Method for preparing key intermediate iii of resmetirom

Abstract

Provided is a method for preparing key intermediate III of Resmetirom, which belongs to the technical field of drug intermediates. Key intermediate III of Resmetirom (formula III) is prepared by using a compound having a structure as shown in formula V and a compound having a structure as shown in formula E. The preparation steps are simple and easy to operate, and require no use of expensive silver nitrate, cesium carbonate, isopropenylmagnesium bromide and lithium chloride. The product yield is high, and the intermediate products are all solid and convenient for purification. In addition, the provided preparation method produces a small amount of solid waste and waste liquid, and is environmentally friendly. Furthermore, the used compound having a structure as shown in formula G has stable properties and is not easily oxidized. In conclusion, the provided method can significantly reduce the production difficulty and production cost of key intermediate III of Resmetirom, and is more beneficial to industrial production.

Description

A preparation method of Resmetirom key intermediate III Technical Field

[0001] The present application relates to the technical field of pharmaceutical intermediates, and in particular to a method for preparing a key intermediate III of Resmetirom. Background Art

[0002] Resmetirom (CAS: 920509-32-6) is a selective thyroid hormone receptor-β agonist developed by Madrigal Pharmaceuticals for the treatment of non-alcoholic steatohepatitis (NASD). In December 2022, Madrigal announced positive top-line results from a pivotal Phase III clinical trial of Resmetirom. In July 2022, Resmetirom submitted a marketing authorization application to the US FDA. If approved, Resmetirom will become the world's first marketed drug for the treatment of non-alcoholic steatohepatitis.

[0003] The molecular structure of Resmetirom is shown in Formula I:

[0004] Patents WO2007009913 and CN112707892A disclose methods for preparing Resmetirom. Synthesis Route 1 is as follows:

[0005] This synthetic route involves reacting compound D with isobutyric acid in the presence of silver nitrate and ammonium persulfate to produce compound C with a yield of 67%. Compound C then reacts with 2,6-dichloro-4-aminophenol to produce compound B with a yield of 53%. Compound B is hydrolyzed to produce compound III with a yield of 50%. Compound III undergoes a diazotization reaction, then adds to compound A and undergoes double bond shift to produce compound II with a yield of 56%. Finally, compound II undergoes ring closure to produce compound I with a yield of 50%.

[0006] Patents WO2014043706 and CN105008335 disclose another method for preparing Resmetirom. Synthesis Route 2 is as follows:

[0007] The synthetic route comprises the following steps: compound D and 2,6-dichloro-4-aminophenol are reacted in the presence of cesium carbonate to prepare compound VII through a substitution reaction; compound VII is reacted with benzoic anhydride to obtain amino-protected compound VI-1c; compound VI-1c is hydrolyzed to obtain compound V-1C; the total yield of these three steps is 74%; compound V-1C and isopropenylmagnesium bromide (3.5 equivalents) are reacted in the presence of lithium chloride (3 equivalents) to obtain compound F; compound F is subjected to alkaline hydrolysis and double bond displacement reaction to obtain compound III with a purity of 87.6%; compound III is subjected to diazotization reaction, double bond displacement reaction, and ring closure reaction to obtain compound I.

[0008] From the above routes, it can be found that compound III is a key intermediate in the synthesis of Resmetirom. However, in the synthesis of compound III in synthetic route one, the yield of each step is low. The first step uses silver nitrate, which is expensive, and compound C is an oily substance that is difficult to purify. The cesium carbonate, isopropylmagnesium bromide, and lithium chloride used in route two are expensive, and the amount of isopropylmagnesium bromide and lithium chloride used is large, resulting in a large amount of solid waste and waste liquid, which is not conducive to environmental protection. Finally, both routes one and two use 2,6-dichloro-4-aminophenol, which has unstable chemical properties and is easily oxidized, making purification difficult.

[0009] Therefore, it is urgent to develop a method for preparing the key intermediate III of Resmetirom with high yield, low cost, easy purification and good environmental protection.

[0010] Summary of the Invention

[0011] In view of this, the present application provides a method for preparing Resmetirom's key intermediate III. This method utilizes a compound represented by Formula V and a compound represented by Formula E to prepare the key intermediate III. The method is simple, low-cost, and high-yield. Furthermore, the intermediate products are all solid, making them easy to purify and environmentally friendly.

[0012] In order to achieve the above-mentioned invention objectives, this application provides the following technical solutions:

[0013] A method for preparing a key intermediate III of Resmetirom comprises the following steps:

[0014] Provide a compound of the structure shown in Formula V:

[0015] In formula V: R1 is H or an amino protecting group, wherein the number of carbon atoms of the amino protecting group is 1 to 10; R2 is H or

[0016] When R1 and R2 in formula V are both H, the preparation method of the Resmetirom key intermediate III comprises the following steps:

[0017] (i) mixing a compound represented by Formula V, a compound represented by Formula E, a basic compound, and an organic solvent to carry out an addition-elimination-double bond shift reaction to obtain a key intermediate III of Resmetirom; the structural formula of the key intermediate III of Resmetirom is shown in Formula III;

[0018] In formula E: R3 is -NO2, -SO2Ph, -SO2Me, -CN, -CF3 or -CCl3;

[0019] When R1 and R2 in formula V are not H at the same time, the preparation method of the Resmetirom key intermediate III comprises the following steps:

[0020] (1) mixing a compound represented by Formula V, a compound represented by Formula E, a basic compound, and an organic solvent to perform an addition-elimination-double bond shift reaction to obtain a compound represented by Formula IV;

[0021] (2) removing the R1 and / or R2 groups in the compound represented by the structure of Formula IV through a deprotection reaction to obtain the key intermediate III of Resmetirom.

[0022] Preferably, the amino protecting group is t-BuOCO-, PhCO-, CH3CO-, CF3CO- or CCl3CO-.

[0023] Preferably, in step (i) and step (1), the basic compound is independently one or more of DBU, 1,1,3,3-tetramethylguanidine, sodium amide, potassium tert-butoxide, sodium hydride, potassium carbonate, sodium carbonate, KOH, and NaOH; and the molar ratio of the compound of formula V to the basic compound is independently 1:(0.5-10);

[0024] In the steps (i) and (1), the molar ratio of the compound represented by the structure of formula V to the compound represented by the structure of formula E is independently 1:(1-5);

[0025] In the step (i) and the step (1), the temperature of the addition-elimination-double bond shift reaction is independently 0 to 120° C., and the time is independently 1 to 50 h.

[0026] Preferably, when R1 in formula IV is t-BuOCO-, R2 is H or When, or when R1 in formula IV is H and R2 is not H, the deprotection reaction in step (2) is an acidic deprotection reaction, and the acid used in the acidic deprotection reaction is selected from hydrogen chloride ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution; the temperature of the acidic deprotection reaction is 0 to 100°C.

[0027] Preferably, when R1 in formula IV is not H and is not t-BuOCO-, and R2 is H, the deprotection reaction in step (2) is an alkaline hydrolysis reaction, and the base used in the alkaline hydrolysis reaction is selected from sodium hydroxide or potassium hydroxide; the molar ratio of the compound of formula IV to the base is 1:(2-10); the solvent for the alkaline hydrolysis reaction is an organic solvent-water mixed solvent, and the organic solvent in the organic solvent-water mixed solvent is selected from one or more of ethanol, methanol, tetrahydrofuran, 1,4-dioxane and DMSO.

[0028] Preferably, when R1 and R2 in formula IV are not H, and R1 is not t-BuOCO-, the deprotection reaction in step (2) comprises an acidic deprotection reaction and an alkaline hydrolysis reaction carried out in sequence; the acid used in the acidic deprotection reaction is selected from one of hydrogen chloride ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution; the temperature of the acidic deprotection reaction is 0 to 100° C.; the base used in the alkaline hydrolysis reaction is selected from sodium hydroxide or potassium hydroxide; the molar ratio of the compound of formula IV to the base is 1:(2 to 10); the solvent for the alkaline hydrolysis reaction is an organic solvent-water mixed solvent, and the organic solvent in the organic solvent-water mixed solvent is selected from one or more of ethanol, methanol, tetrahydrofuran, 1,4-dioxane and DMSO.

[0029] Preferably, when R1 in Formula V is not H and R2 is H, the method for preparing the compound of the structure represented by Formula V comprises the following steps:

[0030] Mixing a compound represented by Formula D, a compound represented by Formula G, a first basic compound, and an organic solvent to carry out a substitution reaction to obtain a compound represented by Formula VI;

[0031] In Formula G and Formula VI, the type of R1 group is the same as in Formula V;

[0032] The compound of the structure represented by the formula VI, acetic acid and sodium acetate are mixed to carry out a substitution-hydrolysis reaction to obtain the compound of the structure represented by the formula V, the structural formula of which is shown in formula V-1;

[0033] When R1 in Formula V is not H and R2 is not H, the preparation method of the compound represented by the structure of Formula V comprises the following steps:

[0034] The compound represented by formula V-1, 3,4-dihydro-2H-pyran, an acid and an organic solvent are mixed to carry out an amide protection reaction to obtain the compound represented by formula V, the structural formula of which is shown in formula V-2;

[0035] When R1 is H and R2 is H in Formula V, the preparation method of the compound represented by the structure of Formula V comprises the following steps:

[0036] The compound represented by formula V-1, a second basic compound, an organic solvent and water are mixed to perform a first hydrolysis reaction to obtain the compound represented by formula V, the structural formula of which is shown in formula V-3;

[0037] In formula V-1: R1 is PhCO-, CF3CO-, CCl3CO- or CH3CO-;

[0038] When R1 in Formula V is H and R2 is not H, the preparation method of the compound represented by the structure of Formula V comprises the following steps:

[0039] The compound represented by formula V-2, a third basic compound, an organic solvent and water are mixed to perform a second hydrolysis reaction to obtain the compound represented by formula V, the structural formula of which is shown in formula V-4;

[0040] In formula V-2: R1 is PhCO-, CF3CO-, CCl3CO- or CH3CO-.

