Preparation method of dihydronaphthalene amide compound

Abstract

The invention provides a preparation method of a dihydronaphthalene amide compound, and provides key body compounds of the dihydronaphthalene amide compound: a formula II, a formula III and a formula IV. The synthesis thought of the dihydronaphthalene amide compound including the fenerenone is constructed through the key intermediates, a 1, 3-butanedione carbamate compound is innovatively used as an initial raw material, and the dihydronaphthalene amide compound including the fenerenone is finally obtained through condensation, ring closing, alkylation, hydrolysis and chiral resolution. The initial material in the synthesis thought is simple to prepare and controllable in cost; high-pressure reaction is not needed; by-products are few, the product purity is high, and the yield is high.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis route design and raw material medicine and intermediate preparation, and specifically relates to a preparation method of dihydronaphthalene amide compounds. Background Art

[0002] Selective mineralocorticoid receptor antagonists (MRAs) can selectively bind to mineralocorticoid receptors (MRs) to inhibit MR overactivation. MRs mainly control electrolyte retention / excretion and fluid volume regulation in renal tubular epithelial cells and are widely expressed in glomeruli, heart, and blood vessels outside renal tubules. Their overexpression and activation can directly cause inflammation and fibrosis. Therefore, inhibiting MR overactivity is believed to help protect organs such as the heart and kidneys.

[0003] The 4-aryl-1,4-dihydro-1,6-naphthoic acid amides shown below have been reported by Bayer and other companies as non-steroidal selective MRAs (WO2008104306, CN101641352A; ChemMedChem 2012, 7) for the treatment of aldosterone, hypertension, chronic heart failure, sequelae of myocardial infarction, cirrhosis, renal failure and stroke (see claim 11 of CN101641352A, the definitions of substituents R1, R2, R3 and Ar are as in claim 1 of CN101641352A)).

[0004]

[0005] Taking finerenone as an example, in July 2021, based on the results of the FIDELIO-DKD study, the US FDA approved finerenone (Finerenone, ) was launched in 2017. Subsequently, the European EMA and the Japanese PMDA successively approved the marketing application of finerenone. In 2022, the National Medical Products Administration approved the marketing of finerenone tablets (trade name: Kerendia), a Class 1 innovative drug applied by Bayer. The drug is suitable for adult patients with chronic kidney disease associated with type 2 diabetes, and can reduce the risk of continued decline in eGFR and end-stage renal disease.

[0006] Finerenone, chemical name is (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, and its structural formula is as follows:

[0007]

[0008] The synthesis of finerenone has been reported in many literatures. The initial synthesis route is described in WO2008104306 and ChemMedChem 2012, 7, 1385. The synthesis method uses a high excess of reagents in many steps and is carried out in very dilute reaction solutions; in addition, many intermediates need to be purified by column chromatography. The synthesis method is not suitable for further large-scale processes.

[0009] WO2016016287A1 optimizes the above route and solves the shortcomings of excessive solvent and the need for column chromatography purification of intermediates. The synthetic route is as follows:

[0010]

[0011] However, the synthesis process still has problems. For example, the ring-closure step requires a high-pressure reaction, which is risky and not conducive to large-scale production. 3-Oxobutyric acid 2-cyanoethyl ester is used as the starting material, and the raw material source is relatively expensive.

[0012] Bayer disclosed a new synthetic route in its invention patent CN107849043B. This route abandons the use of 2-cyanoethyl 3-oxobutyrate and uses 1,3-butanedioneamine instead. The route is as follows:

[0013]

[0014] This route still requires the use of high-pressure reaction equipment for ring-closing reaction, which is not conducive to scale-up in production and poses safety risks. In addition, due to the influence of the amide functional group, side reactions will occur in the next alkylation process, resulting in a low yield. Summary of the invention

[0015] Therefore, the technical problem to be solved by the present invention is to overcome the defects of the synthesis method of dihydronaphthalene amide compounds in the prior art, thereby providing a preparation method of dihydronaphthalene amide compounds, the key intermediates used and the synthesis method of the intermediates. Compared with the existing methods, the preparation of the starting materials of the present invention is simple and the cost is low; high pressure reaction is not required; there are few by-products, the product purity is high, and the yield is high.

[0016] To this end, the present invention provides a key intermediate of a dihydronaphthalene amide compound, wherein the key intermediate of the dihydronaphthalene amide compound is selected from a compound of formula II, a compound of formula III or a compound of formula IV having the following structure:

[0017]

[0018] wherein R1 is a C1-C4 alkyl group, which is unsubstituted or substituted up to three times with fluorine;

[0019] R2 is C1-C6 alkyl, which is unsubstituted or substituted by C3-C7 cycloalkyl or substituted up to three times by fluorine;

[0020] R3 is hydrogen, fluorine, trifluoromethyl or C1-C4 alkyl;

[0021] R4 is hydrogen, fluorine, trifluoromethyl or C1-C4 alkyl;

[0022] X1 is selected from C1-C8 alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl, wherein the alkyl, cycloalkyl, alkenyl or alkynyl is unsubstituted or substituted once or twice by at least one selected from C1-C4 alkyl, halogen, 5-10 membered aryl, 5-10 membered heteroaryl having up to two heteroatoms selected from N, O and / or S;

[0023] Ar is the following group:

[0024]

[0025] Among them, * is the connection point,

[0026] R5 is hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl or C1-C4 alkyl;

[0027] R6 is hydrogen or fluorine;

[0028] R7 is halogen, C1-C4 alkyl, trifluoromethyl, C1-C4 alkoxy or trifluoromethoxy;

[0029] R8 is cyano or nitro;

[0030] R9 is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, di-C1-C4 alkylamino or phenyl, the alkyl in the alkyl, alkoxy or alkylthio is unsubstituted or substituted up to three times by fluorine, the phenyl is unsubstituted or substituted by halogen, C1-C4 alkyl or trifluoromethyl;

[0031] R 10 is hydrogen, halogen or C1-C4 alkyl;

[0032] E is CH, C-R7 or N,

[0033] n is 0, 1, or 2,

[0034] In case the substituent R7 occurs more than once, their meanings may be the same or different.

