A process for the preparation of a resmetirom key intermediate III

Abstract

The application relates to the technical field of pharmaceutical intermediates, and provides a preparation method of a Resmetirom key intermediate III. The application uses a compound with a structure shown in formula V and a compound with a structure shown in formula E to prepare the Resmetirom key intermediate III, the preparation steps are simple and easy to operate, expensive silver nitrate, cesium carbonate, isopropenyl magnesium bromide and lithium chloride do not need to be used, the product yield is high, the intermediate products are all solid, purification is convenient, moreover, the method provided by the application has small solid waste and waste liquid, is good in environmental protection, finally, the compound with the structure shown in formula G used by the application is stable in property and is not easy to be oxidized. In summary, the method provided by the application can significantly reduce the production difficulty and production cost of the Resmetirom key intermediate III, and is more beneficial to industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical intermediates, in particular to a preparation method of Resmetirom key intermediate III. BACKGROUND

[0002] Resmetirom (Chinese name: Ruishemidilu, CAS: 920509-32-6) is a selective thyroid hormone receptor-β agonist developed by Madrigal Pharmaceuticals, which can be used for the treatment of non-alcoholic steatohepatitis. In December 2022, the original research company Madrigal announced that the key phase III clinical trial of Resmetirom reached a positive top line result. In July 2022, Resmetirom submitted a marketing application to the US FDA. After being approved for marketing, Resmetirom will become the first non-alcoholic fatty liver disease treatment drug to be marketed in the world.

[0003] The molecular structure of Resmetirom is shown as formula I:

[0004]

[0005] Patents WO2007009913 and CN112707892A disclose a preparation method of Resmetirom, and the synthesis route I is as follows:

[0006]

[0007] The synthesis route will generate compound C from compound D and isobutyric acid under the action of silver nitrate and ammonium persulfate, with a yield of 67%; compound C and 2,6-dichloro-4-aminophenol undergo substitution reaction to prepare compound B with a yield of 53%; compound B is hydrolyzed to obtain compound III, with a yield of 50%; compound III is subjected to diazotization reaction, then added with compound A and subjected to double bond migration to generate compound II with a yield of 56%; finally, compound II is ring-closed to obtain compound I, with a yield of 50%.

[0008] Patents WO2014043706 and CN105008335 disclose another preparation method of Resmetirom, and the synthesis route II is as follows:

[0009]

[0010] The synthetic route prepares compound VII by substitution reaction of compound D with 2,6-dichloro-4-aminophenol in the presence of cesium carbonate; compound VII and benzoic anhydride are reacted to obtain amino-protected compound VI-1c; compound VI-1c is hydrolyzed to obtain compound V-1C; the total yield of the three steps is 74%; compound V-1C and isopropenyl magnesium bromide (3.5 equivalents) are subjected to addition reaction in the presence of lithium chloride (3 equivalents) to obtain compound F; compound F is subjected to base hydrolysis and double bond shift reaction to obtain compound III with a purity of 87.6%; compound III is subjected to diazotization reaction, double bond shift reaction and ring closure reaction to obtain compound I.

[0011] It can be found from the above routes that compound III is a key intermediate for synthesizing Resmetirom, however, in route one, the yield of each step is low when synthesizing compound III, silver nitrate is used in the first step, which is expensive, and compound C is an oil, which is difficult to purify; in route two, cesium carbonate, isopropyl magnesium bromide and lithium chloride are used, which are expensive, and the use amount of isopropyl magnesium bromide and lithium chloride is large, which causes a large amount of solid waste and waste liquid, which is not conducive to environmental protection; finally, 2,6-dichloro-4-aminophenol is used in route one and route two, which is unstable in chemical properties and is easily oxidized, which brings difficulties to purification. Therefore, it is urgent to develop a method for preparing key intermediate III of Resmetirom with high yield, low cost, easy purification and good environmental protection. SUMMARY

[0012] Therefore, the application provides a preparation method of a Resmetirom key intermediate III. The application uses a compound with a structure shown in formula V and a compound with a structure shown in formula E to prepare the key intermediate III, which has the advantages of simple preparation method, low cost, high yield, easy purification of intermediate products and good environmental protection.

[0013] In order to achieve the above-mentioned application purposes, the application provides the following technical solutions.

[0014] A preparation method of a Resmetirom key intermediate III, comprising the following steps:

[0015] A compound with a structure shown in formula V is provided:

[0016]

[0017] In formula V, R1 is H or an amino protecting group, the number of carbon atoms of the amino protecting group is 1-10; R2 is H or

[0018] When R1 and R2 in formula V are both H, the preparation method of the Resmetirom key intermediate III comprises the following steps:

[0019] (i) mixing a compound of structure V, a compound of structure E, a basic compound and an organic solvent to perform an addition-elimination-double bond migration reaction to obtain a Resmetirom key intermediate III; the structure of the Resmetirom key intermediate III is shown in formula III;

[0020]

[0021] In formula E, R3 is -NO2, -SO2Ph, -SO2Me, -CN, -CF3 or -CCl3;

[0022] 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:

[0023] (1) mixing a compound of structure V, a compound of structure E, a basic compound and an organic solvent to perform an addition-elimination-double bond migration reaction to obtain a compound of structure IV;

[0024]

[0025] (2) removing R1 and / or R2 groups in the compound of structure IV by a deprotection reaction to obtain the Resmetirom key intermediate III.

[0026] Preferably, the amino protecting group is t-BuOCO-, PhCO-, CH3CO-, CF3CO- or CCl3CO-.

[0027] Preferably, in steps (i) and (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, NaOH; and the molar ratio of the compound of structure V to the basic compound is independently 1:(0.5-10).

[0028] In steps (i) and (1), the molar ratio of the compound of structure V to the compound of structure E is independently 1:(1-5).

[0029] In steps (i) and (1), the temperature of the addition-elimination-double bond migration reaction is independently 0-120°C, and the time is independently 1-50h.

[0030] Preferably, when R1 in formula IV is t-BuOCO-, R2 is H or Preferably, when R1in formula IV is not H and not t-BuOCO-, and R2is H, the deprotection reaction in step (2) is an acid deprotection reaction, the acid used in the acid deprotection reaction is selected from hydrogen chloride diethyl ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution; the temperature of the acid deprotection reaction is 0-100°C.

[0031] Preferably, when R1in formula IV is not H and not t-BuOCO-, and R2is H, the deprotection reaction in step (2) is an acid deprotection reaction, the acid used in the acid deprotection reaction is selected from hydrogen chloride diethyl ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution; the temperature of the acid deprotection reaction is 0-100°C.

[0032] Preferably, when R1in formula IV is not H and not t-BuOCO-, and R2is H, the deprotection reaction in step (2) is an acid deprotection reaction, the acid used in the acid deprotection reaction is selected from hydrogen chloride diethyl ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution; the temperature of the acid deprotection reaction is 0-100°C.

[0033] Preferably, when R1in formula IV is not H and not t-BuOCO-, and R2is H, the deprotection reaction in step (2) is an acid deprotection reaction, the acid used in the acid deprotection reaction is selected from hydrogen chloride diethyl ether solution, hydrogen chloride tetrahydrofuran solution or hydrogen chloride 1,4-dioxane solution; the temperature of the acid deprotection reaction is 0-100°C.

