Process for the preparation of indolizine derivatives

Abstract

The present application relates to methods of preparing indolizine derivatives. In particular, the present application discloses methods for preparing compounds of Formula 1, intermediate compounds, and methods of preparing the intermediate compounds.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, specifically to a method for preparing compound of formula 1 ((8'-hydroxy-6'-oxo-3'-phenyl-6'H-spiro[cyclopentyl-1,5'-indoleazine]-7'-carbonyl)glycine compound), an intermediate compound, and a method for preparing the intermediate compound. Background Technology

[0002] Anemia is a disease caused by a decrease in the number of red blood cells or a decrease in the hemoglobin content of red blood cells. Since the main function of hemoglobin is to carry oxygen to various organs for utilization, low hemoglobin levels directly lead to insufficient oxygen supply to these organs. Because normal physiological activities depend on the efficient use of oxygen, different degrees of anemia can cause various clinical symptoms. Common complications of anemia include cardiovascular diseases (heart failure, atrial fibrillation, angina, etc.), urinary system diseases (kidney failure, proteinuria), nervous system diseases (dizziness, headache, tinnitus, blurred vision, lethargy, drowsiness, irritability, and difficulty concentrating; severe anemia can cause fainting), digestive system diseases (loss of appetite, constipation), and reproductive system diseases (decreased libido, menstrual irregularities). Anemia can seriously affect a patient's health and quality of life; if not corrected in time, it can even threaten a patient's life.

[0003] Anemia has many causes, but it is usually due to a decrease in the production of erythropoietin (EPO). Chronic kidney disease (CKD) leads to decreased EPO synthesis, so most patients with CKD suffer from anemia. In addition, cancer patients undergoing radiotherapy and chemotherapy experience suppression of hematopoietic stem cells in the bone marrow, which can also cause anemia. Some antiviral drugs (such as those used to treat hepatitis C and HIV) and inflammation can also lead to anemia.

[0004] Inhibiting proline hydroxylase can stabilize hypoxia-inducible factor (HIF), thereby increasing erythropoietin production (Cell, 2001, 107, 43-54). HIF is a transcription factor that plays a crucial role in regulating oxygen balance in the body's response to hypoxia (Molecular Cellular Biology 1992, 12, 5447-5454). HIF-1 is a heterodimer; when it is linked to the promoter region of a hypoxia-responsive element (HRE), it can upregulate the expression of many genes (Nature Reviews Cancer 2003, 3, 721-732). Proteins encoded by genes regulated by HIF-1 can lead to numerous biological effects, including erythropoiesis, angiogenesis, vasodilation, glycolysis, immunomodulation, neuroprotection, myocardial ischemia protection, and cerebral ischemia protection. Under normal oxygen conditions, a proline residue on the hypoxia-inducible factor-lα subunit is hydroxylated by proline hydroxylase. The hydroxylated hypoxia-inducible factor-lα is then linked to the von Hippel Lindau protein and subsequently degraded by the proteosome via ubiquitination. Under hypoxic conditions, the activity of proline hydroxylase is inhibited, thus stabilizing the hypoxia-inducible factor-lα subunit. Increased levels of the hypoxia-inducible factor-lα subunit regulate genes including elevated erythropoietin levels (Science 2001, 292, 464-468).

[0005] The compound shown in Formula 1 (molecular formula: C) 21 H 20 N2O5 (molecular weight: 380.40) is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor. Its chemical name is 8'-hydroxy-6'-oxo-3'-phenyl-6'H-spiro[cyclopentyl-1,5'-indoleazine]-7'-carbonyl)glycine, and its chemical structure is shown in Figure 1. It is a potential drug for treating anemia and has broad pharmaceutical applications.

[0006] The tautomer 1' of Formula 1 is disclosed in CN108484598A, and its structure is shown below. The tautomerism of this structure is also mentioned in that patent. Since 1 and 1' are inseparable tautomers, they are treated as equivalent in this patent application.

[0007] In CN108484598A, the synthesis of compound 1 (i.e., 1', with 1 replacing 1' in all subsequent sections) does not provide detailed information on synthetic steps, yield, purity, etc., but its route can be summarized as follows: However, the existing techniques for synthesizing compounds of formula 1 have the following drawbacks: Step a, i.e., 2 to 3': Carboxylic acid 2 reacts with HOBt (1-hydroxybenzotriazole, structure shown above) in THF solvent under the action of condensing agent DCC (N,N'-dicyclohexylcarbodiimide, structure shown above) to give product 3', with a yield of 78%. Since DCC generates insoluble urea during the reaction, although most of the urea can be removed by filtration, trace amounts always remain, requiring column chromatography for complete removal; for large-scale production, column chromatography separation is undoubtedly impractical. Furthermore, HOBt is a potentially explosive high-energy substance, and because its production uses hydrazine, a certain amount of hydrazine always remains in the HOBt product, thus giving it a certain degree of carcinogenicity; explosiveness and carcinogenicity are also very detrimental to the production of compound 1. Step b, i.e., 3' to 4a: The prior art method uses sodium hydride, which is very inconvenient for the large-scale production of the compound of formula 1; Step c, i.e., 4a to 5a: The methods disclosed in the prior art use methanesulfonic acid as the acid and dichloromethane as the solvent, and the yield may only be 60%, with the formation of byproduct 5a'. Step d, i.e., 5a to 1: The prior art method uses glycine with 0.5 M sodium methoxide / methanol solution as base and n-propanol as solvent. Although the reaction yield is acceptable, a large amount of solvent is required. Subsequently, 2-methoxyethanol was used, and the yield can reach 90%. However, this solvent can cause reproductive toxicity, which is very unfavorable for large-scale production.

[0008] It is evident that known methods for preparing compounds of formula 1 have various shortcomings. Therefore, the pharmaceutical industry urgently needs a more economical, safer, and more efficient method for preparing compounds of formula 1. Summary of the Invention

[0009] One object of this application is to provide a method for preparing compounds of formula 1, thereby enabling the large-scale production of compounds of formula 1.

[0010] Another objective of this application is to provide an intermediate compound for preparing a compound of formula 1 and a method thereof for preparing the same.

[0011] In embodiments according to this application, two methods for preparing compounds of formula 1 are provided.

[0012] Specifically, method A is as follows: Method A Therefore, in a first aspect, this application provides a method for preparing a compound of formula 1. The method includes the following steps: (I) The compound of formula 2 is subjected to condensation or halogenation to obtain the compound of formula 3; (II) React the compound of formula 3 with a malonate ester to obtain the compound of formula 4; (III) The compound of formula 4 undergoes a ring-closing reaction to give the compound of formula 5; and (IV) The compound of Formula 5 is subjected to an ester-amide exchange reaction with glycine or a glycine salt to obtain the compound of Formula 1; The glycine salt mentioned therein is selected from sodium glycine, potassium glycine, magnesium glycine, calcium glycine, zinc glycine, or iron glycine; R1 is selected from a hydrocarbon group or substituted hydrocarbon group containing 1 to 10 carbon atoms, preferably selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, more preferably methyl; R3 is selected from the following groups: .