[0041] Preferably, the molar ratio of the compound represented by the structure of formula D to the compound represented by the structure of formula G is 1:(1-2);

[0042] The first alkaline compound is one or more of an alkali metal carbonate, an alkali metal hydroxide and an organic base; the molar ratio of the compound of the structure represented by formula D to the first alkaline compound is 1:(1-3);

[0043] The organic solvent used in the substitution reaction is one or more of DMF, DMAc, DMSO, NMP, acetonitrile and 1,4-dioxane; the temperature of the substitution reaction is 40 to 120° C., and the time is 5 to 50 hours;

[0044] The molar ratio of the compound of formula VI to sodium acetate is 1:(1-5); the molar ratio of the compound of formula VI to acetic acid is 1:(10-50);

[0045] The temperature of the substitution-hydrolysis reaction is 60-150° C., and the time is 2-20 hours.

[0046] Preferably, in the amide protection reaction, the molar ratio of the compound of the structure represented by Formula V-1 to the acid is 1:(0.05-0.5), and the molar ratio of the compound of the structure represented by Formula V-1 to 3,4-dihydro-2H-pyran is 1:(1-4);

[0047] The organic solvent used in the amide protection reaction is one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone, and 1,4-dioxane;

[0048] The temperature of the amide protection reaction is 30-80° C., and the time is 1-10 hours.

[0049] Preferably, in the first hydrolysis reaction, the molar ratio of the compound having the structure represented by formula V-1 to the second alkaline compound is 1:(2-6); the second alkaline compound is an alkali metal hydroxide;

[0050] The solvent used in the first hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran, and DMSO;

[0051] The temperature of the first hydrolysis reaction is 50 to 120° C. and the time is 1 to 10 hours;

[0052] In the second hydrolysis reaction, the molar ratio of the compound having the structure represented by formula V-2 to the third basic compound is 1:(2-6); the third basic compound is an alkali metal hydroxide;

[0053] The solvent used in the second hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran, and DMSO;

[0054] The temperature of the second hydrolysis reaction is 50-120° C., and the time is 1-10 hours.

[0055] The present application provides a method for preparing a key intermediate III of Resmetirom. When the R1 and R2 groups in formula V are both H, the compound of the structure shown in formula V, the compound of the structure shown in formula E, the alkaline compound and the organic solvent are mixed and subjected to addition-elimination-double bond shift reaction to directly obtain the key intermediate III of Resmetirom. When the R1 and R2 groups in formula V are not H at the same time, the compound of the structure shown in formula V, the compound of the structure shown in formula E, the alkaline compound and the organic solvent are mixed and subjected to addition-elimination-double bond shift reaction to obtain the compound of the structure shown in formula IV, and then the R1 and / or R2 groups are removed by deprotection reaction to obtain the key intermediate III. The preparation method of the key intermediate III provided in the present application is simple in steps and easy to operate. It does not require the use of expensive silver nitrate, cesium carbonate, isopropyl magnesium bromide, and lithium chloride reagents. The product yield is high, and the intermediate products are all solid, which is easy to purify. The preparation method of the present application has a small amount of solid waste and waste liquid, which is beneficial to environmental protection. Further, the compound of the structure shown in formula G used in the present application is stable in nature and not easily oxidized. In summary, the method provided in this application can significantly reduce the production difficulty and production cost of the key intermediate III, and is more conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 is the H NMR spectrum of the key intermediate III of Resmetirom prepared in Example 20 of the present application. DETAILED DESCRIPTION

[0057] The present application provides a method for preparing a key intermediate III of Resmetirom, comprising the following steps:

[0058] Provide a compound of the structure shown in Formula V:

[0059] In formula V: R1 is H or an amino protecting group, wherein the number of carbon atoms of the amino protecting group is 1 to 10; R2 is H or

[0060] When R1 and R2 in formula V are both H, the preparation method of the Resmetirom key intermediate III comprises the following steps:

[0061] (i) mixing a compound represented by Formula V, a compound represented by Formula E, a basic compound, and an organic solvent to carry out an addition-elimination-double bond shift reaction to obtain a key intermediate III of Resmetirom; the structural formula of the key intermediate III of Resmetirom is shown in Formula III;

[0062] In formula E: R3 is -NO2, -SO2Ph, -SO2Me, -CN, -CF3 or -CCl3;

[0063] When R1 and R2 in formula V are not H at the same time, the preparation method of the Resmetirom key intermediate III comprises the following steps:

[0064] (1) mixing a compound represented by Formula V, a compound represented by Formula E, a basic compound, and an organic solvent to perform an addition-elimination-double bond shift reaction to obtain a compound represented by Formula IV;

[0065] (2) removing the R1 and / or R2 groups in the compound represented by the structure of Formula IV through a deprotection reaction to obtain the key intermediate III of Resmetirom.

[0066] The present application first provides a compound with a structure shown in Formula V. In the present application, when R1 in Formula V is an amino protecting group, the number of carbon atoms of the amino protecting group is preferably 2 to 8. Specifically, the amino protecting group is t-BuOCO-, PhCO-, CH3CO-, CF3CO- or CCl3CO-.

[0067] In the present application, when R1 in formula V is not H and R2 is H, the preparation method of the Resmetirom intermediate preferably comprises the following steps:

[0068] Mixing a compound represented by Formula D, a compound represented by Formula G, a first basic compound, and an organic solvent to carry out a substitution reaction to obtain a compound represented by Formula VI;

[0069] In Formula G and Formula VI, the type of R1 group is the same as in Formula V;

[0070] The compound of formula VI, acetic acid and sodium acetate are mixed to carry out a substitution-hydrolysis reaction to obtain a compound of formula V, the structural formula of which is shown in formula V-1;

[0071] When R1 is not H and R2 is H, the synthetic route of the compound of the structure shown in Formula V is as follows:

[0072] In the present application, a compound of the structure represented by Formula D, a compound of the structure represented by Formula G, a first basic compound, and an organic solvent are mixed for a substitution reaction to obtain a compound of the structure represented by Formula VI. In the present application, the molar ratio of the compound of the structure represented by Formula D to the compound of the structure represented by Formula G is preferably 1:(1-2), more preferably 1:(1-1.3); the first basic compound is preferably one or more of an alkali metal carbonate, an alkali metal hydroxide, and an organic base; the alkali metal carbonate is preferably one or more of potassium carbonate, sodium carbonate, and cesium carbonate; the alkali metal hydroxide is preferably potassium hydroxide and / or sodium hydroxide; the organic base is preferably one or more of sodium methoxide, sodium ethoxide, and potassium tert-butoxide; in a specific embodiment of the present application, the first basic compound is most preferably potassium carbonate; the molar ratio of the compound of the structure represented by Formula D to the first basic compound is preferably 1:(1-3), more preferably 1:(1-2); the organic solvent used in the substitution reaction is preferably one or more of DMF, DMAc, DMSO, NMP (N-methylpyrrolidone), acetonitrile, and 1,4-dioxane, more preferably DMF.

[0073] In the present application, the temperature of the substitution reaction is preferably 40 to 120° C., more preferably 50 to 90° C., and the time of the substitution reaction is preferably 5 to 50 h, more preferably 10 to 40 h.

[0074] After the substitution reaction is completed, the present application preferably performs post-treatment on the obtained substitution reaction liquid. The post-treatment method preferably comprises: mixing the obtained substitution reaction liquid with water, adjusting the pH value of the mixture to 11, stirring at room temperature and then filtering, washing the solid product with water and then drying to obtain a compound with a structure represented by Formula VI; the reagent used to adjust the pH value of the mixture is preferably liquid alkali; and the stirring time at room temperature is preferably 30 minutes.

[0075] After obtaining the compound of formula VI, the present application mixes the compound of formula VI, acetic acid, and sodium acetate to carry out a substitution-hydrolysis reaction to obtain a compound of formula V, the structural formula of which is shown in formula V-1. In the present application, the molar ratio of the compound of formula VI to sodium acetate is preferably 1:(1-5), more preferably 1:(1.5-3); the molar ratio of the compound of formula VI to acetic acid is preferably 1:(10-50), more preferably 1:(15-30); the acetic acid is preferably glacial acetic acid; the temperature of the substitution-hydrolysis reaction is preferably 60-150°C, more preferably 90-120°C, and the time of the substitution-hydrolysis reaction is preferably 2-20 hours, more preferably 5-15 hours.