[0035] In the present invention, the wavy line in the compound refers to the cis isomer, the trans isomer, or a mixture of the two.

[0036] Salts which are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable for pharmaceutical uses per se but can be used, for example, for isolating or purifying the compounds according to the invention.

[0037] Physiologically acceptable salts of the compounds of the invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

[0038] Physiologically acceptable salts of the compounds of the invention also include salts with customary bases, such as and preferably alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

[0039] In the context of the present invention, unless otherwise indicated, substituents have the following meanings:

[0040] C1-C6-alkyl and C1-C4-alkyl in the context of the present invention are straight-chain or branched alkyl radicals having 1 to 6 and 1 to 4 carbon atoms, respectively. Straight-chain or branched alkyl radicals having 1 to 4 carbon atoms are preferred. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl, isopentyl and n-hexyl may be mentioned with preference.

[0041] C3-C7 cycloalkyl in the context of the present invention means a saturated monocyclic cycloalkyl radical having 3 to 7 carbon atoms. Preference is given to cycloalkyl radicals having 3 to 6 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl may be mentioned and are preferred.

[0042] C1-C4-alkoxy in the context of the present invention is a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy may be mentioned with preference.

[0043] C1-C4-alkylthio in the context of the present invention is a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms. For example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and tert-butylthio may be mentioned with preference.

[0044] Di-C1-C4-alkylamino means, within the context of the present invention, an amino group having two identical or different straight-chain or branched alkyl substituents each having 1 to 4 carbon atoms. For example, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N,N-diisopropylamino, N-isopropyl-N-n-propylamino, N-n-butyl-N-methylamino and N-tert-butyl-N-methylamino may be mentioned with preference.

[0045] 5- to 10-membered aryl in the context of the present invention is an aromatic ring having 5 to 10 ring carbon atoms. Mention may be made, for example and preferably, of the phenyl radical.

[0046] 5- to 10-membered heteroaryl is an aromatic heterocycle (heteroaromatic compound) having 5 to 10 ring atoms which includes one or two ring atoms selected from the series N, O and / or S and is bonded via a ring carbon atom. By way of example and preferably mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.

[0047] Halogen within the scope of the present invention includes fluorine, chlorine, bromine and iodine. Fluorine or chlorine are preferred.

[0048] If radicals in the compounds according to the invention are substituted, unless otherwise indicated, the radicals may be substituted one or more times. Within the scope of the present invention, all radicals which occur more than once have mutually independent meanings. Substitution by one, two or three identical or different substituents is preferred. Substitution by one substituent is very particularly preferred.

[0049] In certain preferred embodiments, the key intermediate of the dihydronaphthalene amide compound further satisfies at least one of the following (1)-(5):

[0050] (1) X1 is a C1-C6 alkyl group; the alkyl group is unsubstituted or substituted once or twice by at least one selected from a C1-C4 alkyl group, F, Cl, Br, a 5-10 membered aryl group, or a 5-10 membered heteroaryl group having at most two heteroatoms selected from N, O and / or S; preferably, X1 is selected from methyl, ethyl, isopropyl, isobutyl, sec-butyl or tert-butyl;

[0051] (2) Ar is the following group:

[0052]

[0053] Wherein, * is the connection point, R6 is hydrogen or fluorine; R8 is cyano or nitro; R9 is a C1-C4 alkoxy group, the alkyl group in the alkoxy group is unsubstituted or substituted with fluorine up to three times; R10 is hydrogen, halogen or C1-C4 alkyl;

[0054] (3) R2 is a C1-C6 alkyl group, which is unsubstituted or substituted up to three times with fluorine;

[0055] (4) R1 is methyl;

[0056] (5) R3 is hydrogen and R4 is methyl.

[0057] In certain preferred embodiments, the key intermediate of the dihydronaphthalene amide compound further satisfies at least one of the following AC:

[0058] A. The compound of formula IV has the following structure:

[0059] Wherein X1 and R1 are as defined above; preferably, the compound of formula IV has the following structure:

[0060] Wherein X1 is as defined above; more preferably, the compound of formula IV has the following structural formula: or

[0061] B. The compound of formula III has the following structure:

[0062] wherein X1, R1, R3, and R4 are as defined above;

[0063] Preferably, the compound of formula III has the following structure: Wherein X1 is as defined above; more preferably, the compound of formula III has the following structure: or

[0064] C. Compound II has the following structure:

[0065] Wherein R2, R1, R3, and R4 are as defined above; preferably, the compound of formula II has the following structure:

[0066] Wherein R2 is as defined above; more preferably, the compound of formula II has the following structural formula:

[0067] The present invention also provides a method for preparing a compound of formula I using a compound of formula V, comprising the following steps:

[0068] Condensation step: the compound of formula V and the compound of formula VI are subjected to condensation reaction to obtain the compound of formula Iv;

[0069] Ring-closing step: the compound of formula IV and the compound of formula VII undergo a ring-closing reaction to obtain the compound of formula III;

[0070] Alkylation step: reacting the compound of formula III with an alkylating agent to obtain the compound of formula II;

[0071] Hydrolysis step: the compound of formula II is hydrolyzed in the presence of an alkaline substance to obtain a compound of formula I;

[0072]

[0073] The substituents in the above compounds are defined as in any of the above items.

[0074] The present invention also provides a method for preparing a compound of formula I using a compound of formula II, comprising a hydrolysis step:

[0075]

[0076] The compound of formula II is hydrolyzed in the presence of an alkaline substance to obtain the compound of formula I; the substituents appearing in the above compound are defined as described in any of the above items.

[0077] The above-mentioned preparation method further comprises a splitting step: using the compound of formula I to undergo chiral splitting to obtain a compound of formula a;

[0078]

[0079] The substituents in the above compounds are defined as in any of the above items.

[0080] The present invention also provides a method for preparing the compound of formula V, comprising the following steps:

[0081]

[0082] Acetyl Michaelis acid is reacted with the compound of formula VIII to obtain the compound of formula V; the substituents appearing in the above compound are defined as described in any of the above items.

