A method for synthesizing 7-ketolithocholic acid from BA

Abstract

The application discloses a chemical synthesis method of 7-ketolithocholic acid (3alpha-hydroxy-7-keto-5beta-cholestane-24-oic acid), and belongs to the field of organic chemical synthesis. The 7-ketolithocholic acid is synthesized from a plant source compound BA through steps of glycol or neopentyl glycol protection, oxidation, Wittig reaction, deprotection, reduction and hydrolysis. The raw material used for synthesizing the 7-ketolithocholic acid is cheap and easy to obtain, the synthesis steps are simple and convenient to operate, the yield is high, the environment is friendly, and the industrialized production is facilitated.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis / pharmaceutical synthesis technology, and relates to a method for synthesizing 7-ketolithocholic acid, specifically a method for synthesizing 7-ketolithocholic acid using 21-hydroxy-20-methylpregn-4-en-3-one (BA) as a raw material. Background Technology

[0002] Obeticholic acid (trade name Ocaliva) is a potent farnesoid X receptor (FXR) agonist developed by Intercept Pharmaceuticals in the United States for the treatment of primary biliary cirrhosis. In addition, obeticholic acid is also a candidate drug for the treatment of non-alcoholic steatohepatitis (NASH) and is currently in Phase III clinical trials. Ursodeoxycholic acid (UDCA) is an FDA-approved first-line treatment for primary biliary cirrhosis (PBC) and is also effective in treating gallstones and chronic liver diseases, showing broad market potential.

[0003] 7-Ketolithocholic acid is an important intermediate in the chemical synthesis of obeticholic acid and ursodeoxycholic acid. Therefore, it is particularly important to develop an environmentally friendly, high-yield, low-cost synthetic route for 7-ketolithocholic acid that is suitable for industrialization.

[0004]

[0005] There are two main methods for synthesizing 7-ketolithocholic acid:

[0006] One method involves using chenodeoxycholic acid as a raw material to prepare 7-ketolithocholic acid by electrolysis or oxidation (CN 1912192A, China Pharmaceutical Industry Magazine, 2015, 46(10): 1058-1059, etc.). However, the product requires column chromatography purification, which is not suitable for industrial production.

[0007] The second method is the chemical synthesis method using cholic acid as a raw material, which mainly includes the following synthetic routes.

[0008] Route 1 involves the selective protection of the 3α-hydroxyl group by reacting cholic acid with ethyl chloroformyl ester, the selective oxidation of the 7α-hydroxyl group by NBS, followed by dehydration of the 12α-hydroxyl group by phosphorus oxychloride, hydrolysis with sodium hydroxide, and reduction of the unsaturated double bond by hydrogenation of platinum dioxide to obtain 7-ketolithocholic acid (Journal of Labelled Compounds and Radiopharmaceuticals, 1979, 16(3): 421-434.). This method for preparing 7-ketolithocholic acid requires relatively dangerous and expensive reagents (such as POCl3 and PtO2), has a long reaction time, and a low yield (26%), making it unsuitable for large-scale production. The reaction formula is shown below:

[0009]

[0010] Route 2 involves the methyl esterification of cholic acid, followed by acetylation protection of the 3α-hydroxy and 7α-hydroxy groups. Sodium hypochlorite oxidizes the 12α-hydroxy group, Huangminglong reduces the carbonyl group at C-12, and the ester group at C-24 is hydrolyzed. Sodium hypobromite oxidizes the hydroxyl group at C-7 to a ketone, yielding 7-ketolithocholic acid (WO2014020024A1). This method requires a high-temperature Huangminglong reaction, placing high demands on equipment and resulting in a low yield (58.94%), making it unsuitable for large-scale production. The reaction formula is shown below:

[0011]

[0012] The currently reported synthetic routes for 7-ketolithocholic acid not only suffer from problems such as overly complicated steps, low yield, high pollution, and expensive raw materials, but also all use animal bile acids (chenodeoxycholic acid, cholic acid) as starting materials. However, due to the emergence of diseases such as avian influenza, mad cow disease, streptococcal disease in pigs, and African swine fever, people have raised doubts about the safety of animal-derived raw materials. Therefore, developing an efficient synthetic method for 7-ketolithocholic acid based on plant-derived raw materials is of great significance and industrial value. Summary of the Invention

[0013] This invention overcomes the shortcomings of existing technologies by using 21-hydroxy-20-methylpregn-4-en-3-one ((20S)-21-hydroxy-20-methylpregn-4-en-3-one), also known as BA (bisnoralcohol), as a raw material (obtained from phytosterols through bio-fermentation) to synthesize 7-ketolithocholic acid through steps such as ethylene glycol or neopentyl glycol protection, oxidation, Wittig reaction, deprotection, and reduction. The efficient and simple chemical synthesis method for 7-ketolithocholic acid provided by this invention utilizes the inexpensive and readily available plant-derived raw material BA, ensuring high safety, mild reaction conditions, simple post-processing, low production costs, and facilitating industrial production.

[0014] The raw material used in this invention, 21-hydroxy-20-methylpregn-4-en-3-one ((20S)-21-hydroxy-20-methylpregn-4-en-3-one), also known as BA (bisnoralcohol), is derived from the fermentation of plant sterols, a byproduct of oil processing. It is a green raw material of plant origin, with an annual output of thousands of tons. It is inexpensive and effectively avoids the infection problems of pathogenic bacteria and viruses in existing technologies. The synthetic route of this invention has simple operation steps, high yield, environmental friendliness, and is easy for industrial production.

[0015] In the synthesis method of the present invention, the 21-hydroxy-20-methylpregn-4-en-3-one (BA) raw material is included, but is not limited to, obtained by bio-fermentation of phytosterols or by chemical synthesis methods.

[0016] The method for synthesizing 7-ketolithocholic acid from 21-hydroxy-20-methylpregn-4-en-3-one (BA) provided by the present invention includes the following steps:

[0017] (a) In a first solvent, BA of formula (1) is protected with ethylene glycol to obtain compound of formula (2);

[0018] (b) In a second solvent, compound (2) is oxidized to give compound (3);

[0019] (c) In a third solvent, the compound of formula (3) is subjected to the Wittig reaction to give the compound of formula (6);

[0020] (d) In a fourth solvent, compound (6) is oxidized to give compound (7);

[0021] (e) In the fifth solvent, the compound of formula (7) is deprotected by ethylene glycol or neopentyl glycol under the action of acid to obtain the compound of formula (8);

[0022] (f) In the sixth solvent, under the action of a catalyst and hydrogen, and under pressure, the compound of formula (8) undergoes a reduction reaction to obtain the compound of formula (9).

[0023] (g) In the seventh solvent, under the action of a base, the compound of formula (9) undergoes a hydrolysis reaction to give 7-ketolithocholic acid as shown in formula (10);

[0024] Alternatively, the method for synthesizing 7-ketolithocholic acid from 21-hydroxy-20-methylpregn-4-en-3-one (BA) provided by the present invention further includes the following steps:

[0025] The compound of formula (8) can also be obtained through the following steps;

[0026] (h) In the eighth solvent, the BA shown in formula (1) is oxidized to obtain the compound of formula (4);

[0027] (i) In the ninth solvent, the compound of formula (4) is subjected to the Wittig reaction to give the compound of formula (5);

[0028] (j) In the tenth solvent, the compound of formula (5) is protected with ethylene glycol or neopentyl glycol to obtain the compound of formula (6);

[0029] (d) In a fourth solvent, compound (6) is oxidized to give compound (7);

[0030] (e) In the fifth solvent, the compound of formula (7) undergoes a deethylene glycol or neopentyl glycol protection reaction under the action of acid to obtain the compound of formula (8);

[0031] (f) In the sixth solvent, under the action of a catalyst and hydrogen, and under pressure, the compound of formula (8) undergoes a reduction reaction to obtain the compound of formula (9).

[0032] (g) In the seventh solvent, under the action of a base, the compound of formula (9) undergoes a hydrolysis reaction to give 7-ketolithocholic acid as shown in formula (10);

[0033] The reaction process is shown in route (A):

[0034]

[0035] Route (A)

[0036] Wherein, R is an alkyl group; preferably a C1 to C20 alkyl group; more preferably, a C1 or C2 alkyl group.

[0037] R1 is

[0038] In step (a), the ethylene glycol protection reaction refers to: BA, ethylene glycol, and p-toluenesulfonic acid as shown in formula (1) being dissolved in the first solvent to undergo an ethylene glycol protection reaction to obtain compound (2); or, BA, ethylene glycol, p-toluenesulfonic acid, and triethyl orthoformate as shown in formula (1) being dissolved in the first solvent to undergo an ethylene glycol protection reaction to obtain compound (2); preferably, BA, ethylene glycol, and p-toluenesulfonic acid as shown in formula (1) being dissolved in the first solvent to undergo an ethylene glycol protection reaction to obtain compound (2);

[0039] In step (a), the first solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, hexane, etc.; preferably, it is benzene.

[0040] When the ethylene glycol protection reaction in step (a) is as follows: BA, ethylene glycol, and p-toluenesulfonic acid as shown in formula (1) are dissolved in the first solvent, an ethylene glycol protection reaction occurs, and compound of formula (2) is obtained, wherein the molar ratio of BA, ethylene glycol, and p-toluenesulfonic acid as shown in formula (1) is 1:(1-50):(0.01-1), preferably 1:10:0.01; the temperature of the ethylene glycol protection reaction is 50-130℃, preferably 90℃; and the time of the ethylene glycol protection reaction is 2-36h, preferably 24h.