[0076] After the substitution-hydrolysis reaction is completed, the present application preferably performs post-treatment on the obtained substitution-hydrolysis reaction liquid, and the post-treatment method comprises: rotary evaporating the obtained substitution-hydrolysis reaction liquid to dryness under reduced pressure, mixing the residue with water, stirring at room temperature, filtering, washing the obtained solid product with water, and drying to obtain a compound with a structure represented by Formula V (Formula V-1); the stirring time at room temperature is preferably 2 hours.

[0077] In the present application, when R1 is not H and R2 is not H in Formula V, the preparation method of the Resmetirom intermediate represented by Formula V preferably comprises the following steps:

[0078] The compound represented by formula V-1, 3,4-dihydro-2H-pyran, an acid and an organic solvent are mixed to carry out an amide protection reaction to obtain a compound represented by formula V, the structural formula of which is shown in formula V-2;

[0079] When R1 is not H and R2 is not H, the synthetic route of the compound represented by the structure of Formula V is as follows:

[0080] In the present application, the preparation method of the compound represented by the structure of formula V-1 is consistent with the above scheme and will not be repeated here; the acid is preferably an organic acid, more preferably one or more of p-toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid, more preferably p-toluenesulfonic acid; the molar ratio of the compound represented by the structure of formula V-1 and the acid is preferably 1:(0.05~0.5), more preferably 1:(0.05~0.3); the molar ratio of the compound represented by the structure of formula V-1 and 3,4-dihydro-2H-pyran is preferably 1:(1~4), more preferably 1:(1~2); the organic solvent used in the amide protection reaction is preferably one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone, 1,4-dioxane, more preferably tetrahydrofuran; the temperature of the amide protection reaction is preferably 30~80°C, more preferably 40~70°C, and the time of the amide protection reaction is preferably 1~10h, more preferably 3~8h.

[0081] After the amide protection reaction is completed, the present application preferably performs post-treatment on the obtained amide protection reaction liquid. The post-treatment method preferably comprises: cooling the obtained amide protection reaction liquid to room temperature and mixing it with water, adjusting the pH value of the obtained mixed liquid to 9, stirring at room temperature and then spinning off the organic solvent, filtering the remaining liquid, washing the obtained solid product and drying it to obtain a compound with a structure represented by Formula V (Formula V-2); the reagent used to adjust the pH value of the mixed liquid is preferably potassium carbonate; the stirring time at room temperature is preferably 30 minutes; the washing reagent is preferably a mixed solvent of ethyl acetate and heptane, and the volume ratio of ethyl acetate to heptane in the mixed solvent is preferably 1:2.

[0082] In the present application, when R1 is H and R2 is H in Formula V, the preparation method of the Resmetirom intermediate represented by Formula V preferably comprises the following steps:

[0083] The compound represented by formula V-1, the second basic compound, the organic solvent and water are mixed to perform a first hydrolysis reaction to obtain a compound represented by formula V, the structural formula of which is shown in formula V-3;

[0084] In formula V-1: R1 is PhCO-, CF3CO-, CCl3CO- or CH3CO-.

[0085] When R1 is H and R2 is H, the synthetic route of the compound of the structure shown in Formula V is as follows:

[0086] In this application, the specific preparation method of the compound represented by the structure of formula V-1 is the same as that of the above scheme, and will not be repeated here;

[0087] In the present application, the second alkaline compound is preferably an alkali metal hydroxide, and the alkali metal hydroxide is preferably potassium hydroxide and / or sodium hydroxide; the molar ratio of the compound having the structure shown in formula V-1 and the second alkaline compound is preferably 1:(2 to 6), more preferably 1:(2.5 to 4); the solvent used in the first hydrolysis reaction is preferably one or more of ethanol, methanol, tetrahydrofuran, and DMSO, more preferably ethanol or methanol; the volume ratio of the organic solvent and water is preferably (1 to 4):1; the temperature of the first hydrolysis reaction is preferably 50 to 120°C, more preferably 60 to 100°C, and the time of the first hydrolysis reaction is preferably 1 to 10h, more preferably 3 to 8h.

[0088] After the first hydrolysis reaction is completed, the present application preferably performs post-treatment on the obtained first hydrolysis reaction liquid, and the post-treatment preferably includes the following steps: cooling the obtained first hydrolysis reaction liquid to room temperature and adjusting the pH value to 6 with an acid salt, spinning off the organic solvent, filtering the remaining liquid, washing the obtained solid product with water and then drying it to obtain a compound with the structure shown in Formula V (Formula V-3).

[0089] In the present application, when R1 in Formula V is H and R2 is not H, the preparation method of the Resmetirom intermediate represented by Formula V preferably comprises the following steps:

[0090] The compound represented by formula V-2, a third basic compound, an organic solvent and water are mixed to perform a second hydrolysis reaction to obtain the compound represented by formula V, the structural formula of which is shown in formula V-4;

[0091] In formula V-2: R1 is PhCO-, CF3CO-, CCl3CO- or CH3CO-.

[0092] When R1 is H and R2 is not H, the synthetic route of the compound represented by the structure of Formula V is as follows:

[0093] In the present application, the preparation method of the compound represented by the structure of formula V-2 is the same as the above scheme and will not be described in detail here.

[0094] In the present application, the third alkaline compound is preferably an alkali metal hydroxide, and the alkali metal hydroxide is preferably potassium hydroxide and / or sodium hydroxide; the molar ratio of the compound having the structure shown in formula V-2 to the third alkaline compound is preferably 1:(2 to 6), more preferably 1:(2.5 to 4); the solvent used in the second hydrolysis reaction is preferably one or more of ethanol, methanol, tetrahydrofuran, and DMSO, more preferably ethanol or methanol; the volume ratio of the organic solvent to water is preferably (1 to 4):1; the temperature of the second hydrolysis reaction is preferably 50 to 120°C, more preferably 60 to 100°C, and the time of the second hydrolysis reaction is preferably 1 to 10 hours, more preferably 3 to 8 hours.

[0095] After the second hydrolysis reaction is completed, the present application preferably performs post-treatment on the obtained second hydrolysis reaction liquid, and the post-treatment preferably includes the following steps: cooling the obtained second hydrolysis reaction liquid to room temperature and adjusting the pH value to 6 with an acid salt, spinning off most of the organic solvent, filtering the remaining liquid, and washing the obtained solid product with water to obtain a compound with the structure shown in Formula V (Formula V-4).

[0096] In the present application, when the compound of the structure shown in Formula V is used to prepare the key intermediate III of Resmetirom, depending on whether R1 and R2 in Formula V are both H, the present application provides two preparation methods, which are described in detail below.

[0097] In the present application, when R1 and R2 in formula V are both H, the preparation method of the Resmetirom key intermediate III comprises the following steps:

[0098] A compound represented by Formula V (i.e., Formula V-3), a compound represented by Formula E, a basic compound (denoted as the fourth basic compound), and an organic solvent are mixed to undergo an addition-elimination-double bond shift reaction (denoted as the first addition-elimination-double bond shift reaction) to obtain a key intermediate III of Resmetirom; the structural formula of the key intermediate III of Resmetirom is shown in Formula III;

[0099] In formula E: R3 is -NO2, -SO2Ph, -SO2Me, -CN, -CF3 or -CCl3.

[0100] When R1 and R2 in formula V are both H, the synthetic route of the Resmetirom key intermediate III is as follows:

[0101] In the present application, the fourth basic compound is preferably one or more of DBU, 1,1,3,3-tetramethylguanidine, sodium amide, potassium tert-butoxide, sodium hydride, potassium carbonate, sodium carbonate, KOH, and NaOH, more preferably DBU or sodium amide; the molar ratio of the compound having the structure represented by formula V to the fourth basic compound is preferably 1:(0.5-10), more preferably 1:(1-5); the molar ratio of the compound having the structure represented by formula V (i.e., formula V-3) to the compound having the structure represented by formula E is preferably 1:(1-5), more preferably 1:(1.1-3); the organic solvent used in the addition-elimination-double bond shift reaction is preferably one of DMSO, sulfolane, DMF, DMAc, N-methylpyrrolidone, tetrahydrofuran, and 1,4-dioxane, more preferably DMSO; the temperature of the first addition-elimination-double bond shift reaction is preferably 0-120°C, more preferably 20-80°C, and the time is preferably 1-50h, more preferably 5-30h.

[0102] After the first addition-elimination-double bond shift reaction is completed, the present application preferably performs post-treatment on the obtained first addition-elimination-double bond shift product liquid, and the post-treatment preferably comprises the following steps: mixing the obtained first addition-elimination-double bond shift reaction liquid with water, adjusting the pH value of the obtained mixed liquid to 6 with hydrochloric acid, filtering, and recrystallizing the obtained solid product to obtain the key intermediate III. The recrystallization solvent is preferably a mixed solvent of acetonitrile and isopropyl ether, and the volume ratio of acetonitrile and isopropyl ether in the mixed solvent is preferably (2 to 20):1.

[0103] In the present application, when R1 and R2 in formula V are not H at the same time, the preparation method of the Resmetirom key intermediate III comprises the following steps:

[0104] (1) mixing a compound represented by Formula V, a compound represented by Formula E, a basic compound, and an organic solvent to perform an addition-elimination-double bond shift reaction (referred to as the second addition-elimination-double bond shift reaction) to obtain a compound represented by Formula IV;

[0105] (2) removing the R1 and / or R2 groups in the compound represented by the structure of Formula IV through a deprotection reaction to obtain the key intermediate III of Resmetirom.