[0083] The present invention also provides a method for preparing a compound of formula II using a compound of formula III, comprising an alkylation step: the compound of formula III reacts with an alkylating agent to obtain a compound of formula II;

[0084]

[0085] The substituents in the above compounds are defined as described in any one of the above items; preferably, the alkylating agent is triethyl orthoformate or triethyl orthoacetate.

[0086] The present invention also provides a method for preparing a compound of formula III using a compound of formula IV, comprising a ring closure step:

[0087]

[0088] The compound of formula IV and the compound of formula VII undergo a ring-closing reaction to obtain the compound of formula III; the substituents appearing in the above compound are defined as described in any of the above items.

[0089] A method for preparing a compound of formula IV using a compound of formula V comprises a condensation step: a compound of formula V and a compound of formula VI are subjected to a condensation reaction to obtain a compound of formula IV;

[0090]

[0091] The substituents in the above compounds are defined as in any of the above items.

[0092] The present invention also provides a method for preparing compound 4 using 4-formyl-3-methoxybenzonitrile, comprising the following steps:

[0093] Condensation step: 4-formyl-3-methoxybenzonitrile and 1,3-butanedioneamine formate compound are condensed to obtain compound 1;

[0094]

[0095] Ring-closing step: Compound 1 and 4-amino-5-methylpyridine-2-ol undergo a ring-closing reaction to obtain compound 2;

[0096]

[0097] Alkylation step: Compound 2 reacts with an alkylating agent to obtain compound 3;

[0098]

[0099] Hydrolysis step: Compound 3 is hydrolyzed in the presence of an alkaline substance to obtain compound 4;

[0100]

[0101] Wherein R in compound 1 or compound 2 is C1-C8 alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl, and the alkyl, cycloalkyl, alkenyl or alkynyl is unsubstituted or substituted once or twice by at least one selected from C1-C4 alkyl, halogen, 5-10-membered aryl, or 5-10-membered heteroaryl with up to two heteroatoms selected from N, O and / or S; preferably, R is C1-C6 alkyl; the alkyl is unsubstituted or substituted once or twice by at least one selected from C1-C4 alkyl, F, C1, Br, 5-10-membered aryl, or 5-10-membered heteroaryl with up to two heteroatoms selected from N, O and / or S; more preferably, R is selected from methyl, ethyl, isopropyl, isobutyl, sec-butyl or tert-butyl.

[0102] The present invention also provides a method for preparing compound 4 using compound 3, comprising a hydrolysis step: compound 3 is hydrolyzed in the presence of an alkaline substance to obtain compound 4;

[0103]

[0104] Furthermore, according to the preparation method described above, it also includes a splitting step: using compound 4 to undergo chiral splitting to obtain finerenone;

[0105]

[0106] The present invention also provides a method for preparing compound 3 using compound 2, comprising an alkylation step: compound 2 reacts with an alkylating agent to obtain compound 3;

[0107]

[0108] wherein R in compound 2 is as defined above.

[0109] Preferably, the alkylating agent is triethyl orthoformate or triethyl orthoacetate.

[0110] The present invention also provides a method for preparing compound 2 using compound 1, comprising a ring closing step:

[0111]

[0112] Compound 1 and 4-amino-5-methylpyridine-2-ol undergo a ring-closing reaction to obtain compound 2; wherein the definition of R in compound 1 or compound 2 is as described above.

[0113] The present invention also provides a method for preparing compound 1 using 4-formyl-3-methoxybenzonitrile, comprising a condensation step: 4-formyl-3-methoxybenzonitrile and 1,3-dioneamine formate compound are subjected to a condensation reaction to obtain compound 1;

[0114]

[0115] wherein R in compound 1 is as defined above.

[0116] In certain preferred embodiments, in the condensation step, the reaction solvent is at least one of 2-butanol, acetonitrile, dichloromethane, ethanol, isopropanol, DMF, tetrahydrofuran, dioxane, and ethyl acetate. In the condensation step, the reaction temperature is 20-40°C, more preferably 30°C.

[0117] In certain preferred embodiments, in the above ring-closing step, the reaction solvent is one or more of isopropanol, sec-pentanol and 2-butanol, preferably sec-butanol. In the ring-closing step, the mixture is heated to reflux and the reaction time is 18-36 hours.

[0118] In certain preferred embodiments, in the alkylation step, the alkylation agent is an ethylation agent, preferably, the ethylation agent is one or more of triethyl orthoformate or triethyl orthoacetate, more preferably triethyl orthoacetate. In the alkylation step, the reaction solvent is at least one of dimethylacetamide and dimethylformamide. The reaction temperature is 60-120°C.

[0119] In certain preferred embodiments, in the hydrolysis step, the alkaline substance is selected from one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide. In the hydrolysis step, the reaction solvent is at least one of ethanol, water, tetrahydrofuran, methanol, and dioxane.

[0120] In certain preferred embodiments, the resolution agent used in the resolution step is D-tartaric acid or L-tartaric acid. In the resolution step, the reaction solvent is at least one of 2-propanol, ethanol, n-propanol, and isopropanol. The reaction temperature is 60-80°C.

[0121] In certain preferred embodiments, during the preparation of the compound of formula V, the reaction solvent is acetonitrile. The reaction conditions are: heating to reflux and reacting for 1-3 hours.

[0122] The present invention also provides a method for preparing finerenone, comprising the following steps:

[0123] (1) reacting acetyl Michaelis acid with a carbamate compound to obtain a 1,3-butanedione carbamate compound;

[0124]

[0125] (2) 4-formyl-3-methoxybenzonitrile and 1,3-butanedioneamine formate compounds are condensed to obtain compound 1;

[0126]

[0127] (3) Compound 1 and 4-amino-5-methylpyridine-2-ol undergo a ring-closing reaction to obtain compound 2;

[0128]

[0129] (4) Compound 2 is reacted with triethyl orthoformate or triethyl orthoacetate to obtain compound 3;

[0130]

[0131] (5) Compound 3 is hydrolyzed under alkaline conditions to obtain compound 4;

[0132]

[0133] (6) Compound 4 was subjected to chiral resolution to obtain finerenone.