[0041] When the ethylene glycol protection reaction in step (a) is as follows: BA, ethylene glycol, p-toluenesulfonic acid, and triethyl orthoformate as shown in formula (1) are dissolved in the first solvent, an ethylene glycol protection reaction occurs, and compound of formula (2) is obtained; wherein, the molar ratio of BA, ethylene glycol, p-toluenesulfonic acid, and triethyl orthoformate as shown in formula (1) is 1:(1-50):(0.01-1):(1-20); preferably, it is 1:10:0.1:3; the temperature of the ethylene glycol protection reaction is 0-50℃, preferably 25℃; the time of the ethylene glycol protection reaction is 2-36h, preferably 8h.

[0042] In one specific embodiment, the synthesis steps of compound (2) include: dissolving BA as shown in formula (1) in a first solvent, reacting it with ethylene glycol and p-toluenesulfonic acid to protect the carbonyl group at the 3-position of BA as shown in formula (1) to obtain compound (2).

[0043] In step (b), the oxidation reaction refers to the following: the compound of formula (2), TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and oxidant are dissolved in the second solvent and undergo an oxidation reaction to obtain the compound of formula (3).

[0044] In step (b), the oxidant is selected from one or more of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), 2-iodobenzoic acid (IBX), etc.; preferably, it is N-chlorosuccinimide (NCS).

[0045] In step (b), the molar ratio of compound (2), TEMPO, sodium bicarbonate, tetrabutylammonium bromide and oxidant is 1:(0-1):(0-20):(0-1):(1-5); preferably, it is 1:0.01:1.35:0.1:1.15.

[0046] In step (b), the second solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide, water, etc.; preferably, it is a mixed solvent of dichloromethane and water.

[0047] In step (b), the temperature of the oxidation reaction is 0–30°C; preferably, it is 0°C.

[0048] In step (b), the oxidation reaction takes 2 to 8 hours; preferably, it takes 5 hours.

[0049] In one specific embodiment, the synthesis steps of compound (3) include: dissolving compound (2) in a second solvent, then adding TEMPO, sodium bicarbonate, tetrabutylammonium bromide and NCS, and undergoing an oxidation reaction to obtain compound (3).

[0050] In step (c), the Wittig reaction refers to the reaction in which compound (3) and ethoxyformylmethylenetriphenylphosphine are dissolved in a third solvent to produce compound (6).

[0051] The molar ratio of compound (3) to ethoxyformylmethylenetriphenylphosphine is 1:(1-5); preferably, it is 1:2.

[0052] The third solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, hexane, etc.; preferably, it is toluene.

[0053] The temperature of the Wittig reaction is 50–130°C; preferably, it is 110°C.

[0054] The Wittig reaction time is 2 to 8 hours; preferably, it is 4 hours.

[0055] Alternatively, in step (c), the Wittig reaction refers to the reaction in which the compound of formula (3), sodium hydride, and triethyl phosphonoacetate are dissolved in a third solvent to produce the compound of formula (6).

[0056] The molar ratio of compound (3), sodium hydride, and triethyl phosphonoacetate is 1:(1-5):(1-5); preferably, it is 1:1.5:1.5.

[0057] The third solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, hexane, etc.; preferably, it is tetrahydrofuran.

[0058] The temperature of the Wittig reaction is 0–30°C; preferably, it is 0°C.

[0059] The Wittig reaction time is 2 to 8 hours; preferably, it is 4 hours.

[0060] In one specific embodiment, the synthesis steps of compound (6) include: dissolving compound (3), ethoxyformylmethylenetriphenylphosphine or compound (3), sodium hydride, and triethyl phosphonoacetate in a third solvent, and undergoing a Wittig reaction to obtain compound (6).

[0061] In step (d), the oxidation reaction refers to the following: the compound of formula (6), the oxidant, N-hydroxyphthalimide (NHPI), and acetic acid are dissolved in a fourth solvent and undergo an oxidation reaction to obtain the compound of formula (7).

[0062] In step (d), the oxidant is selected from one or more of Na2Cr2O7, K2Cr2O7, PDC, BPO, etc.; preferably, it is PDC.

[0063] In step (d), the molar ratio of compound (6), oxidant, N-hydroxyphthalimide (NHPI), and acetic acid is 1:(1-5):(1-5):(0-5); preferably, it is 1:1.1:1.1:0.

[0064] In step (d), the fourth solvent is selected from one or more of toluene, acetone, acetonitrile, water, dichloromethane, N,N-dimethylformamide, ethyl acetate, tert-butanol, N-methylpyrrolidone, etc.; preferably, it is a mixed solvent of acetone and water; more preferably, it is a mixed solvent of acetone:water (volume ratio) = 9:1.

[0065] In step (d), the temperature of the oxidation reaction is 0–50°C; preferably, it is 25°C.

[0066] In step (d), the oxidation reaction takes 10 to 48 hours; preferably, it takes 20 hours.

[0067] In one specific embodiment, the synthesis steps of compound (7) include: dissolving compound (6) in a fourth solvent, adding PDC and NHPI, and undergoing an oxidation reaction to obtain compound (7).

[0068] In step (e), the deglycol protection reaction refers to the following: the compound of formula (7) and the acid are dissolved in the fifth solvent, and a deglycol or neopentyl glycol protection reaction occurs to obtain the compound of formula (8).

[0069] In step (e), the molar ratio of the compound of formula (7) to the acid is 1:(1 to 50); preferably, it is 1:5.

[0070] In step (e), the fifth solvent is selected from one or more of tetrahydrofuran, ethyl acetate, methanol, dichloromethane, diethyl ether, water, toluene, acetone, etc.; preferably, it is a mixed solvent of tetrahydrofuran and water; more preferably, it is a mixed solvent of tetrahydrofuran:water (volume ratio) = 9:1.

[0071] In step (e), the acid is selected from one or more of concentrated sulfuric acid, concentrated hydrochloric acid, p-toluenesulfonic acid, etc.; preferably, it is concentrated sulfuric acid.

[0072] In step (e), the temperature of the deethylene glycol or neopentyl glycol protection reaction is 0–50°C; preferably, it is 25°C.

[0073] In step (e), the time for the deethylene glycol or neopentyl glycol protection reaction is 1 to 10 hours; preferably, it is 4 hours.

[0074] In one specific embodiment, the synthesis steps of compound (8) include: dissolving compound (7) in a fifth solvent, adding concentrated sulfuric acid, and undergoing a deprotection reaction to obtain compound (8).

[0075] In step (f), the mass ratio of compound (8) to catalyst is 1:(0.1-5); preferably, it is 1:1.

[0076] In step (f), the sixth solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, tert-butanol, etc.; preferably, it is 1,4-dioxane.

[0077] In step (f), the catalyst is selected from Raney nickel.

[0078] In step (f), the temperature of the reduction reaction is 20–100°C; preferably, it is 70°C.

[0079] In step (f), the reduction reaction takes 3 to 24 hours; preferably, it takes 6 hours.

[0080] In step (f), the reaction is carried out under pressurized hydrogen gas, the pressure of which is in the range of 0.1 to 10 MPa; preferably, it is 1.0 MPa.

[0081] In one specific embodiment, the synthesis steps of compound (9) include: dissolving compound (8) in a sixth solvent, adding Raney nickel, adjusting the hydrogen pressure, and reacting to obtain compound (9).

[0082] In step (g), the molar ratio of the compound of formula (9) to the base is 1:(1-5); preferably, it is 1:2.

[0083] In step (g), the seventh solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, tert-butanol, methanol, and ethanol; preferably, it is methanol.

[0084] In step (g), the alkali is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, and lithium hydroxide; preferably, it is lithium hydroxide.

[0085] In step (g), the temperature of the hydrolysis reaction is 20–80°C; preferably, it is 20°C.

[0086] In step (g), the hydrolysis reaction takes 3 to 24 hours; preferably, it takes 12 hours.

[0087] In one specific embodiment, the synthesis steps of 7-ketolithocholic acid include: dissolving the compound of formula (9) in a seventh solvent, adding a base, and reacting to obtain 7-ketolithocholic acid.

[0088] In step (h), the oxidation reaction refers to the following: BA, TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and oxidant, as shown in formula (1), are dissolved in the eighth solvent and undergo an oxidation reaction to obtain the compound of formula (4).

[0089] In step (h), the oxidant is selected from one or more of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), 2-iodobenzoic acid (IBX), etc.; preferably, it is N-chlorosuccinimide (NCS).

[0090] In step (h), the molar ratio of BA, TEMPO, sodium bicarbonate, tetrabutylammonium bromide and oxidant shown in formula (1) is 1:(0-1):(0-20):(0-1):(1-5); preferably, it is 1:0.01:1.35:0.1:1.15.

[0091] In step (h), the eighth solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide, and water; preferably, it is a mixed solvent of dichloromethane and water.

[0092] In step (h), the temperature of the oxidation reaction is 0–30°C; preferably, it is 0°C.

[0093] In step (h), the oxidation reaction takes 2 to 8 hours; preferably, it takes 5 hours.

[0094] In one specific embodiment, the synthesis steps of compound (4) include: dissolving BA as shown in formula (1) in an eighth solvent, and then adding TEMPO, sodium bicarbonate, tetrabutylammonium bromide and NCS to undergo an oxidation reaction to obtain compound (4).

[0095] In step (i), the Wittig reaction refers to the following: the compound of formula (4), methoxyformylmethylenetriphenylphosphine, ethoxyformylmethylenetriphenylphosphine, or propoxyformylmethylenetriphenylphosphine are dissolved in the ninth solvent and undergo a Wittig reaction to obtain the compound of formula (5).