[0034] The compound of formula D, the compound of formula G, a first basic compound and an organic solvent are mixed to carry out a substitution reaction to obtain a compound of formula VI;

[0035]

[0036] In formula G and formula VI, the type of R1group is the same as in formula V;

[0037] The compound of formula VI, acetic acid and sodium acetate are mixed to carry out a substitution-hydrolysis reaction to obtain the compound of formula V, the structural formula of which is shown in formula V-1;

[0038]

[0039] When R1 in formula V is H and R2 in formula V is H, the method for preparing the compound of formula V comprises the following steps:

[0040] The compound of formula V-1, 3, 4-dihydro-2H-pyran, an acid and an organic solvent are mixed to perform an amide protection reaction to obtain the compound of formula V, which has the structural formula of formula V-2;

[0041]

[0042] When R1 in formula V is H and R2 in formula V is H, the method for preparing the compound of formula V comprises the following steps:

[0043] The compound of formula V-1, a second basic compound, an organic solvent and water are mixed to perform a first hydrolysis reaction to obtain the compound of formula V, which has the structural formula of formula V-3;

[0044]

[0045] In formula V-1, R1 is PhCO-, CF3CO-, CCl3CO- or CH3CO-.

[0046] When R1 in formula V is H and R2 in formula V is H, the method for preparing the compound of formula V comprises the following steps:

[0047] The compound of formula V-2, a third basic compound, an organic solvent and water are mixed to perform a second hydrolysis reaction to obtain the compound of formula V, which has the structural formula of formula V-4;

[0048]

[0049] In formula V-2, R1 is PhCO-, CF3CO-, CCl3CO- or CH3CO-.

[0050] Preferably, the molar ratio of the compound of formula D and the compound of formula G is 1: (1-2) ;

[0051] The first basic compound is one or more of alkali metal carbonate, alkali metal hydroxide and organic base; the molar ratio of the compound of formula D and the first basic compound is 1: (1-3) ;

[0052] 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 40-120℃, and the time is 5-50h;

[0053] The molar ratio of the compound of the structure shown in formula VI to sodium acetate is 1: (1-5); the molar ratio of the compound of the structure shown in formula VI to acetic acid is 1: (10-50);

[0054] The temperature of the substitution-hydrolysis reaction is 60-150℃, and the time is 2-20h.

[0055] Preferably, in the amide protection reaction, the molar ratio of the compound of the structure shown in formula V-1 to acid is 1: (0.05-0.5), and the molar ratio of the compound of the structure shown in formula V-1 to 3, 4-dihydro-2H-pyran is 1: (1-4);

[0056] The organic solvent used in the amide protection reaction is one or more of tetrahydrofuran, ethyl acetate, dichloromethane, acetonitrile, acetone, 1, 4-dioxane;

[0057] The temperature of the amide protection reaction is 30-80℃, and the time is 1-10h.

[0058] Preferably, in the first hydrolysis reaction, the molar ratio of the compound of the structure shown in formula V-1 to the second basic compound is 1: (2-6); the second basic compound is an alkali metal hydroxide;

[0059] The solvent used in the first hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran, DMSO;

[0060] The temperature of the first hydrolysis reaction is 50-120℃, and the time is 1-10h;

[0061] In the second hydrolysis reaction, the molar ratio of the compound of the structure shown in formula V-2 to the third basic compound is 1: (2-6); the third basic compound is an alkali metal hydroxide;

[0062] The solvent used in the second hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran, DMSO;

[0063] The temperature of the second hydrolysis reaction is 50-120℃, and the time is 1-10h.

[0064] The application provides a preparation method of a Resmetirom key intermediate III, when R1 and R2 in formula V are both H, a compound shown in formula V, a compound shown in formula E, a basic compound and an organic solvent are mixed to perform addition-elimination-double bond shift reaction, so that the Resmetirom key intermediate III can be directly obtained; when R1 and R2 in formula V are not both H, a compound shown in formula V, a compound shown in formula E, a basic compound and an organic solvent are mixed to perform addition-elimination-double bond shift reaction, so that a compound shown in formula IV is obtained, then R1 and / or R2 are removed through deprotection reaction, so that the key intermediate III can be obtained. The preparation method of the key intermediate III provided by the application has simple steps and is easy to operate, does not need to use expensive silver nitrate, cesium carbonate, isopropyl magnesium bromide and lithium chloride reagent, has high product yield, and intermediate products are all solids, so that purification is facilitated, the preparation method has small solid waste and waste liquid amount, and is beneficial to environmental protection. Further, the compound shown in formula G used in the application has stable properties and is not easy to be oxidized. In summary, the method provided by the application can significantly reduce the production difficulty and production cost of the key intermediate III, and is more beneficial to industrialized production. BRIEF DESCRIPTION OF DRAWINGS

[0065] Figure 1 The nuclear magnetic hydrogen spectrum of the Resmetirom key intermediate III prepared for the embodiment 20 of the application. DETAILED DESCRIPTION

[0066] The application provides a preparation method of a Resmetirom key intermediate III, including the following steps:

[0067] The compound shown in formula V is provided:

[0068]

[0069] In formula V, R1 is H or an amino protecting group, the number of carbon atoms of the amino protecting group is 1-10, R2 is H or

[0070] When R1 and R2 in formula V are both H, the preparation method of the Resmetirom key intermediate III includes the following steps:

[0071] (i) a compound shown in formula V, a compound shown in formula E, a basic compound and an organic solvent are mixed to perform addition-elimination-double bond shift reaction, so that the Resmetirom key intermediate III is obtained; the structural formula of the Resmetirom key intermediate III is shown in formula III;

[0072]

[0073] R3 is -NO2, -SO2Ph, -SO2Me, -CN, -CF3 or -CCl3 in formula E;

[0074] 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:

[0075] (1) mixing the compound shown in formula V, the compound shown in formula E, a basic compound and an organic solvent to perform an addition-elimination-double bond shift reaction to obtain a compound shown in formula IV;

[0076]

[0077] (2) removing the R1 and / or R2 groups in the compound shown in formula IV by a deprotection reaction to obtain the Resmetirom key intermediate III.

[0078] The present application first provides a compound shown in formula V, wherein the number of carbon atoms of the amino protecting group is preferably 2-8 when R1 in formula V is an amino protecting group in the present application, and the amino protecting group is specifically t-BuOCO-, PhCO-, CH3CO-, CF3CO- or CCl3CO-.

[0079] When R1 in formula V is not H and R2 is H in the present application, the preparation method of the Resmetirom intermediate preferably comprises the following steps:

[0080] mixing the compound shown in formula D, the compound shown in formula G, a first basic compound and an organic solvent to perform a substitution reaction to obtain a compound shown in formula VI;

[0081]

[0082] The type of R1 group in formula G and formula VI is the same as that in formula V;

[0083] mixing the compound shown in formula VI, acetic acid and sodium acetate to perform a substitution-hydrolysis reaction to obtain a compound shown in formula V, and the structural formula is shown in formula V-1;

[0084]

[0085] When R1 is not H and R2 is H, the synthesis route of the compound shown in formula V is as follows:

[0086]

[0087] The compound of the structure shown in formula D, the compound of the structure shown in formula G, the first basic compound and the organic solvent are mixed to carry out a substitution reaction to obtain the compound of the structure shown in formula VI. In the present application, the molar ratio of the compound of the structure shown in formula D and the compound of the structure shown in formula G is preferably 1: (1-2), more preferably 1: (1-1.3) ; the first basic compound is preferably one or more of alkali metal carbonate, alkali metal hydroxide and 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 shown in formula D and 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-methyl pyrrolidone), acetonitrile and 1, 4-dioxane, more preferably DMF.

[0088] In the present application, the temperature of the substitution reaction is preferably 40-120℃, more preferably 50-90℃, and the time of the substitution reaction is preferably 5-50h, more preferably 10-40h.