[0106] In the present application, the specific conditions of the second addition-elimination-double bond shift reaction in step (1) are consistent with the conditions of the first addition-elimination-double bond shift reaction in the above scheme, except that the compound with the structure shown in formula V-3 is replaced by a compound with the structure shown in formula V in which R1 and R2 are not H at the same time. The other operating conditions are the same, and the type and amount of the alkaline compound are also the same as those of the fourth alkaline compound, which will not be repeated here.

[0107] After the second addition-elimination-double bond shift reaction is completed, the post-treatment method of the obtained second addition-elimination-double bond shift reaction solution is the same as the post-treatment method of the first addition-elimination-double bond shift reaction solution to obtain a compound with a structure shown in Formula IV.

[0108] After obtaining the compound of formula IV, the present invention selects acidic deprotection reaction and / or alkaline hydrolysis reaction to remove the protecting groups according to the types of R1 and R2 groups to obtain the key intermediate III of Resmetirom. Detailed description is given below.

[0109] In the present application, when R1 in formula IV is t-BuOCO-, R2 is H or When, or when R1 in formula IV is H and R2 is not H (referred to as case 1), the deprotection reaction in step (2) is preferably an acidic deprotection reaction; the acid used in the acidic deprotection reaction is selected from hydrogen chloride ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution; the mass fraction of hydrogen chloride in the hydrogen chloride ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution is independently preferably 10-50%; the amount ratio of the compound represented by the structure of formula IV and the acid is preferably 1 g: (2-20) mL; the temperature of the acidic deprotection reaction is preferably 0-100° C., more preferably 20-80° C., and the time of the acidic deprotection reaction is preferably 1-10 h.

[0110] In the present application, after the acidic deprotection reaction is completed, the obtained reaction solution is preferably spin-dried, and the remaining solid product is washed with sodium bicarbonate solution and vacuum-dried to obtain a crude product, and the obtained crude product is recrystallized to obtain the Resmetirom key intermediate III; the recrystallization solvent is preferably a mixed solvent of acetonitrile and isopropyl ether, and the volume ratio of acetonitrile and isopropyl ether in the mixed solvent is preferably (2 to 20):1.

[0111] In the present application, when R1 in formula IV is not H and is not t-BuOCO-, and R2 is H (referred to as case 2), the deprotection reaction in step (2) is an alkaline hydrolysis reaction, and the base used in the alkaline hydrolysis reaction is selected from sodium hydroxide or potassium hydroxide; the molar ratio of the compound of formula IV to the base is preferably 1:(2-10), more preferably 1:(3-8); the solvent for the alkaline hydrolysis reaction is preferably an organic solvent-water mixed solvent, and the organic solvent in the organic solvent-water mixed solvent is selected from one or more of ethanol, methanol, tetrahydrofuran, 1,4-dioxane and DMSO, more preferably ethanol or methanol; the volume ratio of the organic solvent to water in the organic solvent-water mixed solvent is preferably (1-4):1; the temperature of the alkaline hydrolysis reaction is preferably 30-130°C, more preferably 50-110°C, and the time of the alkaline hydrolysis reaction is preferably 2-20h.

[0112] In the present application, after the alkaline hydrolysis reaction is completed, the resulting reaction solution is preferably cooled to room temperature and the organic solvent is spun off, followed by addition of ice water and adjustment of the pH value to 6 with hydrochloric acid to precipitate the product. The resulting solid product is filtered, washed with water, and dried to obtain a crude product, which is then recrystallized to obtain the Resmetirom key intermediate III; the solvent used for recrystallization is the same as that in the above scheme and will not be repeated here.

[0113] In the present application, when R1 and R2 in formula IV are not H, and R1 is not t-BuOCO- (referred to as case three), the deprotection reaction in step (2) includes an acidic deprotection reaction and an alkaline hydrolysis reaction carried out sequentially; the conditions for the acidic deprotection reaction in case three are the same as those in case one and are not described in detail here; the conditions for the alkaline hydrolysis reaction in case three are the same as those in case two and are not described in detail here; in a specific embodiment of the present application, it is preferred that after the acidic deprotection reaction is completed, the reaction solution is spin-dried, and then an alkaline hydrolysis reagent is added to carry out an alkaline hydrolysis reaction; the post-treatment method after the alkaline hydrolysis reaction is the same as that in case two and is not described in detail here.

[0114] The following will be combined with the embodiments of this application to clearly and completely describe the technical solutions in this application. Obviously, the embodiments described are only part of the embodiments of this application, not all of them. Based on the embodiments of this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of this application.

[0115] Example 1 Preparation of the compound of formula V-1a

[0116] Method 1: Add 14.9g (100mmol) of compound D, 26.4g of structural formula G-1 compound (120mmol), 20.7g of potassium carbonate powder (150mmol) and 200mL of DMF to the reaction flask, heat to 65℃ and stir to react for 24h, pour into 1000mL of water, adjust the pH to 11 with liquid alkali, stir at room temperature for 30min, filter, wash with 100mL of water, and dry to obtain compound VI-1a; add 120mL of glacial acetic acid and 16.4g of sodium acetate (200mmol) to the obtained product, heat to 110℃ and react for 5h, spin off the glacial acetic acid, add 150mL of water, stir at room temperature for 2h, filter, wash with 50mL of water, and dry to obtain 29.2g of off-white solid compound V-1a with a yield of 93%.

[0117] Method 2: Add 14.9 g (100 mmol) of compound D, 24.2 g of the compound shown in structural formula G-1 (110 mmol), 21.2 g of sodium carbonate powder (200 mmol) and 200 mL of DMSO to the reaction flask, heat to 75°C and stir to react for 16 hours, pour into 1000 mL of water, adjust the pH to 11 with liquid alkali, stir at room temperature for 30 minutes, filter, wash with 100 mL of water, and dry to obtain compound VI-1a; add 100 mL of glacial acetic acid and 12.3 g of sodium acetate (150 mmol) to the obtained product, heat to 100°C and react for 8 hours, spin off the glacial acetic acid, add 150 mL of water, stir at room temperature for 2 hours, filter, wash with 50 mL of water, and dry to obtain 28.3 g of off-white solid compound V-1a with a yield of 90%.

[0118] The NMR data of compound V-1a obtained by method 1 are as follows: 1 H-NMR (400M, DMSO-d6): 12.27 (1H, s), 10.30 (1H, s), 7.77 (2H, s), 7.58 (1H, d), 7.07 (1H, d), 2.07 (3H, s).

[0119] Example 2 Preparation of the compound of formula V-1b

[0120] To the reaction flask, 14.9 g (100 mmol) of compound D, 30.6 g of the compound represented by structural formula G-2 (110 mmol), 42.4 g of cesium carbonate powder (130 mmol) and 200 mL of DMAc were added, the temperature was raised to 65 ° C and stirred for reaction for 24 h, poured into 1000 mL of water, the pH was adjusted to 11 with liquid alkali, stirred at room temperature for 30 min, filtered, washed with 100 mL of water, and dried to obtain compound VI-1b; 120 mL of glacial acetic acid and 16.4 g of sodium acetate (200 mmol) were added to the resulting product, the temperature was raised to 110 ° C and the reaction was carried out for 5 h, the glacial acetic acid was spun off, 150 mL of water was added, stirred at room temperature for 2 h, filtered, washed with 50 mL of water, and dried to obtain 30.9 g of off-white solid compound V-1b with a yield of 83%. 1 H-NMR (400M, DMSO-d6): 12.23 (1H, s), 10.09 (1H, s), 7.75 (2H, s), 7.57 (1H, d), 7.01 (1H, d), 1.28 (9H, s).

[0121] Example 3 Preparation of Compound of Formula V-1c

[0122] To the reaction flask, 14.9 g (100 mmol) of compound D, 31.0 g of the structural compound represented by formula G-3 (110 mmol), 15.7 g of potassium tert-butoxide powder (140 mmol) and 200 mL of DMF were added, the temperature was raised to 65 ° C and stirred for reaction for 24 h, poured into 1000 mL of water, the pH was adjusted to 11 with liquid alkali, stirred at room temperature for 30 min, filtered, washed with 100 mL of water, and dried to obtain compound VI-1c; 120 mL of glacial acetic acid and 13.1 g of sodium acetate (160 mmol) were added to the resulting product, the temperature was raised to 105 ° C and the reaction was carried out for 8 h, the glacial acetic acid was spun off, 150 mL of water was added, stirred at room temperature for 2 h, filtered, washed once with 50 mL of water, and dried to obtain 32.7 g of off-white solid compound V-1c with a yield of 87%. 1 H-NMR (400M, DMSO-d6): 12.25 (1H, s), 10.26 (1H, s), 7.98 (2H, m), 7.76 (2H, s), 7.63 (1H, m), 7.58 (1H, d), 7.47 (2H, m), 7.05 (1H, d).