[0013] The inventors further discovered that intermediate compound 5 obtained in method A undergoes an ester exchange reaction with benzyl alcohol to obtain intermediate compound 6; intermediate compound 6 undergoes a hydrogenation reaction under metal catalysis to obtain intermediate compound 7; intermediate compound 7 undergoes an acylation reaction with oxalyl chloride to obtain the active intermediate acyl chloride 7'; 7' then undergoes an amidation reaction with glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride to obtain intermediate compound 8; or intermediate compound 5 obtained in method A undergoes a decarboxylation reaction to obtain intermediate compound 9, and intermediate compound 9 undergoes an addition reaction with isocyanate in the presence of a base to obtain intermediate compound 8; intermediate compound 8 undergoes a hydrolysis reaction under alkaline conditions to obtain compound of formula 1, i.e., the so-called method B.

[0014] In Method B, the reaction from intermediate compound 7 or intermediate compound 9 to intermediate compound 8 and then to the target product requires only room temperature, without the need for high-temperature reactions. Furthermore, the hydrolysis reaction from intermediate compound 8 to the compound of Formula 1 does not produce any detectable impurities. Therefore, Method B offers milder reaction conditions and yields a product with higher purity.

[0015] The second aspect of this application relates to a method for preparing a compound of formula 1. The method includes the following steps: Steps (I)-(III) are as defined in the first aspect of this application; Alternatively (V) the compound of formula 5 is subjected to transesterification with benzyl alcohol to obtain the compound of formula 6; (VI) In the presence of a metal catalyst, the compound of formula 6 is subjected to a hydrogenation reaction to obtain the compound of formula 7; and (VII) The compound of Formula 7 is subjected to an acylation reaction with oxaloyl chloride to obtain an active intermediate acyl chloride 7', and the active intermediate acyl chloride 7' is then subjected to an amidation reaction with glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride to obtain the compound of Formula 8. Alternatively, (V') in the presence of a base, the compound of formula 5 undergoes a decarboxylation reaction to yield the compound of formula 9; and (VI') In the presence of a base, the compound of formula 9 is reacted with an isocyanate to give the compound of formula 8; Then (VIII) In the presence of a base, the compound of formula 8 is subjected to a hydrolysis reaction to obtain the compound of formula 1; R2 is selected from hydrocarbon groups or substituted hydrocarbon groups containing 1 to 10 carbon atoms, preferably from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, and more preferably from methyl.

[0016] The inventors have discovered that some intermediate compounds are novel in the preparation of compounds of Formula 1, and therefore this application also relates to these novel intermediate compounds and their preparation methods.

[0017] In the third aspect, this application provides compounds of formula 3: R3 is selected from: .

[0018] In the fourth aspect, this application provides a compound of formula 7: .

[0019] In the fifth aspect, this application provides a compound of formula 9: .

[0020] In the sixth aspect, this application provides a compound of formula 8: , R2 is selected from hydrocarbon groups or substituted hydrocarbon groups containing 1 to 10 carbon atoms, preferably from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, and more preferably from methyl.

[0021] In some embodiments according to this application, the compound of formula 8 is prepared by the following method: the compound of formula 7 as described in the fourth aspect of this application is acylated with oxaloyl chloride to obtain an acyl chloride of formula 7', and the acyl chloride of formula 7' is then amidated with glycine ester hydrochloride to obtain the compound of formula 8. R2 is selected from a hydrocarbon group or substituted hydrocarbon group containing 1 to 10 carbon atoms, preferably selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, more preferably methyl; and The glycine ester hydrochloride is selected from glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride.

[0022] In some embodiments according to this application, the compound of formula 8 is prepared by an addition reaction of the compound of formula 9 as described in the fifth aspect of this application with an isocyanate: R2 is selected from hydrocarbon groups or substituted hydrocarbon groups containing 1 to 10 carbon atoms, preferably from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, and more preferably from methyl.

[0023] In summary, this application provides a method for preparing compounds of Formula 1. This method represents a significant improvement over existing technologies, offering greater economy, safety, and efficiency, and fully meeting the needs of large-scale production of active pharmaceutical ingredients and corresponding formulations. Specifically, this method optimizes the synthetic route, utilizes inexpensive and readily available starting materials and reagents, and reduces purification steps, thereby significantly lowering production costs. Simultaneously, it avoids the use of highly toxic or risky chemicals and harsh reaction conditions, significantly improving the safety of the operation. Furthermore, the reaction conditions are mild, the operation is simple, the yield and purity of the target product are improved, and it is easily scaled up, making it suitable for industrial production and laying a solid foundation for the widespread application of compounds of Formula 1. Detailed Implementation

[0024] The embodiments of the technical solution of this application are described in detail below. In these detailed descriptions, some technical terms are used. In this application, unless otherwise specified, all terms have the meanings commonly understood by those skilled in the art.

[0025] For the sake of brevity, the term “compound 1” as used herein encompasses a compound of formula (1), an isotopically labeled compound of formula (1), an optical isomer of a compound of formula (1), a geometric isomer of a compound of formula (1), a tautomer of a compound of formula (1), or a mixture of isomers of a compound of formula (1).

[0026] The term "optical isomer" refers to the various isomers formed when a compound has one or more chiral centers, each of which can exist in either an R or S configuration. Optical isomers include all diastereomers, enantiomers, meso compounds, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or by chiral synthesis.

[0027] The term "geometric isomer" refers to the fact that when a compound contains a double bond, it can exist as cis isomers, trans isomers, E-isomers, and Z-isomers. Geometric isomers include cis isomers, trans isomers, E-isomers, Z-isomers, or mixtures thereof.

[0028] The term "tautomer" refers to an isomer that results from the rapid movement of an atom in a molecule to two different positions. Those skilled in the art will understand that tautomers can interconvert and may coexist in an equilibrium state under certain conditions. The term "compound represented by formula (1)" as used herein also encompasses any tautomer of the compound of formula (1).

[0029] Unless otherwise specified, when this document refers to “compound 1”, it also includes isotopically labeled compounds obtained by replacing any one atom of a compound of formula (1) with its isotopic atom.

[0030] The term "isotope-labeled compound" refers to a compound in which one or more atoms are replaced by atoms having the same atomic number as atoms normally found in nature but with different atomic masses or mass numbers.

[0031] Examples of isotopes suitable for inclusion in compounds of this application include isotopes of hydrogen, such as... 2 H(D) and 3 H(T), isotopes of carbon, such as 11 C 13 C and 14 C, isotopes of chlorine, such as36 Cl, an isotope of fluorine, such as 18 F, an isotope of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, an isotope of oxygen, such as 15 O、 17 O and 18 O, and isotopes of sulfur, such as 35 S.

[0032] Certain isotope-labeled compounds of formula (1) (e.g., those containing radioactive isotopes) can be used for drug and / or substrate tissue distribution studies. Considering ease of introduction and convenience of detection, the radioactive isotope deuterium (i.e., 2 H) and carbon-14 (i.e. 14 C) This is particularly useful for this purpose.

[0033] Using, for example, deuterium (i.e. 2 Substituting heavier isotopes of H can provide certain therapeutic benefits and may therefore be preferred in some cases, said therapeutic benefits being due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements).

[0034] Using positron-emitting isotopes (such as 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to detect substrate receptor occupancy status.

[0035] Isotope-labeled compounds of formula (1) can generally be prepared by conventional techniques known to those skilled in the art or by using suitable isotope-labeled reagents instead of previously used unlabeled reagents in a manner similar to that described in the examples and preparations appended herein.

[0036] Unless otherwise stated, the terms used herein have the following meanings.

[0037] The term "hydroxyl group" refers to -OH.

[0038] The term "halogen" or "halogen" refers to -F, -Cl, -Br, or -I.

[0039] The term "amino" refers to -NH2.