[0134]

[0135] Its synthetic route is:

[0136]

[0137] Among them, in the carbamate compounds, 1,3-butanedionecarbamate compounds, compound 1 or compound 2, R is a C1-C8 alkyl group, a C3-C7 cycloalkyl group, a C2-C8 alkenyl group or a C2-C8 alkynyl group, and the alkyl group, cycloalkyl group, alkenyl group or alkynyl group is unsubstituted or substituted once or twice by at least one selected from a C1-C4 alkyl group, a halogen, a 5-10-membered aryl group, or a 5-10-membered heteroaryl group having at most two heteroatoms selected from N, O and / or S; preferably, R is a C1-C6 alkyl group; the alkyl group is unsubstituted or substituted once or twice by at least one selected from a C1-C4 alkyl group, F, C1, Br, a 5-10-membered aryl group, or a 5-10-membered heteroaryl group having at most two heteroatoms selected from N, O and / or S; more preferably, R is selected from methyl, ethyl, isopropyl, isobutyl, sec-butyl or tert-butyl.

[0138] In certain preferred embodiments, the method for preparing finerenone comprises the following steps:

[0139] (1) Using acetonitrile as solvent, acetyl Michaelis acid and carbamate are reacted under hot reflux for 1-3 hours. After the reaction is completed, the solvent is concentrated under reduced pressure to obtain a yellow to brown oil, which is directly used in the next reaction; wherein the molar ratio of acetyl Michaelis acid to carbamate is 1:1.0 to 1:1.3.

[0140] (2) Using 2-butanol as solvent, 4-formyl-3-methoxybenzonitrile and 1,3-butanedioneamine formate are reacted at 20-40° C. for 3-4 hours; after the reaction, the compound 1 is obtained by filtration;

[0141] (3) Using 2-butanol as solvent, compound 1 and 4-amino-5-methylpyridin-2-ol were reacted under hot reflux for 18-36 hours; after the reaction, the temperature was lowered to 10-20° C. and filtered to obtain compound 2;

[0142] (4) Using dimethylacetamide as solvent, compound 2 and triethyl orthoacetate are reacted at 60-120° C. for 1-4 hours; after the reaction, the temperature is lowered to 40-70° C., purified water is added dropwise, and the product is precipitated; the temperature is lowered to 10-20° C., and filtered to obtain compound 3;

[0143] (5) Using ethanol and water as solvents, compound 3 and sodium hydroxide were reacted at room temperature for 4-8 hours; after the reaction, the pH was adjusted to 6-7, purified water was added, the product was precipitated, and filtered to obtain compound 4;

[0144] (6) Compound 5 was dissolved in 2-propanol, tartaric acid was added, and the mixture was reacted at 60-80°C for 1 hour, then cooled to room temperature and stirred overnight; filtered, the solid was dissolved in an ethanol / water mixture, sodium bicarbonate solution was added, the pH value was adjusted to 7-8, and stirred overnight; filtered to obtain finerenone.

[0145] The methyl (3-oxobutyryl)carbamate in the present invention can be prepared in-house or purchased from the market, and its CAS number is 143602-94-2, while the other ethyl (3-oxobutyryl)carbamate, isopropyl (3-oxobutyryl)carbamate, sec-butyl (3-oxobutyryl)carbamate, and tert-butyl (3-oxobutyryl)carbamate are all prepared in-house.

[0146] The technical solution of the present invention has the following advantages:

[0147] 1. The key intermediates or salts thereof of dihydronaphthalene dextrin amide compounds provided by the present invention are innovatively designed and synthesized. A synthesis strategy for dihydronaphthalene dextrin amide compounds including finerenone is constructed through these key intermediates. 1,3-butanedione amine formate compounds are innovatively used as starting materials. After condensation, ring closure, alkylation, hydrolysis, and chiral resolution, dihydronaphthalene dextrin amide compounds including finerenone are finally obtained. The starting materials in the synthesis strategy are simple to prepare and cost-controllable; high-pressure reaction is not required; there are few by-products, and the product purity is high and the yield is high.

[0148] 2. The key intermediates of dihydronaphthylamide compounds and the preparation methods of dihydronaphthylamide compounds including finerenone provided by the present invention provide a new synthesis process of finerenone, which overcomes the deficiencies of the prior art and provides a simple new synthesis process. The raw materials of the present invention are easily available, the reaction conditions are mild, and the operation is simple, which is convenient for large-scale preparation and production of finerenone.

[0149] 3. The present invention also provides a method for preparing a compound of formula V. In the prior art, the compound of formula V is generally obtained by reacting 2,2,6-trimethyl-4H-1,3-dioxin-4-one with carbamate, but the reaction requires a high temperature reaction (110-130° C.), a long reaction time, and an alkaline condition is required for the reaction, resulting in a low reaction yield. The present invention innovatively uses acetyl Michaelis acid to react with a compound of formula VIII to obtain a compound of formula V, which has simple reaction conditions, greatly shortens the reaction time, and has a high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0150] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0151] Figure 1 is the chiral liquid phase spectrum of compound 4 prepared in Example 18 of the present invention;

[0152] Figure 2 is the chiral liquid phase spectrum of phenerenone prepared in Example 19 of the present invention;

[0153] Figure 3 is the mass spectrum of compound 1-2 prepared in Example 7 of the present invention;

[0154] Figure 4 is the mass spectrum of compound 1-3 prepared in Example 8 of the present invention;

[0155] Figure 5 is the mass spectrum of compound 1-4 prepared in Example 9 of the present invention;

[0156] Figure 6 is the mass spectrum of compound 1-5 prepared in Example 10 of the present invention;

[0157] Figure 7 is the mass spectrum of compound 2-2 prepared in Example 11 of the present invention;

[0158] Figure 8is the mass spectrum of compound 2-3 prepared in Example 12 of the present invention;