[0123] Example 4 Preparation of Compound of Formula V-1d

[0124] To the reaction flask, 14.9 g (100 mmol) of compound D, 30.1 g of the structural compound represented by formula G-4 (110 mmol), 20.7 g of potassium carbonate powder (150 mmol) and 200 mL of DMF were added, the temperature was raised to 65 ° C and stirred for reaction for 24 h, poured into 1000 mL of water, the pH was adjusted to 11 with liquid alkali, stirred at room temperature for 30 min, filtered, washed with 100 mL of water, and dried to obtain compound VI-1d; 120 mL of glacial acetic acid and 13.1 g of sodium acetate (160 mmol) were added to the resulting product, the temperature was raised to 105 ° C and the reaction was carried out for 8 h, the glacial acetic acid was spun off, 150 mL of water was added, stirred at room temperature for 2 h, filtered, washed with 50 mL of water, and dried to obtain 33.9 g of off-white solid compound V-1d with a yield of 92%. 1 H-NMR (400M, DMSO-d6): 12.27 (1H, s), 10.54 (1H, s), 7.85 (2H, s), 7.58 (1H, d), 7.05 (1H, d).

[0125] Example 5 Preparation of Compound of Formula V-1e

[0126] 14.9 g (100 mmol) of compound D, 34.0 g (105 mmol) of compound G-5, 22.1 g of potassium carbonate powder (160 mmol) and 200 ml of DMAc were added to the reaction flask, the temperature was raised to 80 ° C and stirred for reaction for 12 h, poured into 1000 ml of water, the pH was adjusted to 11 with liquid alkali, stirred at room temperature for 30 min, filtered, and washed with 100 ml of water to obtain compound VI-1e; 10.7 g (130 mmol) of sodium acetate and 80 ml of glacial acetic acid were added to the resulting product, the temperature was raised to 100 ° C and reacted for 8 h, the glacial acetic acid was spun off, 100 ml of water was added, stirred for 10 min, filtered, washed with 50 ml of water, and dried to obtain 38.4 g of off-white solid compound V-1e with a yield of 92%. 1 H-NMR (400M, DMSO-d6): 12.26 (1H, s), 10.45 (1H, s), 7.83 (2H, s), 7.58 (1H, d), 7.05 (1H, d).

[0127] Example 6 Preparation of Compound of Formula V-2a

[0128] Method 1: Add 9.42 g (30 mmol) of compound V-1a, 3.78 g (45 mmol) of 3,4-dihydro-2H-pyran, 0.52 g (3.0 mmol) of p-toluenesulfonic acid and 100 mL of tetrahydrofuran to a reaction flask, heat to 60 ° C and react for 5 hours; cool to room temperature, add 100 mL of water, adjust the pH to 9 with potassium carbonate, and stir at room temperature for 30 minutes; spin off the tetrahydrofuran to precipitate a large amount of solid, filter, wash with 50 mL of ethyl acetate: heptane = 1:2 solvent, and dry to obtain 11.8 g of off-white solid compound V-2a, with a yield of 99%.

[0129] Method 2: Add 9.42 g (30 mmol) of compound V-1a, 5.04 g (60 mmol) of 3,4-dihydro-2H-pyran, 0.77 g (8.0 mmol) of methanesulfonic acid and 100 mL of acetonitrile to the reaction flask, heat to 70 ° C and react for 3 hours; cool to room temperature, add 100 mL of water, adjust the pH to 9 with potassium carbonate, and stir at room temperature for 30 minutes; spin off the acetonitrile to precipitate a large amount of solid, filter, wash with 50 mL of ethyl acetate: heptane = 1:2 solvent, and dry to obtain 11.6 g of off-white solid compound V-2a, with a yield of 97%.

[0130] The NMR data of compound V-2a obtained by method 1 are: 1 H-NMR (400M, DMSO-d6): 10.31 (1H, brs), 7.80 (2H, s), 7.60 (1H, d), 7.17 (1H, d), 5.69 (1H, dd), 3.79 (1H, d), 3.49 (1H, t), 2.08 (3H, s), 1.49-1.22 (6H, m).

[0131] Example 7 Preparation of Compound of Formula V-2b

[0132] To the reaction flask, 11.17 g (30 mmol) of compound V-1b, 3.78 g (45 mmol) of 3,4-dihydro-2H-pyran, 0.46 g (4.0 mmol) of trifluoroacetic acid and 100 mL of ethyl acetate were added, and the temperature was raised to 60 ° C. and the reaction was allowed to react for 5 h; cooled to room temperature, 100 mL of water was added, and the pH was adjusted to 9 with potassium carbonate, and stirred at room temperature for 30 min; the ethyl acetate was spun off to precipitate a large amount of solid, which was filtered and washed with 50 mL of ethyl acetate: heptane = 1:2 solvent, and dried to obtain 11.6 g of off-white solid compound V-2b with a yield of 85%.

[0133] 1H-NMR (400M, DMSO-d6): 10.09 (1h, brs), 7.71 (2H, s), 7.55 (1H, d), 7.13 (1H, d), 5.65 (1H, dd), 3.74 (1H, m), 3.53 (1H, m), 1.58-1.26 (15H, m).

[0134] Example 8 Preparation of Compound of Formula V-2c

[0135] To the reaction flask, 11.3 g (30 mmol) of compound V-1c, 5.04 g (60 mmol) of 3,4-dihydro-2H-pyran, 1.04 g (6.0 mmol) of p-toluenesulfonic acid and 100 mL of tetrahydrofuran were added, and the temperature was raised to 60 ° C for 5 h; cooled to room temperature, 100 mL of water was added, and the pH was adjusted to 9 with potassium carbonate, and stirred at room temperature for 30 min; the tetrahydrofuran was spun off to precipitate a large amount of solid, which was filtered, washed with 50 mL of ethyl acetate: heptane = 1:2 solvent, and dried to obtain 13.5 g of off-white solid compound V-2c with a yield of 98%. 1 H-NMR (400M, DMSO-d6): 10.21 (1h, brs), 7.98 (2H, m), 7.80 (2H, s), 7.63 (1H, m), 7.56- 7.47(3H,m), 7.15(1H,d), 5.65(1H,dd), 3.76(1H,m), 3.53(1H,m), 1.59-1.28(6H,m).

[0136] Example 9 Preparation of Compound of Formula V-2d

[0137] To the reaction flask, 11.0 g (30 mmol) of compound V-1d, 5.04 g (60 mmol) of 3,4-dihydro-2H-pyran, 1.39 g (8.0 mmol) of p-toluenesulfonic acid and 100 mL of acetone were added, and the temperature was raised to 60°C for 5 h. The mixture was cooled to room temperature, 100 mL of water was added, and the pH was adjusted to 9 with potassium carbonate. The mixture was stirred at room temperature for 30 min. The acetone was removed and a large amount of solid precipitated. The solid was filtered, washed with 50 mL of ethyl acetate:heptane = 1:2 solvent, and dried to obtain 13.0 g of off-white solid compound V-2d with a yield of 96%. 1 H-NMR (400M, DMSO-d6): 10.52 (1h, brs), 7.85 (2H, s), 7.61 (1H, d), 7.19 (1H, d), 5.66 (1H, dd), 3.79 (1H, m), 3.54 (1H, m), 1.59-1.28 (6H, m).

[0138] Example 10 Preparation of Compound of Formula V-2e

[0139] To the reaction flask, 12.5 g (30 mmol) of compound V-1e, 5.04 g (60 mmol) of 3,4-dihydro-2H-pyran, 2.08 g (12.0 mmol) of p-toluenesulfonic acid and 100 mL of tetrahydrofuran were added, and the temperature was raised to 60 ° C for 5 h; cooled to room temperature, 100 mL of water was added, and the pH was adjusted to 9 with potassium carbonate, and stirred at room temperature for 30 min; the tetrahydrofuran was spun off to precipitate a large amount of solid, which was filtered and washed with 50 mL of ethyl acetate: heptane = 1:2 solvent, and dried to obtain 14.6 g of off-white solid compound V-2e with a yield of 97%. 1 H-NMR (400M, DMSO-d6): 10.46 (1h, brs), 7.84 (2H, s), 7.61 (1H, d), 7.19 (1H, d), 5.65 (1H, dd), 3.78 (1H, m), 3.52 (1H, m), 1.59-1.28 (6H, m).

[0140] Example 11 Preparation of the compound of formula V-3

[0141] Method 1: Add 9.42g of compound V-1a (30mmol), 100mL of ethanol, 50mL of water and 5.6g of potassium hydroxide (100mmol) to the reaction flask, heat to 90℃ and react for 5h, cool to room temperature, adjust the pH to 6 with hydrochloric acid, spin off the ethanol, precipitate a large amount of solid, filter, wash with 50mL of water, and dry to obtain 7.83g of brown solid compound V-3 with a yield of 96%.

[0142] Method 2: Add 9.42 g of compound V-1a (30 mmol), 100 mL of tetrahydrofuran, 50 mL of water and 4.8 g of sodium hydroxide (120 mmol) to the reaction flask, heat to 80 ° C and react for 10 hours, cool to room temperature, adjust the pH to 6 with hydrochloric acid, spin off the tetrahydrofuran, precipitate a large amount of solid, filter, wash with 50 mL of water, and dry to obtain 7.75 g of brown solid compound V-3 with a yield of 95%.

