of 93.33%.

[0436] 2n:

[0437]

[0438] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (60.0 g) were added to a 250 ml reaction bottle, and 85% phosphoric acid (12.8 g, 1.5 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (47.5 g, 2 equiv.) was slowly added after stirring for 15 min. After the addition was completed, 85% phosphoric acid (12.8 g, 1.5 equiv.) was slowly added dropwise. After the addition was completed, the mixture was heated to 45°C-50°C and kept for 1 h. Sodium bicarbonate aqueous solution was added for neutralization, and the aqueous phase was retained after extraction with dichloromethane, acidified to pH 3-4, and the filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60°C with air blast to constant weight to obtain an off-white compound II-A weighing 14.3 g, with a yield of 64.5% and a purity of 91.79%.

[0439] 2o:

[0440]

[0441] Compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (60.0 g) were added to a 250 ml reaction bottle, and acetic acid (10.8 g, 1.5 equiv.) was slowly added dropwise. After the addition was completed, iodobenzene diacetate (47.5 g, 2 equiv.) was slowly added after stirring for 15 min. After the addition was completed, acetic acid (10.8 g, 1.5 equiv.) was slowly added dropwise. After the addition was completed, the mixture was heated to 45°C-50°C and kept warm for 1 h. Sodium bicarbonate aqueous solution was added for neutralization, and the aqueous phase was retained after extraction with dichloromethane, acidified to pH 3-4, and the filter cake was filtered and washed with water until the filtrate was nearly neutral. The mixture was dried at 60°C with air blast to constant weight to obtain an off-white compound II-A weighing 12.4 g, with a yield of 55.7% and a purity of 88.67%.

[0442] 2p:

[0443]

[0444] Add compound IA (20.0 g, 1 equiv.) and trimethyl orthoformate (60 g) to a 250 ml reaction bottle, stir and mix well, and then cool the reaction solution to 0°C-10°C. Slowly add concentrated sulfuric acid (11.1 g, 1.5 equiv.), control the temperature below 10°C, stir for 15 min, then slowly add iodobenzene diacetate (47.5 g, 2 equiv.), control the temperature below 20°C, for about 10-15 min, and stir for 15 min after addition. Cool down to 0°C-10°C, slowly add concentrated sulfuric acid (11.1 g, 1.5 equiv.), control the temperature below 10°C, after the concentrated sulfuric acid is added, heat to 25°C-30°C, and keep the temperature for 1 h. Sodium bicarbonate aqueous solution was added for neutralization, and the aqueous phase was retained after extraction with dichloromethane, acidified to pH 3-4, and the filter cake was filtered and washed with water until the filtrate was nearly neutral, and dried at 60° C. to constant weight to obtain an off-white compound II-A weighing 16.2 g, with a yield of 73.1% and a purity of 94.96%.

[0445]

[0446]

[0447] Preparation Example 3a-3g: Preparation of methyl 2-(10-oxo-9-oxa-1-azaanthen-6-yl)propanoate (Compound III-A) and ethyl 2-(10-oxo-9-oxa-1-azaanthen-6-yl)propanoate (Compound III-B)

[0448] 3a:

[0449]

[0450] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop oxalyl chloride (12.6 g, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (17.7 g, 2 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours after the reaction is completed. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 16.3 g, with a yield of 86.8% and a purity of 99.55%.

[0451] 3b:

[0452]

[0453] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop oxalyl chloride (12.6 g, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (26.6 g, 2 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 15.8 g, with a yield of 84.1% and a purity of 99.59%.

[0454] 3c:

[0455]

[0456] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop oxalyl chloride (12.6 g, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (35.4 g, 4 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours after the reaction is completed. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 15.9 g, with a yield of 84.3% and a purity of 99.54%.

[0457] 3d:

[0458]

[0459] Add compound II-B (40.0 g, 1 equiv.), dichloromethane (200 ml), and N,N-dimethylformamide (0.9 g) to a 500 ml reaction bottle A, stir and mix, and add oxalyl chloride (24.2 g, 1.5 equiv.) dropwise at 15°C-25°C. After the addition, keep the mixture at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (33.9 g, 2 equiv.) and dichloromethane (200 ml) to a 1000 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in the reaction bottle A dropwise to the reaction bottle B, control the temperature at 15°C-25°C, and keep the mixture at 1-1.5 hours after the addition. After the reaction is complete, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (80 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (200 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (200 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-B weighing 32.2 g, with a yield of 85.7% and a purity of 99.26%.

[0460] 3e:

[0461]

[0462] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop thionyl chloride (11.8, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (17.7 g, 2 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 16.4 g, with a yield of 87.1% and a purity of 99.67%.

[0463] 3f:

[0464]

[0465] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop thionyl chloride (11.8, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (17.7 g, 2 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30min, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100ml). Concentrate under reduced pressure to recover dichloromethane, add methanol / dichloromethane mixed solvent (100ml, solvent ratio 1:0.1) when the fraction is no longer distilled, beat at 20℃-25℃ for 5-6h, filter, rinse the filter cake with methanol, and dry it with air at 45℃ to obtain compound III-A weighing 16.1g, with a yield of 85.6% and a purity of 99.71%.

[0466] 3g:

[0467]

[0468] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop thionyl chloride (11.8, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (17.7 g, 2 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol / dichloromethane mixed solvent (100 ml, solvent ratio 1: 0.2) when the fraction is no longer distilled, beat at 20 ° C -25 ° C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45 ° C with air blast to obtain compound III-A weighing 15.7 g, with a yield of 83.5% and a purity of 99.73%.

[0469] Comparative Examples 3h-3p

[0470] 3h:

[0471]

[0472] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop oxalyl chloride (9.3 g, 1.1 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (9.7 g, 1.1 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 14.4 g, with a yield of 76.8% and a purity of 91.26%.

[0473] 3i:

[0474]

[0475] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop oxalyl chloride (12.6 g, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (9.7 g, 1.1 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours after the reaction is completed. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 14.9 g, with a yield of 79.2% and a purity of 94.07%.

[0476] 3j:

[0477]

[0478] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop oxalyl chloride (16.9 g, 2 equiv.), and keep warm at 15°C-25°C for 1 h. Add anhydrous aluminum chloride (9.7 g, 1.1 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 h. After the reaction is complete, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 14.8 g, with a yield of 78.7% and a purity of 94.11%.

[0479] 3k:

[0480]

[0481] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop oxalyl chloride (25.3 g, 3 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (9.7 g, 1.1 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 14.7 g, with a yield of 78.2% and a purity of 93.84%.

[0482] 3l:

[0483]

[0484] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop oxalyl chloride (12.6 g, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (13.3 g, 1.5 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 15.4 g, with a yield of 81.8% and a purity of 98.57%.