[0159] Fig. 9 is the mass spectrum of compound 2-4 prepared in Example 13 of the present invention;

[0160] Fig.10 is the mass spectrum of compound 3 prepared in Example 17 of the present invention;

[0161] Fig.11 is the mass spectrum of compound 4 obtained in Example 18 of the present invention;

[0162] Fig.12 is the H NMR spectrum of compound 1-5 prepared in Example 10 of the present invention;

[0163] Fig.13 is the H NMR spectrum of compound 2-4 prepared in Example 13 of the present invention;

[0164] Fig.14 It is the H NMR spectrum of compound 3 obtained in Example 17 of the present invention. DETAILED DESCRIPTION

[0165] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0166] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0167] Example 1

[0168] This embodiment provides a method for synthesizing a compound of formula V. In this embodiment, the compound of formula V is: 1,3-butanedioneamine methyl formate. The synthesis route and steps of the compound are as follows:

[0169]

[0170] Under nitrogen protection, 11.31 g (60.78 mmol) of acetyl Michler's acid and 5.01 g (66.85 mmol) of methyl carbamate were added to 200 mL of ethanol. After addition, the mixture was heated to reflux and reacted for 2 h. After the reaction was completed, the solvent was concentrated under reduced pressure to obtain 1.23 g of a dark yellow oil with a yield of 108%. The purity of the product detected by HPLC was 94%. The product was directly used for the next step reaction.

[0171] Example 2

[0172] This embodiment provides a method for synthesizing a compound of formula V. In this embodiment, the compound of formula V is: 1,3-butanedioneamine ethyl formate. The synthesis route and steps of the compound are as follows:

[0173]

[0174] Under nitrogen protection, 10.00 g (53.72 mmol) of acetyl Michler's acid and 5.26 g (59.09 mmol) of ethyl carbamate were added to 200 mL of ethanol. After the addition, the mixture was heated to reflux and reacted for 2 h. After the reaction, the solvent was concentrated under reduced pressure to obtain 10.25 g of a dark yellow oil with a yield of 110%. The purity of the product was 96% by HPLC. The product was directly used for the next step reaction.

[0175] Example 3

[0176] This embodiment provides a method for synthesizing a compound of formula V. In this embodiment, the compound of formula V is: 1,3-butanedioneamine isopropyl formate. The synthesis route and steps of the compound are as follows:

[0177]

[0178] Under nitrogen protection, 11.31 g (60.78 mmol) of acetyl Michler's acid and 6.90 g (66.85 mmol) of isopropyl carbamate were added to 200 mL of ethanol. After the addition, the mixture was heated to reflux and reacted for 2 h. After the reaction, the solvent was concentrated under reduced pressure to obtain 12.23 g of a dark yellow oil with a yield of 107%. The purity of the product was 96% by HPLC. The product was directly used for the next step reaction.

[0179] Example 4

[0180] This embodiment provides a method for synthesizing a compound of formula V. In this embodiment, the compound of formula V is: 1,3-butanedioneamine formate sec-butyl ester. The synthesis route and steps of the compound are as follows:

[0181]

[0182] Under nitrogen protection, 9.39 g (50.44 mmol) of acetyl Michler's acid and 6.50 g (66.85 mmol) of sec-butyl carbamate were added to 100 mL of ethanol. After the addition, the mixture was heated to reflux and reacted for 2 h. After the reaction, the solvent was concentrated under reduced pressure to obtain 11.38 g of a dark yellow oil with a yield of 112%. The purity of the product detected by HPLC was 97%. The product was directly used for the next step reaction.

[0183] Example 5

[0184] This embodiment provides a method for synthesizing a compound of formula V. In this embodiment, the compound of formula V is: 1,3-butanedioneamine formate tert-butyl ester. The synthesis route and steps of the compound are as follows:

[0185]

[0186] Under nitrogen protection, 18.00 g (96.69 mmol) of acetyl Michler's acid and 13.02 g (111.19 mmol) of sec-butyl carbamate were added to 180 mL of ethanol. After the addition, the mixture was heated to reflux and reacted for 2 h. After the reaction, the solvent was concentrated under reduced pressure to obtain 21.07 g of a dark yellow oil with a yield of 108%. The purity of the product detected by HPLC was 98%. The product was directly used for the next step reaction.

[0187] Example 6

[0188] This embodiment provides a method for synthesizing a compound of formula IV. In this embodiment, the compound of formula IV is: compound 1-1. The synthesis route and steps of the compound are as follows:

[0189]

[0190] 1.31 g (8.15 mmol) of 4-formyl-3-methoxybenzonitrile and 3.65 g (10.60 mmol) of 1,3-butanedioneamine methyl formate prepared in Example 1 were added to 7 ml of sec-butyl alcohol, and 81 μl of piperidine and 49 μl of acetic acid were added, and the mixture was reacted at 30° C. for 16 h. After the reaction, the mixture was cooled to 10° C. and filtered to obtain 2.24 g of a white powder (Compound 1-1), with a yield of 91%. The purity of the product was 95% by HPLC, and ESI (-): 301.1.

[0191] Example 7

[0192] This embodiment provides a method for synthesizing a compound of formula IV. In this embodiment, the compound of formula IV is: compound 1-2. The synthesis route and steps of the compound are as follows:

[0193]

[0194] 7.21 g (44.75 mmol) of 4-formyl-3-methoxybenzonitrile and 9.30 g (53.71 mmol) of 1,3-butanedione ethyl formate obtained in Example 2 were added to 36 ml of sec-butyl alcohol, and 440 μl of piperidine and 255 μl of acetic acid were added, and the mixture was reacted at 30° C. for 16 h. After the reaction, the mixture was cooled to 10° C. and filtered to obtain 12.12 g of a white powder (Compound 1-2) with a yield of 86%. The purity of the product was 96% by HPLC, and ESI(-): 315.1.