[0143] The NMR data of compound V-3 obtained by method 1 are: 1 H-NMR (400M, DMSO-d6): 12.22 (1h, brs), 7.50 (1H, d), 7.03 (1H, d), 6.68 (2H, s), 5.63 (2H, brs).

[0144] Example 12 Preparation of the compound of formula V-3

[0145] To a reaction flask, 11.3 g of compound V-1c (30 mmol), 100 mL of ethanol, 50 mL of water, and 6.0 g of sodium hydroxide (150 mmol) were added. The temperature was raised to 100°C and the reaction was allowed to react for 5 h. The mixture was cooled to room temperature and the pH was adjusted to 6 with hydrochloric acid. The ethanol was removed by spinning to remove a large amount of precipitated solid, which was filtered, washed with 50 mL of water, and dried to obtain 8.0 g of compound V-3 as a brownish-yellow solid in a 98% yield. NMR data were consistent with those of Example 11.

[0146] Example 13 Preparation of the compound of formula V-3

[0147] To a reaction flask, 11.0 g of compound V-1d (30 mmol), 100 mL of ethanol, 50 mL of water, and 5.6 g of potassium hydroxide (100 mmol) were added. The temperature was raised to 80°C and the reaction was allowed to proceed for 2 h. The mixture was cooled to room temperature and the pH was adjusted to 6 with hydrochloric acid. The ethanol was removed by spinning to remove a large amount of precipitated solid, which was filtered, washed with 50 mL of water, and dried to obtain 8.0 g of compound V-3 as a brownish-yellow solid in a 98% yield. NMR data were consistent with those of Example 11.

[0148] Example 14 Preparation of Compound of Formula V-3

[0149] To a reaction flask, 12.5 g of compound V-1e (30 mmol), 100 mL of tetrahydrofuran, 50 mL of water, and 8.0 g of sodium hydroxide (200 mmol) were added. The temperature was raised to 80°C and the reaction was allowed to proceed for 2 h. The mixture was cooled to room temperature and the pH was adjusted to 6 with hydrochloric acid. The tetrahydrofuran was removed by spinning to remove a large amount of solid, which was filtered, washed with 50 mL of water, and dried to obtain 8.0 g of compound V-3 as a brownish-yellow solid in a 98% yield. NMR data were consistent with those of Example 11.

[0150] Example 15 Preparation of Compound of Formula V-4

[0151] To the reaction flask, 12.0 g of compound V-2a (30 mmol), 100 mL of ethanol, 50 mL of water and 3.36 g of potassium hydroxide (60 mmol) were added. The temperature was raised to 90 °C and the reaction was carried out for 6 h. The mixture was cooled to room temperature and the pH was adjusted to 6 with hydrochloric acid. The ethanol was removed and a large amount of solid was precipitated. The solid was filtered, washed with 50 mL of water and dried to obtain 8.76 g of light yellow solid compound V-4 with a yield of 82%. 1 H-NMR (400M, DMSO-d6): 7.56 (1H, d), 7.15 (1H, d), 6.68 (2H, s), 5.76 (2H, brs), 5.63 (1H, dd), 3.78 (1H, m), 3.52 (1H, m), 1.51-1.25 (6H, m).

[0152] Example 16 Preparation of the compound of formula V-4

[0153] To a reaction flask, 13.8 g of compound V-2c (30 mmol), 100 mL of methanol, 50 mL of water, and 4.8 g of sodium hydroxide (120 mmol) were added. The temperature was raised to 100°C and the reaction was allowed to react for 5 h. The mixture was cooled to room temperature and the pH was adjusted to 6 with hydrochloric acid. The methanol was removed by spinning to remove a large amount of precipitated solid, which was filtered, washed with 50 mL of water, and dried to obtain 9.6 g of compound V-4 as a pale yellow solid in a 90% yield. NMR data were consistent with those of Example 15.

[0154] Example 17 Preparation of Compound of Formula V-4

[0155] To a reaction flask, 13.6 g of compound V-2d (30 mmol), 100 mL of ethanol, 50 mL of water, and 5.04 g of potassium hydroxide (90 mmol) were added. The temperature was raised to 70°C and the reaction was allowed to proceed for 3 h. The mixture was cooled to room temperature and the pH was adjusted to 6 with hydrochloric acid. The ethanol was removed by spinning to remove a large amount of precipitated solid, which was filtered, washed with 50 mL of water, and dried to obtain 9.7 g of compound V-4 as a pale yellow solid in a 91% yield. NMR data were consistent with those of Example 15.

[0156] Example 18 Preparation of Compound of Formula V-4

[0157] To a reaction flask, 15.0 g of compound V-2e (30 mmol), 100 mL of methanol, 50 mL of water, and 4.0 g of sodium hydroxide (100 mmol) were added. The temperature was raised to 70°C and the reaction was allowed to proceed for 3 h. The mixture was cooled to room temperature and the pH was adjusted to 6 with hydrochloric acid. The methanol was removed by spinning to remove a large amount of precipitated solid, which was filtered, washed with 50 mL of water, and dried to obtain 9.6 g of compound V-4 as a pale yellow solid in a 90% yield. NMR data were consistent with those of Example 15.

[0158] Example 19 Preparation of Compound of Formula III

[0159] To a reaction flask, 3.14 g of compound V-1a (10 mmol), 1.34 g of compound E-1 (15 mmol), 3.45 g of 1,1,3,3-tetramethylguanidine (30 mmol), and 30 mL of DMSO were added and stirred at 50°C for 20 h. The mixture was then poured into 120 mL of ice water, adjusted to pH 6 with hydrochloric acid, filtered, and washed once with 20 mL of water to yield compound IV-1a. To the resulting product, 20 mL of ethanol, 10 mL of water, and 2.0 g of sodium hydroxide (50 mmol) were added and the temperature was raised to 100°C for 5 h. The mixture was cooled to room temperature, the ethanol was removed by swirl, and 20 mL of ice water was added. The pH was adjusted to 6 with hydrochloric acid to precipitate a large amount of solid. The solid was filtered, washed once with 20 mL of water, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to yield 2.54 g of compound III as an off-white solid in 81% yield. Nuclear magnetic resonance imaging confirmed the product to have the desired structure.

[0160] Example 20 Preparation of compound of formula III

[0161] To a reaction flask, 3.72 g of compound V-1b (10 mmol), 2.2 g of compound E-2 (12 mmol), 1.29 g of sodium amide (33 mmol), and 30 mL of DMAc were added and reacted at 40°C for 15 h. The mixture was then poured into 120 mL of ice water, adjusted to pH 6 with hydrochloric acid, filtered, washed once with 20 mL of water, and dried under vacuum to obtain compound IV-1b. To the resulting product, 10 mL of hydrogen chloride in ether was added and stirred at room temperature for 2 h. The mixture was then spin-dried, washed with 20 mL of sodium bicarbonate solution, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to obtain 2.61 g of compound III as an off-white solid in an 83% yield. The NMR data of the product are as follows: 1 H-NMR (400M, DMSO-d6): 12.12 (1H, s), 7.27 (1H, s), 6.67 (2H, s), 5.61 (2H, brs), 3.03 (1H, m), 1.17 (6H, d); the nuclear magnetic spectrum is shown in Figure 1.

[0162] Example 21 Preparation of Compound of Formula III

[0163] To a reaction flask, 3.76g of compound V-1c (10mmol), 1.38g of compound E-3 (20mmol), 1.08g of sodium hydride (45mmol), and 40mL of DMF were added and stirred at 60°C for 12h. 150mL of water and 1.5g of sodium hypochlorite were added, stirred at room temperature for 5h, filtered, and washed once with 20mL of water to obtain compound IV-1c. To the resulting product, 20mL of methanol, 10mL of water, and 2.8g of potassium hydroxide (50mmol) were added, and the temperature was raised to 90°C for 8h. The product was cooled to room temperature, the methanol was removed by swirl, and 20mL of ice water was added. The pH was adjusted to 6 with hydrochloric acid, resulting in a large amount of precipitated solid. This solid was filtered, washed once with 20mL of water, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to obtain 2.51g of compound III as an off-white solid in 80% yield. Nuclear magnetic resonance imaging confirmed the product to have the desired structure.

[0164] Example 22 Preparation of compound of formula III

[0165] To a reaction flask, 3.68g of compound V-1d (10mmol), 1.07g of compound E-1 (12mmol), 1.83g of DBU (12mmol), and 30mL of sulfolane were added and stirred at 50°C for 20h. The mixture was then poured into 120mL of ice water, adjusted to pH 6 with hydrochloric acid, filtered, and washed once with 20mL of water to yield compound VI-1d. To the resulting product, 20mL of ethanol, 10mL of water, and 2.0g of sodium hydroxide (50mmol) were added and the temperature was raised to 80°C for 2h. The mixture was cooled to room temperature, the ethanol was removed, and 20mL of ice water was added. The pH was adjusted to 6 with hydrochloric acid, resulting in a large amount of precipitated solid. The solid was filtered, washed once with 20mL of water, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to yield 2.70g of compound III as an off-white solid in 85% yield. Nuclear magnetic resonance imaging confirmed the product to have the desired structure.