[0096] Wherein, the molar ratio of compound of formula (4), methoxyformylmethylenetriphenylphosphine or ethoxyformylmethylenetriphenylphosphine or propoxyformylmethylenetriphenylphosphine is 1:(1-5); preferably, it is 1:2.

[0097] The ninth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, hexane, etc.; preferably, it is toluene.

[0098] The temperature of the Wittig reaction is 50–130°C; preferably, it is 110°C.

[0099] The Wittig reaction time is 2 to 8 hours; preferably, it is 4 hours.

[0100] Alternatively, in step (i), the Wittig reaction refers to the following: the compound of formula (4), sodium hydride, diethyl methyl phosphonoacetate or triethyl phosphonoacetate or diethyl propyl phosphonoacetate are dissolved in the ninth solvent and undergo a Wittig reaction to obtain the compound of formula (5).

[0101] The ninth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, and hexane; preferably, it is tetrahydrofuran.

[0102] The molar ratio of compound (4), sodium hydride, diethyl methyl phosphonoacetate, triethyl phosphonoacetate, or diethyl propyl phosphonoacetate is 1:(1-5):(1-5); preferably, it is 1:1.5:1.5.

[0103] The temperature of the Wittig reaction is 0–30°C; preferably, it is 0°C.

[0104] The Wittig reaction time is 2 to 8 hours; preferably, it is 4 hours.

[0105] In one specific embodiment, the synthesis steps of compound (5) include: dissolving compound (4), ethoxyformylmethylene triphenylphosphine or compound (4), sodium hydride, diethyl phosphonoacetate or triethyl phosphonoacetate or diethyl propyl phosphonoacetate in a ninth solvent, and undergoing a Wittig reaction to obtain compound (5).

[0106] In step (j), the ethylene glycol or neopentyl glycol protection reaction refers to: the compound of formula (5), ethylene glycol or neopentyl glycol, and p-toluenesulfonic acid are dissolved in the tenth solvent, and an ethylene glycol or neopentyl glycol protection reaction occurs to obtain the compound of formula (6); or, the compound of formula (5), ethylene glycol or neopentyl glycol, p-toluenesulfonic acid, and triethyl orthoformate are dissolved in the tenth solvent, and an ethylene glycol or neopentyl glycol protection reaction occurs to obtain the compound of formula (6); preferably, the compound of formula (5), ethylene glycol or neopentyl glycol, and p-toluenesulfonic acid are dissolved in the tenth solvent, and an ethylene glycol or neopentyl glycol protection reaction occurs to obtain the compound of formula (6);

[0107] In step (j), the tenth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, hexane, etc.; preferably, it is toluene.

[0108] When the ethylene glycol or neopentyl glycol protection reaction in step (j) is as follows: the compound of formula (5), ethylene glycol or neopentyl glycol, and p-toluenesulfonic acid are dissolved in the tenth solvent, and the ethylene glycol or neopentyl glycol protection reaction occurs to obtain the compound of formula (6), wherein the molar ratio of the compound of formula (5), ethylene glycol or neopentyl glycol, and p-toluenesulfonic acid is 1:(1-50):(0.01-1), preferably 1:10:0.01; the temperature of the ethylene glycol or neopentyl glycol protection reaction is 50-130°C, preferably 110°C; and the time of the ethylene glycol or neopentyl glycol protection reaction is 2-36 h, preferably 24 h.

[0109] When the ethylene glycol or neopentyl glycol protection reaction in step (j) is as follows: the compound of formula (5), ethylene glycol or neopentyl glycol, p-toluenesulfonic acid, and triethyl orthoformate are dissolved in the tenth solvent, and the ethylene glycol or neopentyl glycol protection reaction occurs to obtain the compound of formula (6), wherein the molar ratio of the compound of formula (5), ethylene glycol or neopentyl glycol, p-toluenesulfonic acid, and triethyl orthoformate is 1:(1-50):(0.01-1):(1-20); preferably, it is 1:10:0.1:3; the temperature of the ethylene glycol or neopentyl glycol protection reaction is 0-50°C, preferably 25°C; the time of the ethylene glycol or neopentyl glycol protection reaction is 2-36h, preferably 8h.

[0110] In one specific embodiment, the synthesis steps of compound (6) include: dissolving compound (5) in a tenth solvent, reacting it with ethylene glycol or neopentyl glycol and p-toluenesulfonic acid to protect the carbonyl group at the 3-position of compound (5) to obtain compound (6).

[0111] The present invention also provides compounds as shown in formula (6′), formula (6"), formula (7′), formula (7") or formula (8):

[0112]

[0113] Wherein, R is an alkyl group; preferably a C1 to C20 alkyl group; more preferably, a C1 or C2 alkyl group.

[0114] The compounds represented by formula (6) of this invention include compounds of formula (6′) and compounds of formula (6"), wherein compounds of formula (6′) include compounds of formula (6′-A), compounds of formula (6′-B), compounds of formula (6′-C), etc.; and compounds of formula (6") include compounds of formula (6"-A), compounds of formula (6"-B), compounds of formula (6"-C), etc.

[0115] The compounds represented by formula (7) of the present invention include compounds of formula (7′) and compounds of formula (7"), wherein compounds of formula (7′) include compounds of formula (7′-B) and the like; compounds of formula (7") include compounds of formula (7"-B) and the like.

[0116] The beneficial effects of the present invention include that the raw material BA used in the preparation method of 7-ketolithocholic acid of the present invention is a plant-derived raw material, which avoids the problem of infection by pathogenic bacteria and viruses, and is inexpensive and readily available; the synthesis steps of 7-ketolithocholic acid are simple to operate, have a high yield, are environmentally friendly, have mild reaction conditions, are easy to process, have low cost, and are convenient for industrial production. Attached Figure Description

[0117] Figure 1 The results of TLC analysis of the PDC oxidized (11-A) compound are shown in Comparative Example 1.

[0118] Figure 2 The results of TLC analysis of the PDC oxidized (11-B) compound are shown in Comparative Example 1.

[0119] Figure 3 The results of TLC analysis of the Pd / C-H2 reduced compound (8) are presented for Comparative Example 2.

[0120] Figure 4 The results of TLC analysis of the NaBH4-reduced compound (8) are presented for Comparative Example 2. Detailed Implementation

[0121] The present invention will be further described in detail below with reference to specific embodiments. The processes, conditions, reagents, experimental methods, etc. of implementing the present invention are all common knowledge and general knowledge in the field, except for the contents specifically mentioned below. The present invention does not have any special limitations.

[0122] Preparation of compound (2) in Example 1

[0123] In a 250 mL single-necked flask, BA (10.0 g, 30.26 mmol), p-toluenesulfonic acid (57 mg, 0.30 mmol), ethylene glycol (16.8 mL, 302.60 mmol), triethyl orthoformate (15.1 mL, 90.78 mmol), and tetrahydrofuran (150 mL) were added sequentially, and the mixture was reacted at room temperature for 8 h. After the reaction was complete, the mixture was concentrated under reduced pressure, extracted with water (100 mL) and ethyl acetate (60 mL × 3), and the organic phase was washed sequentially with water (50 mL × 2) and saturated sodium chloride solution (50 mL). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (2) (5.0 g, white solid), with a molar yield of 44%.

[0124] In a 250 mL single-necked flask, BA (10.0 g, 30.26 mmol), p-toluenesulfonic acid (57 mg, 0.30 mmol), ethylene glycol (16.8 mL, 302.60 mmol), and benzene (300 mL) were added sequentially, and the mixture was refluxed to remove water for 24 h. After the reaction was complete and cooled, saturated sodium bicarbonate solution (20 mL) was added and stirred for 10 min. The mixture was concentrated under reduced pressure, and then water (100 mL) was added. The mixture was extracted with ethyl acetate (60 mL × 3), washed with water (50 mL × 2), washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to obtain compound (2) (10.0 g, white solid), with a molar yield of 88%. mp: 175-177 °C. 1 H NMR (500MHz, CDCl3) δ5.36-5.32(m,1H),3.97-3.90(m,4H),3.63(dd,J=10.5,3.2Hz,1H),3.35(d d,J=10.5,6.9Hz,1H),2.58-2.53(m,1H),2.11(dd,J=14.2,2.9Hz,1H),2.03-1.91(m,2H),1.85-1 .72(m,3H),1.69-1.58(m,3H),1.57-1.49(m,2H),1.49-1.39(m,2H),1.36-1.27(m,3H),1.22-1. 15(m,2H),1.12-1.07(m,1H),1.04(d,J=6.7Hz,3H),1.02(s,3H),1.00-0.97(m,1H),0.70(s,3H). 13C NMR (125MHz, CDCl3) δ140.26,122.25,109.60,68.12,64.55,64.34,56.59,52.52,49.79,42.55,41.91,39.7 4,38.90,36.73,36.45,32.04,31.84,31.19,27.85,24.51,21.16,19.00,16.89,12.07.HRMS(ESI):calcdfor C 24 H 38 NaO3[M+Na] + ,397.2713,found 397.2704.

[0125]

[0126] Example 2 Preparation of compound (3)

[0127] Compound (2) (5.0 g, 13.35 mmol), IBX (7.5 g, 26.70 mmol), THF (50 mL), and DMSO (50 mL) were added sequentially to a 250 mL single-necked flask and reacted at room temperature for 5 h. After the reaction was complete as detected by TLC, water was added to quench the reaction, and the mixture was filtered. The filtrate was extracted with dichloromethane (50 mL × 3), washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to obtain compound (3) (4.9 g, white solid) with a molar yield of 98%.