[0195] Example 8

[0196] This embodiment provides a method for synthesizing a compound of formula IV. In this embodiment, the compound of formula IV is: compound 1-3. The synthesis route and steps of the compound are as follows:

[0197]

[0198] 5.44 g (33.76 mmol) of 4-formyl-3-methoxybenzonitrile and 8.21 g (43.86 mmol) of 1,3-butanedioneamine formate isopropyl ester prepared in Example 3 were added to 27 ml of sec-butyl alcohol, and 334 μl of piperidine and 196 μl of acetic acid were added, and the mixture was reacted at 30° C. for 16 h. After the reaction was completed, the mixture was cooled to 10° C. and filtered to obtain 9.51 g of a white powder (Compound 1-3) with a yield of 85%. The purity of the product was 97% by HPLC, and ESI (-): 329.2.

[0199] Example 9

[0200] This embodiment provides a method for synthesizing a compound of formula IV. In this embodiment, the compound of formula IV is: compound 1-4. The synthesis route and steps of the compound are as follows:

[0201]

[0202] 3.55 g (22.03 mmol) of 4-formyl-3-methoxybenzonitrile and 5.77 g (28.64 mmol) of 1,3-dioneamine sec-butyl formate obtained in Example 4 were added to 18 ml of sec-butyl alcohol, and 218 μl of piperidine and 126 μl of acetic acid were added, and the mixture was reacted at 30° C. for 16 h. After the reaction was completed, the mixture was cooled to 10° C. and filtered to obtain 6.32 g of a white powder (Compound 1-4) with a yield of 83%. The purity of the product was 97% by HPLC, and ESI (-): 343.2.

[0203] Example 10

[0204] This embodiment provides a method for synthesizing a compound of formula IV. In this embodiment, the compound of formula IV is: compound 1-5. The synthesis route and steps of the compound are as follows:

[0205]

[0206] 12.98 g (22.03 mmol) of 4-formyl-3-methoxybenzonitrile and 19.48 g (96.69 mmol) of 1,3-dioneamine formate tert-butyl ester prepared in Example 5 were added to 18 ml of sec-butyl alcohol, and 218 μl of piperidine and 126 μl of acetic acid were added, and the mixture was reacted at 30°C for 16 h. After the reaction was completed, the mixture was cooled to 10°C and filtered to obtain 23.5 g of white powder (Compound 1-5) with a yield of 85%. The purity of the product was 95% by HPLC. 1 H NMR (500MHz, Chloroform-d) δ7.67 (s, 1H), 7.63 (s, 1H), 7.47 (d, J=7.9Hz, 1H), 7.23 ( dd, J=8.0, 1.4Hz, 1H), 7.12 (d, J=1.4Hz, 1H), 3.90 (s, 3H), 2.49 (s, 3H), 1.43 (s, 9H). ESI(-): 343.2.

[0207] Embodiment 11

[0208] This embodiment provides a method for synthesizing a compound of formula III. In this embodiment, the compound of formula III is: compound 2-2. The synthesis route and steps of the compound are as follows:

[0209]

[0210] 3.76 g (30.30 mmol) of 4-amino-5-methylpyridine-2-ol and 11.50 g (36.36 mmol) of compound 1-2 prepared in Example 7 were suspended in 75 mL of sec-butyl alcohol and refluxed for 24 h under nitrogen protection. After the reaction, the temperature was lowered to 10° C. and filtered to obtain 12.79 g of a light yellow solid (compound 2-2) with a yield of 93%. The purity of the product was 92% by HPLC, and ESI (+): 423.2.

[0211] Example 12

[0212] This embodiment provides a method for synthesizing a compound of formula III. In this embodiment, the compound of formula III is: compound 2-3. The synthesis route and steps of the compound are as follows:

[0213]

[0214] 2.04 g (16.40 mmol) of 4-amino-5-methylpyridine-2-ol and 6.50 g (19.68 mmol) of compound 1-3 prepared in Example 8 were suspended in 60 mL of sec-butyl alcohol and refluxed for 24 h under nitrogen protection. After the reaction, the temperature was lowered to 10° C. and filtered to obtain 6.17 g of a light yellow solid (compound 2-3) with a yield of 93%. The purity of the product was 94% by HPLC, and ESI (+): 437.2.

[0215] Embodiment 13

[0216] This embodiment provides a method for synthesizing a compound of formula III. In this embodiment, the compound of formula III is: compound 2-4. The synthesis route and steps of the compound are as follows:

[0217]

[0218] 7.54 g (60.72 mmol) of 4-amino-5-methylpyridine-2-ol and 23.00 g (66.79 mmol) of compound 1-5 obtained in Example 10 were suspended in 113 mL of sec-butyl alcohol and refluxed for 24 h under nitrogen protection. After the reaction, the temperature was lowered to 10° C. and filtered to obtain 24.59 g of a light yellow solid (compound 2-4) with a yield of 93%. The purity of the product was 95% by HPLC. 1 H NMR (500MHz, DMSO-d6) δ10.76 (s, 1H), 10.18 (d, J = 2.7Hz, 1H), 7.78 (d, J = 1.5Hz, 1H), 7.3 5 (t, J=2.0Hz, 1H), 7.27 (dt, J=7.8, 1.4Hz, 1H), 6.91 (dd, J=7.9, 2.3Hz, 1H), 5.33 (d, J=5. 7Hz, 1H), 4.724.62 (m, 1H), 3.76 (s, 3H), 2.072.01 (m, 3H), 1.99 (d, J=2.5Hz, 3H), 1.55 (dq , J=12.7, 7.0Hz, 2H), 1.20 (t, J=6.7Hz, 3H), 0.88 (dt, J=11.7, 7.4Hz, 3H). ESI (+): 451.2.

[0219] Embodiment 14

[0220] This embodiment provides a method for synthesizing a compound of formula III. In this embodiment, the compound of formula III is: compound 2-4. The synthesis route and steps of the compound are as follows:

[0221]

[0222] 1.44 g (11.59 mmol) of 4-amino-5-methylpyridine-2-ol and 4.79 g (13.91 mmol) of compound 1-4 obtained in Example 9 were suspended in 29 mL of sec-butyl alcohol and refluxed for 24 h under nitrogen protection. After the reaction, the temperature was lowered to 10° C. and filtered to obtain 4.25 g of a light yellow solid with a yield of 81%. The purity of the product was 98% by HPLC, and ESI (+): 451.2.