[0485] 3m:

[0486]

[0487] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop oxalyl chloride (12.6 g, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (44.3 g, 5 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 16.0 g, with a yield of 85.1% and a purity of 98.71%.

[0488] 3n:

[0489]

[0490] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop thionyl chloride (11.8 g, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add titanium tetrachloride (25.2 g, 2 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30 minutes, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40 ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100 ml). Concentrate under reduced pressure to recover dichloromethane, add methanol (100 ml) when the fraction is no longer distilled, beat at 20°C-25°C for 5-6 hours, filter, rinse the filter cake with methanol, and dry it at 45°C to obtain compound III-A weighing 13.6 g, with a yield of 72.4% and a purity of 95.43%.

[0491] 3o:

[0492]

[0493] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop thionyl chloride (11.8, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (17.7 g, 2 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30min, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100ml). Concentrate under reduced pressure to recover dichloromethane, add methanol / dichloromethane mixed solvent (100ml, solvent ratio 1:0.3) when the fraction is no longer distilled, slurry at 20℃-25℃ for 5-6h, filter, rinse the filter cake with methanol, and dry it with air at 45℃ to obtain compound III-A weighing 15.0g, with a yield of 79.9% and a purity of 99.78%.

[0494] 3p:

[0495]

[0496] Add compound II-A (20.0 g, 1 equiv.), dichloromethane (100 ml), and N,N-dimethylformamide (0.5 g) to a 250 ml reaction bottle A, stir and mix, control the temperature at 15°C-25°C, drop thionyl chloride (11.8, 1.5 equiv.), and keep warm at 15°C-25°C for 1 hour. Add anhydrous aluminum chloride (17.7 g, 2 equiv.) and dichloromethane (100 ml) to a 500 ml reaction bottle B, stir and mix. Transfer the acyl chloride solution in reaction bottle A to reaction bottle B, control the temperature at 15°C-25°C, and keep warm for 1-1.5 hours. After the reaction is completed, cool the reaction solution to -10°C. Slowly transfer the reaction solution into cold water to quench, and control the temperature below 20°C. After the addition, stir for 15-30min, separate the liquids, retain the dichloromethane phase, extract the aqueous phase with dichloromethane (40ml), separate the liquids, combine the dichloromethane phases, and adjust the pH to 7-8 with sodium bicarbonate solution. Separate the liquids, wash the dichloromethane layer once with purified water (100ml). Concentrate under reduced pressure to recover dichloromethane, add methanol / dichloromethane mixed solvent (100ml, solvent ratio 1:0.4) when the fraction is no longer distilled, beat at 20℃-25℃ for 5-6h, filter, rinse the filter cake with methanol, and dry it with air at 45℃ to obtain compound III-A weighing 14.5g, with a yield of 77.0% and a purity of 99.81%.

[0497]

[0498] Preparation Example 4a-4b: Preparation of methyl 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl)propanoate (Compound IV-A) and ethyl 2-(10-hydroxy-9-oxa-1-azaanthen-6-yl)propanoate (Compound IV-B)

[0499] 4a:

[0500]

[0501] Compound III-A (20.0 g, 1 equiv.), dichloromethane (80 ml) and methanol (80 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (2.7 g, 1 equiv.) was slowly added, and the addition was completed over about 30 min. The mixture was kept warm at 25°C-30°C for 8 h, and the temperature was lowered to -5°C to 5°C. A 30% aqueous acetic acid solution was slowly added dropwise to a pH of 5.5-6.5. After the addition was completed, the mixture was kept warm at -5°C to 5°C and stirred for 15 min. Purified water (120 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (40 ml), and the dichloromethane phases were combined and washed once with a saturated aqueous sodium bicarbonate solution (20 ml); and the mixture was washed once with purified water (40 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (20.0g), and a methanol / acetone (50ml / 50ml) mixed solution was added, and the mixture was dissolved and dispersed at 25°C-30°C and stirred for 15min to obtain a yellow-green clear solution. Purified water (200ml) was slowly added dropwise to crystallize for 2h, filtered, and the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-A weighing 16.4g, with a yield of 81.5% and a purity of 96.72%.

[0502] 4b:

[0503]

[0504] Compound III-A (20.0 g, 1 equiv.), dichloromethane (80 ml) and methanol (80 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (2.7 g, 1 equiv.) was slowly added, and the addition was completed in about 30 min. The mixture was kept at 35°C-40°C for 6 h, and the temperature was lowered to -5°C to 5°C. A 30% aqueous acetic acid solution was slowly added dropwise to a pH of 5.5-6.5. After the addition was completed, the mixture was kept at -5°C to 5°C and stirred for 15 min. Purified water (120 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (40 ml), and the dichloromethane phases were combined and washed once with a saturated aqueous sodium bicarbonate solution (20 ml); and the mixture was washed once with purified water (40 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (20.0g), and a methanol / acetone (50ml / 50ml) mixed solution was added, and the mixture was dissolved and dispersed at 25°C-30°C and stirred for 15min to obtain a yellow-green clear solution. Purified water (200ml) was slowly added dropwise to crystallize for 2h, filtered, and the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-A weighing 16.6g, with a yield of 82.5% and a purity of 98.46%.

[0505] 4c:

[0506]

[0507] Compound III-B 30.0 g, 1 equiv.), dichloromethane (120 ml) and methanol (120 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (3.8 g, 1 equiv.) was slowly added, and the addition was completed in about 30 min. The mixture was kept warm at 35°C-40°C for 6 h, cooled to -5°C to 5°C, transferred to a 1 L beaker, and 30% acetic acid aqueous solution was slowly added dropwise to pH 5.5-6.5. After the addition was completed, the mixture was kept warm at -5°C to 5°C and stirred for 15 min. Purified water (180 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (60 ml), the dichloromethane phases were combined, and the mixture was washed once with saturated sodium bicarbonate aqueous solution (30 ml); and the mixture was washed once with purified water (60 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (30.0g), and a methanol / acetone (75ml / 75ml) mixed solution was added, and the mixture was dissolved and dispersed at 20°C-30°C and stirred for 15min to obtain a yellow-green clear solution. Purified water (300ml) was slowly added dropwise to crystallize for 2h, filtered, and the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-B weighing 24.1g, with a yield of 79.8% and a purity of 98.77%.