[0166] Example 23 Preparation of compound of formula III

[0167] To a reaction flask, 4.18g of compound V-1e (10mmol), 1.07g of compound E-1 (12mmol), 1.83g of DBU (12mmol), and 30mL of DMSO were added and stirred at 50°C for 20h. The mixture was then poured into 120mL of ice water, adjusted to pH 6 with hydrochloric acid, filtered, and washed once with 20mL of water to yield compound VI-1e. To the resulting product, 20mL of ethanol, 10mL of water, and 2.0g of sodium hydroxide (50mmol) were added and the temperature was raised to 80°C for 2h. The mixture was cooled to room temperature, the ethanol was removed, and 20mL of ice water was added. The pH was adjusted to 6 with hydrochloric acid to precipitate a large amount of solid. The solid was filtered, washed once with 20mL of water, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to yield 2.64g of compound III as an off-white solid in 84% yield. Nuclear magnetic resonance imaging confirmed the product to have the desired structure.

[0168] Example 24 Preparation of Compound of Formula III

[0169] To a reaction flask, 3.98g of compound V-2a (10mmol), 1.34g of compound E-1 (15mmol), 3.8g of DBU (15mmol), and 40mL of DMSO were added and stirred at 50°C for 12h. The mixture was then poured into 160mL of water, adjusted to pH 6 with hydrochloric acid, filtered, washed once with 20mL of water, and dried to yield compound IV-2a. To the resulting product, 10mL of hydrogen chloride in tetrahydrofuran was added, the mixture was heated to 50°C for 2h, and then spin-dried. 20mL of ethanol, 10mL of water, and 2.4g of sodium hydroxide (60mmol) were then added, and the mixture was heated to 100°C for 5h. The mixture was cooled to room temperature, the ethanol was removed, and 20mL of ice water was added. The pH was adjusted to 6 with hydrochloric acid, resulting in the precipitation of a large amount of solid. The solid was filtered, washed once with 20mL of water, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to yield 2.76g of compound III as an off-white solid in 88% yield. Nuclear magnetic resonance imaging confirmed the product to have the desired structure.

[0170] Example 25 Preparation of compound of formula III

[0171] To a reaction flask, 4.56 g of compound V-2b (10 mmol), 2.2 g of compound E-2 (12 mmol), 0.86 g of sodium amide (22 mmol), and 40 mL of DMF were added and allowed to react at room temperature for 10 h. The mixture was then poured into 120 mL of ice water, adjusted to pH 6 with hydrochloric acid, filtered, washed once with 20 mL of water, and dried under vacuum to obtain compound IV-2b. To the resulting product, 15 mL of a solution of hydrogen chloride in 1,4-dioxane was added, the temperature was raised to 60°C, and the reaction was continued for 2 h. The mixture was then spin-dried, washed with 20 mL of sodium bicarbonate solution, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to obtain 2.64 g of compound III as an off-white solid in an 84% yield. Nuclear magnetic resonance imaging confirmed the product to have the desired structure.

[0172] Example 26 Preparation of Compound of Formula III

[0173] Add 4.60 g of compound V-2c (10 mmol), 1.79 g of compound E-4 (16 mmol), 0.72 g of sodium hydride (30 mmol) and 40 mL of DMSO to the reaction flask, and react at 60 ° C for 6 h; pour into 160 mL of ice water, adjust the pH to 6 with hydrochloric acid, filter, wash once with 20 mL of water, and then wash with 20 mL of ethyl acetate: heptane = 1:2 solvent, and dry to obtain compound IV-2c. To the resulting product, 20 mL of hydrogen chloride in tetrahydrofuran was added, the temperature was raised to 55°C, the reaction was allowed to proceed for 2 hours, and the mixture was then spin-dried to dryness. 20 mL of ethanol, 10 mL of water, and 2.4 g of sodium hydroxide (60 mmol) were then added, the temperature was raised to 100°C, and the reaction was allowed to proceed for 5 hours. The mixture was cooled to room temperature, the ethanol was removed by spinning, and 20 mL of ice water was added. The pH was adjusted to 6 with hydrochloric acid, resulting in a large amount of precipitated solid. This solid was filtered, washed once with 20 mL of water, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to yield 2.61 g of Compound III as an off-white solid in an 83% yield. Nuclear magnetic resonance imaging confirmed the product to have the desired structure.

[0174] Example 27 Preparation of Compound of Formula III

[0175] To a reaction flask, 4.52 g of compound V-2d (10 mmol), 1.95 g of compound E-6 (16 mmol), 1.01 g of sodium amide (26 mmol), and 40 mL of DMF were added and reacted at 60°C for 6 h. The mixture was then poured into 160 mL of ice water, adjusted to pH 6 with hydrochloric acid, filtered, washed once with 20 mL of water, and then washed with 20 mL of a 1:2 mixture of ethyl acetate and heptane. The mixture was then dried to yield compound IV-2d. To the resulting product, 20 mL of a solution of hydrogen chloride in tetrahydrofuran was added, the temperature was raised to 60°C, and the reaction was continued by spin drying. 20 mL of ethanol, 10 mL of water, and 2.4 g of sodium hydroxide (60 mmol) were then added, the temperature was raised to 70°C, and the reaction was continued for 3 h. The mixture was cooled to room temperature, the ethanol was removed by spin drying, and 20 mL of ice water was added. The pH was adjusted to 6 with hydrochloric acid, resulting in the precipitation of a large amount of solid. The solid was filtered, washed once with 20 mL of water, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to yield 2.67 g of compound III as an off-white solid in an 85% yield. Nuclear magnetic resonance identification showed that the product had the target structure.

[0176] Example 28 Preparation of Compound of Formula III

[0177] To a reaction flask, 5.02g of compound V-2e (10mmol), 1.16g of compound E-1 (13mmol), 3.8g of DBU (15mmol), and 40mL of DMSO were added and stirred at 60°C for 8h. The mixture was then poured into 160mL of water, adjusted to pH 6 with hydrochloric acid, filtered, washed once with 20mL of water, and dried to yield compound IV-2e. To the resulting product, 15mL of hydrogen chloride in ether was added, the mixture was heated to 40°C and reacted for 4h, then spin-dried. 20mL of methanol, 10mL of water, and 2.4g of sodium hydroxide (60mmol) were then added, and the mixture was heated to 70°C and reacted for 3h. The mixture was cooled to room temperature, the methanol was removed, and 20mL of ice water was added. The pH was adjusted to 6 with hydrochloric acid, resulting in the precipitation of a large amount of solid. The solid was filtered, washed once with 20mL of water, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to yield 2.83g of compound III as an off-white solid in a 90% yield. Nuclear magnetic resonance imaging confirmed the product to have the desired structure.

[0178] Example 29 Preparation of Compound of Formula III

[0179] To a reaction flask, 2.72 g of compound V-3 (10 mmol), 1.07 g of compound E-1 (12 mmol), 2.3 g of 1,1,3,3-tetramethylguanidine (20 mmol), and 30 mL of sulfolane were added and reacted at 60°C for 20 h. The mixture was then poured into 120 mL of ice water, the pH adjusted to 6 with hydrochloric acid, filtered, washed once with 20 mL of water, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to obtain 2.45 g of an off-white solid III in a 78% yield. Nuclear magnetic resonance imaging confirmed the product to have the desired structure.

[0180] Example 30 Preparation of compound of formula III

[0181] To a reaction flask, 3.56 g of compound V-4 (10 mmol), 2.42 g of compound E-5 (15 mmol), 0.78 g of sodium amide (20 mmol), and 30 mL of DMAc were added and reacted at 60°C for 8 h. The mixture was then poured into 160 mL of ice water, adjusted to pH 6 with hydrochloric acid, filtered, washed once with 20 mL of water, and dried under vacuum to obtain compound IV-4. To the resulting product, 15 mL of a solution of hydrogen chloride in 1,4-dioxane was added, the temperature was raised to 50°C, reacted for 2 h, dried by spin drying, washed with 20 mL of sodium bicarbonate solution, and dried under vacuum. The crude product was recrystallized from acetonitrile and isopropyl ether to obtain 2.57 g of an off-white solid III in an 82% yield. Nuclear magnetic resonance imaging confirmed the product to have the desired structure.

[0182] Example 31 Preparation of Compound of Formula I

[0183] Preparation of compound II: 3.14 g of compound III (10.0 mmol), 1.72 g of compound A (11.0 mmol) and 60 mL of water were added to the reaction flask, the ice water was cooled to 0-10 ° C, and 30 mL of hydrochloric acid (37% mass fraction) was added in batches; maintaining 5-10 ° C, 6.9 g of sodium nitrite (100 mmol) and 20 mL of water were added dropwise within 30 min, and then 23.0 g of sodium acetate (280 mmol) and 90 mL of water were added dropwise within 50 min; the ice-water bath was removed, the reaction was stirred at room temperature for 2 h, filtered, washed with 30 mL of water, then washed with 20 mL of isopropyl ether, and dried to obtain 4.23 g of yellow-brown solid compound II with a yield of 88%. 1 H-NMR (400M, DMSO-d6): δ 12.26 (2H, brs), 10.90 (1H, s), 8.00 (2H, s), 7.36 (1H, s), 4.23 (2H, q), 3.07 (1H, m), 1.28-1.20 (9H, m).