[0089] After the substitution reaction is completed, the present application preferably carries out post-treatment on the obtained substitution reaction solution, and the method of the post-treatment preferably comprises: mixing the obtained substitution reaction solution and water, adjusting the pH value of the mixed solution to 11, stirring at room temperature and then filtering, and drying the solid product after water washing to obtain the compound of the structure shown in formula VI; the reagent used for adjusting the pH value of the mixed solution is preferably liquid alkali; the time of stirring at room temperature is preferably 30min.

[0090] After obtaining the compound of the structure shown in formula VI, the present application mixes the compound of the structure shown in formula VI, acetic acid and sodium acetate to carry out a substitution-hydrolysis reaction to obtain the compound of the structure shown in formula V, and the structural formula is shown in formula V-1. In the present application, the molar ratio of the compound of the structure shown in formula VI and sodium acetate is preferably 1: (1-5), more preferably 1: (1.5-3) ; the molar ratio of the compound of the structure shown in formula VI and 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℃, more preferably 90-120℃, and the time of the substitution-hydrolysis reaction is preferably 2-20h, more preferably 5-15h.

[0091] After the substitution-hydrolysis reaction, the obtained substitution-hydrolysis reaction solution is preferably post-treated according to the present application, and the post-treatment method comprises the following steps: the obtained substitution-hydrolysis reaction solution is rotary evaporated to dryness under reduced pressure, the residue is mixed with water and stirred at room temperature, filtered, and the obtained solid product is washed with water and dried to obtain a compound with the structure shown in formula V (formula V-1); the stirring time at room temperature is preferably 2 h.

[0092] In the present application, when R1 is not H and R2 is not H in formula V, the preparation method of the Resmetirom intermediate shown in formula V preferably comprises the following steps:

[0093] The compound shown in formula V-1, 3,4-dihydro-2H-pyran, an acid and an organic solvent are mixed to perform an amide protection reaction to obtain a compound with the structure shown in formula V, and the structural formula is shown in formula V-2;

[0094]

[0095] When R1 is not H and R2 is not H, the synthesis route of the compound with the structure shown in formula V is as follows:

[0096]

[0097] In the present application, the preparation method of the compound shown in formula V-1 is consistent with the above-mentioned 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 shown in formula V-1 to the acid is preferably 1:(0.05-0.5), more preferably 1:(0.05-0.3); the molar ratio of the compound shown in formula V-1 to 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 and 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 1-10 h, more preferably 3-8 h.

[0098] After the amide protection reaction is completed, the obtained amide protection reaction solution is preferably subjected to post-treatment in the present application, and the method of the post-treatment preferably comprises: mixing the obtained amide protection reaction solution with water after cooling to room temperature, adjusting the pH value of the obtained mixed solution to 9, stirring at room temperature, spinning off the organic solvent, filtering the remaining liquid, washing the obtained solid product, and drying to obtain a compound with the structure shown in formula V (formula V-2); the reagent used for adjusting the pH value of the mixed solution is preferably potassium carbonate; the stirring time at room temperature is preferably 30 min; 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.

[0099] In the present application, when R1 is H and R2 is H in formula V, the preparation method of the Resmetirom intermediate shown in formula V preferably comprises the following steps:

[0100] The compound shown in formula V-1, a second basic compound, an organic solvent and water are mixed to perform a first hydrolysis reaction to obtain a compound shown in formula V, and the structural formula is shown in formula V-3.

[0101]

[0102] In formula V-1, R1 is PhCO-, CF3CO-, CCl3CO- or CH3CO-.

[0103] When R1 is H and R2 is H, the synthesis route of the compound shown in formula V is as follows:

[0104]

[0105] In the present application, the specific preparation method of the compound shown in formula V-1 is the same as the above scheme, and will not be described here again.

[0106] In the present application, the second basic 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 shown in formula V-1 to the second basic compound is preferably 1:(2-6), and more preferably 1:(2.5-4); the solvent used for the first hydrolysis reaction is preferably one or more of ethanol, methanol, tetrahydrofuran and DMSO, and more preferably ethanol or methanol; the volume ratio of the organic solvent to water is preferably (1-4):1; the temperature of the first hydrolysis reaction is preferably 50-120°C, and more preferably 60-100°C; and the time of the first hydrolysis reaction is preferably 1-10 h, and more preferably 3-8 h.

[0107] After the first hydrolysis reaction, the present application preferably carries out post-treatment on the obtained first hydrolysis reaction solution, and the post-treatment preferably comprises the following steps: after cooling the obtained first hydrolysis reaction solution to room temperature, adjusting the pH value to 6 with an acid salt, spinning off the organic solvent, filtering the remaining liquid, and drying the obtained solid product after water washing to obtain a compound with the structure shown in formula V (formula V-3).

[0108] In the present application, when R1 in formula V is H and R2 is not H, the preparation method of the Resmetirom intermediate with the structure shown in formula V preferably comprises the following steps:

[0109] The compound with the structure shown in formula V-2, a third basic compound, an organic solvent and water are mixed to carry out a second hydrolysis reaction to obtain the compound with the structure shown in formula V, and the structure is shown in formula V-4;

[0110]

[0111] In formula V-2, R1 is PhCO-, CF3CO-, CCl3CO- or CH3CO-.

[0112] When R1 is H and R2 is not H, the synthesis route of the compound with the structure shown in formula V is as follows:

[0113]

[0114] In the present application, the preparation method of the compound with the structure shown in formula V-2 is the same as the above-mentioned scheme, and will not be described here.

[0115] In the present application, the third basic 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 with the structure shown in formula V-2 and the third basic compound is preferably 1:(2-6), and more preferably 1:(2.5-4); the solvent used in the second hydrolysis reaction is preferably one or more of ethanol, methanol, tetrahydrofuran and DMSO, and more preferably ethanol or methanol; the volume ratio of the organic solvent and water is preferably (1-4):1; the temperature of the second hydrolysis reaction is preferably 50-120°C, and more preferably 60-100°C; and the time of the second hydrolysis reaction is preferably 1-10h, and more preferably 3-8h.

[0116] After the second hydrolysis reaction, the present application preferably carries out post-treatment on the obtained second hydrolysis reaction solution, and the post-treatment preferably comprises the following steps: after cooling the obtained second hydrolysis reaction solution to room temperature, adjusting the pH value to 6 with an acid salt, spinning off most of the organic solvent, filtering the remaining liquid, and water washing the obtained solid product to obtain a compound with the structure shown in formula V (formula V-4).

[0117] In the present application, when the compound of the structure shown in Formula V is used to prepare the Resmetirom key intermediate III, two preparation methods are provided according to whether R1 and R2 in Formula V are both H, which are described in detail as follows.

[0118] 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:

[0119] The compound of the structure shown in Formula V (i.e. Formula V-3), the compound of the structure shown in Formula E, a basic compound (denoted as a fourth basic compound) and an organic solvent are mixed to perform an addition-elimination-double bond migration reaction (denoted as a first addition-elimination-double bond migration reaction), to obtain the Resmetirom key intermediate III; the structural formula of the Resmetirom key intermediate III is shown in Formula III.

[0120]

[0121] In Formula E, R3 is -NO2, -SO2Ph, -SO2Me, -CN, -CF3 or -CCl3.