[0508] Comparative Examples 4d-4l

[0509] 4d:

[0510]

[0511] Compound III-A (20.0 g, 1 equiv.), dichloromethane (80 ml) and methanol (80 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (1.3 g, 0.5 equiv.) was slowly added, and the addition was completed in about 30 min. The mixture was kept at 15°C-20°C for 12 h, and the temperature was lowered to -5°C to 5°C. A 30% aqueous acetic acid solution was slowly added dropwise to a pH of 5.5-6.5. After the addition was completed, the mixture was kept at -5°C to 5°C and stirred for 15 min. Purified water (120 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (40 ml), and the dichloromethane phases were combined and washed once with a saturated aqueous sodium bicarbonate solution (20 ml); and the mixture was washed once with purified water (40 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (20.0g), and acetone (100ml) was added, and the mixture was dissolved and dispersed at 25°C-30°C with stirring for 15min to obtain a yellow-green clear solution. Purified water (200ml) was slowly added dropwise to crystallize for 2h, filtered, and the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-A weighing 15.0g, with a yield of 74.7% and a purity of 89.86%.

[0512] 4e:

[0513]

[0514] Compound III-A (20.0 g, 1 equiv.), dichloromethane (80 ml) and methanol (80 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (1.6 g, 0.6 equiv.) was slowly added, and the addition was completed in about 30 min. The mixture was kept at 15°C-20°C for 12 h, and the temperature was lowered to -5°C to 5°C. A 30% aqueous acetic acid solution was slowly added dropwise to a pH of 5.5-6.5. After the addition was completed, the mixture was kept at -5°C to 5°C and stirred for 15 min. Purified water (120 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (40 ml), and the dichloromethane phases were combined and washed once with a saturated aqueous sodium bicarbonate solution (20 ml); and the mixture was washed once with purified water (40 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (20.0g), and acetone (100ml) was added, and the mixture was dissolved and dispersed at 25°C-30°C with stirring for 15min to obtain a yellow-green clear solution. Purified water (200ml) was slowly added dropwise to crystallize for 2h, filtered, and the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-A weighing 15.4g, with a yield of 76.4% and a purity of 92.58%.

[0515] 4f:

[0516]

[0517] Compound III-A (20.0 g, 1 equiv.), dichloromethane (80 ml) and methanol (80 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (2.7 g, 1 equiv.) was slowly added, and the addition was completed over about 30 min. The mixture was kept at 15°C-20°C for 10 h, and the temperature was lowered to -5°C to 5°C. A 30% aqueous acetic acid solution was slowly added dropwise to a pH of 5.5-6.5. After the addition was completed, the mixture was kept at -5°C to 5°C and stirred for 15 min. Purified water (120 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (40 ml), and the dichloromethane phases were combined and washed once with a saturated aqueous sodium bicarbonate solution (20 ml); and the mixture was washed once with purified water (40 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (20.0g), and acetone (100ml) was added, and the mixture was dissolved and dispersed at 25°C-30°C and stirred for 15min to obtain a yellow-green clear solution. Purified water (200ml) was slowly added dropwise to crystallize for 2h, filtered, and the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-A weighing 16.4g, with a yield of 81.4% and a purity of 94.86%.

[0518] 4g:

[0519]

[0520] Compound III-A (20.0 g, 1 equiv.), dichloromethane (80 ml) and methanol (80 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (2.7 g, 1 equiv.) was slowly added, and the addition was completed over about 30 min. The mixture was kept at 15°C-20°C for 10 h, and the temperature was lowered to -5°C to 5°C. A 30% aqueous acetic acid solution was slowly added dropwise to a pH of 5.5-6.5. After the addition was completed, the mixture was kept at -5°C to 5°C and stirred for 15 min. Purified water (120 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (40 ml), and the dichloromethane phases were combined and washed once with a saturated aqueous sodium bicarbonate solution (20 ml); and the mixture was washed once with purified water (40 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (20.0g), methanol (100ml) was added, and the mixture was dissolved and dispersed at 25°C-30°C with stirring for 15min to obtain a yellow-green clear solution. Purified water (200ml) was slowly added dropwise to crystallize for 2h, filtered, the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-A weighing 17.8g, with a yield of 83.5% and a purity of 93.97%.

[0521] 4h:

[0522]

[0523] Compound III-A (20.0 g, 1 equiv.), dichloromethane (80 ml) and methanol (80 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (2.7 g, 1 equiv.) was slowly added, and the addition was completed over about 30 min. The mixture was kept at 15°C-20°C for 10 h, and the temperature was lowered to -5°C to 5°C. A 30% aqueous acetic acid solution was slowly added dropwise to a pH of 5.5-6.5. After the addition was completed, the mixture was kept at -5°C to 5°C and stirred for 15 min. Purified water (120 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (40 ml), and the dichloromethane phases were combined and washed once with a saturated aqueous sodium bicarbonate solution (20 ml); and the mixture was washed once with purified water (40 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (20.0g), and a methanol / acetone (50ml / 50ml) mixed solution was added, and the mixture was dissolved and dispersed at 25°C-30°C and stirred for 15min to obtain a yellow-green clear solution. Purified water (200ml) was slowly added dropwise to crystallize for 2h, filtered, and the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-A weighing 16.3g, with a yield of 81.0% and a purity of 95.23%.

[0524] 4i:

[0525]

[0526] Compound III-A (20.0 g, 1 equiv.), dichloromethane (80 ml) and methanol (80 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (3.8 g, 1 equiv.) was slowly added, and the addition was completed over about 30 min. The mixture was kept at 15°C-20°C for 10 h, and the temperature was lowered to -5°C to 5°C. A 30% aqueous acetic acid solution was slowly added dropwise to a pH of 5.5-6.5. After the addition was completed, the mixture was kept at -5°C to 5°C and stirred for 15 min. Purified water (120 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (40 ml), and the dichloromethane phases were combined and washed once with a saturated aqueous sodium bicarbonate solution (20 ml); and the mixture was washed once with purified water (40 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (20.0g), and a methanol / acetone (50ml / 50ml) mixed solution was added, and the mixture was dissolved and dispersed at 25°C-30°C and stirred for 15min to obtain a yellow-green clear solution. Purified water (200ml) was slowly added dropwise to crystallize for 2h, filtered, and the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-A weighing 16.1g, with a yield of 80.0% and a purity of 95.28%.

[0527] 4j:

[0528]

[0529] Compound III-A (20.0 g, 1 equiv.), dichloromethane (80 ml) and methanol (80 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (3.8 g, 1 equiv.) was slowly added, and the addition was completed over about 30 min. The mixture was kept at 15°C-20°C for 10 h, and the temperature was lowered to -5°C to 5°C. A 30% aqueous acetic acid solution was slowly added dropwise to a pH of 5.5-6.5. After the addition was completed, the mixture was kept at -5°C to 5°C and stirred for 15 min. Purified water (120 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (40 ml), and the dichloromethane phases were combined and washed once with a saturated aqueous sodium bicarbonate solution (20 ml); and the mixture was washed once with purified water (40 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (20.0g), and a methanol / acetone (50ml / 50ml) mixed solution was added, and the mixture was dissolved and dispersed at 25°C-30°C and stirred for 15min to obtain a yellow-green clear solution. Purified water (200ml) was slowly added dropwise to crystallize for 2h, filtered, and the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-A weighing 15.9g, with a yield of 78.7% and a purity of 94.03%.