[0128] In a 500 mL single-necked flask, compound (2) (10.1 g, 26.96 mmol), TEMPO (42 mg, 0.27 mmol), dichloromethane (100 mL), sodium bicarbonate (3.1 g, 36.40 mmol), tetrabutylammonium bromide (870 mg, 2.70 mmol) in water (40 mL) and NCS (4.1 g, 31.00 mmol) were added sequentially, and the mixture was reacted at 0 °C for 5 h. After the reaction was completed as detected by TLC, sodium thiosulfate pentahydrate solution (1.3 g sodium thiosulfate pentahydrate / 25 mL water) was added, and the mixture was stirred at 5-10 °C for 20 min. The mixture was separated, extracted with dichloromethane (50 mL × 3), and 1% sodium hydroxide solution (120 mL) was added. The mixture was stirred for 30 min, separated, and the aqueous phase was back-extracted once with dichloromethane (50 mL). The phase was washed with water and concentrated under reduced pressure to obtain compound (3) (9.6 g, pale yellow solid), with a molar yield of 95%. mp:168-171℃. 1H NMR (500MHz, CDCl3) δ9.56 (d, J = 3.3Hz, 1H), 5.36-5.31 (m, 1H), 3.97-3.90 (m, 4H), 2.58-2.5 3(m,1H),2.39-2.31(m,1H),2.11(dd,J=14.2,2.9Hz,1H),2.00-1.93(m,2H),1.91-1.82(m,1 H),1.81-1.73(m,2H),1.68-1.62(m,3H),1.59-1.53(m,1H),1.52-1.44(m,3H),1.40-1.29(m ,2H),1.28-1.15(m,2H),1.12(d,J=6.8Hz,3H),1.11-1.03(m,2H),1.02(s,3H),0.72(s,3H). 13 C NMR (125MHz, CDCl3) δ205.20,140.26,122.10,109.54,64.56,64.35,56.11,51.08,49.79,49.61,43.09,41 .90,39.58,36.74,36.45,32.01,31.80,31.19,27.16,24.78,21.10,19.00,13.59,12.37.HRMS(ESI):calcd for C 24 H 36 NaO3[M+Na] + ,395.2557,found 395.2542.

[0129]

[0130] Example 3 Preparation of compound (6′)

[0131] Compound (3) (1.0 g, 2.68 mmol), methoxyformylmethylenetriphenylphosphine (1.7 g, 5.36 mmol), and toluene (15 mL) were added sequentially to a single-necked flask, and the mixture was refluxed for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (6′-A) (1.13 g, white solid), with a molar yield of 98%.

[0132] Sodium hydride (161 mg, 4.02 mmol) and tetrahydrofuran were added to a 100 mL single-necked flask. After stirring for 15 min, trimethyl phosphonoacetate (0.65 mL, 4.02 mmol) and compound (3) (1.0 g, 2.68 mmol) were added sequentially. The reaction was carried out at 0 °C for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (6′-A) (1.12 g, white solid) with a molar yield of 97%. mp: 161-162 °C. 1 H NMR (500MHz, CDCl3) δ6.83 (dd, J=15.6, 9.0Hz, 1H), 5.73 (d, J=15.6Hz, 1H), 5.36-5.30 (m, 1H), 3.97-3.90(m,4H),3.71(s,3H),2.62-2.51(m,1H),2.31-2.23(m,1H),2.13-2.08(m,1H),2.01 -1.91(m,2H),1.81-1.64(m,5H),1.63-1.51(m,3H),1.51-1.41(m,2H),1.36-1.29(m,1H),1.2 7-1.20(m,3H),1.08(d,J=6.6Hz,3H),1.04(dd,J=11.0,4.0Hz,2H),1.02(s,3H),0.71(s,3H). 13 C NMR (125MHz, CDCl3) δ167.61,155.18,140.24,122.20,118.65,109.57,64.56,64.35,56.62,54.98,51.49,49. 77,42.80,41.90,39.88,39.71,36.75,36.45,32.02,31.80,31.19,28.22,24.42,21.13,19.37,19.00,12.25.

[0133]

[0134] Compound (3) (9.6 g, 25.77 mmol), ethoxyformylmethylenetriphenylphosphine (18.0 g, 51.54 mmol), and toluene (150 mL) were added sequentially to a 500 mL single-necked flask, and the mixture was refluxed for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (6′-B) (11.2 g, white solid), with a molar yield of 98%.

[0135] Sodium hydride (805 mg, 20.13 mmol) and tetrahydrofuran (50 mL) were added to a 250 mL single-necked flask. After stirring for 15 min, triethyl phosphonoacetate (4.0 mL, 20.13 mmol) and compound (3) (5.0 g, 13.42 mmol) were added sequentially. The reaction was carried out at 0 °C for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure and slurried with methanol to obtain compound (6′-B) (5.65 g, white solid), with a molar yield of 95%. mp: 122-124 °C. 1 H NMR (500MHz, CDCl3) δ6.82 (dd, J=15.6, 8.9Hz, 1H), 5.72 (d, J=15.6Hz, 1H), 5.39-5.28 (m, 1H), 4.16 (q, J=7.1Hz, 2H),3.97-3.90(m,4H),2.58-2.53(m,1H),2.26(d,J=6.7Hz,1H),2.11(dd,J=14.2,2.9Hz,1H),2.00-1.92(m,2H) ,1.81-1.73(m,2H),1.72-1.61(m,3H),1.60-1.52(m,2H),1.51-1.41(m,2H),1.37-1.30(m,1H),1.27(t,J=7.1H z,3H),1.25-1.18(m,3H),1.08(d,J=6.7Hz,3H),1.04-1.06(m,2H),1.02(s,3H),1.00-0.97(m,1H),0.71(s,3H). 13 C NMR (125MHz, CDCl3) δ167.20,154.84,140.24,122.20,119.07,109.57,64.56,64.35,60.22,56.63,55.01,49.78,42.79,4 1.91,39.85,39.72,36.75,36.45,32.02,31.80,31.20,28.25,24.42,21.14,19.38,19.00,14.42,12.24.HRMS(ESI):calcd for C 28 H 42 NaO4[M+Na] + ,465.2975,found 465.2990.

[0136]

[0137] Compound (3) (1.0 g, 2.68 mmol), propoxyformylmethylenetriphenylphosphine (1.85 g, 5.36 mmol), and toluene (15 mL) were added sequentially to a 100 mL single-necked flask, and the mixture was refluxed for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (6′-C) (1.2 g, white solid), with a molar yield of 98%. mp: 108-110 °C. 1 H NMR(500MHz, CDCl3)δ6.82(dd,J=15.6,8.9Hz,1H),5.73(d,J=15.6Hz,1H),5.40-5.30(m,1H),4.07(t,J=6.7H z,,2H),3.97-3.89(m,4H),2.55(dd,J=14.2,2.6Hz,1H),2.30-2.23(m,1H),2.11(dd,J=14.2,2.8Hz,1H),2.0 1-1.92(m,2H),1.81-1.73(m,2H),1.70-1.62(m,5H),1.60-1.52(m,2H),1.50-1.41(m,2H),1.36-1.18(m,5H) ,1.08(d,J=6.6Hz,3H),1.06-1.04(m,1H),1.02(s,3H),1.01-0.97(m,1H),0.95(t,J=7.4Hz,3H),0.71(s,3H). 13 C NMR (125MHz, CDCl3) δ167.30,154.82,140.24,122.20,119.06,109.57,65.88,64.56,64.35,56.63,55.02,49.78,42. 79,41.91,39.84,39.72,36.75,36.45,32.02,31.80,31.20,28.24,24.42,22.18,21.14,19.37,19.00,12.24,10.58.

[0138]

[0139] Preparation of compound (4) in Example 4

[0140] BA (5.0 g, 15.13 mmol), IBX (8.5 g, 30.26 mmol), THF (50 mL), and DMSO (50 mL) were added sequentially to a 250 mL single-necked flask and reacted at room temperature for 5 h. After the reaction was complete as detected by TLC, water was added to quench the reaction, and the mixture was filtered, extracted with dichloromethane (50 mL × 3), washed sequentially with water (50 mL × 2) and saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to obtain compound (4.9 g, white solid) of formula (4), with a molar yield of 98%.

[0141] In a 500 mL single-necked flask, BA (10.0 g, 30.26 mmol), TEMPO (47 mg, 0.30 mmol), dichloromethane (100 mL), sodium bicarbonate (3.43 g, 40.85 mmol), tetrabutylammonium bromide (977 mg, 3.03 mmol) in water (40 mL) and NCS (4.65 g, 34.80 mmol) were added sequentially, and the mixture was reacted at 0 °C for 5 h. After the reaction was completed as detected by TLC, sodium thiosulfate pentahydrate solution (1.5 g sodium thiosulfate pentahydrate / 30 mL water) was added, and the mixture was stirred at 5-10 °C for 20 min. The mixture was separated, extracted with dichloromethane (50 mL × 3), and 1% sodium hydroxide solution (135 mL) was added. The mixture was stirred for 30 min, separated, and the aqueous phase was back-extracted once with dichloromethane (50 mL). The phase was washed with water and concentrated under reduced pressure to obtain compound (4) (9.5 g, pale yellow solid), with a molar yield of 95%. mp:155-157℃. 1 HNMR (400MHz, CDCl3) δ9.55(s,1H),5.71(s,1H),2.45-2.23(m,5H),1.99(t,J=13.7Hz,2H),1.91-1.78(m,2H),1.68( t,J=10.2Hz,2H),1.43(m,5H),1.30-1.19(m,2H),1.17(s,3H),1.11(d,J=5.5Hz,3H),1.06-0.89(m,3H),0.75(s,3H). 13 C NMR (100MHz, CDCl3) δ205.00,199.65,171.31,123.99,55.25,53.84,51.04,49.54,43.10,39.39,38 .68,35.80,35.68,34.06,32.93,32.05,27.11,24.64,21.06,17.48,13.53,12.44.HRMS(ESI):calcd forC 22 H 32 NaO2[M+Na]+ ,351.2295,found 351.2292.