[0122] When R1 and R2 in Formula V are both H, the synthesis route of the Resmetirom key intermediate III is as follows:

[0123]

[0124] 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, NaOH, and is more preferably DBU or sodium amide; the molar ratio of the compound of the structure shown in Formula V and the fourth basic compound is preferably 1:(0.5-10), and is more preferably 1:(1-5); the molar ratio of the compound of the structure shown in Formula V (i.e. Formula V-3) and the compound of the structure shown in Formula E is preferably 1:(1-5), and is more preferably 1:(1.1-3); the organic solvent used in the addition-elimination-double bond migration reaction is preferably one of DMSO, sulfolane, DMF, DMAc, N-methylpyrrolidone, tetrahydrofuran and 1,4-dioxane, and is more preferably DMSO; the temperature of the first addition-elimination-double bond migration reaction is preferably 0-120°C, and is more preferably 20-80°C, and the time is preferably 1-50h, and is more preferably 5-30h.

[0125] After the first addition-elimination-double-bond migration reaction is completed, the present application preferably carries out post-treatment on the obtained first addition-elimination-double-bond migration product liquid, and the post-treatment preferably comprises the following steps: mixing the obtained first addition-elimination-double-bond migration 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 to isopropyl ether in the mixed solvent is preferably (2-20):1.

[0126] In the present application, when R1 and R2 in formula V are not simultaneously H, the preparation method of the Resmetirom key intermediate III comprises the following steps:

[0127] (1) mixing a compound of the structure shown in formula V, a compound of the structure shown in formula E, a basic compound and an organic solvent to carry out an addition-elimination-double-bond migration reaction (denoted as a second addition-elimination-double-bond migration reaction), to obtain a compound of the structure shown in formula IV;

[0128]

[0129] (2) removing the R1 and / or R2 groups in the compound of the structure shown in formula IV by a deprotection reaction to obtain the Resmetirom key intermediate III.

[0130] In the present application, the specific conditions of the second addition-elimination-double-bond migration reaction in step (1) are consistent with the conditions of the first addition-elimination-double-bond migration reaction described in the above scheme, only the compound of the structure shown in formula V-3 is replaced by the compound of the structure shown in formula V in which R1 and R2 are not simultaneously H, and the other operation conditions are the same, the type and amount of the basic compound are the same as those of the fourth basic compound, and details are not described here.

[0131] After the second addition-elimination-double-bond migration reaction is completed, the post-treatment method of the obtained second addition-elimination-double-bond migration reaction liquid is the same as that of the first addition-elimination-double-bond migration reaction liquid, and a compound of the structure shown in formula IV is obtained.

[0132] After obtaining the compound of the structure shown in formula IV, the present application removes the protecting group according to the type of the R1 and R2 groups by an acidic deprotection reaction and / or an alkaline hydrolysis reaction to obtain the Resmetirom key intermediate III. Details are described below.

[0133] In the present application, when R1 in formula IV is t-BuOCO-, R2 is H or When R1in Formula IV is H and R2is not H (denoted as Case One), 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 in ethyl ether, hydrogen chloride in tetrahydrofuran, or hydrogen chloride in 1,4-dioxane; the mass fraction of hydrogen chloride in the hydrogen chloride in ethyl ether, hydrogen chloride in tetrahydrofuran, or hydrogen chloride in 1,4-dioxane is independently preferably 10-50%; the amount ratio of the compound of Formula IV to 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.

[0134] In the present application, after the acidic deprotection reaction, the obtained reaction solution is preferably spin-dried, the remaining solid product is washed with a sodium bicarbonate solution and vacuum-dried to obtain a crude product, and the 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 to isopropyl ether in the mixed solvent is preferably (2-20):1.

[0135] In the present application, when R1in Formula IV is not H and not t-BuOCO-, and R2is H (denoted as Case Two), the deprotection reaction in Step (2) is a basic hydrolysis reaction, and the base used in the basic 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 of the basic 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 basic hydrolysis reaction is preferably 30-130°C, more preferably 50-110°C; and the time of the basic hydrolysis reaction is preferably 2-20 h.

[0136] In the present application, after the basic hydrolysis reaction, the obtained reaction solution is preferably cooled to room temperature, the organic solvent is spin-dried, ice water is then added, the pH value is adjusted to 6 with hydrochloric acid, the product is precipitated, the obtained solid product is filtered, washed with water, and dried to obtain a crude product, and the crude product is recrystallized to obtain the Resmetirom key intermediate III; the recrystallization solvent is the same as in the above-mentioned Scheme One, and is not described here again.

[0137] In this invention, when R1 and R2 in formula IV are not both H, and R1 is not t-BuOCO- (referred to as case three), the hydrolysis reaction 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 in case one, and will not be repeated here; the conditions for the alkaline hydrolysis reaction in case three are the same as in case two, and will not be repeated here; in a specific embodiment of this invention, it is preferable that after the acidic deprotection reaction is completed, the reaction solution is evaporated to dryness, and then an alkaline hydrolysis reagent is added to carry out the alkaline hydrolysis reaction; the post-treatment method after the alkaline hydrolysis reaction is the same as in case two, and will not be repeated here.

[0138] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0139] Example 1: Preparation of compound with structural formula V-1a

[0140]

[0141] Method 1: 14.9 g (100 mmol) of compound D, 26.4 g of compound with structure G-1 (120 mmol), 20.7 g of potassium carbonate powder (150 mmol), and 200 mL of DMF were added to a reaction flask. The mixture was heated to 65 °C and stirred for 24 h. The solution was poured into 1000 mL of water, and the pH was adjusted to 11 with liquid alkali. The mixture was stirred at room temperature for 30 min, filtered, washed with 100 mL of water, and dried to obtain compound VI-1a. 120 mL of glacial acetic acid and 16.4 g of sodium acetate (200 mmol) were added to the product, and the mixture was heated to 110 °C and reacted for 5 h. The glacial acetic acid was removed by rotary evaporation, and 150 mL of water was added. The mixture was stirred at room temperature for 2 h, filtered, washed with 50 mL of water, and dried to obtain 29.2 g of grayish-white solid compound V-1a, with a yield of 93%.

[0142] Method 2: Into a reaction flask, 14.9 g (100 mmol) of compound D, 24.2 g of compound shown in structural formula G-1 (110 mmol), 21.2 g of sodium carbonate powder (200 mmol) and 200 mL of DMSO were added, the reaction was stirred at 75 °C for 16 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-1a; 100 mL of glacial acetic acid and 12.3 g of sodium acetate (150 mmol) were added to the obtained product, heated to 100 °C for 8 h, the glacial acetic acid was removed, 150 mL of water was added, stirred at room temperature for 2 h, filtered, washed with 50 mL of water, and dried to obtain 28.3 g of off-white solid compound V-1a with a yield of 90%.

[0143] The nuclear magnetic resonance 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).

[0144] Preparation of compound of structural formula V-1b in example 2

[0145]

[0146] Into a reaction flask, 14.9 g (100 mmol) of compound D, 30.6 g of compound shown in structural formula G-2 (110 mmol), 42.4 g of cesium carbonate powder (130 mmol) and 200 mL of DMAc were added, the reaction was stirred at 65 °C 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 obtained product, heated to 110 °C for 5 h, the glacial acetic acid was removed, 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).

[0147] Preparation of compound of structural formula V-1c in example 3

[0148]

[0149] Into a reaction flask was added 14.9 g (100 mmol) of compound D, 31.0 g of a compound having the structure shown in Formula G-3 (110 mmol), 15.7 g of potassium tert-butoxide powder (140 mmol), and 200 mL of DMF. The reaction was stirred at 65 °C for 24 h, poured into 1000 mL of water, and the pH was adjusted to 11 with liquid base. The mixture was stirred at room temperature for 30 min, filtered, washed with 100 mL of water, and dried to obtain compound VI-1c. To the resulting product was added 120 mL of glacial acetic acid and 13.1 g of sodium acetate (160 mmol), and the reaction was heated to 105 °C for 8 h. The glacial acetic acid was removed, 150 mL of water was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, washed with 50 mL of water, and dried to obtain 32.7 g of off-white solid compound V-1c in 87% yield. 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).