[0530] 4k:

[0531]

[0532] Compound III-A (20.0 g, 1 equiv.), dichloromethane (80 ml) and methanol (80 ml) were added to a 500 ml reaction bottle, and the mixture was stirred and dissolved at 15°C-30°C for 5-10 min to obtain a clear solution. Sodium borohydride (3.8 g, 1 equiv.) was slowly added, and the addition was completed over about 30 min. The mixture was kept warm at 20°C-25°C for 8 h, and the temperature was lowered to -5°C to 5°C. A 30% aqueous acetic acid solution was slowly added dropwise to a pH of 5.5-6.5. After the addition was completed, the mixture was kept warm at -5°C to 5°C and stirred for 15 min. Purified water (120 ml) was added, and the mixture was stirred and separated to separate the organic phase. The aqueous phase was extracted once with dichloromethane (40 ml), and the dichloromethane phases were combined and washed once with a saturated aqueous sodium bicarbonate solution (20 ml); and the mixture was washed once with purified water (40 ml). The obtained dichloromethane solution was concentrated to dryness under reduced pressure (-0.09Mpa) at 35°C to obtain a yellow-green oil (20.0g), and a methanol / acetone (50ml / 50ml) mixed solution was added, and the mixture was dissolved and dispersed at 25°C-30°C and stirred for 15min to obtain a yellow-green clear solution. Purified water (200ml) was slowly added dropwise to crystallize for 2h, filtered, and the filter cake was washed with purified water, and dried in a vacuum at 40°C in the dark to obtain compound IV-A weighing 16.4g, with a yield of 81.5% and a purity of 95.86%.

[0533]

[0534] Preparation Examples 5a-5g: Preparation of Pranoprofen

[0535] 5a:

[0536]

[0537] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), and keep warm at 50°C-55°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of pranoprofen was dried under vacuum at 40°C to obtain 14.3 g, with a yield of about 79.9% and a purity of 99.62%. The finished product of pranoprofen was obtained by recrystallization from methanol, with a purity of >99.9% and a single impurity of less than 0.05%.

[0538] 5b:

[0539]

[0540] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 60°C-65°C, keep warm for 2.5 hours, and concentrate at 55°C under reduced pressure until there is no fraction, to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), keep warm for 2 hours at 50°C-55°C. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of pranoprofen was dried under vacuum at 40°C to obtain 14.4 g, with a yield of about 80.5% and a purity of 99.27%. The finished product of pranoprofen was obtained by recrystallization from methanol, with a purity of >99.9% and a single impurity of less than 0.05%.

[0541] 5c:

[0542]

[0543] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 70°C-75°C, and react for 2.5 hours. Concentrate at 55°C under reduced pressure until there is no fraction, and obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), and react at 50°C-55°C for 2 hours. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of pranoprofen was dried under vacuum at 40°C to obtain 14.3 g, with a yield of about 79.9% and a purity of 99.48%. The finished product of pranoprofen was obtained by recrystallization from methanol, with a purity of >99.9% and a single impurity of less than 0.05%.

[0544] 5d:

[0545]

[0546] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add potassium hydroxide solution prepared from potassium hydroxide (15.7 g, 4 quiv.) and purified water (40 ml), and keep warm at 50°C-55°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of pranoprofen was dried under vacuum at 40°C to obtain 14.2 g, with a yield of about 79.4% and a purity of 99.63%. The finished product of pranoprofen was obtained by recrystallization from methanol, with a purity of >99.9% and a single impurity of less than 0.05%.

[0547] 5e:

[0548]

[0549] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), and keep warm at 40°C-45°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of pranoprofen was dried under vacuum at 40°C to obtain 14.6 g, with a yield of about 81.6% and a purity of 99.68%. The finished product of pranoprofen was obtained by recrystallization from methanol, with a purity of >99.9% and a single impurity of less than 0.05%.

[0550] 5f:

[0551]

[0552] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), and keep warm at 40°C-45°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 10% dilute hydrochloric acid, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of pranoprofen was dried under vacuum at 40°C to obtain 14.6 g, with a yield of about 81.6% and a purity of 99.67%. The finished product of pranoprofen was obtained by recrystallization from methanol, with a purity of >99.9% and a single impurity of less than 0.05%.

[0553] 5g:

[0554]

[0555] Add compound IV-B (20.0 g, 1 equiv.), hydrochloric acid (23.8 g, 3.5 equiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (10.7 g, 4 equiv.) and purified water (40 ml), and keep warm at 40°C-45°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase with ethyl acetate (100 ml) 4 times. After separating the aqueous phase, adjust the pH to 5-6 with 10% dilute hydrochloric acid, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of pranoprofen was dried under vacuum at 40°C to obtain 13.6 g of the product, with a yield of about 79.5% and a purity of 99.62%. The finished product of pranoprofen was obtained by recrystallization from methanol, with a purity of >99.9% and a single impurity of less than 0.05%.

[0556] Comparative Examples 5h-5t

[0557] 5h:

[0558]

[0559] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (10.6 g, 1.5 euqiv.), isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 50°C-55°C, keep warm for 4 hours, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), keep warm for 2 hours at 50°C-55°C. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 13.1 g, with a yield of about 73.2% and a purity of 97.76%.

[0560] 5i:

[0561]

[0562] Add compound IV-A (20.0 g, 1 euqiv.), isopropanol hydrochloride (29.0 g, 13.2 wt.%, 1.5 euqiv.), isopropanol (208 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 50°C-55°C, keep warm for 4 hours, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), keep warm for 2 hours at 50°C-55°C. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 13.1 g, with a yield of about 73.2% and a purity of 97.78%.

[0563] 5j:

[0564]

[0565] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (14.2 g, 2 euqiv.), isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 50°C-55°C, keep warm for 4 hours, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), keep warm for 2 hours at 50°C-55°C. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 13.3 g, with a yield of about 74.3% and a purity of 98.12%.

[0566] 5k:

[0567]

[0568] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (17.7 g, 2.5 euqiv.), isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 50°C-55°C, keep warm for 4 hours, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), keep warm for 2 hours at 50°C-55°C. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 13.6 g, with a yield of about 76.0% and a purity of 98.63%.

[0569] 5l:

[0570]

[0571] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 50°C-55°C, keep warm for 4 hours, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), keep warm for 2 hours at 50°C-55°C. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 13.7 g, with a yield of about 76.6% and a purity of 98.77%.