[0040] The term "carboxyl group" refers to -C(=O)OH.

[0041] The term “substitution” refers to the independent replacement of one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in a group by the corresponding number of substituents.

[0042] The term "independently" means that when there are more than one substituent, these substituents can be the same or different.

[0043] The terms “optional” or “optionally” indicate that the event described may or may not occur. For example, “optionally substituted” means that the group may be unsubstituted or substituted.

[0044] The term "hydrocarbon group" refers to a group consisting of only carbon and hydrogen atoms, including alkyl, alkenyl, alkynyl, aryl, etc.

[0045] As used herein, the term "ring-closure (or cyclic formation)" refers to the formation of cyclic structures such as cycloalkane rings, cycloalkene rings, cycloalkyne rings, aromatic rings, heterocyclic alkane rings, heterocyclic alkene rings, heterocyclic alkyne rings, and heteroaromatic rings. These cyclic structures can be monocyclic, bicyclic, or polycyclic, including fused rings, bridged rings, and spirocyclic structures. The cyclic structure is optionally substituted by one or more (e.g., 1-3) substituents.

[0046] Unless otherwise stated, “room temperature” or “room temperature” as used herein refers to a temperature range of 15°C to 35°C, preferably 20°C to 30°C, and more preferably about 25°C.

[0047] In this article, the ranges related to the number of substituents, carbon atoms, and ring atoms represent a list of all integers within that range; the range is merely a simplified representation. For example: "1-10 carbon atoms" or "C1-C10" means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7), 8 (C8), 9 (C9), or 10 carbon atoms (C10). "1-6 carbon atoms" or "C1-C6" means 1 (C1), 2 (C2), 3 (C3), 4 (C4), 5 (C5), or 6 carbon atoms (C6). "2-6 carbon atoms" or "C2-C6" means 2 (C2), 3 (C3), 4 (C4), 5 (C5), or 6 carbon atoms (C6). “C3-C8” means 3 (C3), 4 (C4), 5 (C5), 6 (C6), 7 (C7), or 8 carbon atoms (C8); Therefore, the range of numbers related to the number of substituents, the number of carbon atoms, and the number of ring atoms also covers any of its subranges, and each subrange is also considered to be disclosed herein.

[0048] Unless otherwise specified, all raw materials used in this article are prepared according to the method described in patent application CN108484598A.

[0049] I. Methods for preparing compounds of formula 1 As prior art to this application, CN108484598A discloses the chemical structural formula of compound 1 and related synthetic methods. As mentioned above, the methods of the prior art are not suitable for large-scale production, and the reagents used may be carcinogenic or reproductively toxic, resulting in unsatisfactory purity and yield of the obtained product.

[0050] Therefore, the inventors of this application have conducted extensive and in-depth research on the method disclosed in CN108484598A and developed the method for preparing compound of formula 1 as described below.

[0051] Specifically, this application provides a method for preparing compound of formula 1. The method includes the following steps: (I) The compound of formula 2 is subjected to condensation or halogenation to obtain the compound of formula 3; (II) React the compound of formula 3 with a malonate ester to obtain the compound of formula 4; (III) The compound of formula 4 undergoes a ring-closing reaction to give the compound of formula 5; and (IV) The compound of Formula 5 is subjected to an ester-amide exchange reaction with glycine or a glycine salt to obtain the compound of Formula 1; The glycine salt mentioned therein is selected from sodium glycine, potassium glycine, magnesium glycine, calcium glycine, zinc glycine, or iron glycine; R1 is selected from a hydrocarbon group or substituted hydrocarbon group containing 1 to 10 carbon atoms, preferably selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, more preferably methyl; R3 is selected from the following groups: .

[0052] In step (I), the compound of formula 2 is converted into the compound of formula 3 through a condensation reaction or a halogenation reaction.

[0053] Specifically, the compound of formula 2 can undergo a condensation reaction with a condensing agent to activate the carbonyl group or introduce a specific carbonyl derivative structure; alternatively, the compound of formula 2 can also undergo a halogenation reaction with a halogenating agent, such as substitution of an acyl halide or α-halogenation, to obtain a compound of formula 3 with specific substituents. These two transformation pathways can be selected according to the specific structural requirements of the target product.

[0054] Therefore, in some embodiments of this application, in step (I), the compound of formula 2 undergoes a condensation reaction with the condensing agent. In this case, R3 is selected from: Preferably, the condensing agent is selected from amine compounds (such as carbodiimides, including N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), etc.), azole compounds (such as N,N'-carbonyldiimidazole (CDI), hydroxybenzotriazole, etc.) and pyridine compounds (such as 4-dimethylaminopyridine (DMAP), etc.). These condensing agents can effectively activate the substrate and improve the reaction yield.

[0055] More preferably, the condensing agent is selected from azole compounds, which generally have good reactivity and stability, can promote the smooth progress of the condensation reaction under mild conditions, and reduce the formation of by-products.

[0056] Even more preferably, the condensing agent is N,N'-carbonyldiimidazole (CDI). CDI is inexpensive and readily available; the reaction conditions are mild, and the post-processing is very simple. After the reaction, water can be added directly to precipitate the product, and then filtration and washing can yield a high-purity, high-yield product, which is beneficial for product purification and subsequent large-scale production.

[0057] In step (I), when the compound of formula 2 is converted into the compound of formula 3 by a condensation reaction, it is simple and safe compared with the prior art.

[0058] In some alternative embodiments of this application, in step (I), the compound of formula 2 undergoes a halogenation reaction with the halogenating agent. In this case, R3 is selected from F, Cl, Br, or I, preferably Cl.

[0059] This halogenation pathway is suitable for converting carboxylic acids into more reactive acyl halide intermediates, or for halogen substitution at specific positions to introduce functional groups required for subsequent reactions. The specific type of halogenation reaction can be selected according to the structural requirements of the compound in Formula 3: if an acyl chloride compound is to be prepared, an acyl chloride reagent is used; if a halogen is to be introduced at the α-position of the carboxylic acid, an α-halogenation reagent is used. During the reaction, the halogenation reagent can effectively replace the hydroxyl group in the carboxyl group with a halogen atom, or achieve electrophilic halogenation at the α-position in the presence of a base.

[0060] The halogenating reagents used include, but are not limited to, inorganic acyl halogenating reagents (such as thionyl chloride, phosphorus oxychloride, and oxalyl chloride), organic halogenating reagents, and some haloammonium salts with special structures. As a specific example of this application, the halogenating reagent is selected from 1-chloro-N,N,2-trimethylpropenylamine. This reagent is a highly efficient and mild organic halogenating reagent containing the active moieties of enamine and chloroimine in its structure, capable of rapidly converting carboxylic acids to the corresponding acyl chlorides without the need for catalysts or harsh conditions. Compared with conventional thionyl chloride, 1-chloro-N,N,2-trimethylpropenylamine exhibits milder reaction conditions and fewer side reactions, making it particularly suitable for substrates sensitive to strong acids or high temperatures. Furthermore, the byproducts generated during the reaction are neutral substances that are easily removed through simple post-treatment, which is beneficial for improving the purity and yield of the product.

[0061] In step (I), when the compound of formula 2 undergoes a halogenation reaction with the halogenating reagent, the reaction and the subsequent conversion into intermediate compound 4 are highly economical, and the reaction reagent is liquid, thus the feeding is simple and the reaction conditions are mild.