[0150] Example 4 Preparation of a compound having the structure of Formula V-1d

[0151]

[0152] Into a reaction flask was added 14.9 g (100 mmol) of compound D, 31.0 g of a compound having the structure shown in Formula G-3 (110 mmol), 15.7 g of potassium tert-butoxide powder (140 mmol), and 200 mL of DMF. The reaction was stirred at 65 °C for 24 h, poured into 1000 mL of water, and the pH was adjusted to 11 with liquid base. The mixture was stirred at room temperature for 30 min, filtered, washed with 100 mL of water, and dried to obtain compound VI-1c. To the resulting product was added 120 mL of glacial acetic acid and 13.1 g of sodium acetate (160 mmol), and the reaction was heated to 105 °C for 8 h. The glacial acetic acid was removed, 150 mL of water was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, washed with 50 mL of water, and dried to obtain 32.7 g of off-white solid compound V-1c in 87% yield. 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).

[0153] Example 5 Preparation of a compound having the structure of Formula V-1e

[0154]

[0155] Into a reaction flask was added 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, and the mixture was stirred at 80°C for 12 h. The reaction mixture was poured into 1000 mL of water, and the pH was adjusted to 11 with liquid alkali. The mixture was stirred at room temperature for 30 min, filtered, and washed with 100 mL of water to obtain compound VI-1e. Into the obtained product was added 10.7 g (130 mmol) of sodium acetate and 80 mL of glacial acetic acid, and the mixture was stirred at 100°C for 8 h. The glacial acetic acid was removed, 100 mL of water was added, and the mixture was stirred for 10 min. The mixture was filtered, washed with 50 mL of water, and dried to obtain 38.4 g of compound V-1e as an off-white solid in 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).

[0156] Example 6 Preparation of compound of structural formula V-2a

[0157]

[0158] Method 1: Into a reaction flask was added 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, and the mixture was stirred at 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 tetrahydrofuran was removed, and a large amount of solid was precipitated. The mixture was filtered, washed with 50 mL of a solvent mixture of ethyl acetate:heptane = 1:2, and dried to obtain 11.8 g of compound V-2a as an off-white solid in a yield of 99%.

[0159] Method 2: Into a reaction flask was added 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, and the mixture was stirred at 70°C for 3 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 acetonitrile was removed, and a large amount of solid was precipitated. The mixture was filtered, washed with 50 mL of a solvent mixture of ethyl acetate:heptane = 1:2, and dried to obtain 11.6 g of compound V-2a as an off-white solid in a yield of 97%.

[0160] The NMR data of compound V-2a obtained in Method 1 are as follows: 1H-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).

[0161] Preparation of compound of formula V-2b in example 7

[0162]

[0163] Into a reaction flask was added 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, and the mixture was heated 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 the mixture was stirred at room temperature for 30 min; the ethyl acetate was removed, and a large amount of solid was precipitated, which was filtered, washed with 50 mL of a solvent mixture of ethyl acetate:heptane = 1:2, and dried to obtain 11.6 g of off-white solid compound V-2b in a yield of 85%.

[0164] 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).

[0165] Preparation of compound of formula V-2c in example 8

[0166]

[0167] Into a reaction flask was added 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, and the mixture was heated 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 the mixture was stirred at room temperature for 30 min; the ethyl acetate was removed, and a large amount of solid was precipitated, which was filtered, washed with 50 mL of a solvent mixture of ethyl acetate:heptane = 1:2, and dried to obtain 11.6 g of off-white solid compound V-2b in a yield of 85%. 1H-NMR (400M, DMSO-d6): 10.21 (1 h, brs), 7.98 (2H, m), 7.80 (2H, s), 7.63 (1 H, m), 7.56-7.47 (3H, m), 7.15 (1 H, d), 5.65 (1 H, dd), 3.76 (1 H, m), 3.53 (1 H, m), 1.59-1.28 (6H, m).

[0168] Preparation of compound of formula V-2d in example 9

[0169]

[0170] Into a reaction flask was added 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, and the mixture was heated to 60°C for 5 h. After cooling 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 was precipitated. The solid was filtered, washed with 50 mL of a solvent mixture of ethyl acetate:heptane = 1:2, and dried to obtain 13.0 g of off-white solid compound V-2d at a yield of 96%. 1 H-NMR (400M, DMSO-d6): 10.21 (1 h, brs), 7.98 (2H, m), 7.80 (2H, s), 7.63 (1 H, m), 7.56-7.47 (3H, m), 7.15 (1 H, d), 5.65 (1 H, dd), 3.76 (1 H, m), 3.53 (1 H, m), 1.59-1.28 (6H, m).

[0171] Preparation of compound of formula V-2e in example 10

[0172]

[0173] Into a reaction flask was added 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, and the mixture was heated to 60°C for 5 h. After cooling 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 was precipitated. The solid was filtered, washed with 50 mL of a solvent mixture of ethyl acetate:heptane = 1:2, and dried to obtain 13.0 g of off-white solid compound V-2d at a yield of 96%. 1H-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).

[0174] Example 11 Preparation of compound of structure V-3

[0175]

[0176] Method 1: To a reaction flask was added 9.42 g of compound V-la (30 mmol), 100 mL of ethanol, 50 mL of water and 5.6 g of potassium hydroxide (100 mmol), heated to 90 °C for 5 h, cooled to room temperature, adjusted pH to 6 with hydrochloric acid, spun off the ethanol, a large amount of solid precipitated, filtered, washed with 50 mL of water, oven dried to give 7.83 g of brown yellow solid compound V-3, yield 96%.

[0177] Method 2: To a reaction flask was added 9.42 g of compound V-la (30 mmol), 100 mL of tetrahydrofuran, 50 mL of water and 4.8 g of sodium hydroxide (120 mmol), heated to 80 °C for 10 h, cooled to room temperature, adjusted pH to 6 with hydrochloric acid, spun off the tetrahydrofuran, a large amount of solid precipitated, filtered, washed with 50 mL of water, oven dried to give 7.75 g of brown yellow solid compound V-3, yield 95%.

[0178] The nuclear magnetic resonance data of compound V-3 obtained by method 1 is as follows: 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).

[0179] Example 12 Preparation of compound of structure V-3

[0180]

[0181] To a reaction flask was added 11.3 g of compound V-lc (30 mmol), 100 mL of ethanol, 50 mL of water and 6.0 g of sodium hydroxide (150 mmol), heated to 100 °C for 5 h, cooled to room temperature, adjusted pH to 6 with hydrochloric acid, spun off the ethanol, a large amount of solid precipitated, filtered, washed with 50 mL of water, oven dried to give 8.0 g of brown yellow solid compound V-3, yield 98%. The nuclear magnetic resonance data was consistent with that of Example 11.

[0182] Example 13 Preparation of compound of structure V-3

[0183]

[0184] Into a reaction flask was added 11.0 g of compound V-Id (30 mmol), 100 mL of ethanol, 50 mL of water and 5.6 g of potassium hydroxide (100 mmol), warmed to 80 °C for 2 h, cooled to room temperature, adjusted pH to 6 with hydrochloric acid, spun off the ethanol, a large amount of solid was precipitated, filtered, washed with 50 mL of water, oven dried to give 8.0 g of brown yellow solid compound V-3, yield 98%. The NMR data was consistent with Example 11.