[0142]

[0143] Preparation of compound (5) in Example 5

[0144] Compound (4) (1.0 g, 3.04 mmol), methoxyformylmethylenetriphenylphosphine (1.92 g, 6.08 mmol), and toluene (15 mL) were added sequentially to a 100 mL single-necked flask, and the mixture was refluxed for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (5-A) (1.15 g, white solid) in a molar yield of 98%.

[0145] Sodium hydride (182 mg, 4.56 mmol) and tetrahydrofuran (10 mL) were added to a 100 mL single-necked flask. After stirring for 15 min, diethyl methyl phosphonoacetate (0.75 mL, 4.56 mmol) and compound (4) (1.0 g, 3.04 mmol) were added sequentially. The reaction was carried out at 0 °C for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (5-A) (1.14 g, white solid), with a molar yield of 97%. mp: 142-144 °C. 1 H NMR(500MHz, CDCl3) δ6.81(dd,J=15.6,9.0Hz,1H),5.73(d,J=15.8Hz,1H),5.71(s,1H),3 .70(s,3H),2.43-2.23(m,5H),2.04-1.97(m,2H),1.86-1.82(m,1H),1.67-1.70(m,2H),1. 64-1.55(m,1H),1.51-1.54(m,2H),1.50-1.38(m,1H),1.28-1.19(m,3H),1.17(s,3H),1. 15-1.09(m,1H),1.07(d,J=6.6Hz,3H),1.05-0.97(m,2H),0.96-0.88(m,1H),0.73(s,3H). 13C NMR (125MHz, CDCl3) δ199.63,171.43,167.53,154.86,123.94,118.80,55.77,54.97,53.85,51.51,42. 83,39.81,39.54,38.69,35.81,35.70,34.08,32.98,32.06,28.17,24.28,21.10,19.32,17.49,12.33.

[0146]

[0147] Compound (4) (9.5 g, 28.92 mmol), ethoxyformylmethylenetriphenylphosphine (20.2 g, 57.84 mmol), and toluene (150 mL) were added sequentially to a 500 mL single-necked flask, and the mixture was refluxed for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (5-B) (11.3 g, white solid), with a molar yield of 98%.

[0148] Sodium hydride (913 mg, 22.83 mmol) and tetrahydrofuran (50 mL) were added to a 250 mL single-necked flask. After stirring for 15 min, triethyl phosphonoacetate (4.5 mL, 22.83 mmol) and compound (3) (5.0 g, 15.22 mmol) were added sequentially. The reaction was carried out at 0 °C for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure and slurried with methanol to obtain compound (5-B) (5.6 g, white solid), with a molar yield of 92%. mp: 160-162 °C. 1 H NMR (400MHz, CDCl3) δ6.81(dd,J=15.3,9.0Hz,1H),5.71(d,J=13.4Hz,2H),4.24-4.09(m,2H),2.45-2.21(m,5H),2.00(d,J=1 2.6Hz,2H),1.80(m,1H),1.76-1.33(m,7H),1.26(m,6H),1.17(s,3H),1.08(d,J=6.2Hz,3H),1.05-0.86(m,3H),0.73(s,3H). 13C NMR (100MHz, CDCl3) δ199.70,171.51,167.16,154.56,123.94,119.21,60.27,55.78,54.98,53.84,42.82,39.80,39. 54,38.69,35.80,35.70,34.08,32.98,32.06,28.19,24.28,21.10,19.31,17.49,14.40,12.32.HRMS(ESI):calcdfor C 26 H 38 NaO3[M+Na] + ,421.2713,found 421.2708.

[0149]

[0150] Compound (4) (1.0 g, 3.04 mmol), propoxyformylmethylenetriphenylphosphine (2.1 g, 6.08 mmol), and toluene (15 mL) were added sequentially to a 100 mL single-necked flask, and the mixture was refluxed for 4 h. After the reaction was confirmed to be complete by TLC, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (5-C) (1.23 g, white solid), with a molar yield of 98%. mp: 144-146 °C. 1 HNMR(500MHz, CDCl3)δ6.81(dd,J=15.6,8.9Hz,1H),5.73(d,J=16.3Hz,1H),5.71(s,1H),4.06(t, J=6.7Hz,2H),2.44-2.22(m,5H),2.03-1.97(m,2H),1.85-1.78(m,1H),1.74-1.64(m,4H),1.63-1. 57(m,1H),1.57-1.50(m,2H),1.48-1.39(m,1H),1.29-1.20(m,3H),1.17(s,3H),1.15-1.09(m,1H ),1.08(d,J=6.6Hz,3H),1.06-0.97(m,2H),0.94(t,J=7.4Hz,3H),0.93-0.89(m,1H),0.74(s,3H).

[0151]

[0152] Example 6: Preparation of compound (6′-B)

[0153] In a 250 mL single-necked flask, compound (5.0 g, 12.54 mmol), p-toluenesulfonic acid (25 mg, 0.13 mmol), ethylene glycol (7.0 mL, 125.40 mmol), triethyl orthoformate (6.3 mL, 37.62 mmol), and tetrahydrofuran (150 mL) were added sequentially, and the mixture was reacted at room temperature for 8 h. After the reaction was complete, the mixture was concentrated under reduced pressure, extracted with water (100 mL) and ethyl acetate (60 mL × 3), washed successively with water (50 mL × 2) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (6′-B) (3.0 g, white solid), with a molar yield of 54%.

[0154] In a 250 mL single-necked flask, compound (5.0 g, 12.54 mmol), p-toluenesulfonic acid (25 mg, 0.13 mmol), ethylene glycol (7.0 mL, 125.40 mmol), and toluene (150 mL) were added sequentially, and the mixture was refluxed to remove water for 24 h. After the reaction was complete and cooled, 20 mL of saturated sodium bicarbonate solution was added and stirred for 10 min. The mixture was concentrated under reduced pressure and extracted with water (100 mL) and ethyl acetate (50 mL × 3). The organic phase was then washed sequentially with water (50 mL × 2) and saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (6′-B) (4.9 g, white solid), with a molar yield of 88%. mp: 122–124 °C. 1 H NMR (500MHz, CDCl3) δ6.82 (dd, J=15.6, 8.9Hz, 1H), 5.72 (d, J=15.6Hz, 1H), 5.39-5.28 (m, 1H), 4.16 (q, J=7.1Hz, 2H),3.97-3.90(m,4H),2.58-2.53(m,1H),2.26(d,J=6.7Hz,1H),2.11(dd,J=14.2,2.9Hz,1H),2.00-1.92(m,2H) ,1.81-1.73(m,2H),1.72-1.61(m,3H),1.60-1.52(m,2H),1.51-1.41(m,2H),1.37-1.30(m,1H),1.27(t,J=7.1H z,3H),1.25-1.18(m,3H),1.08(d,J=6.7Hz,3H),1.04-1.06(m,2H),1.02(s,3H),1.00-0.97(m,1H),0.71(s,3H). 13C NMR (125MHz, CDCl3) δ167.20,154.84,140.24,122.20,119.07,109.57,64.56,64.35,60.22,56.63,55.01,49.78,42.79,4 1.91,39.85,39.72,36.75,36.45,32.02,31.80,31.20,28.25,24.42,21.14,19.38,19.00,14.42,12.24.HRMS(ESI):calcd for C 28 H 42 NaO4[M+Na] + ,465.2975,found 465.2990.

[0155]

[0156] Example 7 Preparation of compound (6"-B)

[0157] In a 100 mL single-necked flask, compound (5-B) (10.0 g, 25.09 mmol), neopentyl glycol (6.33 g, 60.7 mmol), p-toluenesulfonic acid monohydrate (215 mg, 1.13 mmol), and toluene (25 mL) were added sequentially. Triethyl orthoformate (7.5 mL, 45.16 mmol) was added dropwise, and the mixture was reacted at room temperature for 2 h. After the starting material was found to be substantially complete by TLC, saturated NaHCO3 (30 mL) was added to the reaction mixture, and the mixture was stirred for 10 min. Water (100 mL) and ethyl acetate (150 mL) were added for extraction. The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a pale yellow solid. This pale yellow solid was added to ethanol (25 mL), stirred at room temperature for 12 h, and filtered to give compound 6"-B (9 g, white solid), with a molar yield of 74%. 1 HNMR(500MHz, CDCl3)δ6.83(dd,J=15.6,8.9Hz,1H),5.73(d,J=15.6Hz,1H),5.41–5 .16(m,1H),4.17(q,J=7.1Hz,2H),3.49(m,4H),2.56(dd,J=14.3,2.8Hz,1H),2.37– 2.13(m,3H),2.03–1.85(m,2H),1.67(dd,J=21.0,8.2Hz,2H),1.57–1.38(m,8H),1. 34–1.15(m,7H),1.08(t,J=7.7Hz,3H),1.04–0.94(m,7H),0.91(s,3H),0.71(s,3H). 13C NMR (126MHz, CDCl3) δ167.11,154.75,139.61,122.07,118.93,98.40,70.21,69.88,60.11,56.51,54.89,49.60,42.67,39. 97,39.74,39.60,36.88,34.97,31.89,31.69,30.12,28.13,27.66,24.29,22.79,22.65,20.98,19.24,19.05,14.29,12.11.