[0184] Preparation of compound I: 2.41 g of compound II (5.0 mmol), 0.54 g of potassium acetate (5.5 mmol) and 20 mL of DMF were added to the reaction flask, heated to 110 ° C for 3 h; cooled to 80 ° C, 1.0 mL of glacial acetic acid was added and the reaction was continued for 2 h; cooled to room temperature, 100 mL of water was added, and the pH was adjusted to 7 with potassium carbonate. The mixture was stirred for 5 min, filtered, washed with 20 mL of acetonitrile: water = 1:2 solvent, and dried to obtain 1.96 g of yellow-brown solid compound I with a yield of 90%. 1 H-NMR (400M, DMSO-d6): 13.21 (1H, brs), 12.261H, brs), 7.81 (2H, s), 7.46 (1H, s), 3.06 (1H, m), 1.18 (6H, d).

[0185] The above is only a preferred embodiment of the present application. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present application. These improvements and modifications should also be regarded as the scope of protection of the present application.

Claims

1. A method for preparing a key intermediate III of Resmetirom, characterized in that: The following steps are involved: Provide a compound of structure shown in formula V: In Formula V: R1 is H or an amino protecting group, wherein the number of carbon atoms in the amino protecting group is 1 to 10; R2 is H or When R1 and R2 in formula V are both H, the preparation method of the Resmetirom key intermediate III comprises the following steps: (i) mixing a compound represented by formula V, a compound represented by formula E, a basic compound and an organic solvent to carry out an addition-elimination-double bond shift reaction to obtain a key intermediate III of Resmetirom; the key intermediate III of Resmetirom has a structural formula as shown in formula III; In formula E: R3 is -NO2, -SO2Ph, -SO2Me, -CN, -CF3 or -CCl3; When R1 and R2 in formula V are not H at the same time, the preparation method of the Resmetirom key intermediate III comprises the following steps: (1) mixing a compound represented by formula V, a compound represented by formula E, a basic compound and an organic solvent to carry out an addition-elimination-double bond shift reaction to obtain a compound represented by formula IV; (2) removing the R1 and / or R2 groups in the compound represented by the structure of Formula IV through a deprotection reaction to obtain the Resmetirom key intermediate III.

2. The preparation method according to claim 1, characterized in that: The amino protecting group is t-BuOCO-, PhCO-, CH3CO-, CF3CO- or CCl3CO-.

3. The preparation method according to claim 1, characterized in that: In the step (i) and step (1), the alkaline compound is independently one or more of DBU, 1,1,3,3-tetramethylguanidine, sodium amide, potassium tert-butoxide, sodium hydride, potassium carbonate, sodium carbonate, KOH, and NaOH; the molar ratio of the compound of the structure represented by formula V to the alkaline compound is independently 1:(0.5-10); In the step (i) and step (1), the molar ratio of the compound represented by the structure of formula V to the compound represented by the structure of formula E is independently 1:(1-5); In the step (i) and step (1), the temperature of the addition-elimination-double bond shift reaction is independently 0 to 120° C., and the time is independently 1 to 50 hours.

4. The preparation method according to claim 2, characterized in that: When R1 in Formula IV is t-BuOCO-, R2 is H or When, or when R1 in formula IV is H and R2 is not H, the deprotection reaction in step (2) is an acidic deprotection reaction, and the acid used in the acidic deprotection reaction is selected from hydrogen chloride ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution; the temperature of the acidic deprotection reaction is 0 to 100° C., and the time is 1 to 10 h.

5. The preparation method according to claim 4, characterized in that: In the hydrogen chloride ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution, the mass fraction of hydrogen chloride is independently 10-50%; the dosage ratio of the compound of the structure represented by formula IV and the acid is 1g:(2-20)mL.

6. The preparation method according to claim 2, characterized in that: When R1 in formula IV is not H and is not t-BuOCO-, and R2 is H, the deprotection reaction in step (2) is an alkaline hydrolysis reaction, and the base used in the alkaline hydrolysis reaction is selected from sodium hydroxide or potassium hydroxide; the molar ratio of the compound of formula IV structure to the base is 1:(2-10); the solvent of the alkaline hydrolysis reaction is an organic solvent-water mixed solvent, and the organic solvent in the organic solvent-water mixed solvent is selected from one or more of ethanol, methanol, tetrahydrofuran, 1,4-dioxane and DMSO; the temperature of the alkaline hydrolysis reaction is 30-130°C, and the time is 2-20h.

7. The preparation method according to claim 2, characterized in that: When R1 and R2 in formula IV are not H, and R1 is not t-BuOCO-, the deprotection reaction in step (2) comprises an acidic deprotection reaction and an alkaline hydrolysis reaction carried out in sequence; the acid used in the acidic deprotection reaction is selected from one of hydrogen chloride ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution; the temperature of the acidic deprotection reaction is 0-100° C. and the time is 1-10 h; the base used in the alkaline hydrolysis reaction is selected from sodium hydroxide or potassium hydroxide; the molar ratio of the compound of formula IV to the base is 1:(2-10); the solvent of the alkaline hydrolysis reaction is an organic solvent-water mixed solvent, and the organic solvent in the organic solvent-water mixed solvent is selected from one or more of ethanol, methanol, tetrahydrofuran, 1,4-dioxane and DMSO; the temperature of the alkaline hydrolysis reaction is 30-130° C. and the time is 2-20 h.

8. The preparation method according to claim 1, characterized in that: When R1 in Formula V is not H and R2 is H, the preparation method of the compound of the structure shown in Formula V comprises the following steps: Mixing a compound having a structure represented by Formula D, a compound having a structure represented by Formula G, a first basic compound and an organic solvent for a substitution reaction to obtain a compound having a structure represented by Formula VI; In Formula G and Formula VI, the type of R1 group is the same as in Formula V; The compound of the structure represented by the formula VI, acetic acid and sodium acetate are mixed to carry out a substitution-hydrolysis reaction to obtain the compound of the structure represented by the formula V, the structural formula of which is shown in formula V-1; 9. The preparation method according to claim 1, characterized in that: When R1 in Formula V is not H and R2 is not H, the preparation method of the compound of the structure shown in Formula V comprises the following steps: The compound of formula V-1, 3,4-dihydro-2H-pyran, acid and organic solvent are mixed to carry out amide protection reaction to obtain the compound of formula V, the structural formula of which is shown in formula V-2; In formula V-1: R1 is an amino protecting group.

10. [Corrected 09.07.2024 according to Rule 26] The method according to claim 1, characterized in that When R1 in Formula V is H and R2 is H, the preparation method of the compound of the structure shown in Formula V comprises the following steps: The compound of formula V-1, the second alkaline compound, the organic solvent and water are mixed to perform a first hydrolysis reaction to obtain the compound of formula V, the structural formula of which is shown in formula V-3; In formula V-1: R1 is PhCO-, CF3CO-, CCl3CO- or CH3CO-.

11. The preparation method according to claim 1, characterized in that: When R1 in Formula V is H and R2 is not H, the preparation method of the compound of the structure shown in Formula V comprises the following steps: The compound of formula V-2, the third basic compound, the organic solvent and water are mixed to perform a second hydrolysis reaction to obtain the compound of formula V, the structural formula of which is shown in formula V-4; In formula V-2: R1 is PhCO-, CF3CO-, CCl3CO- or CH3CO-.

12. The preparation method according to claim 8, characterized in that: The molar ratio of the compound represented by the structure of formula D to the compound represented by the structure of formula G is 1:(1-2); The first alkaline compound is one or more of an alkali metal carbonate, an alkali metal hydroxide and an organic base; the molar ratio of the compound of the structure represented by formula D to the first alkaline compound is 1:(1-3); The organic solvent used in the substitution reaction is one or more of DMF, DMAc, DMSO, NMP, acetonitrile and 1,4-dioxane; the temperature of the substitution reaction is 40 to 120° C., and the time is 5 to 50 hours; The molar ratio of the compound of the structure represented by Formula VI to sodium acetate is 1:(1-5); the molar ratio of the compound of the structure represented by Formula VI to acetic acid is 1:(10-50); The temperature of the substitution-hydrolysis reaction is 60-150° C. and the time is 2-20 hours.

13. The preparation method according to claim 9, characterized in that: In the amide protection reaction, the molar ratio of the compound of the structure represented by the formula V-1 to the acid is 1:(0.05-0.5), and the molar ratio of the compound of the structure represented by the formula V-1 to 3,4-dihydro-2H-pyran is 1:(1-4); The organic solvent used in the amide protection reaction is one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone, and 1,4-dioxane; The temperature of the amide protection reaction is 30-80° C. and the time is 1-10 h.

14. The preparation method according to claim 10, characterized in that: In the first hydrolysis reaction, the molar ratio of the compound having the structure represented by the formula V-1 to the second alkaline compound is 1:(2-6); the second alkaline compound is an alkali metal hydroxide; The solvent used in the first hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran, and DMSO; The temperature of the first hydrolysis reaction is 50-120° C. and the time is 1-10 hours.

15. The preparation method according to claim 11, characterized in that: In the second hydrolysis reaction, the molar ratio of the compound of the structure represented by the formula V-2 to the third alkaline compound is 1:(2-6); the third alkaline compound is an alkali metal hydroxide; The solvent used in the second hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran, and DMSO; The temperature of the second hydrolysis reaction is 50-120° C. and the time is 1-10 hours.

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