[0572] 5m:

[0573]

[0574] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium carbonate solution prepared from sodium carbonate (29.7 g, 4 quiv.) and purified water (40 ml), and keep warm at 50°C-55°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 13.9 g, with a yield of about 77.7% and a purity of 98.79%.

[0575] 5n:

[0576]

[0577] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add potassium carbonate solution prepared from potassium carbonate (38.8 g, 4 quiv.) and purified water (40 ml), and keep warm at 50°C-55°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 13.8 g, with a yield of about 77.1% and a purity of 98.92%.

[0578] 5o:

[0579]

[0580] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), and keep warm at 60°C-65°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to give 14.0 g of the product, with a yield of about 78.2% and a purity of 98.86%.

[0581] 5p:

[0582]

[0583] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), and keep warm at 40°C-45°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 10% dilute sulfuric acid, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 13.7 g, with a yield of about 76.6% and a purity of 98.81%.

[0584] 5q:

[0585]

[0586] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), and keep warm at 40°C-45°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 5-6 with 10% dilute sulfuric acid, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 13.9 g, with a yield of about 77.7% and a purity of 98.64%.

[0587] 5r:

[0588]

[0589] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), and keep warm at 40°C-45°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 4-5 with 10% dilute hydrochloric acid, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 14.7 g, with a yield of about 82.1% and a purity of 98.74%.

[0590] 5s:

[0591]

[0592] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), and keep warm at 40°C-45°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 6-7 with 10% dilute hydrochloric acid, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 13.3 g, with a yield of about 74.3% and a purity of 99.77%.

[0593] 5t:

[0594]

[0595] Add compound IV-A (20.0 g, 1 euqiv.), hydrochloric acid (24.8 g, 3.5 euqiv.), and isopropanol (240 ml) to a 250 ml reaction bottle, stir and dissolve, heat to 80°C-85°C, reflux for 2 h, and concentrate at 55°C under reduced pressure until there is no fraction to obtain a foamy oil (24 g). After cooling to room temperature, add methanol (10 ml), stir and dissolve, add sodium hydroxide solution prepared from sodium hydroxide (11.2 g, 4 quiv.) and purified water (40 ml), and keep warm at 40°C-45°C for 2 h. Transfer to a 500 ml beaker, add purified water (300 ml), and then extract the aqueous phase 4 times with ethyl acetate (100 ml). After separating the aqueous phase, adjust the pH to 3-4 with 10% dilute hydrochloric acid, and gradually precipitate a white powdery solid. Filter, and rinse the filter cake with purified water and cold methanol in turn. The crude product of Pranoprofen was dried under vacuum at 40°C to obtain 15.0 g, with a yield of about 83.8% and a purity of 98.53%.

[0596]

[0597]

[0598] Experimental Example 1: Structural Characterization

[0599] Pranoprofen samples were synthesized according to the process described above in the present invention, and the synthesis process of this batch of samples was carried out according to the preparation conditions of 1a, 2c, 3c, 4b, and 5a. Pranoprofen standard products can be purchased directly from the China National Institute for Inspection and Quarantine.

[0600] The structure was confirmed.

[0601] Elemental composition of compounds:

[0602] (1) High resolution mass spectrometry (HRMS)

[0603] Instrument model: Bruker SolariX 7.0T (FT-ICR MS).

[0604] Test conditions: ESI ionization mode.

[0605] Test results: Figure 1 The results showed that the quasi-molecular ion peak m / z 254.081876 in the high-resolution mass spectrum was [MH] - Peak, the corresponding element composition is C 15 H 12 NO3, the elemental composition of the sample is C 15 H 13 NO3, which corresponds to the elemental composition of the free base portion of the molecule.

[0606] (2) Infrared spectrum (IR)

[0607] Instrument model: Bruker IFS-55 infrared photometer (calibrated according to General Rule 0402 of the 2015 edition of the Chinese Pharmacopoeia).

[0608] Experimental method: KBr tablet method.

[0609] Experimental results: The measured data are shown in Table 6 below. The standard infrared spectrum is as follows Figure 2A The infrared spectrum of the sample is as follows Figure 2B .

[0610] Table 6: Infrared spectrum measurement data of samples

[0611]

[0612]

[0613] Analysis:

[0614] a.3427.6cm -1 It is the stretching vibration peak of -OH, indicating that there may be a carboxyl group in the molecule.

[0615] b.2968.2,2943.1,2881.9 and 1465~1376cm -1 Multiple absorption peaks are CH stretching and bending vibration peaks, indicating that methyl and methylene groups may exist in the molecule.

[0616] c.1706.7cm -1 It is the C=O stretching vibration peak, indicating that there may be a carbonyl group in the molecule.

[0617] d.1608.6、1584.3、1499.5cm -1 C=C stretching vibration of benzene ring, 767.8 cm -1 The CH bending vibration peak of the benzene ring is 804.0 cm -1 It is the C=C bending vibration peak of the benzene ring, indicating the presence of a benzene ring in the molecule.

[0618] Conclusion: The position, peak shape and intensity of the absorption peaks of each functional group in the infrared spectrum of the sample are consistent with the molecular structure of pranoprofen; the infrared spectra of the sample and the reference substance are consistent with the reference spectrum of the Japanese Pharmacopoeia JP17 edition.

[0619] (3) Ultraviolet spectrum (UV)

[0620] Instrument model: Agilent cary-60 UV spectrometer

[0621] Solution preparation: Take 0.02g of this product, add 1mol / L hydrochloric acid solution to dissolve and dilute to 100ml as the mother solution; take 10ml of the above mother solution, add water to dilute to 100ml as the neutral test sample.

[0622] Take 10 ml of the above mother solution and dilute it to 100 ml with 1 mol / L hydrochloric acid solution as the acidic test sample; take 10 ml of the above mother solution and dilute it to 100 ml with 1 mol / L sodium hydroxide solution as the alkaline test sample. The test results are shown in Table 7 and Figures 3A-3F .

[0623] Table 7: UV measurement results of samples and standards

[0624]

[0625]

[0626] Analysis: The peak shapes of the sample and the reference substance in UV scanning are consistent, and the maximum absorption wavelengths are consistent.

[0627] Conclusion: The UV absorption of the sample is consistent with the molecular structure of pranoprofen; the UV spectra of the sample and the reference are consistent.

[0628] (4) Nuclear magnetic resonance spectroscopy (NMR)

[0629] 1 H-NMR

[0630] Instrument model: Bruker AV-600 NMR instrument.

[0631] Test conditions: solvent DMSO-d6, TMS internal standard.

[0632] The measurement data are shown in Table 8 below.

[0633]

[0634] Table 8: Sample NMR H spectrum data analysis

[0635]

[0636]

[0637] Analysis:

[0638] The single peak at δ12.34 ppm is carboxyl hydrogen.

[0639] 1H at δ7.09ppm is the hydrogen at position 8 of the benzene ring.