[0062] In some embodiments of this application, in step (II), the compound of formula 3 is reacted with a malonic ester in the presence of a base to give the compound of formula 4. .

[0063] In step (II) of the above method, the base used is selected from a series of strong bases or non-nucleophilic bases, depending on the specific reaction mechanism and substrate activity requirements. Specifically, the base is selected from lithium bis(trimethylsilyl)amino (LiHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), sodium hydride (NaH), lithium diisopropylamino (LDA), or n-butyllithium. These bases all have strong proton-extracting or metallizing abilities and are suitable for generating carbanions, enol anions, or performing other conversions requiring strong base conditions. Among them, LiHMDS, NaHMDS, and KHMDS, as alkali metal salts of hexamethyldisilazane, have the characteristics of large steric hindrance and weak nucleophilicity, and are particularly suitable for kinetically controlled deprotonation reactions; NaH, as a strong basic hydride, is often used for thorough deprotonation; LDA and n-butyllithium are typical representatives of organolithium reagents, with extremely high reactivity and a wide range of applications.

[0064] In some embodiments of this application, in step (II), the reaction is carried out in an aprotic organic solvent. The use of an aprotic solvent avoids the solvent itself participating in the proton transfer reaction, thereby ensuring the activity of the strong base and the selectivity of the reaction. Suitable aprotic solvents include, but are not limited to, tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, benzene, n-hexane, cyclohexane, and N-methylpyrrolidone (NMP). In particular, N-methylpyrrolidone (NMP), as a strongly polar aprotic solvent, has the characteristics of strong solubility, good thermal stability, and good chemical stability, and is especially suitable for dissolving substrates with high polarity or complex structures.

[0065] In some embodiments of this application, in step (III), the reaction is carried out in the presence of an acid, which provides an acidic environment to promote the transformation of specific functional groups or regulate reaction equilibrium. The acid may be selected from inorganic or organic acids. The inorganic acid is selected from hydrochloric acid (HCl), sulfuric acid (H2SO4), or phosphoric acid (H3PO4); the organic acid is selected from carboxylic acids containing 1 to 5 carbon atoms, preferably formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, 2-methylbutyric acid, neovaleric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, and trifluoroacetic acid (TFA), more preferably trifluoroacetic acid (TFA). In practice, the type and amount of acid used need to be optimized according to the substrate structure and reaction requirements to ensure efficient reaction and avoid side reactions such as excessive acidolysis.

[0066] The inventors further discovered that intermediate compound 8 undergoes a hydrolysis reaction under alkaline conditions to yield compound 1, i.e., the so-called Method B. Specifically, intermediate compound 8 can be obtained through the following two pathways: intermediate compound 5 obtained in Method A undergoes an ester exchange reaction with benzyl alcohol to obtain intermediate compound 6; intermediate compound 6 undergoes a hydrogenation reaction under metal catalysis to obtain intermediate compound 7; intermediate compound 7 undergoes an acylation reaction with oxalyl chloride to obtain active intermediate acyl chloride 7', which is then subjected to an amidation reaction with glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride to obtain intermediate compound 8; or intermediate compound 5 obtained in Method A undergoes a decarboxylation reaction to obtain intermediate compound 9, which is then subjected to an addition reaction with isocyanate in the presence of an alkaline base to obtain intermediate compound 8.

[0067] In Method B, the reaction from intermediate compound 7 or intermediate compound 9 to intermediate compound 8 and then to target product 1 can be carried out at room temperature, without the need for high-temperature reactions. Furthermore, the hydrolysis reaction from intermediate compound 8 to compound of formula 1 produces virtually no detectable impurities. Therefore, compared to Method A, Method B offers milder reaction conditions and yields a higher purity product, making it more advantageous than existing methods.

[0068] Therefore, this application further provides a method for preparing compound of formula 1. The method includes the following steps: Steps (I)-(III), as defined above; Alternatively (V) the compound of formula 5 is subjected to transesterification with benzyl alcohol to obtain the compound of formula 6; (VI) In the presence of a metal catalyst, the compound of formula 6 is subjected to a hydrogenation reaction to obtain the compound of formula 7; and (VII) The compound of Formula 7 is subjected to an acylation reaction with oxaloyl chloride to obtain an active intermediate acyl chloride, and the active intermediate acyl chloride is then subjected to an amidation reaction with glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride to obtain the compound of Formula 8. Alternatively, (V') in the presence of a base, the compound of formula 5 undergoes a decarboxylation reaction to yield the compound of formula 9; and (VI') In the presence of a base, the compound of formula 9 is reacted with an isocyanate to give the compound of formula 8; Then (VIII) In the presence of a base, the compound of formula 8 is subjected to a hydrolysis reaction to obtain the compound of formula 1; R2 is selected from hydrocarbon groups or substituted hydrocarbon groups containing 1 to 10 carbon atoms, preferably selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, and more preferably methyl.

[0069] In step (V) of the above method, the reaction system is usually carried out in the presence of a base to ensure efficient reaction and suppress the formation of byproducts. The main role of the base is to neutralize the acidic byproducts generated during the reaction, adjust the pH of the reaction system, or act as a catalyst to activate the nucleophile, thereby promoting the formation of the target product.

[0070] In some embodiments of this application, in step (V), the reaction is carried out in the presence of a base. Specifically, the base is selected from organic bases. Compared with inorganic bases, organic bases have good solubility in organic solvents, mild reaction conditions, and are easily removed from the system through post-treatment, which is beneficial for improving product purity and simplifying the operation process. Preferably, the organic base is selected from triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), pyridine, and 4-dimethylaminopyridine (DMPA); more preferably, the organic base is triethylamine (TEA). Triethylamine can not only effectively neutralize the acid generated in the reaction, but also has a low boiling point, and is easily removed from the system after the reaction by means of vacuum distillation or water washing, reducing the risk of base residue in the product. At the same time, triethylamine has low cost and wide industrial availability, meeting the requirements of large-scale production for economy and ease of operation.

[0071] In some embodiments of this application, in step (VI), the reaction is carried out in the presence of a metal catalyst. The metal catalyst can effectively lower the activation energy of the reaction, increasing the reaction rate and selectivity. Specifically, the metal catalyst can be selected from different types such as supported transition metal catalysts, nickel catalysts, copper catalysts, and iron catalysts. Preferably, the metal catalyst is selected from palladium on carbon, platinum on carbon, ruthenium on carbon, Raney nickel, copper powder, or iron salt catalysts; more preferably, the metal catalyst is palladium on carbon, which has high activity, good selectivity, safe operation, and is easy to recover through filtration.

[0072] As described above, in the transformation process from intermediate compound 7 or intermediate compound 9 to intermediate compound 8 and then to the final compound of formula 1, each step of the reaction can be carried out under mild conditions, without the need for harsh conditions such as high temperature and high pressure. This feature not only reduces energy consumption and equipment requirements, but also effectively avoids decomposition or side reactions that may occur due to high temperature.

[0073] Therefore, in some embodiments of this application, steps (VI'), (VII), and (VIII) are all performed at room temperature. As mentioned above, room temperature conditions typically refer to a temperature range of 15°C to 35°C (preferably 20°C to 30°C). Operating within this temperature range eliminates the need for additional heating or cooling equipment, significantly simplifying the production process and reducing energy consumption and equipment investment costs. Simultaneously, the mild reaction conditions at room temperature are beneficial for maintaining the stability of the substrate and product, improving reaction selectivity and yield, and providing a safer, more economical, and controllable process for the large-scale production of active pharmaceutical ingredients and formulations.