[0223] Embodiment 15

[0224] This embodiment provides a method for synthesizing a compound of formula II. In this embodiment, the compound of formula II is: compound 3. The synthesis route and steps of the compound are as follows:

[0225]

[0226] 10.21 g (24.17 mmol) of compound 2-2 prepared in Example 11 was dissolved in 61 ml of dimethylacetamide, and 11.76 g (72.51 mmol) of triethyl orthoacetate was added. The mixture was reacted at 100°C for 2 h. The temperature was lowered to 20°C, and 200 ml of purified water was slowly added. The product precipitated. After filtration, 10.11 g of a light yellow solid (compound 3) was obtained. The yield was 91%. The purity of the product was 93% as determined by HPLC. ESI (+): 451.2.

[0227] Example 16

[0228] This embodiment provides a method for synthesizing a compound of formula II. In this embodiment, the compound of formula II is: compound 3. The synthesis route and steps of the compound are as follows:

[0229]

[0230] 5.00 g (11.45 mmol) of compound 2-3 prepared in Example 12 was dissolved in 30 ml of dimethylacetamide, and 11.76 g (34.37 mmol) of triethyl orthoacetate was added. The mixture was reacted at 100°C for 2 h. The temperature was lowered to 20°C, and 100 ml of purified water was slowly added. The product precipitated. After filtration, 4.79 g of a light yellow solid (compound 3) was obtained. The yield was 93%. The purity of the product was 93% as determined by HPLC. ESI (+): 451.2.

[0231] Embodiment 17

[0232] This embodiment provides a method for synthesizing a compound of formula II. In this embodiment, the compound of formula II is: compound 3. The synthesis route and steps of the compound are as follows:

[0233]

[0234] 6.71 g (14.91 mmol) of compound 2-4 prepared in Example 14 was dissolved in 30 ml of dimethylacetamide, and 11.76 g (44.73 mmol) of triethyl orthoacetate was added. The mixture was reacted at 100°C for 2 h. The temperature was lowered to 20°C, and 100 ml of purified water was slowly added. The product precipitated. After filtration, 6.37 g of a light yellow solid (compound 3) was obtained. The yield was 95%. The purity of the product was 92% as determined by HPLC. 1 H NMR (500MHz, Chloroform-d) δ8.80 (s, 1H), 7.69 (s, 1H), 7.24 (d, J=7.9Hz, 1H), 7.15 (dd, J=7.9, 1.5Hz, 1H), 7.09 (s, 1H), 6.04 (s, 1H), 5.48 (s, 1H), 4.22 (tt, J=7.2, 3.6Hz, 2H), 4.16 (q, J=7.5, 6.8Hz, 2H), 4.01 (s, 3H), 2.52 (s, 3H ), 2.17 (s, 3H), 1.32 (t, J = 7.1Hz, 3H), 1.19 (t, J = 7.0Hz, 3H). ESI (+): 451.2.

[0235] Embodiment 18

[0236] This embodiment provides a method for synthesizing a compound of formula I. In this embodiment, the compound of formula II is: compound 4. The synthesis route and steps of the compound are as follows:

[0237]

[0238] Take 10.00g (22.20mmol) of compound 3 obtained in Example 15 and dissolve it in a mixed solvent of ethanol / water (60ml of ethanol and 15ml of water). Add 1.97g of 45% (mass percentage) sodium hydroxide solution under ice bath. Continue stirring for 4h, add dilute hydrochloric acid, adjust the pH value to 6.5, add 100ml of purified water, filter, and obtain 8.06g of white solid (compound 4), with a yield of 96%. The purity of the product detected by HPLC is 98%, and the ee is 0.5%. ESI (+): 379.2.

[0239] The chromatographic conditions were as follows:

[0240] Chromatographic column: Daicel Chiralpak IA, length 250 mm, inner diameter 4.6 mm, particle size 5 μm.

[0241] Mobile phase: A: acetonitrile; B: methyl tert-butyl ether. A: B = 9: 1.

[0242] Conditions: 40°C, 0.8 ml / min.

[0243] Detection wavelength: 255nm.

[0244] The results showed that compound 4 was a racemate, and the peak information was shown in the following table:

[0245]

[0246] Embodiment 19

[0247] This embodiment provides a method for synthesizing a compound of formula a. In this embodiment, the compound of formula a is finerenone. The steps for synthesizing and purifying the compound are as follows:

[0248] Take 9.00g (23.81mmol) of compound 4 obtained in Example 18 and dissolve it in a mixed solvent of n-propanol / water (144ml of n-propanol, 36ml of water). Add 0.55 molar equivalents of D-tartaric acid at room temperature. After the addition is completed, heat to 80 degrees Celsius, stir for 1 hour, cool to room temperature and filter. Wash the filter cake with a small amount of n-propanol / water mixed solvent (4; 1). Add the filter cake obtained above to a mixed solvent of n-propanol / water (20ml of n-propanol, 80ml of water), stir, add sodium phosphate, adjust the pH value to about 6-7, continue stirring for 1 hour, filter, and obtain a crude product of finerenone. The above crude product is recrystallized from ethanol to obtain 3.37g of pure finerenone with the following configuration, with a yield of 75% (based on theoretical yield), wherein the liquid phase and nuclear magnetic spectrum of finerenone are as follows Figure 1 and Figure 4 The identification showed that the configuration of finerenone was correct, with an ee of 100%.

[0249]

[0250] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the scope of protection of the invention.