[0158]

[0159] Example 8: Preparation of compound (7′-B)

[0160] In the preparation of compound (7′-B), the present invention tested various oxidation reaction conditions (as shown in Table 1) and obtained the optimal oxidation reaction conditions (as shown in Table 1, Entry 23).

[0161] Table 1

[0162] Oxidation of compound (6′-B) a

[0163]

[0164]

[0165] All reaction times were 20 h, and the ratio of oxidant to compound 6′-B was 1.1:1 (mol:mol).

[0166] b. No response.

[0167] As shown in Table 1, the optimal reaction conditions were obtained through screening and optimization of solvent, oxidant and reaction temperature. The optimal reaction solvent is acetone / water (9:1), the optimal oxidant is PDC, the optimal reaction temperature is 25℃, and the reaction yield reached 85%.

[0168] Some of the embodiments are shown below:

[0169] In a 250 mL single-necked flask, compound (6′-B) (1.0 g, 2.26 mmol), acetone (20 mL), NHPI (400 mg, 2.49 mmol), and PDC (940 mg, 2.49 mmol) were added sequentially, and the mixture was reacted at room temperature for 20 h. After the reaction was confirmed to be complete by TLC, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (7′-B) (743 mg, white solid), with a molar yield of 72%.

[0170] In a 250 mL single-necked flask, compound (6′-B) (1.0 g, 2.26 mmol), acetonitrile (20 mL), NHPI (400 mg, 2.49 mmol), and PDC (940 mg, 2.49 mmol) were added sequentially, and the mixture was reacted at room temperature for 20 h. After the reaction was confirmed to be complete by TLC, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (7′-B) (722 mg, white solid), with a molar yield of 70%.

[0171] In a 250 mL single-necked flask, compound (6′-B) (1.0 g, 2.26 mmol), 20 mL acetone, NHPI (400 mg, 2.49 mmol), Na₂Cr₂O₇·2H₂O (742 mg, 2.49 mmol), and AcOH (0.4 mL, 6.78 mmol) were added sequentially, and the mixture was reacted at room temperature for 20 h. After the reaction was confirmed to be complete by TLC, the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (7′-B) (640 mg, white solid), with a molar yield of 62%.

[0172] In a 250 mL single-necked flask, compound (6′-B) (5.0 g, 11.30 mmol), acetone (90 mL), water (10 mL), NHPI (2.0 g, 12.43 mmol), and PDC (4.7 g, 12.43 mmol) were added sequentially, and the reaction was carried out at room temperature for 20 h. After the reaction was confirmed to be complete by TLC, the mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound (7′-B) (4.4 g, white solid), with a molar yield of 85%. mp: 139–141 °C. 1 H NMR(500MHz, CDCl3) δ6.82(dd,J=15.6,9.0Hz,1H),5.72(d,J=15.6Hz,1H),5.65(d,J=1.7H z,1H),4.16(q,J=7.1Hz,2H),3.98-3.90(m,4H),2.66(dd,J=14.7,1.8Hz,1H),2.44-2.36(m ,1H),2.34-2.18(m,3H),2.02-1.95(m,1H),1.89-1.83(m,2H),1.78-1.71(m,2H),1.64-1. 52(m,3H),1.52-1.43(m,1H),1.27(m,8H),1.19(s,3H),1.08(d,J=6.6Hz,3H),0.70(s,3H). 13C NMR (125MHz, CDCl3) δ201.52,167.11,164.66,154.53,126.73,119.23,108.98,64.70,64.62,60.24,53.82,50.01,49.65,4 5.41,43.58,41.84,39.59,38.65,38.35,35.73,31.16,28.34,26.44,21.25,19.58,17.08,14.40,12.40.HRMS(ESI):calcd for C 28 H 40 NaO5[M+Na] + ,479.2768,found 479.2770.

[0173]

[0174] Example 9: Preparation of compound (7"-B)

[0175] In a 250 mL single-necked flask, compound (6"-B) (2.1 g, 4.21 mmol), acetone (33.5 mL), H₂O (3.7 mL), NHPI (1.38 g, 8.42 mmol), and PDC (3.17 g, 8.42 mmol) were added sequentially, and the mixture was reacted at room temperature for 24 h. Post-treatment: After the reaction proceeded completely as determined by TLC, the solvent was removed by rotary evaporation under reduced pressure. Then, DCM (50 mL) was added and stirred to dissolve the residue. The mixture was filtered through diatomaceous earth, and the filter cake was washed with DCM (20 mL x 3). The filtrate was concentrated under reduced pressure to obtain a light brown solid. The crude product was then added to ethanol (5 mL + 0.05 mL LTEA) and stirred at room temperature for 12 h. After filtration, compound 7"-B (1.5 g, pale yellow solid) was obtained, with a molar yield of 70%. 1HNMR (600MHz, CDCl3) δ6.83 (dd, J=15.6, 9.0Hz, 1H), 5.70 (dd, J=24.9, 8.5Hz, 2H), 4.16 (q, J=7.1Hz, 2H),3.65–3.50(m,2H),3.41(q,J=11.5Hz,2H),2.83(dd,J=14.8,3.0Hz,1H),2.50–2.33(m,2H),2.2 5(m,3H),1.98(d,J=12.9Hz,1H),1.81–1.69(m,3H),1.68–1.52(m,4H),1.47–1.31(m,3H),1.25(m,7 H),1.18(s,3H),1.17(d,J=12.9Hz,1H),1.08(d,J=6.6Hz,3H),0.95(d,J=11.1Hz,6H),0.70(s,3H). 13 C NMR (151MHz, CDCl3) δ201.59,167.05,164.52,154.47,126.81,119.12,98.07,70.39,70.01,60.15,53.73,49.89,49.60, 45.37,43.49,39.50,39.28,38.54,38.52,34.44,30.08,28.42,28.25,26.33,22.62,21.13,19.46,17.12,14.29,12.28.

[0176]

[0177] Preparation of Compound (8) in Example 10

[0178] In a 100 mL single-necked flask, compound (7′-B) (4.4 g, 9.64 mmol), tetrahydrofuran (45 mL), and water (5 mL) were added sequentially. Concentrated sulfuric acid (2 mL) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 4 h. After the reaction was confirmed to be complete by TLC, saturated sodium bicarbonate solution (80 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate (30 mL * 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to obtain compound (8) (3.9 g, white solid), with a molar yield of 98%.

[0179]

[0180] Compound (7"-B) (5.70 g, 11.1 mmol), THF (51 mL), and H₂O (5.8 mL) were added sequentially to a 100 mL single-necked flask. Concentrated sulfuric acid (2.3 mL) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 12 h. After the reaction proceeded completely as determined by TLC, the reaction was quenched with saturated sodium bicarbonate solution (80 mL), extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The mixture was washed with saturated brine (35 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow solid. This solid was added to 16 mL of a petroleum ether / ethyl acetate mixture (PE:EA = 3:1), stirred at room temperature for 12 h, and filtered to give compound 8 (3.7 g, white solid), with a molar yield of 81%. mp: 167-169 °C. 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),6.74(dd,J=15.4,9.0Hz,1H),5.78(d,J=15.5Hz,1H),5.29(s,1H),5.27(s,1H),4.09(dd,J=13.2, 6.4Hz,2H),2.37-2.13(m,5H),1.94-1.85(m,2H),1.58-1.42(m,4H),1.34-1.25(m,3H),1.20(m,6H),1.05(d,J=7.0Hz,6H),0.69(s,3H). 13 CNMR(100MHz,DMSO-d6)δ198.89,165.98,165.30,164.15,154.50,118.79,117.65,99.83,59.69,53.03,50.42,48.87 ,44.90,43.47,38.80,38.27,35.45,32.49,27.95,26.30,25.43,21.04,19.19,16.91,14.17,12.09.HRMS(ESI):calcd for C 26 H 36 NaO4[M+Na] + ,435.2506,found 435.2501.

[0181]

[0182] Preparation of compound of formula (9) in Example 11

[0183] For the preparation of compound (9), the present invention tested various reduction reaction conditions (as shown in Table 2) and obtained the optimal reduction reaction conditions (as shown in Table 2, Entry 12).

[0184] Table 2

[0185] Preparation of compound (9)

[0186]

[0187] As shown in Table 2, the optimal reaction conditions were obtained through screening and optimization of reaction temperature, Raney nickel dosage, and time. The optimal reaction solvent was 1,4-dioxane, the optimal reaction temperature was 70℃, the optimal Raney nickel dosage was 1 times the amount, the optimal reaction time was 6h, and the reaction yield reached 90%.

[0188] Some of the embodiments are shown below:

[0189] Compound (8) (4.0 g, 9.68 mmol), 1,4-dioxane (20 mL), Raney Ni (4.0 g), and H2 (1.0 MPa) were added sequentially to a high-pressure reactor and reacted at 70 °C for 6 h. After the reaction was confirmed to be complete by TLC, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to obtain compound (9) (3.6 g, white solid), with a molar yield of 90%.