[0640] 1H at δ7.16ppm is the hydrogen at position 7 of the benzene ring.

[0641] The hydrogen at position 5 of the 1H benzene ring is at δ7.18.

[0642] 1H at δ7.15ppm is the hydrogen at position 3 of the pyridine ring.

[0643] 1H at δ7.72ppm is the hydrogen at position 4 of the pyridine ring.

[0644] 1H at δ8.13ppm is the hydrogen at position 2 on the pyridine ring.

[0645] The 2H singlet at δ4.11ppm is the hydrogen on the 10-position methylene.

[0646] The 1H quartet at δ3.66ppm is the isopropyl hydrogen at position 15, which couples with the methyl hydrogen at position 17 and splits into a quartet.

[0647] The 3H doublet at δ1.36ppm is the methyl hydrogen at position 17, which couples with the isopropyl hydrogen at position 15 and splits into two peaks.

[0648] Conclusion: The sample 1 The H-NMR spectrum data are consistent with the structure of pranoprofen, and the spectra of the sample and the reference are consistent.

[0649] 13 C-NMR

[0650] Instrument model: Bruker AV-600 NMR instrument.

[0651] Test conditions: solvent DMSO-d6, TMS internal standard.

[0652] The measurement data are shown in Table 9 below.

[0653] Table 9: Sample NMR C spectrum data analysis

[0654]

[0655]

[0656] Analysis:

[0657] The molecule of Pranoprofen contains 15 carbon atoms, including 1 primary carbon, 1 secondary carbon, 7 tertiary carbons, and 6 quaternary carbons; it contains 13 hydrogen atoms, which are analyzed as follows:

[0658] 1. The carbon at δ175.39ppm is a quaternary carbon atom, which is correlated with the hydrogens on the 15- and 17-position carbons in the HMBC spectrum, and can be determined to be the 16-position carboxyl carbon.

[0659] 2. The carbon at δ157.83ppm is a quaternary carbon atom, which is correlated with the hydrogens on the 2- and 4-position pyridine rings and the hydrogen on the 10-position methylene in the HMBC spectrum, and can be determined to be the 11-position oxygen-linked pyridine ring carbon.

[0660] 3. The carbon at δ150.03ppm is a quaternary carbon atom, which is related to the hydrogens on the 5-, 7-, 8-position benzene ring and the 10-position methylene carbon in the HMBC spectrum. It is the 14-position oxygen-linked benzene ring carbon.

[0661] 4. The carbon at δ136.71ppm is a quaternary carbon atom, which is related to the hydrogen on the 7-position benzene ring carbon, the hydrogen on the 15-position isopropyl carbon, and the hydrogen on the 17-position methyl in the HMBC spectrum. It is the 6-position benzene ring carbon.

[0662] 5. The position at δ120.00ppm is a quaternary carbon atom, which is related to the hydrogen on the 8-position benzene ring carbon and the hydrogen on the 10-position methylene carbon in the HMBC spectrum, and is the 14-position benzene ring carbon.

[0663] 6. The quaternary carbon atom at δ115.62 ppm is related to the hydrogen on the 4-position pyridine ring carbon and the hydrogen on the 10-position methylene carbon in the HMBC spectrum, and is the 12-position pyridine ring carbon.

[0664] 7. The tertiary carbon atom at δ146.26 ppm is related to the hydrogen on the 2-position pyridine ring carbon in the HSQC spectrum and to the hydrogen on the 3-position and 4-position pyridine ring carbon in the HMBC spectrum. It is the 2-position pyridine ring carbon.

[0665] 8. The tertiary carbon atom at δ138.89 ppm is related to the hydrogen on the 4-position pyridine ring carbon in the HSQC spectrum, and to the hydrogen on the 2-position pyridine ring carbon and the hydrogen on the 10-position methylene carbon in the HMBC spectrum, which is the 4-position pyridine ring carbon.

[0666] The tertiary carbon atom at δ127.79ppm is related to the hydrogen on the 5-position benzene ring carbon in the HSQC spectrum, and is related to the methylene hydrogen at the 10-position and the isopropyl hydrogen at the 15-position in the HMBC spectrum, which is the 5-position benzene ring carbon.

[0667] 10. The tertiary carbon atom at δ127.01ppm is related to the hydrogen on the carbon at position 7 of the benzene ring in the HSQC spectrum, and is related to the hydrogen on the carbon at position 5 of the benzene ring and the isopropyl hydrogen at position 15 in the HMBC spectrum, which is the carbon at position 7 of the benzene ring.

[0668] 11. The tertiary carbon atom at δ120.27ppm is related to the 3-position pyridine ring carbon hydrogen in the HSQC spectrum and to the 10-position methylene hydrogen in the HMBC spectrum. It is the 3-position pyridine ring carbon.

[0669] 12. The tertiary carbon atom at δ116.41ppm is related to the hydrogen on the 8-position benzene ring carbon in the HSQC spectrum, but not related to hydrogen in the HMBC spectrum, so it is the 8-position benzene ring carbon.

[0670] 13. The tertiary carbon atom at δ27.19 ppm is related to the hydrogen on the isopropyl carbon at position 15 in the HSQC spectrum and to the hydrogen on the benzene ring carbons at positions 5 and 7 in the HMBC spectrum, which is the isopropyl carbon at position 15.

[0671] 14. The secondary carbon atom at δ43.94 ppm is related to the hydrogen of the methylene at position 10 in the HSQC spectrum, and is the methylene carbon at position 10.

[0672] 15. The primary carbon atom at δ18.54 ppm is related to the hydrogen on the methyl carbon at position 17 in the HSQC spectrum and to the isopropyl hydrogen at position 15 in the HMBC spectrum, which is the methyl carbon at position 17.

[0673] Conclusion: The sample 13 The C-NMR spectrum data were consistent with the structure of pranoprofen, and the spectra of the sample and the reference were consistent.

[0674] summary:

[0675] (1) The IR, UV, NMR and MS test results of this sample and the reference substance are consistent, and they have the same structure and the same crystal form, that is, this sample is pranoprofen.

[0676] (2) High-resolution mass spectrometry measured the sample m / z 295.201619 as [MH] - Peak, the corresponding element composition is C 15 H 12 NO3, the elemental composition of the sample is C 15 H 13 NO3, which is consistent with the structure of the organic base part of the molecule.

[0677] (3) UV spectrum shows strong absorption peaks at 260-270nm, IR spectrum 1591.9, 1521.1cm -1 、804.0cm -1 and 767.8cm -1 The absorption peak at 1 H-NMR spectrum has absorption peaks at δ7.30ppm, δ7.25ppm, and δ6.87ppm. 13 The absorption peaks at δ118.14 ppm, δ113.35 ppm and δ109.91 ppm in the C-NMR spectrum indicate the presence of a trisubstituted benzene ring structure fragment.