[0185] Example 14 Preparation of compound of structural formula V-3

[0186]

[0187] Into a reaction flask was added 12.5 g of compound V-le (30 mmol), 100 mL of tetrahydrofuran, 50 mL of water and 8.0 g of sodium hydroxide (200 mmol), warmed to 80 °C for 2 h, cooled to room temperature, adjusted pH to 6 with hydrochloric acid, spun off the tetrahydrofuran, a large amount of solid was precipitated, filtered, washed with 50 mL of water, oven dried to give 8.0 g of brown yellow solid compound V-3, yield 98%. The NMR data was consistent with Example 11.

[0188] Example 15 Preparation of compound of structural formula V-4

[0189]

[0190] Into a reaction flask was added 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), warmed to 90 °C for 6 h, cooled to room temperature, adjusted pH to 6 with hydrochloric acid, spun off the ethanol, a large amount of solid was precipitated, filtered, washed with 50 mL of water, oven dried to give 8.76 g of light yellow solid compound V-4, yield 82%. 1 H-NMR (400M, DMSO-d6): 7.56 (IH, d), 7.15 (IH, d), 6.68 (2H, s), 5.76 (2H, brs), 5.63 (IH, dd), 3.78 (IH, m), 3.52 (IH, m), 1.51-1.25 (6H, m).

[0191] Example 16 Preparation of compound of structural formula V-4

[0192]

[0193] To a reaction flask was added 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). The reaction was heated to 70 °C for 3 h, cooled to room temperature, and acidified with hydrochloric acid to a pH of 6. The ethanol was removed by rotary evaporation and a large amount of solid precipitated. The solid was filtered, washed with 50 mL of water, and oven dried to give 9.7 g of compound V-4 as a light yellow solid in 91% yield. The NMR data were consistent with Example 15.

[0194] Example 17 Preparation of compound of formula V-4

[0195]

[0196] To a reaction flask was added 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). The reaction was heated to 70 °C for 3 h, cooled to room temperature, and acidified with hydrochloric acid to a pH of 6. The ethanol was removed by rotary evaporation and a large amount of solid precipitated. The solid was filtered, washed with 50 mL of water, and oven dried to give 9.7 g of compound V-4 as a light yellow solid in 91% yield. The NMR data were consistent with Example 15.

[0197] Example 18 Preparation of compound of formula V-4

[0198]

[0199] To a reaction flask was added 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). The reaction was heated to 70 °C for 3 h, cooled to room temperature, and acidified with hydrochloric acid to a pH of 6. The ethanol was removed by rotary evaporation and a large amount of solid precipitated. The solid was filtered, washed with 50 mL of water, and oven dried to give 9.7 g of compound V-4 as a light yellow solid in 91% yield. The NMR data were consistent with Example 15.

[0200] Example 19 Preparation of compound of formula III

[0201]

[0202] Into a reaction flask was added 3.14 g of compound V-la (10 mmol), 1.34 g of compound E-l (15 mmol), 3.45 g of 1,1,3,3-tetramethylguanidine (30 mmol), and 30 mL of DMSO, and the reaction was stirred at 50°C for 20 h. The reaction mixture was poured into 120 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. The mixture was filtered, washed once with 20 mL of water, and dried under vacuum to obtain compound IV-la. To the resulting product was added 20 mL of ethanol, 10 mL of water, and 2.0 g of sodium hydroxide (50 mmol), and the reaction was heated to 100°C for 5 h. The reaction mixture was cooled to room temperature, the ethanol was removed by evaporation, 20 mL of ice water was added, the pH was adjusted to 6 with hydrochloric acid, and a large amount of solid was precipitated. The mixture was filtered, washed once with 20 mL of water, and dried under vacuum. The resulting crude product was recrystallized from acetonitrile and isopropyl ether to obtain 2.54 g of compound III as an off-white solid in 81% yield. The product was identified by NMR to have the target structure.

[0203] Example 20 Preparation of a compound of structural formula III

[0204]

[0205] Into a reaction flask was added 3.72 g of compound V-lb (10 mmol), 2.2 g of compound E-2 (12 mmol), 1.29 g of sodium amide (33 mmol), and 30 mL of DMAc, and the reaction was stirred at 40°C for 15 h. The reaction mixture was poured into 120 mL of ice water, the pH was adjusted to 6 with hydrochloric acid, the mixture was filtered, washed once with 20 mL of water, and dried under vacuum to obtain compound IV-lb. To the resulting product was added 10 mL of hydrogen chloride in ethyl ether, and the reaction was stirred at room temperature for 2 h. The reaction mixture was evaporated, washed with 20 mL of a sodium bicarbonate solution, and dried under vacuum. The resulting crude product was recrystallized from acetonitrile and isopropyl ether to obtain 2.61 g of compound III as an off-white solid in 83% yield. The NMR data of the product are as follows: 1 H-NMR (400 MHz, 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 NMR spectrum is shown in Figure 1

[0206] Example 21 Preparation of a compound of structural formula III

[0207]

[0208] ​Into a reaction flask was added 3.76 g of compound V-1c (10 mmol), 1.38 g of compound E-3 (20 mmol), 1.08 g of sodium hydride (45 mmol), and 40 mL of DMF, and the reaction was stirred at 60°C for 12 h; 150 mL of water and 1.5 g of sodium hypochlorite were added, and the reaction was stirred at room temperature for 5 h, filtered, washed once with 20 mL of water, to obtain compound IV-1c. Into the obtained product was added 20 mL of methanol, 10 mL of water, and 2.8 g of potassium hydroxide (50 mmol), and the reaction was heated to 90°C for 8 h; cooled to room temperature, the methanol was distilled off, 20 mL of ice water was added, and the pH was adjusted to 6 with hydrochloric acid, a large amount of solid was precipitated, filtered, washed once with 20 mL of water, and dried in vacuum; the obtained crude product was recrystallized with acetonitrile and isopropyl ether to obtain 2.51 g of off-white solid compound III, with a yield of 80%. NMR identification showed that the product had the target structure.

[0209] Example 22 Preparation of compound of structural formula III

[0210]

[0211] Into a reaction flask was added 3.68 g of compound V-1d (10 mmol), 1.07 g of compound E-1 (12 mmol), 1.83 g of DBU (12 mmol), and 30 mL of sulfolane, and the reaction was stirred at 50°C for 20 h; poured into 120 mL of ice water, the pH was adjusted to 6 with hydrochloric acid, filtered, washed once with 20 mL of water, to obtain compound VI-1d. Into the obtained product was added 20 mL of ethanol, 10 mL of water, and 2.0 g of sodium hydroxide (50 mmol), and the reaction was heated to 80°C for 2 h; cooled to room temperature, the ethanol was distilled off, 20 mL of ice water was added, the pH was adjusted to 6 with hydrochloric acid, a large amount of solid was precipitated, filtered, washed once with 20 mL of water, and dried in vacuum; the obtained crude product was recrystallized with acetonitrile and isopropyl ether to obtain 2.70 g of off-white solid compound III, with a yield of 85%. NMR identification showed that the product had the target structure.

[0212] Example 23 Preparation of compound of structural formula III

[0213]

[0214] Into a reaction flask was added 4.18 g of compound V-le (10 mmol), 1.07 g of compound E-l (12 mmol), 1.83 g of DBU (12 mmol), and 30 mL of DMSO, and the mixture was stirred at 50°C for 20 h. The reaction mixture was poured into 120 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. The mixture was filtered, washed once with 20 mL of water, and dried to obtain compound VI-le. To the resulting product was added 20 mL of ethanol, 10 mL of water, and 2.0 g of sodium hydroxide (50 mmol), and the mixture was heated to 80°C for 2 h. The mixture was cooled to room temperature, and the ethanol was distilled off. The mixture was added to 20 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. A large amount of solid was precipitated, which was filtered, washed once with 20 mL of water, and dried in vacuo. The resulting crude product was recrystallized from acetonitrile and isopropyl ether to obtain 2.64 g of compound III as an off-white solid in a yield of 84%. The product was identified by NMR to have the target structure.