Claims

1. A key intermediate of a dihydronaphthalene amide compound or a salt thereof, characterized in that: The key intermediate of the dihydronaphthalene amide compound is selected from the compound of formula II, the compound of formula III or the compound of formula IV having the following structure; wherein R1 is a C1-C4 alkyl group, which is unsubstituted or substituted up to three times with fluorine; R2 is C1-C6 alkyl, which is unsubstituted or substituted by C3-C7 cycloalkyl or substituted up to three times by fluorine; R3 is hydrogen, fluorine, trifluoromethyl or C1-C4 alkyl; R4 is hydrogen, fluorine, trifluoromethyl or C1-C4 alkyl; X1 is C1-C8 alkyl, C3-C7 cycloalkyl, C2-C8 alkenyl or C2-C8 alkynyl, wherein the alkyl, cycloalkyl, alkenyl or alkynyl is unsubstituted or substituted once or twice by at least one selected from C1-C4 alkyl, halogen, 5-10 membered aryl, 5-10 membered heteroaryl having up to two heteroatoms selected from N, O and / or S; Ar is the following group: Among them, * is the connection point, R5 is hydrogen, fluorine, chlorine, cyano, nitro, trifluoromethyl or C1-C4 alkyl; R6 is hydrogen or fluorine; R7 is halogen, C1-C4 alkyl, trifluoromethyl, C1-C4 alkoxy or trifluoromethoxy; R8 is cyano or nitro; R9 is hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, di-C1-C4 alkylamino or phenyl, the alkyl in the alkyl, alkoxy or alkylthio is unsubstituted or substituted up to three times by fluorine, the phenyl is unsubstituted or substituted by halogen, C1-C4 alkyl or trifluoromethyl; R 10 is hydrogen, halogen or C1-C4 alkyl; E is CH, C-R7 or N, n is 0, 1, or 2, In case the substituent R7 occurs more than once, their meanings may be the same or different.

2. The key intermediate of the dihydronaphthalene amide compound or its salt according to claim 1, characterized in that: The key intermediate of the dihydronaphthalene amide compound also satisfies at least one of the following (1)-(5): (1) X1 is a C1-C6 alkyl group; the alkyl group is unsubstituted or substituted once or twice by at least one selected from a C1-C4 alkyl group, F, Cl, Br, a 5-10 membered aryl group, or a 5-10 membered heteroaryl group having at most two heteroatoms selected from N, O and / or S. Preferably, X1 is selected from methyl, ethyl, isopropyl, isobutyl, sec-butyl or tert-butyl; (2) Ar is the following group: Wherein, * is the connection point, R6 is hydrogen or fluorine; R8 is cyano or nitro; R9 is a C1-C4 alkoxy group, the alkyl group in the alkoxy group is unsubstituted or substituted with fluorine up to three times; R 10 is hydrogen, halogen or C1-C4 alkyl; preferably (3) R2 is a C1-C6 alkyl group, which is unsubstituted or substituted up to three times with fluorine. Preferably, R2 is selected from methyl, ethyl, isopropyl, isobutyl, sec-butyl or tert-butyl; (4) R1 is methyl; (5) R3 is hydrogen and R4 is methyl.

3. The key intermediate of the dihydronaphthalene amide compound or its salt according to claim 1 or 2, characterized in that: The key intermediate of the dihydronaphthalene amide compound also satisfies at least one of the following AC: A. The compound of formula IV has the following structure: Wherein X1 and R1 are as defined in claim 1 or 2; preferably, the compound of formula IV has the following structure: Wherein X1 is as defined in claim 1 or 2; More preferably, the compound of formula IV has the following structural formula: or B. The compound of formula III has the following structure: Wherein X1, R1, R3, R4 are as defined in claim 1 or 2; Preferably, the compound of formula III has the following structure: Wherein X1 is as defined in claim 1 or 2; More preferably, the compound of formula III has the following structure: or C. The compound of formula II has the following structure: Wherein R2, R1, R3, R4 are as defined in claim 1 or 2; Preferably, the compound of formula II has the following structure: Wherein R2 is as defined in claim 1 or 2; More preferably, the compound of formula II has the following structural formula:

4. A method for preparing a compound of formula I using a compound of formula V, characterized in that: The steps include: Condensation step: the compound of formula V and the compound of formula VI are subjected to condensation reaction to obtain the compound of formula IV; Ring-closing step: the compound of formula IV and the compound of formula VII undergo a ring-closing reaction to obtain the compound of formula III; Alkylation step: reacting the compound of formula III with an alkylating agent to obtain the compound of formula II; Hydrolysis step: the compound of formula II is hydrolyzed in the presence of an alkaline substance to obtain a compound of formula I; The substituents present in the above compounds are defined as described in any one of claims 1 to 3.

5. A method for preparing a compound of formula I using a compound of formula II, characterized in that: The hydrolysis step includes: The compound of formula II is hydrolyzed in the presence of an alkaline substance to obtain a compound of formula I; the substituents appearing in the above compound are defined as described in any one of claims 1-3.

6. The preparation method according to claim 4 or 5, characterized in that: The step also includes: chiral splitting of the compound of formula I to obtain a compound of formula a; The substituents present in the above compounds are defined as described in any one of claims 1 to 3.

7. A method for preparing a compound of formula V, characterized in that: The steps include: Acetyl Michaelis acid is reacted with a compound of formula VIII to obtain a compound of formula V; the substituents in the above compound are defined as described in any one of claims 1 to 3.

8. A method for preparing a compound of formula II using a compound of formula III, characterized in that: The method comprises an alkylation step: reacting a compound of formula III with an alkylating agent to obtain a compound of formula II; The substituents appearing in the above compounds are defined as described in any one of claims 1 to 3; preferably, the alkylating agent is triethyl orthoformate or triethyl orthoacetate.

9. A method for preparing a compound of formula III using a compound of formula IV, characterized in that: The loop closing steps include: The compound of formula IV and the compound of formula VII undergo a ring-closing reaction to obtain the compound of formula III; the substituents appearing in the above compound are defined as described in any one of claims 1-3.

10. A method for preparing a compound of formula IV using a compound of formula V, characterized in that: The method comprises a condensation step: a compound of formula V and a compound of formula VI are subjected to a condensation reaction to obtain a compound of formula IV; The substituents present in the above compounds are defined as described in any one of claims 1 to 3.

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