[0190] Compound (8) (4.0 g, 9.68 mmol), 1,4-dioxane (20 mL), Raney Ni (4.0 g), and H2 (1.0 MPa) were added sequentially to a high-pressure reactor and reacted at 60 °C for 12 h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain crude compound 9. The crude compound 9 was purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to obtain compound (9) (3.2 g, white solid), with a molar yield of 80%. 1 H NMR(600MHz, CDCl3)δ4.12(q,J=7.1Hz,2H),3.66–3.53(m,1H),2.85(dd,J=12.6,6.1Hz,1H),2.41–2.29(m,2H),2.23–2.17(m,2H),2.00–1.7 7(m,7H),1.70(t,J=11.1Hz,2H),1.53–1.38(m,5H),1.35–1.24(m,6H) ,1.22–1.17(m,3H),1.16–1.09(m,2H),0.99–0.90(m,4H),0.65(s,3H). 13C NMR (151MHz, CDCl3) δ211.94,174.27,70.94,60.21,54.77,49.53,48.91,46.09,45.41,42.72,42.65,38 .96,37.42,35.22,35.16,34.16,31.34,31.00,29.91,28.28,24.84,23.06,21.69,18.39,14.27,12.06.

[0191]

[0192] Example XII: Preparation of 7-Ketolithocholic Acid (Compound 10)

[0193] Lithium hydroxide (0.82 g, 19.36 mmol) was added to a methanol (20 mL) solution of compound 9 (4.04 g, 9.68 mmol), and the reaction was carried out at room temperature for 12 h. After the reaction was complete as determined by TLC, methanol was removed by rotary evaporation under reduced pressure, and the mixture was dissolved in water (20 mL). The pH of the aqueous solution was then adjusted to 4-5 with 2 mol / L hydrochloric acid, resulting in the formation of a large amount of white solid. The solid was filtered, the filter cake was washed with water, and dried to obtain 7-ketolithocholic acid (3.59 g, white solid), with a molar yield of 95%. 1 HNMR(600MHz,DMSO-d6)δ3.33–3.29(m,1H),2.91(dd,J=12.3,6.0Hz,1H),2.45(t,J=1 1.3Hz,1H),2.27–2.22(m,1H),2.13–2.04(m,2H),1.93(d,J=12.7Hz,1H),1.81(dd,J= 16.9,11.0Hz,2H),1.73–1.67(m,4H),1.49(dd,J=22.1,10.5Hz,2H),1.43–1.28(m,4H ),1.24–1.21(m,2H),1.15(s,3H),1.13–1.00(m,5H),0.95–0.85(m,4H),0.62(s,3H). 13 C NMR(151MHz,DMSO-d6)δ175.34,69.55,54.79,49.26,49.04,45.85,45.54,42.65,39.04,3 7.89,35.23,35.20,34.33,31.20,31.18,30.29,28.31,24.87,23.25,21.68,18.69,12.36.

[0194]

[0195] Comparative Example 1

[0196] When protecting the carbonyl group at the 3-position of compound (5-B) to synthesize alkenyl ether and alkenyl ester structures (the structures of which are shown in formulas (11-A) and (11-B) respectively), the resulting compounds (11-A) and (11-B) have poor stability and are prone to deterioration. Furthermore, when further oxidizing compounds (11-A) and (11-B) at the 7-position using PDC and NHPI respectively, the reaction results are complicated, and the target compounds (12) and (13) cannot be separated (the reaction formulas are as follows).

[0197]

[0198] Compound (5-B) (1.0 g, 2.51 mmol) and 1.5 M HCl / EtOH (20 mL) solution were added sequentially to a 100 mL single-necked flask and reacted at room temperature for 4 h. After the reaction was complete, the solution was concentrated under reduced pressure to obtain compound (11-A) (1.1 g, white solid), which was used directly in the next step.

[0199] Compound (11-A) (1.1 g, 2.51 mmol), acetone (18 mL), water (2 mL), NHPI (444 mg, 2.76 mmol), and PDC (1.0 g, 2.76 mmol) were added sequentially to a 100 mL single-necked flask, and the mixture was reacted at room temperature for 20 h. The TLC results are shown below. Figure 1 As shown (PE / EA=3 / 1, v / v), the ether compounds have poor stability and complex reaction results, and the compound of formula (12) was not isolated.

[0200]

[0201] Compound (5-B) (1.0 g, 2.51 mmol), acetyl chloride (10 mL), and acetic anhydride (10 mL) were added sequentially to a 100 mL single-necked flask, and the mixture was refluxed for 4 h. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain compound (11-B) (1.1 g, white solid), which was used directly in the next step.

[0202] Compound (11-B) (1.1 g, 2.51 mmol), acetone (18 mL), water (2 mL), NHPI (444 mg, 2.76 mmol), and PDC (1.0 g, 2.76 mmol) were added sequentially to a 100 mL single-necked flask, and the mixture was reacted at room temperature for 20 h. The TLC results are shown below. Figure 2 As shown (PE / EA=3 / 1, v / v), ester compounds have poor stability and complex reaction results, and compound (13) was not isolated.

[0203] As can be seen from Comparative Example 1, compounds with alkenyl ether and alkenyl ester structures have poor stability and are prone to deterioration. Furthermore, when using PDC and NHPI for 7-position oxidation, the reaction results are complex, and the target compounds (12) and (13) cannot be separated.

[0204] Comparative Example 2

[0205] When compound (8) was reduced by Pd / C-H2, NaBH4, etc., the reaction results were complicated and the target compound (9) and compound (14) were not separated (reaction formula is as follows).

[0206]

[0207] Compound of formula (8) (1.0 g, 2.42 mmol), methanol (20 mL), 0.1 g 10% Pd / C, and H2 (1.0 MPa) were added sequentially to a high-pressure reactor, and the reaction was carried out at 70 °C for 24 h. The TLC results are as follows: Figure 3 As shown (PE / EA=1 / 1, v / v), when compound (8) was reduced with Pd / C-H2, the reaction results were complicated and compound (9) was not isolated.

[0208]

[0209] Compound of formula (8) (1.0 g, 2.42 mmol), methanol (20 mL), and NaBH4 (458 mg, 12.10 mmol) were added sequentially to a 100 mL single-necked flask, and the mixture was stirred at room temperature for 4 h. The TLC results are as follows: Figure 4 As shown (PE / EA=1 / 1, v / v), when compound (8) was reduced with NaBH4, the reaction results were complicated and compound (14) was not isolated.

[0210] As can be seen from Comparative Example 2, when using Pd / C-H2, NaBH4, etc. for reduction, the reaction results are complicated and the target compound (9) and compound (14) are not separated.

[0211] The scope of protection of this invention is not limited to the above embodiments. Variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in the invention and are protected by the appended claims.

Claims

1. A method for synthesizing 7-ketolithocholic acid from BA as a raw material, characterized in that, The method includes the following steps: (a) In the first solvent, BA of formula (1) is protected with ethylene glycol to obtain compound of formula (2); (b) In a second solvent, compound (2) is oxidized to give compound (3); (c) In a third solvent, compound (3) undergoes a Wittig reaction to give compound (6); (d) In a fourth solvent, compound (6) undergoes an oxidation reaction to obtain compound (7); the oxidation reaction refers to: compound (6), oxidant, N-hydroxyphthalimide, and acetic acid being dissolved in the fourth solvent and undergoing an oxidation reaction to obtain compound (7); wherein the molar ratio of compound (6), oxidant, N-hydroxyphthalimide, and acetic acid is 1:(1-5):(1~5):(0~5); wherein the oxidant is selected from one or more of Na2Cr2O7, K2Cr2O7, PDC, and BPO; the fourth solvent is selected from one or more of toluene, acetone, acetonitrile, water, dichloromethane, N,N-dimethylformamide, ethyl acetate, tert-butanol, and N-methylpyrrolidone; the temperature of the oxidation reaction is 0~50 °C; and / or the time of the oxidation reaction is 10~48 h; (e) In the fifth solvent, the compound of formula (7) undergoes a deglycolization protection reaction under the action of acid to give the compound of formula (8); (f) In the sixth solvent, under the action of a catalyst and hydrogen, and under pressure, the compound of formula (8) undergoes a reduction reaction to obtain the compound of formula (9); the catalyst is selected from Raney nickel; the mass ratio of the compound of formula (8) to the catalyst is 1:(0.1~5); the sixth solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, and tert-butanol; the temperature of the reduction reaction is 20~100 °C; the time of the reduction reaction is 3~24 h; the reaction is carried out under hydrogen pressure, the pressure range of which is 0.1~10 MPa; (g) In the seventh solvent, under the action of a base, the compound of formula (9) undergoes a hydrolysis reaction to give 7-ketolithocholic acid as shown in formula (10); The reaction process of the method is shown in route (A): ; Route (A).

2. A method for synthesizing 7-ketolithocholic acid from BA as a raw material, characterized in that, The method includes the following steps: (h) In the eighth solvent, the BA shown in formula (1) is oxidized to obtain the compound of formula (4); (i) In the ninth solvent, the compound of formula (4) is subjected to the Wittig reaction to give the compound of formula (5); (j) In the tenth solvent, the compound of formula (5) is protected with ethylene glycol or neopentyl glycol to obtain the compound of formula (6); (d) In a fourth solvent, compound (6) undergoes an oxidation reaction to obtain compound (7); the oxidation reaction refers to: compound (6), oxidant, N-hydroxyphthalimide, and acetic acid being dissolved in the fourth solvent and undergoing an oxidation reaction to obtain compound (7); wherein the molar ratio of compound (6), oxidant, N-hydroxyphthalimide, and acetic acid is 1:(1-5):(1~5):(0~5); wherein the oxidant is selected from one or more of Na2Cr2O7, K2Cr2O7, PDC, and BPO; the fourth solvent is selected from one or more of toluene, acetone, acetonitrile, water, dichloromethane, N,N-dimethylformamide, ethyl acetate, tert-butanol, and N-methylpyrrolidone; and / or, the temperature of the oxidation reaction is 0~50℃; the time of the oxidation reaction is 10~48h; (e) In the fifth solvent, the compound of formula (7) undergoes a deethylene glycol or neopentyl glycol protection reaction under the action of acid to obtain the compound of formula (8); (f) In a sixth solvent, under the action of a catalyst and hydrogen, and under pressure, the compound of formula (8) undergoes a reduction reaction to obtain the compound of formula (9); the catalyst is selected from Raney nickel; the mass ratio of the compound of formula (8) to the catalyst is 1:(0.1-5); the sixth solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, and tert-butanol; the temperature of the reduction reaction is 20-100°C; the time of the reduction reaction is 3-24 h; the reaction is carried out under hydrogen pressure, the pressure of which is 0.1-10 MPa. (g) In the seventh solvent, under the action of a base, the compound of formula (9) undergoes a hydrolysis reaction to give 7-ketolithocholic acid as shown in formula (10); The reaction process of the method is shown in route (B): ； Route (B).