[0074] II. Intermediate compounds and their preparation methods The inventors have discovered that some intermediate compounds are novel in the preparation of compounds of Formula 1, and therefore this application also relates to these novel intermediate compounds and their preparation methods.

[0075] This application provides a compound of formula 3: R3 is selected from: .

[0076] This application also provides compounds of formula 7: .

[0077] This application further provides a compound of formula 9: .

[0078] This application further provides a compound of formula 8: , R2 is selected from hydrocarbon groups or substituted hydrocarbon groups containing 1 to 10 carbon atoms, preferably from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, and more preferably from methyl.

[0079] As described above, intermediate compound 8 can be obtained through the following two pathways: intermediate compound 5 obtained in method A undergoes an ester exchange reaction with benzyl alcohol to obtain intermediate compound 6; intermediate compound 6 undergoes a hydrogenation reaction under metal catalysis to obtain intermediate compound 7; intermediate compound 7 undergoes an acylation reaction with oxalyl chloride to obtain active intermediate acyl chloride 7', which is then subjected to an amidation reaction with glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride to obtain intermediate compound 8; or intermediate compound 5 obtained in method A undergoes a decarboxylation reaction to obtain intermediate compound 9, which is then subjected to an addition reaction with isocyanate in the presence of a base to obtain intermediate compound 8.

[0080] Therefore, in some embodiments of this application, the compound of formula 8 is prepared by the following method: the compound of formula 7 as described above is subjected to an acylation reaction with oxaloyl chloride to obtain an acyl chloride of formula 7', and the acyl chloride of formula 7' is then subjected to an amidation reaction with glycine ester hydrochloride to obtain the compound of formula 8: R2 is selected from a hydrocarbon group or substituted hydrocarbon group containing 1 to 10 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl. The methyl group has the least steric hindrance and the highest reactivity, and glycine methyl ester hydrochloride (i.e., the glycine ester hydrochloride corresponding to R2 being methyl) is one of the most common and inexpensive glycine ester derivatives, offering significant economic advantages in large-scale production. Furthermore, methyl esters undergo mild conditions and fewer side reactions during subsequent hydrolysis or conversion, which is beneficial for improving the purity and yield of the final product; therefore, R2 is more preferably methyl. The glycine ester hydrochloride is selected from glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride, preferably glycine methyl ester hydrochloride. These two salts are stable solids existing in the form of hydrochloride after glycine esterification, exhibiting good storage stability and ease of handling. They are readily soluble in water and polar organic solvents, and during the reaction, they can release free glycine ester nucleophiles in situ with the base, participating in the addition reaction with isocyanates.

[0081] In some alternative embodiments of this application, the compound of formula 8 is prepared by an addition reaction of the compound of formula 9 with an isocyanate as described above: R2 is selected from hydrocarbon groups or substituted hydrocarbon groups containing 1 to 10 carbon atoms, preferably from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, and more preferably from methyl.

[0082] In the addition reaction of compounds of Formula 9 with isocyanates, the alkaline environment of the reaction system and the choice of solvent affect the reaction rate, product purity, and control of side reactions. This addition reaction is essentially a nucleophilic addition process. The carbon atom in the isocyanate group (-N=C=O) is highly electrophilic and readily reacts with active nucleophilic sites (such as hydroxyl and amino groups) in the Formula 9 compound to generate the corresponding carbamate derivatives. In this process, the addition of a base aims to neutralize any acidic byproducts that may be generated during the reaction, activate the nucleophile, or promote the conversion of reaction intermediates, thereby improving the reaction yield and selectivity.

[0083] Therefore, in some embodiments of this application, the addition reaction of the compound of formula 9 with the isocyanate is carried out in the presence of a base, preferably an organic base.

[0084] Specifically, the organic base includes at least one of triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), pyridine, and 4-dimethylaminopyridine (DMAP). These organic bases have good solubility in organic solvents, can be uniformly dispersed in the reaction system, and can effectively control the reaction process. Due to its large steric hindrance and weak nucleophilicity, DIPEA is particularly suitable for systems that are sensitive to bases or prone to side reactions, and can effectively prevent isocyanates from self-polymerizing or reacting with bases unexpectedly under strong alkaline conditions. Considering both reaction selectivity and side reaction control, N,N-diisopropylethylamine (DIPEA) is preferably used as the organic base.

[0085] Furthermore, in some embodiments of this application, the addition reaction of Formula 9 compound with isocyanate is carried out in an aprotic organic solvent. Aprotic organic solvents do not contain active protons, do not react with isocyanate groups, and do not inhibit the activity of nucleophiles through proton transfer; therefore, they are ideal media for isocyanate addition reactions. The aprotic organic solvent includes at least one of dichloromethane (DCM), ethyl acetate (EA), tetrahydrofuran (THF), and acetonitrile (ACN). These solvents can all dissolve Formula 9 compound and isocyanate well and have good compatibility with reaction intermediates. Considering reaction efficiency, ease of post-processing, and applicability to large-scale production, dichloromethane (DCM) is preferred as the aprotic organic solvent for this reaction.

[0086] By using N,N-diisopropylethylamine (DIPEA) as the base and dichloromethane (DCM) as the solvent, the addition reaction of compound 9 with isocyanate can be carried out efficiently under mild conditions, with short reaction time, high product yield, high purity, and few side reactions, laying the foundation for the smooth implementation of subsequent steps. Detailed Implementation

[0087] The following examples illustrate the implementation of this application. For those skilled in the art, these examples are merely exemplary and do not constitute a limitation on the scope of protection claimed in this application.

[0088] Example (1): Preparation of intermediate compound 3a Add tetrahydrofuran (150 L) to a 500 L reactor, start stirring, add compound 2 (24 kg) and carbonyl diimidazole (22.8 kg), and heat for 20-30 minutes. oThe mixture was stirred at C for 6-10 hours, then water (1000 L) was added, and stirring continued for 1.5-2.5 hours. After filtration, washing, and drying, 26.8 kg of a white solid (intermediate compound 3a) was obtained. HPLC purity: 100%, yield: 93%. Molecular weight: 305.38, LC-MS (m / z): 306.09 (M+H). + Molecular formula: C 19 H 19 N3O, 1 H NMR (400 MHz, DMSO- d 6) δ 7.31 (2H), 7.23 - 7.19 (3H), 6.96 (1H), 6.79 - 6.76 (3H), 6.31(1H), 6.01 (1H), 2.52 - 2.45(3H), 1.88 (2H), 1.70 - 1.68 (2H).

[0089] Example (2): Preparation of intermediate compound 3b Add 20 mL of DCM to a 100 mL reaction flask, start stirring, and add compound 2 (2.0 g), pentafluorophenol (2.2 g), EDCI (2.3 g), and DMAP (1.9 g). Stir at room temperature for 16 hours. Add 20 mL of water and 10 mL of ethyl acetate to the reaction mixture, stir, and separate the phases. Extract the aqueous phase with 10 mL of ethyl acetate. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and evaporate to dryness. Separate by column chromatography to obtain 3.0 g of intermediate compound 3b, HPLC purity: 99%, yield: 91%. Molecular weight: 421.37, LC-MS (m / z): 422.40 (M+H). + Molecular formula: C 22 H 16 F5NO2, 1 H NMR (500MHz, DMSO- d 6) δ 7.38 (3H), 7.23 (2H), 7.17 (1H), 6.15 (1H), 6.06 (1H), 2.34(4H), 1.73 (4H).