[0215] Example 24 Preparation of a compound of structural formula III

[0216]

[0217] Into a reaction flask was added 4.18 g of compound V-le (10 mmol), 1.07 g of compound E-l (12 mmol), 1.83 g of DBU (12 mmol), and 30 mL of DMSO, and the mixture was stirred at 50°C for 20 h. The reaction mixture was poured into 120 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. The mixture was filtered, washed once with 20 mL of water, and dried to obtain compound VI-le. To the resulting product was added 20 mL of ethanol, 10 mL of water, and 2.0 g of sodium hydroxide (50 mmol), and the mixture was heated to 80°C for 2 h. The mixture was cooled to room temperature, and the ethanol was distilled off. The mixture was added to 20 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. A large amount of solid was precipitated, which was filtered, washed once with 20 mL of water, and dried in vacuo. The resulting crude product was recrystallized from acetonitrile and isopropyl ether to obtain 2.64 g of compound III as an off-white solid in a yield of 84%. The product was identified by NMR to have the target structure.

[0218] Example 25 Preparation of a compound of structural formula III

[0219]

[0220] Into a reaction flask was added 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, and the mixture was reacted at room temperature for 10 h. The reaction mixture was poured into 120 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. The mixture was filtered, washed once with 20 mL of water, and dried under vacuum to obtain compound IV-2b. To the obtained product was added 15 mL of a hydrogen chloride 1,4-dioxane solution, and the mixture was reacted at 60°C for 2 h. The mixture was dried under vacuum, and washed with 20 mL of sodium bicarbonate solution, and dried under vacuum. The obtained crude product was recrystallized with acetonitrile and isopropyl ether to obtain 2.64 g of compound III as an off-white solid in a yield of 84%. The product was identified by NMR to have the target structure.

[0221] Example 26 Preparation of a compound of structural formula III

[0222]

[0223] Into a reaction flask was added 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, and the mixture was reacted at room temperature for 10 h. The reaction mixture was poured into 120 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. The mixture was filtered, washed once with 20 mL of water, and dried under vacuum to obtain compound IV-2b. To the obtained product was added 15 mL of a hydrogen chloride 1,4-dioxane solution, and the mixture was reacted at 60°C for 2 h. The mixture was dried under vacuum, and washed with 20 mL of sodium bicarbonate solution, and dried under vacuum. The obtained crude product was recrystallized with acetonitrile and isopropyl ether to obtain 2.64 g of compound III as an off-white solid in a yield of 84%. The product was identified by NMR to have the target structure.

[0224] Example 27 Preparation of a compound of structural formula III

[0225]

[0226] Into a reaction flask was added 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, and the mixture was reacted at 60°C for 6 h. The reaction mixture was poured into 160 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. The mixture was filtered, washed once with 20 mL of water, and then washed with 20 mL of a solvent mixture of ethyl acetate and heptane (1:2). The mixture was dried in an oven to obtain compound IV-2d. To the obtained product was added 20 mL of a hydrogen chloride tetrahydrofuran solution, and the mixture was reacted at 60°C for 2 h. The mixture was dried by distillation. Then, 20 mL of ethanol, 10 mL of water, and 2.4 g of sodium hydroxide (60 mmol) were added, and the mixture was reacted at 70°C for 3 h. The mixture was cooled to room temperature, and the ethanol was distilled off. Then, 20 mL of ice water was added, and the pH was adjusted to 6 with hydrochloric acid. A large amount of solid was precipitated, and the mixture was filtered. The solid was washed once with 20 mL of water and dried in a vacuum. The obtained crude product was recrystallized with acetonitrile and isopropyl ether to obtain 2.67 g of compound III as an off-white solid, with a yield of 85%. The product was identified by NMR to have the target structure.

[0227] Example 28 Preparation of a compound of structural formula III

[0228]

[0229] Into a reaction flask was added 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, and the mixture was reacted at 60°C for 6 h. The reaction mixture was poured into 160 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. The mixture was filtered, washed once with 20 mL of water, and then washed with 20 mL of a solvent mixture of ethyl acetate and heptane (1:2). The mixture was dried in an oven to obtain compound IV-2d. To the obtained product was added 20 mL of a hydrogen chloride tetrahydrofuran solution, and the mixture was reacted at 60°C for 2 h. The mixture was dried by distillation. Then, 20 mL of ethanol, 10 mL of water, and 2.4 g of sodium hydroxide (60 mmol) were added, and the mixture was reacted at 70°C for 3 h. The mixture was cooled to room temperature, and the ethanol was distilled off. Then, 20 mL of ice water was added, and the pH was adjusted to 6 with hydrochloric acid. A large amount of solid was precipitated, and the mixture was filtered. The solid was washed once with 20 mL of water and dried in a vacuum. The obtained crude product was recrystallized with acetonitrile and isopropyl ether to obtain 2.67 g of compound III as an off-white solid, with a yield of 85%. The product was identified by NMR to have the target structure.

[0230] Example 29 Preparation of a compound of structural formula III

[0231]

[0232] Into a reaction flask was added 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, and the mixture was reacted at 60°C for 8 h. The reaction mixture was poured into 160 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. The mixture was filtered, washed with 20 mL of water, and dried under vacuum to obtain compound IV-4. To the obtained product was added 15 mL of a hydrogen chloride 1,4-dioxane solution, and the mixture was reacted at 50°C for 2 h. The mixture was spin-dried, washed with 20 mL of a sodium bicarbonate solution, and dried under vacuum. The obtained crude product was recrystallized with acetonitrile and isopropyl ether to obtain 2.57 g of a gray-white solid III at a yield of 82%. The product was identified by NMR to have the target structure.

[0233] Example 30 Preparation of a compound of structural formula III

[0234]

[0235] Into a reaction flask was added 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, and the mixture was reacted at 60°C for 8 h. The reaction mixture was poured into 160 mL of ice water, and the pH was adjusted to 6 with hydrochloric acid. The mixture was filtered, washed with 20 mL of water, and dried under vacuum to obtain compound IV-4. To the obtained product was added 15 mL of a hydrogen chloride 1,4-dioxane solution, and the mixture was reacted at 50°C for 2 h. The mixture was spin-dried, washed with 20 mL of a sodium bicarbonate solution, and dried under vacuum. The obtained crude product was recrystallized with acetonitrile and isopropyl ether to obtain 2.57 g of a gray-white solid III at a yield of 82%. The product was identified by NMR to have the target structure.

[0236] Example 31 Preparation of a compound of structural formula I

[0237]

[0238] Preparation of compound II: Into a reaction flask was added 3.14 g of compound III (10.0 mmol), 1.72 g of compound A (11.0 mmol), and 60 mL of water, and the mixture was cooled with ice water to 0-10°C. Then, 30 mL of hydrochloric acid (37% by mass) was added in portions. The mixture was maintained at 5-10°C, and a solution of 6.9 g of sodium nitrite (100 mmol) in 20 mL of water was added dropwise over 30 min. Then, a solution of 23.0 g of sodium acetate (280 mmol) in 90 mL of water was added dropwise over 50 min. The ice water bath was removed, and the mixture was stirred at room temperature for 2 h. The mixture was filtered, washed with 30 mL of water, and then washed with 20 mL of isopropyl ether. The mixture was dried to obtain 4.23 g of yellow-brown solid compound II at a yield of 88%. 1H-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).