[0678] (4) IR spectrum 1706.7 cm -1 The absorption peak at 13 The absorption peak at δ175.39 ppm in the C-NMR spectrum indicated the presence of a carbonyl structure fragment.

[0679] In summary, the molecular structure of the sample is consistent with that of pranoprofen.

[0680] Experimental Example 2: Stability Study

[0681] 1. Experimental samples

[0682] According to this process, three batches of kilogram-scale scale-up batches were prepared under the preferred experimental conditions, and they were named 20190101, 20190201, and 20190202. The three batches of products were prepared in independent batches, and the synthesis process was carried out according to the preparation conditions of 1a, 2c, 3c, 4b, and 5a, and were obtained by methanol refining and purification (i.e., methanol recrystallization). The purity of the three batches of products was 99.91%, 99.90%, and 99.95%, respectively.

[0683] 2. Experimental Methods

[0684] According to the relevant provisions of the Technical Guidelines for Stability Studies of Chemical Drugs, the three batches of samples mentioned above were tested for 6 months at 40℃±2℃ and RH75%±5%. Samples were taken at the end of the 0th, 1st, 2nd, 3rd and 6th month to test the indicators.

[0685] Chromatographic conditions:

[0686] The test was conducted according to the high performance liquid chromatography method (General Rules 0512 of the 2015 edition of the Chinese Pharmacopoeia). Octadecylsilane bonded silica gel was used as the filler (5 μm, 250 mm × 4.6 mm); 0.05 mol / L sodium perchlorate aqueous solution-methanol = (90:10, with perchloric acid added to adjust the pH to 3.2) was used as the mobile phase A, methanol was used as the mobile phase B, and the 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.

[0687] Table 10: Elution schedule

[0688] time Mobile phase A Mobile phase B 0 80 20 40 55 45 60 45 55

[0689] Accurately measure 10 μl of the test solution and inject it into the liquid chromatograph. If there are impurity peaks in the chromatogram of the test solution, the single impurity should not exceed 0.1%, and the sum of all impurities should not exceed 0.5%.

[0690] The impurity objects detected are total impurities, impurity A, impurity C, impurity D, impurity L and the largest single impurity; the detection conditions are the same as above.

[0691] Preparation method of impurity A: Add purified water (140 ml) and sodium hydroxide (14.8 g) to a 1000 ml three-necked flask, stir to dissolve, then add compound III-A (35 g) and anhydrous methanol (20 ml), heat to 45°C for 2 hours, cool to 20°C-30°C, add 70 ml of purified water to dilute, extract the reaction solution with 105 ml of ethyl acetate, and collect the aqueous phase. Adjust the pH of the aqueous phase to 5-6 with 20% phosphoric acid aqueous solution to precipitate a white solid, stir for 30 minutes, filter with suction, and wash the filter cake with 105 ml of water. Dry at 50°C with air blast to obtain the target product.

[0692] Preparation method of impurity C: Add 2-chloronicotinic acid (30g, 0.19mol), 4-ethylphenol (69.6g, 0.57mol), anhydrous potassium carbonate (52.5g, 0.38mol), cuprous iodide (1.8g, 0.01mol), N,N-dimethylformyl (30ml) to a 500ml three-necked flask, heat to 100℃-110℃ and react for 6 hours, cool to 30℃-35℃, add 120ml of water to dilute, transfer to a 2L plastic beaker, adjust pH to 3-4 with 30% phosphoric acid, filter, and rinse the filter cake with petroleum ether. Add the filter cake to 100ml of water, adjust pH to 7-8 with saturated sodium bicarbonate aqueous solution, filter, collect the filtrate, adjust pH to 3-4 with 30% phosphoric acid, filter, and dry the filter cake.

[0693] Take 37g of solid and add it to a 1000ml three-necked flask, add 125g of polyphosphoric acid, heat to 120℃-130℃ and react for 4 hours, then cool to 20℃-30℃, add 600ml of water, filter with suction, wash the filter cake with 200ml of water, and dry the filter cake at 60℃ to obtain the target product.

[0694] Preparation method of impurity D: Add pranoprofen (15g), N,N-dimethylformamide (4.5ml), and anhydrous methanol (90ml) to a 250ml three-necked flask, and the system is suspended. Add a solution of dichlorothionyl (8.4g) in dichloromethane (20ml) dropwise, and react at 20℃-30℃ for 4 hours. After the reaction is completed, the system is transferred to a 500ml single-necked bottle, concentrated under reduced pressure at 55℃ water bath until there is no obvious fraction, the concentrate is diluted with 150ml of dichloromethane, the pH is adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, stirred for 10 minutes, and allowed to stand for separation. The organic phase is washed with 100ml of saturated sodium bicarbonate aqueous solution and 100ml of saturated brine respectively. The organic phase is concentrated under reduced pressure at 45℃ water bath until there is no obvious fraction to obtain a white solid, 100ml of n-hexane is added and stirred for 30 minutes, filtered, and the filter cake is vacuum dried at 40℃ to obtain the target product.

[0695] Preparation method of impurity L: Add THF (150ml) and compound IV-A (25g) to a 500ml single-mouth bottle, add acetone (30.7g) after dissolving, and stir to obtain a colorless solution. Add aluminum chloride (23.5g) in batches, and after addition, obtain a light yellow solution, and keep warm for 4 hours. Concentrate under pressure at 45℃ until there is no obvious fraction, pour into 100ml water, and adjust the pH value to 2-3 with saturated sodium bicarbonate aqueous solution. Extract with DCM100ml*2, wash with 50ml of combined organic phases, take the organic phase, and concentrate under reduced pressure at 45℃ until there is no obvious fraction. Column chromatography to obtain the product. The obtained product (25g), methanol (125ml), water (12.5ml), and sodium hydroxide (9.2g) are stirred and reacted for 1 hour. Transfer to a 500ml beaker, add purified water (300g), then extract the aqueous phase with ethyl acetate (90g) 4 times, separate the aqueous phase, adjust the pH to about 5.8 with 20% acetic acid aqueous solution, and gradually precipitate a white powdery solid. Filter, rinse the filter cake with purified water and cold methanol in turn. Dry under vacuum at 40°C to obtain the target product.

[0696] Preparation of test solution: Take 50 mg of the product, add solvent (acetonitrile-water = 1:1) to dissolve and dilute to 50 ml as the test solution.

[0697] Mixed impurity control stock solution: Weigh 10.0 mg of impurities A, C, D, and L respectively, place them in 10.0 ml volumetric flasks, add methanol to dissolve and dilute to the scale, take 1.0 ml of each of the above solutions into a 100.0 ml volumetric flask, add solvent to dilute to the scale as the impurity control stock solution.