[0090] Example (3): Preparation of intermediate compound 3c Add 10 mL of DCM to a 50 mL reaction flask, start stirring, add compound 2 (1 g) and 1-chloro-N,N,2-trimethylpropyleneamine (0.68 g), and stir at room temperature for 4 hours. Concentrate the reaction solution and separate by column chromatography to obtain 0.7 g of an off-white solid (intermediate compound 3c), HPLC purity 97%, yield: 84%. Molecular weight: 273.76, LC-MS (m / z): 274.4 (M+H). + Molecular formula: C 16 H 16 ClNO.

[0091] Preparation Example (4-1): Preparation of Intermediate Compound 4a N-methylpyrrolidone (237 L) was added to a 1000 L reactor, stirring was started, and intermediate compound 3a (26.3 kg) and dimethyl malonate (31.6 kg) prepared in Example (1) were added. The temperature was raised to 35-45°C. o C, add potassium bis(trimethylsilyl)amino(KHMDS) (142.8 kg) dropwise. At 35-45°C... o After reacting at C for 14-20 hours, cool to 10-20°C. o C. Adjust the pH to 6.0-8.0 by adding hydrochloric acid dropwise, concentrate to 12.5-13.5 times the volume of 3a, add water (179 L), stir for 2-4 hours, filter, wash, and dry to give 27.26 kg of white solid (intermediate compound 4a), HPLC purity: 100%, yield: 84%. Molecular weight: 369.42, LC-MS (m / z): 370.51 (M+H). + Molecular formula: C 21 H 23 NO 5， 1H NMR (500 MHz, DMSO- d 6 )δ 7.35 - 7.30 (3H), 7.25 - 7.21 (2H), 7.19 (1H), 6.17 (1H), 6.04 (1H), 5.26(1H), 3.59 (6H), 2.37 - 2.23 (2H), 1.92 - 1.75 (2H), 1.59 (2H), 1.46 - 1.30 (2H).

[0092] Preparation Example (4-2): Preparation of Intermediate Compound 4a Add N-methylpyrrolidone (5 mL), intermediate compound 3b (0.5 g) prepared in Example (2), and dimethyl malonate (0.4 g) to a 10 mL reaction flask, and purge with nitrogen. Heat to 40 °C. o C. Add KHMDS (3 mL) to the reaction system and control the temperature at 40°C. o The mixture was stirred at C for 20 hours. After cooling to room temperature, the pH was adjusted to 3-4 with 6 M HCl to quench the reaction. The mixture was separated, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Column chromatography was then used to obtain 0.2 g of a white solid product (intermediate compound 4a), with an HPLC purity of 99%. Molecular weight: 369.42, LC-MS (m / z): 370.51 (M+H). + Molecular formula: C 21 H 23 NO 5， 1H NMR (500 MHz, DMSO- d 6 ) δ 7.35 -7.30 (3H), 7.25 - 7.21 (2H), 7.19 (1H), 6.17 (1H), 6.04 (1H), 5.26 (1H), 3.59(6H), 2.37 - 2.23 (2H), 1.92 - 1.75 (2H), 1.59 (2H), 1.46 - 1.30 (2H).

[0093] Preparation Example (4-3): Preparation of Intermediate Compound 4a Add N-methylpyrrolidone (10 mL), the intermediate compound 3c (1 g) prepared in Example (3), and dimethyl malonate (1.03 g) to a 20 mL reaction flask, and purge with nitrogen. Cool to -5 °C. o C. Add 3 mL of NaHMDS to the reaction system, and then heat to 35°C. o Stir for 2 hours. Cool to room temperature, then maintain the temperature at -10°C. o C was used to adjust the pH to 3-4 with 6 M HCl to quench the reaction; the mixture was separated, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Column chromatography was then used to separate the product into a white solid of 0.68 g (intermediate compound 4a), with an HPLC purity of 98%. Molecular weight: 369.42, LC-MS (m / z): 370.51 (M+H). + Molecular formula: C 21 H 23 NO5， 1H NMR (500 MHz, DMSO- d 6 ) δ 7.35 - 7.30 (3H), 7.25 - 7.21 (2H), 7.19 (1H), 6.17(1H), 6.04 (1H), 5.26 (1H), 3.59 (6H), 2.37 - 2.23 (2H), 1.92 - 1.75 (2H),1.59 (2H), 1.46 - 1.30 (2H).

[0094] Preparation Example (5): Preparation of intermediate compound 4b Add NMP (450 mL) to a 1000 mL reaction flask, start stirring, add intermediate compound 3a (50 g) and diethyl malonate (60 g) prepared in Example (1), purge with nitrogen, and heat to 40 °C. o C, add KHMDS (271.5g), at 40 o Stir at C for 4 hours. Then cool to 10-20°C. o C. Adjust the pH to 6.0-8.0 by adding hydrochloric acid, add ethyl acetate (500 mL), and separate the layers. Wash the organic phase with water (500 mL) and dry it with anhydrous sodium sulfate. Filter and evaporate to dryness. Separate by column chromatography to obtain 60 g of oil (intermediate compound 4b). Molecular weight: 397.47, LC-MS (m / z): 398.45 (M+H) + Molecular formula: C 23 H 27 NO5.

[0095] Preparation Example (6): Preparation of intermediate compound 5a Add 136 L of trifluoroacetic acid to a 500 L reactor, start stirring, and add 27.1 kg of intermediate compound 4a prepared in Preparation Example (4); heat at 25-35°C. o After stirring at C for 22-26 hours, water (190 L) was added dropwise, and stirring was continued for 0.5-1.5 hours. Water (81 L) was then added dropwise, and stirring was continued for another 14-18 hours. The mixture was filtered and washed. Water (81 L) was added to the wet product, and the mixture was slurried for 1.0-3.0 hours. After filtration, washing, and drying, 23.14 kg of a white solid (intermediate compound 5a) was obtained. HPLC purity: 100%, yield: 94%. Molecular weight: 337.38, LC-MS (m / z): 338.1396 (M+H). + Molecular formula: C20 H 19 NO4 1 HNMR (400 MHz, CDCl3) δ 14.35 (1H), 7.45 - 7.36 (5H), 7.11 (1H), 6.29 (1H), 3.94 (3H), 2.39 (2H), 2.07 (2H), 1.63 (2H), 1.03 (2H).

[0096] Preparation Example (7): Preparation of intermediate compound 5b Add 420 g of trifluoroacetic acid to a 1000 mL reaction flask, start stirring, add 60 g of intermediate compound 4b prepared in Preparation Example (5), and heat at 25-35 °C. o The mixture was stirred at C for 16 hours. Water (300 mL) was added dropwise, and the mixture was stirred for 72 hours. After filtration, washing, and drying, 42 g of a yellow solid (intermediate compound 5b) was obtained. HPLC purity: 98%, yield: 79%. Molecular weight: 351.40, LC-MS (m / z): 352.37 (M+H). + Molecular formula: C 21 H 21 NO4 1 H NMR (500 MHz, DMSO- d 6 ) δ14.04 (1H), 7.62 - 7.38 (5H), 7.09 (1H), 6.35 (1H), 4.30 (2H), 2.25 (2H), 2.05 (2H), 1.54 - 1.36 (2H), 1.29 (3H), 0.93 (2H).