3. The method as described in claim 1, characterized in that, R is a C1~C20 alkyl group.

4. The method as described in claim 1, characterized in that, In step (a), the ethylene glycol protection reaction refers to: BA, ethylene glycol, and p-toluenesulfonic acid as shown in formula (1) are dissolved in a first solvent to undergo an ethylene glycol protection reaction to obtain compound (2); wherein, the molar ratio of BA, ethylene glycol, and p-toluenesulfonic acid as shown in formula (1) is 1:(1-50):(0.01-1); and / or, the first solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, and hexane; and / or, the temperature of the ethylene glycol protection reaction is 50~130 ℃; and / or, the time of the ethylene glycol protection reaction is 2~36 h.

5. The method as described in claim 1, characterized in that, In step (a), the ethylene glycol protection reaction refers to: BA, ethylene glycol, p-toluenesulfonic acid, and triethyl orthoformate as shown in formula (1) are dissolved in a first solvent and undergo an ethylene glycol protection reaction to obtain compound (2); wherein, the molar ratio of BA, ethylene glycol, p-toluenesulfonic acid, and triethyl orthoformate as shown in formula (1) is 1:(1-50):(0.01-1):(1-20); and / or, the first solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, and hexane; and / or, the temperature of the ethylene glycol protection reaction is 0~50 ℃; and / or, the time of the ethylene glycol protection reaction is 2~36 h.

6. The method as described in claim 1, characterized in that, In step (b), the oxidation reaction refers to the following: the compound of formula (2), TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and oxidant are dissolved in a second solvent and undergo an oxidation reaction to obtain the compound of formula (3); wherein the molar ratio of the compound of formula (2), TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and oxidant is 1:(0-1):(0-20):(0-1):(1-5); and / or, the oxidation reaction is carried out under the action of an oxidant, wherein the oxidant is selected from one or more of N-chlorosuccinimide, N-bromosuccinimide, and 2-iodobenzoic acid; and / or, the second solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide, and water; and / or, the temperature of the oxidation reaction is 0~30 ℃; and / or, the time of the oxidation reaction is 2~8 h.

7. The method as described in claim 1, characterized in that, In step (c), the Wittig reaction refers to: the compound of formula (3) and ethoxyformylmethylenetriphenylphosphine are dissolved in a third solvent and undergo a Wittig reaction to obtain the compound of formula (6); wherein the molar ratio of the compound of formula (3) and ethoxyformylmethylenetriphenylphosphine is 1:(1~5); and / or, the third solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, and hexane; and / or, the temperature of the Wittig reaction is 50~130 °C; and / or, the time of the Wittig reaction is 2~8 h.

8. The method as described in claim 1, characterized in that, In step (c), the Wittig reaction refers to the following: the compound of formula (3), sodium hydride, and triethyl phosphonoacetate are dissolved in a third solvent and undergo a Wittig reaction to obtain the compound of formula (6); wherein the molar ratio of the compound of formula (3), sodium hydride, and triethyl phosphonoacetate is 1:(1~5):(1~5); and / or, the third solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, and hexane; and / or, the temperature of the Wittig reaction is 0~30 °C; and / or, the time of the Wittig reaction is 2~8 h.

9. The method as described in claim 2, characterized in that, In step (h), the oxidation reaction refers to: BA, TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and oxidant as shown in formula (1) being dissolved in the eighth solvent and undergoing an oxidation reaction to obtain compound of formula (4); wherein, the molar ratio of BA, TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and oxidant as shown in formula (1) is 1:(0-1):(0-20):(0-1):(1-5); and / or, the oxidation reaction is carried out under the action of an oxidant, wherein the oxidant is selected from one or more of N-chlorosuccinimide, N-bromosuccinimide, and 2-iodobenzoic acid; and / or, the eighth solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide, and water; and / or, the temperature of the oxidation reaction is 0~30 ℃; and / or, the time of the oxidation reaction is 2~8 h.

10. The method as described in claim 2, characterized in that, In step (i), the Wittig reaction refers to: the compound of formula (4), methoxyformylmethylenetriphenylphosphine, ethoxyformylmethylenetriphenylphosphine, or propoxyformylmethylenetriphenylphosphine are dissolved in a ninth solvent and undergo a Wittig reaction to obtain the compound of formula (5); wherein the molar ratio of the compound of formula (4), methoxyformylmethylenetriphenylphosphine, ethoxyformylmethylenetriphenylphosphine, or propoxyformylmethylenetriphenylphosphine is 1:(1~5); and / or, the ninth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, and hexane; and / or, the temperature of the Wittig reaction is 50~130 °C; and / or, the time of the Wittig reaction is 2~8 h.

11. The method as described in claim 2, characterized in that, In step (i), the Wittig reaction refers to the following: the compound of formula (4), sodium hydride, diethyl phosphonoacetate, triethyl phosphonoacetate, or diethyl propyl phosphonoacetate are dissolved in a ninth solvent and undergo a Wittig reaction to obtain the compound of formula (5); wherein the ninth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, and hexane; and / or, the molar ratio of the compound of formula (4), sodium hydride, diethyl phosphonoacetate, triethyl phosphonoacetate, or diethyl propyl phosphonoacetate is 1:(1~5):(1~5); and / or, the temperature of the Wittig reaction is 0~30 °C; and / or, the time of the Wittig reaction is 2~8 h.

12. The method as described in claim 2, characterized in that, In step (j), the ethylene glycol or neopentyl glycol protection reaction refers to: the compound of formula (5), ethylene glycol or neopentyl glycol, and p-toluenesulfonic acid are dissolved in the tenth solvent, and the ethylene glycol or neopentyl glycol protection reaction occurs to obtain the compound of formula (6); wherein the molar ratio of the compound of formula (5), ethylene glycol or neopentyl glycol, and p-toluenesulfonic acid is 1:(1-50):(0.01-1); and / or, the tenth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, and hexane; and / or, the temperature of the ethylene glycol or neopentyl glycol protection reaction is 50~130 °C; and / or, the time of the ethylene glycol or neopentyl glycol protection reaction is 2~36 h.

13. The method as described in claim 2, characterized in that, In step (j), the ethylene glycol or neopentyl glycol protection reaction refers to: the compound of formula (5), ethylene glycol or neopentyl glycol, p-toluenesulfonic acid, and triethyl orthoformate are dissolved in the tenth solvent, and an ethylene glycol protection reaction occurs to obtain the compound of formula (6); wherein, the molar ratio of the compound of formula (5), ethylene glycol or neopentyl glycol, p-toluenesulfonic acid, and triethyl orthoformate is 1:(1-50):(0.01-1):(1-20); and / or, the tenth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, and hexane; and / or, the temperature of the ethylene glycol or neopentyl glycol protection reaction is 0~50 ℃; and / or, the time of the ethylene glycol or neopentyl glycol protection reaction is 2~36 h.

14. The method as described in claim 1, characterized in that, In step (e), the deglycolization protection reaction refers to: the compound of formula (7) and the acid are dissolved in a fifth solvent to undergo a deglycolization protection reaction to obtain the compound of formula (8); wherein the molar ratio of the compound of formula (7) and the acid is 1:(1~50); and / or, the fifth solvent is selected from one or more of tetrahydrofuran, ethyl acetate, methanol, dichloromethane, diethyl ether, water, toluene, and acetone; and / or, the acid is selected from one or more of concentrated sulfuric acid, concentrated hydrochloric acid, and p-toluenesulfonic acid; and / or, the temperature of the deglycolization protection reaction is 0~50℃; and / or, the time of the deglycolization protection reaction is 1~10 h.

15. The method as described in claim 2, characterized in that, In step (e), the deglycolization or neopentyl glycol protection reaction refers to: the compound of formula (7) and the acid are dissolved in a fifth solvent, and a deglycolization or neopentyl glycol protection reaction occurs to obtain the compound of formula (8); wherein the molar ratio of the compound of formula (7) and the acid is 1:(1-50); and / or, the fifth solvent is selected from one or more of tetrahydrofuran, ethyl acetate, methanol, dichloromethane, diethyl ether, water, toluene, and acetone; and / or, the acid is selected from one or more of concentrated sulfuric acid, concentrated hydrochloric acid, and p-toluenesulfonic acid; and / or, the temperature of the deglycolization or neopentyl glycol protection reaction is 0-50°C; and / or, the time of the deglycolization or neopentyl glycol protection reaction is 1-10 h.

16. The method as described in claim 1 or 2, characterized in that, In step (g), the molar ratio of compound (9) to base is 1:(1~5); and / or, the seventh solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, tert-butanol, methanol, and ethanol; and / or, the base is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, and lithium hydroxide; and / or, the temperature of the hydrolysis reaction is 20~80 °C; and / or, the time of the hydrolysis reaction is 3~24 h.

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