[0698] Mixed impurity control solution: Accurately measure 1.0 ml of the test sample solution and dilute it to 100.0 ml with solvent; accurately measure 1.0 ml of the above solution, add 1.0 ml of the mixed impurity control stock solution, and add solvent to 10.0 ml as the mixed impurity control solution.

[0699] Preparation of system suitability solution: Accurately measure 1.0 ml of the mixed impurity control stock solution and dilute it to 10 ml with the test sample solution as the system suitability solution.

[0700] Preparation of control solution: Take 1.0 ml of the test solution and dilute it to 10.0 ml with solvent; take 1.0 ml of the above solution and dilute it to 100.0 ml with solvent as the control solution.

[0701] 3. Experimental results

[0702] The experimental results are shown in Table 11 below.

[0703] Table 11

[0704]

[0705]

[0706] Note: The maximum single impurity usually refers to the maximum unknown single impurity, and known impurities are directly represented by impurity codes.

[0707] The results show that the three batches of products prepared by the present invention have stable and reliable quality.

[0708] Although the specific embodiments of the present invention have been described in detail, it will be understood by those skilled in the art. According to all the teachings disclosed, various modifications and replacements can be made to those details, and these changes are all within the protection scope of the present invention. The full scope of the present invention is given by the attached claims and any equivalents thereof.

Claims

1. A method for preparing pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen, comprising the following steps: The step of reacting a compound of formula A with a compound of formula B to produce a compound of formula I: in, X is a halogen; R is ethyl; The step of reacting a compound of formula I with a compound of formula C to produce a compound of formula II: in, R is ethyl; R1 is a methyl group; Steps for preparing a compound of formula III from a compound of formula II: Wherein, R1 is methyl; Steps for preparing a compound of formula IV from a compound of formula III: Wherein, R1 is methyl; Steps for preparing pranoprofen from the compound of formula IV: Wherein, R1 is methyl, Wherein, the temperature of the reaction system in the step of reacting the compound of formula A with the compound of formula B to generate the compound of formula I is 60°C-150°C.

2. The preparation method according to claim 1, wherein X is fluorine, chlorine, bromine or iodine.

3. The preparation method according to claim 1, wherein X is chlorine or bromine.

4. The preparation method according to claim 1, wherein The compound of formula A reacts with the compound of formula B under the action of a catalyst, Wherein, the reaction system also contains an acid binding agent, and Wherein, calculated by molar ratio, the compound of formula A: the compound of formula B: the catalyst: the acid binding agent is 1: (1-3): (0.05-0.1): (1-2).

5. The preparation method according to claim 1, wherein The compound of formula A is selected from 2-chloronicotinic acid, 2-bromonicotinic acid and 2-iodonicotinic acid.

6. The preparation method according to any one of claims 1 to 5, wherein: The compound of formula B is selected from 4-hydroxypropiophenone.

7. The preparation method according to claim 1, wherein The temperature of the reaction system in the step of reacting the compound of formula A with the compound of formula B to generate the compound of formula I is 80°C-120°C.

8. The preparation method according to claim 1, wherein The temperature of the reaction system in the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 95°C-120°C.

9. The preparation method according to claim 1, wherein The temperature of the reaction system in the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 95°C-110°C.

10. The preparation method according to claim 1, wherein: The temperature of the reaction system in the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 105°C-120°C.

11. The preparation method according to claim 1, wherein: The temperature of the reaction system in the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 105°C-115°C.

12. The preparation method according to claim 1, wherein: The temperature of the reaction system in the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 110°C-120°C.

13. The preparation method according to claim 1, wherein The temperature of the reaction system in the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 95°C-105°C.

14. The preparation method according to claim 1, wherein: The temperature of the reaction system in the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 105°C-110°C.

15. The preparation method according to any one of claims 1 to 5, wherein: The reaction time of the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is at least 1 hour.

16. The preparation method according to claim 15, wherein: The reaction time of the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is at least 2 hours.

17. The preparation method according to claim 15, wherein: The reaction time of the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is at least 3 hours.

18. The preparation method according to claim 15, wherein: The reaction time of the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is at least 4 hours.

19. The preparation method according to claim 15, wherein: The reaction time of the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is at least 5 hours.

20. The preparation method according to claim 15, wherein: The reaction time of the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 1 to 10 hours.

21. The preparation method according to claim 15, wherein: The reaction time of the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 2-8 hours.

22. The preparation method according to claim 15, wherein: The reaction time of the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 3-7 hours.

23. The preparation method according to claim 15, wherein: The reaction time of the step of reacting the compound of formula A with the compound of formula B to produce the compound of formula I is 4-6 hours.

24. The preparation method according to any one of claims 1 to 5, wherein: The compound of formula A is reacted with the compound of formula B in an organic solvent as a reaction solvent.

25. The preparation method according to claim 24, wherein: The organic solvent is N,N-dimethylformamide or dimethyl sulfoxide.

26. The preparation method according to claim 24, wherein: The organic solvent is N,N-dimethylformamide.

27. The preparation method according to claim 4, wherein: The catalyst is cuprous iodide.

28. The preparation method according to claim 4, wherein The acid binding agent is selected from potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate.

29. The preparation method according to any one of claims 1 to 5, wherein: The method also includes the step of separating the compound of formula I from the reaction system.

30. The preparation method according to claim 29, wherein: The steps include: After cooling the reaction system, water is added to acidify to pH 3-4, the precipitated solid is collected, dispersed with water, the pH is adjusted to 7-7.5, the solid is filtered out, the filtrate is acidified to pH 3-4, the precipitated solid is collected, washed with water and dried to obtain the compound of formula I.

31. The preparation method according to claim 30, wherein: The reaction system was cooled to 50°C or lower.

32. The preparation method according to any one of claims 1 to 5, comprising the steps of: Put the compound of formula A, cuprous iodide and reaction solvent into a reaction vessel, control the temperature to 60°C-150°C, add the acid binding agent and the compound of formula B in batches, control the temperature to 60°C-150°C, and keep the temperature to react for 2-8 hours; After cooling, water is added to acidify to pH 3-4, the precipitated solid is collected, dispersed with water, the pH value is adjusted to 7-7.5, the solid is filtered out, the filtrate is acidified to pH 3-4, the precipitated solid is collected, washed with water and dried to obtain the compound of formula I.

33. The preparation method according to claim 32, wherein: Adjust pH to 7-7.5 with sodium bicarbonate.

34. Use of a compound of formula I or a pharmaceutically acceptable salt or ester thereof in the preparation of pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen, wherein pranoprofen or a pharmaceutically acceptable salt or ester of pranoprofen is prepared by the preparation method according to any one of claims 1 to 33.

Images