[0097] Example (8): Preparation of Compound 1 Dimethylacetamide (345 L), intermediate compound 5a (23 kg) prepared in Preparation Example (6), and sodium glycinate (16.4 kg) were added to a 1000 L reactor and heated to 89-95 °C. o Stir at room temperature for 30-36 hours. Cool to 15-25°C. oC. Add water (460 L) and isopropyl acetate (184 L), separate the layers, collect the aqueous phase, adjust the pH to 1.5-3.5 with hydrochloric acid, stir for 1.0-3.0 hours, filter and wash to obtain a wet product. Add trifluoroacetic acid (345 L) to the obtained wet product and stir until the reaction solution is clear. Add water (161 L), a solid precipitates, continue stirring for 4.0-10.0 hours, filter, wash and dry to obtain compound 1, a white solid, 22.65 kg, HPLC purity 100%, yield: 91%. Molecular weight: 380.40, LC-MS (m / z): 381.1449 (M+H). + Molecular formula: C 21 H 20 N2O5, 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.94 (1H), 10.56- 9.87 (1H), 7.49 - 7.48 (5H), 7.06 (1H), 6.33 (1H), 4.07 (2H), 2.28 (2H), 2.12 (2H), 1.52 (2H), 0.92 (2H).

[0098] Example (9): Preparation of Compound 1 Dimethylacetamide (210 mL), intermediate compound 5b (15 g) prepared in Preparation Example (7), and sodium glycine (10.4 g) were added to a 1000 mL reaction flask, and the mixture was heated to 89-95 °C. o Stir at room temperature for 30-36 hours. Cool to 15-25°C. o C. Add water (300 mL), adjust the pH to 2-3 with hydrochloric acid, filter and wash to obtain a wet product. Add trifluoroacetic acid (345 g) to the wet product and stir until the reaction solution is clear. Add water (105 mL), stir for 16 hours, filter, wash and dry to obtain compound 1, a white solid of 13.7 g, HPLC purity 99%; yield 85%. Molecular weight: 380.40, LC-MS (m / z): 381.1449 (M+H). + Molecular formula: C 21 H 20 N2O5, 1 H NMR (400 MHz, DMSO- d 6) δ 12.94 (1H), 10.56 - 9.87(1H), 7.49 - 7.48 (5H), 7.06 (1H), 6.33 (1H), 4.07 (2H), 2.28 (2H), 2.12(2H), 1.52 (2H), 0.92 (2H).

[0099] Preparation Example (10): Preparation of Intermediate Compound 6 Benzyl alcohol (150.0 mL), intermediate compound 5a (15.0 g) prepared in Preparation Example (6) and triethylamine (13.5 g) were added to a 500 mL reaction flask and heated to 120 °C. o Stir at C for 6 hours. Cool to room temperature, add water (150 mL) and ethyl acetate (150 mL) for extraction, separate the liquid and ester phase, wash the ethyl acetate phase 6 times with water (150 mL), dry with anhydrous sodium sulfate, filter and evaporate to dryness, and separate by column chromatography to obtain crude product (100% yield), which can be used directly in the next step.

[0100] Example (11): Preparation of intermediate compound 7 Anhydrous methanol (185 mL) and crude intermediate compound 6 obtained in Preparation Example (10) were added to a 500 mL reaction flask. 10% wet palladium on carbon (1.8 g) was added, and after hydrogen purging, hydrogen was kept flowing freely. The reaction was carried out at 30 °C. o The mixture was stirred at C for 1 hour. The reaction solution was filtered through diatomaceous earth, the organic phase was collected, evaporated to dryness, and separated by column chromatography to obtain 6.6 g of an off-white solid product (intermediate compound 7), with an HPLC purity of 97%. Molecular weight: 323.35, LC-MS (m / z): 324.27 (M+H). + Molecular formula: C 19 H 17 NO4 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.70 (1H), 7.46 (5H), 6.68 (1H), 6.16(1H), 5.35 (1H), 2.28 (4H), 1.54 (2H), 0.85 (2H).

[0101] Example (12): Preparation of intermediate compound 8a Dichloromethane (4.0 mL), intermediate compound 7 (0.2 g) prepared in Example (11), and N,N-dimethylformamide (4.5 mg) were added to a 50 mL reaction flask, purged with nitrogen, and oxaloyl chloride (86 mg) was added. The mixture was then heated to 30 °C. o Stir at C for 1 hour. Add glycine methyl ester hydrochloride (0.16 g) and triethylamine (0.2 g) to the reaction solution, and stir at 30 °C. o The mixture was stirred at C for 3 hours. The reaction was quenched with water (4 mL), extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and separated by column chromatography to give 0.15 g of a yellow solid product (intermediate compound 8a), HPLC purity 98%. Molecular weight: 394.43, LC-MS (m / z): 395.48 (M+H). + Molecular formula: C 22 H 22 N2O5, 1 H NMR (500 MHz, DMSO- d 6 ) δ 17.79 (1H), 9.90 (1H), 7.52 (5H), 7.09 (1H), 6.37 (1H), 4.17 (2H), 3.68 (3H), 2.32 (4H), 1.53 (2H), 0.95 (2H).

[0102] Example (13): Preparation of Compound 1 Anhydrous ethanol (3.0 mL), intermediate compound 8a (0.15 g) prepared in Example (12), and 4 M sodium hydroxide solution (0.3 mL) were added to a 50 mL reaction flask, and the mixture was heated at 30 °C. o Stir at C for 3 hours. After LC-MS confirms complete reaction, cool to 5°C. o C, add 6 M HCl to adjust the pH to 3-4, and heat to 30°C. o After step C, water (6.0 mL) was added and stirred for 2 h; the mixture was filtered, and the filter cake was dried to obtain 0.11 g of compound 1, with an HPLC purity of 99%. Molecular weight: 380.40, LC-MS (m / z): 381.1449 (M+H). + Molecular formula: C 21 H 20 N2O5, 1 H NMR (400 MHz, DMSO- d 6) δ 12.94 (1H), 10.56 - 9.87 (1H), 7.49 - 7.48 (5H), 7.06 (1H), 6.33 (1H), 4.07 (2H), 2.28 (2H), 2.12 (2H), 1.52(2H), 0.92 (2H).

[0103] Example (14): Preparation of intermediate compound 9 Anhydrous ethanol (20.0 mL), intermediate compound 5a (2.0 g) prepared in Preparation Example (6), and 4 M sodium hydroxide solution (7.4 mL) were added to a 100 mL reaction flask, and the mixture was heated at 80 °C. o Stir at C for 5 hours. Cool to room temperature, add 6 M HCl to adjust the pH to 6-7, add water (20.0 mL), and stir for 1 hour. Filter, and transfer the filter cake to a vacuum drying oven at 40°C. o Drying at C, 1.5 g of an off-white solid (intermediate compound 9) was obtained, with an HPLC purity of 99% and a yield of 88%. Molecular weight: 279.34, LC-MS (m / z): 280.47 (M+H). + Molecular formula: C 18 H 17 NO2, 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.69 (1H), 7.46 (5H), 6.68 (1H), 6.16 (1H), 5.31 (1H), 2.17 (4H), 1.45 (2H), 0.85 (2H).