[0239] 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 a reaction flask, and the mixture was heated to 110 °C and reacted for 3 h. The mixture was then cooled to 80 °C, and 1.0 mL of glacial acetic acid was added to continue the reaction for 2 h. The mixture was then cooled to room temperature, and 100 mL of water was added. The pH was adjusted to 7 with potassium carbonate, and the mixture was stirred for 5 min. The mixture was filtered, washed with 20 mL of acetonitrile:water = 1:2 solvent, and dried to obtain 1.96 g of yellowish-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).

[0240] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing Resmetirom key intermediate III, characterized in that, Includes the following steps: The compound with the structure shown in Formula V, the compound with the structure shown in Formula E, the basic compound, and the organic solvent were mixed and subjected to an addition-elimination-double bond shift reaction to obtain Resmetirom key intermediate III; The structural formula of the key intermediate III of Resmetirom is shown in Formula III. In the compound with the structure shown in Formula V, both R1 and R2 are H; In the compound with the structure shown in Formula E, R3 is -NO2, -SO2Ph, -SO2Me, -CN, -CF3 or -CCl3; The basic compound is one or more of DBU, 1,1,3,3-tetramethylguanidine, sodium amino, potassium tert-butoxide, sodium hydride, potassium carbonate, sodium carbonate, KOH, and NaOH.

2. A method for preparing Resmetirom key intermediate III, characterized in that, Includes the following steps: (1) The compound with the structure shown in Formula V, the compound with the structure shown in Formula E, the basic compound and the organic solvent are mixed and subjected to an addition-elimination-double bond shift reaction to obtain the compound with the structure shown in Formula IV; The basic compound is one or more of DBU, 1,1,3,3-tetramethylguanidine, sodium amino, potassium tert-butoxide, sodium hydride, potassium carbonate, sodium carbonate, KOH, and NaOH. (2) By removing the R1 and / or R2 groups from the compound with the structure shown in Formula IV through a deprotection reaction, the key intermediate III of Resmetirom is obtained; The structural formula of the key intermediate III of Resmetirom is shown in Formula III. In the compound with the structure shown in Formula V, R1 is H or an amino protecting group, wherein the amino protecting group is t-BuOCO-, PhCO-, CH3CO-, CF3CO-, or CCl3CO-; R2 is H or R1 and R2 are not both H.

3. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of the compound with the structure shown in Formula V to the basic compound is 1:(0.5~10); The molar ratio of the compound with the structure shown in Formula V to the compound with the structure shown in Formula E is 1:(1~5); The addition-elimination-double bond shift reaction is carried out at a temperature of 0–120 °C for a time of 1–50 h.

4. The preparation method according to claim 2, characterized in that, When the compound with the structure shown in Formula IV has R1 as t-BuOCO- and R2 as H, or R1 as t-BuOCO- and R2 as Or R1 is H and R2 is In this case, 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 0–100°C.

5. The preparation method according to claim 2, characterized in that, When R1 in the compound with the structure shown in Formula IV is not H or 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 with the structure shown in Formula IV to the base is 1:(2-10); The solvent for the alkaline hydrolysis reaction is an organic solvent-water mixture, wherein the organic solvent in the organic solvent-water mixture is selected from one or more of ethanol, methanol, tetrahydrofuran, 1,4-dioxane and DMSO.

6. The preparation method according to claim 2, characterized in that, When R1 in the compound with the structure shown in Formula IV is not H or t-BuOCO-, and R2 is In this case, the deprotection reaction in step (2) includes an acidic deprotection reaction and an alkaline hydrolysis reaction carried out sequentially; The acid used in the acidic deprotection reaction is one of the following: hydrogen chloride diethyl ether solution, hydrogen chloride tetrahydrofuran solution, or hydrogen chloride 1,4-dioxane solution. The temperature for the acidic deprotection reaction is 0–100°C; The alkali used in the alkaline hydrolysis reaction is sodium hydroxide or potassium hydroxide; The molar ratio of the compound with the structure shown in Formula IV to the base is 1:(2-10); The solvent for the alkaline hydrolysis reaction is an organic solvent-water mixture, wherein the organic solvent in the organic solvent-water mixture is one or more of ethanol, methanol, tetrahydrofuran, 1,4-dioxane and DMSO.

7. A method for preparing a compound of formula V for preparing Resmetirom key intermediate III, characterized in that, Includes the following steps: The compound with the structure shown in Formula D, the compound with the structure shown in Formula G, the first basic compound, and an organic solvent were mixed and subjected to a substitution reaction to obtain the compound with the structure shown in Formula VI. The compound with the structure shown in Formula VI, acetic acid, and sodium acetate were mixed and subjected to a substitution-hydrolysis reaction to obtain the compound of Formula V, the structural formula of which is shown in Formula V-1. Wherein, R1 is an amino protecting group, and the amino protecting group is t-BuOCO-, PhCO-, CH3CO-, CF3CO- or CCl3CO-; The molar ratio of the compound with the structure shown in Formula D to the compound with the structure shown in Formula G is 1:(1~2); The first alkaline compound is one or more of alkali metal carbonates, alkali metal hydroxides, and organic bases; The molar ratio of the compound with the structure shown in Formula D to the first basic 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 substitution reaction is carried out at a temperature of 40–120°C for a time of 5–50 h. The molar ratio of the compound with the structure shown in Formula VI to sodium acetate is 1:(1-5); the molar ratio of the compound with the structure shown in Formula VI to acetic acid is 1:(10-50). The substitution-hydrolysis reaction is carried out at a temperature of 60–150 °C for a time of 2–20 h.

8. The method for preparing compound V according to claim 7, characterized in that, Includes the following steps: The compound with the structure shown in Formula V-1, 3,4-dihydro-2H-pyran, an acid and an organic solvent were mixed and subjected to an amide protection reaction to obtain the compound of Formula V, the structural formula of which is shown in Formula V-2. Wherein, R1 is an amino protecting group, and the amino protecting group is t-BuOCO-, PhCO-, CH3CO-, CF3CO- or CCl3CO-; In the amide protection reaction, the molar ratio of the compound with the structure shown in Formula V-1 to the acid is 1:(0.05~0.5), and the molar ratio of the compound with the structure shown in 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 amide protection reaction is carried out at a temperature of 30–80°C for a time of 1–10 h.

9. The method for preparing compound V according to claim 7, characterized in that, Includes the following steps: A first hydrolysis reaction is carried out by mixing the compound with the structure shown in Formula V-1, a second basic compound, an organic solvent, and water to obtain the compound of Formula V, the structural formula of which is shown in Formula V-3. In the compounds with the structure shown in Formula V-1, R1 is PhCO-, CF3CO-, CCl3CO-, or CH3CO-; The second basic compound is an alkali metal hydroxide; In the first hydrolysis reaction, the molar ratio of the compound with the structure shown in Formula V-1 and the second basic compound is 1:(2-6); The organic 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 h.

10. The method for preparing compound V according to claim 8, characterized in that, Includes the following steps: A second hydrolysis reaction is carried out by mixing the compound with the structure shown in Formula V-2, a third basic compound, an organic solvent, and water to obtain the compound of Formula V, the structural formula of which is shown in Formula V-4. In the compounds with the structure shown in Formula V-2, R1 is PhCO-, CF3CO-, CCl3CO-, or CH3CO-; The third basic compound is an alkali metal hydroxide; In the second hydrolysis reaction, the molar ratio of the compound with the structure shown in Formula V-2 to the third basic compound is 1:(2-6); The organic solvent used in the second hydrolysis reaction is one or more of ethanol, methanol, tetrahydrofuran, and DMSO; The second hydrolysis reaction is carried out at a temperature of 50–120°C for 1–10 hours.

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