[0104] Example (15): Preparation of intermediate compound 8b Dichloromethane (28.0 mL), intermediate compound 9 (1.4 g) prepared in Example (14), N,N-diisopropylethylamine (1.3 g), and ethyl isocyanate (1.3 g) were added to a 100 mL reaction flask, purged with nitrogen, and the mixture was heated to 30 °C. o The mixture was stirred at C for 20 hours. After cooling to room temperature, the reaction was quenched with water (30.0 mL). The mixture was separated, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Column chromatography was used to obtain 1.26 g of solid product (intermediate compound 8b), with an HPLC purity of 99% and a yield of 59%. Molecular weight: 408.45, LC-MS (m / z): 409.49 (M+H).+ Molecular formula: C 23 H 24 N2O5, 1 H NMR (500 MHz, DMSO- d 6 ) δ 17.81 (1H), 9.90 (1H), 7.52 (5H), 7.08(1H), 6.37 (1H), 4.17 (4H), 2.32 (4H), 1.53 (2H), 1.23 (3H), 0.94 (2H).

[0105] Example (16): Preparation of Compound 1 Anhydrous ethanol (25.0 mL), intermediate compound 8b (1.25 g) prepared in Example (15), and 4 M sodium hydroxide solution (2.3 mL) were added to a 50 mL reaction flask, and the mixture was heated at 30 °C. o Stir at C for 3 hours. Cool to 5°C. o C, add 6 M HCl to adjust the pH to 3-4, then heat to 30°C. o After step C, water (50.0 mL) was added, and the mixture was stirred for 2 h. The mixture was filtered, and the filter cake was dried to give 0.99 g of compound 1, with an HPLC purity of 99% and a yield of 86%. Molecular weight: 380.40, LC-MS (m / z): 381.1449 (M+H). + Molecular formula: C 21 H 20 N2O5, 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm: 12.94 (1H), 10.56 - 9.87(1H), 7.49 - 7.48 (5H), 7.06 (1H), 6.33 (1H), 4.07 (2H), 2.28 (2H), 2.12(2H), 1.52 (2H), 0.92 (2H). 13 C NMR (100 MHz, DMSO- d 6 ) δ ppm: 196.69, 173.77,171.36, 170.74, 142.48, 133.53, 132.02, 129.39, 128.41, 123.51, 115.99,113.33, 93.22, 74.78, 42.91, 41.35, 26.37.

[0106] While specific embodiments of this application have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of this application. Rather, the language used in this specification is merely descriptive and not restrictive. It will be apparent to those skilled in the art that various other changes and modifications can be made without departing from the general scope of this disclosure. Therefore, all such changes and modifications within the scope of this application are intended to be included in the appended claims.

Claims

1. A method for preparing a compound of formula 1, The method includes the following steps: (I) The compound of formula 2 is subjected to condensation or halogenation to obtain the compound of formula 3; (II) React the compound of formula 3 with a malonate ester to obtain the compound of formula 4; (III) The compound of Formula 4 undergoes a ring-closing reaction to obtain the compound of Formula 5; as well as (IV) The compound of Formula 5 is subjected to an ester-amide exchange reaction with glycine or a glycine salt to obtain the compound of Formula 1; The glycine salt mentioned therein is selected from sodium glycine, potassium glycine, magnesium glycine, calcium glycine, zinc glycine, or iron glycine; R1 is selected from a hydrocarbon group or substituted hydrocarbon group containing 1 to 10 carbon atoms, preferably selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, more preferably methyl; R3 is selected from the following groups: 。 2. The method as described in claim 1, wherein, In step (I), the compound of formula 2 undergoes a condensation reaction with a condensing agent; preferably, the condensing agent is selected from amine compounds, azole compounds and pyridine compounds, more preferably from azole compounds, and even more preferably N,N'-carbonyldiimidazole (CDI); R3 is selected from: 。 3. The method as described in claim 1, wherein, In step (I), the compound of formula 2 undergoes a halogenation reaction with the halogenating agent. R3 is selected from F, Cl, Br, or I, with Cl being the preferred choice.

4. The method as described in any one of claims 1 to 3, wherein, In step (II), in the presence of a base, the compound of formula 3 reacts with a malonate ester to give the compound of formula 4. The alkali is selected from lithium bis(trimethylsilyl)amino (LiHMDS), sodium bis(trimethylsilyl)amino (NaHMDS), potassium bis(trimethylsilyl)amino (KHMDS), sodium hydride (NaH), lithium diisopropylamino (LDA), or n-butyllithium; and R1 and R3 are as defined in claim 1.

5. The method as described in any one of the preceding claims, wherein, In step (III), the reaction is carried out in the presence of an acid selected from inorganic or organic acids.

6. The method of claim 5, wherein, The inorganic acid is selected from hydrochloric acid (HCl), sulfuric acid (H2SO4), or phosphoric acid (H3PO4).

7. The method of claim 5, wherein, The organic acid is selected from carboxylic acids containing 1 to 5 carbon atoms, preferably from formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, 2-methylbutyric acid, neovaleric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid (TFA), and more preferably trifluoroacetic acid (TFA).

8. A method for preparing a compound of formula 1, The method includes the following steps: Steps (I)-(III) are as defined in any one of claims 1-7; Alternatively (V) the compound of formula 5 is subjected to transesterification with benzyl alcohol to obtain the compound of formula 6; (VI) In the presence of a metal catalyst, the compound of formula 6 is subjected to a hydrogenation reaction to obtain the compound of formula 7; and (VII) The compound of Formula 7 is subjected to an acylation reaction with oxaloyl chloride to obtain an active intermediate acyl chloride 7', and the active intermediate acyl chloride 7' is then subjected to an amidation reaction with glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride to obtain the compound of Formula 8. Alternatively, (V') in the presence of a base, the compound of formula 5 undergoes a decarboxylation reaction to yield the compound of formula 9; and (VI') In the presence of a base, the compound of formula 9 is reacted with an isocyanate to give the compound of formula 8; Then (VIII) In the presence of a base, the compound of formula 8 is subjected to a hydrolysis reaction to obtain the compound of formula 1; R1 is selected from a hydrocarbon group or substituted hydrocarbon group containing 1 to 10 carbon atoms, preferably selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, more preferably methyl; and R2 is selected from hydrocarbon groups or substituted hydrocarbon groups containing 1 to 10 carbon atoms, preferably from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, and more preferably from methyl.

9. The method of claim 8, wherein, Steps (VI'), (VII) and (VIII) are all performed at room temperature.

10. Compound of Formula 3: R3 is selected from: 。 11. Compound of Formula 7: 。 12. Compound of Formula 9: 。 13. Compound of Formula 8: ， R2 is selected from hydrocarbon groups or substituted hydrocarbon groups containing 1 to 10 carbon atoms, preferably from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, and more preferably from methyl.

14. The compound of formula 8 as claimed in claim 13, prepared by the following method: acylation of the compound of formula 7 as claimed in claim 11 with oxaloyl chloride to obtain an acyl chloride of formula 7', wherein the acyl chloride of formula 7' is further amidated with glycine ester hydrochloride to obtain the compound of formula 8: R2 is selected from a hydrocarbon group or substituted hydrocarbon group containing 1 to 10 carbon atoms, preferably selected from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, more preferably methyl; and The glycine ester hydrochloride is selected from glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride.

15. The compound of formula 8 as claimed in claim 13, prepared by an addition reaction of the compound of formula 9 as claimed in claim 12 with an isocyanate: R2 is selected from hydrocarbon groups or substituted hydrocarbon groups containing 1 to 10 carbon atoms, preferably from methyl, ethyl, propyl, isopropyl, allyl, butyl, isobutyl, sec-butyl, tert-butyl, or benzyl, and more preferably from methyl.

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