Synthesis method of 24-norursodesoxycholic acid

Abstract

The invention discloses a synthesis method of 24-norursodesoxycholic acid, which comprises a route 1 and a route 2, in the route 1, seal cholic acid, namely PCA, is oxidized to obtain an intermediate I; continuously oxidizing the intermediate I to obtain an intermediate II; further oxidizing the intermediate II to obtain an intermediate III; carrying out reduction reaction on the compound III to obtain 24-norursodesoxycholic acid; in the route 2, seal cholic acid, namely PCA, is oxidized by a one-pot method to directly obtain a compound III. According to the synthesis method of 24-norursodesoxycholic acid, seal cholic acid is used as a starting material, and 24-norursodesoxycholic acid is obtained through two-step reaction oxidation of sodium hypochlorite or other oxidants, sodium chlorite oxidation and hydrogenation reduction, or seal cholic acid is subjected to one-pot oxidation of sodium hypochlorite or other oxidants, and 24-norursodesoxycholic acid is obtained through one-pot reaction of sodium hypochlorite or other oxidants. 24-norursodesoxycholic acid is obtained through two-step reaction of hydrogenation reduction, the route raw materials are easy to obtain, the reaction conditions are mild, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical synthesis, and in particular to a method for synthesizing 24-norursodeoxycholic acid. Background Art

[0002] 24-norursodeoxycholic acid (Nor-UDCA) is an analog of ursodeoxycholic acid (UDCA) with its side chain shortened to C23. Like UDCA, it can affect the biological properties of bile acid and is used to treat various hepatobiliary diseases. Relevant studies have shown that Nor-UDCA is more effective than UDCA in improving liver function, inflammation and fibrosis markers, and inducing and transporting bile acid detoxification enzymes. Therefore, the clinical application prospects of Nor-UDCA are very broad, and the research on its synthesis process has very important market value. With the continuous development of science and technology, people have higher and higher requirements for the preparation process of the synthesis method of 24-norursodeoxycholic acid.

[0003] The existing synthesis methods of 24-norursodeoxycholic acid have certain drawbacks when used. Currently, there are many routes for synthesizing 24-norursodeoxycholic acid, such as: Patent WO2012 / 07268A1 discloses a method for synthesizing Nor-UDCA. The patented route uses ursodeoxycholic acid (UDCA) as a starting material and obtains Nor-UDCA through a five-step reaction. The route has a large number of reaction steps and a low total yield, resulting in high production and raw material costs. It has no advantages in industrial production and has brought certain adverse effects on people's use process. Therefore, we propose a method for synthesizing 24-norursodeoxycholic acid. Summary of the invention

[0004] Technical problem to be solved: In view of the deficiencies in the prior art, the present invention provides a method for synthesizing 24-norursodeoxycholic acid, which uses seal cholic acid as a starting material, undergoes two-step oxidation with sodium hypochlorite or other oxidants, and then undergoes two-step oxidation with sodium chlorite and hydrogenation reduction to obtain 24-norursodeoxycholic acid, or one-pot oxidation with sodium hypochlorite or other oxidants, and then undergoes two-step hydrogenation and reduction to obtain 24-norursodeoxycholic acid. The raw materials of the route are easily available, the reaction conditions are mild, and the route is suitable for industrial production, which can effectively solve the problems in the background technology.

[0005] Technical solution: To achieve the above purpose, the technical solution adopted by the present invention is: a method for synthesizing 24-norursodeoxycholic acid, including route 1 and route 2, wherein route 1 includes the following steps: S1: The first step of oxidation: oxidation of seal bile acid (PCA) to obtain intermediate I; S2: The second oxidation step: Intermediate I is further oxidized to obtain intermediate II; S3: The third oxidation step: Intermediate II is further oxidized to obtain intermediate III; S4: Reduction reaction: Compound III is subjected to reduction reaction to obtain 24-demethylursodeoxycholic acid; The route 2 includes the following steps: P1: One-pot oxidation: PCA is directly oxidized to give compound III; P2: Reduction reaction: Compound III is subjected to reduction reaction to obtain 24-demethylursodeoxycholic acid.

[0006] As a preferred technical solution of the present application, in the step S1, seal bile acid is oxidized to obtain compound I, comprising adding seal bile acid and an acidic substance to an organic solvent, adding a catalyst, controlling the reaction temperature to -10~10°C, and adding an oxidant in batches to react to obtain compound I; wherein the acid is preferably one of glacial acetic acid, citric acid and hydrochloric acid; the solvent is preferably one of methanol, ethanol, isopropanol and tert-butanol, and the catalyst is preferably one of sodium bromide, lithium bromide and potassium bromide; the oxidant is preferably one of sodium hypochlorite solution and calcium hypochlorite.

[0007] As a preferred technical solution of the present application, in the step S2, intermediate I is oxidized to obtain compound II, comprising adding intermediate I and alkali solution to an organic solvent, controlling the reaction temperature to 30-60° C., and adding an oxidant in batches to react to obtain compound II; wherein the alkali solution is preferably one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and lithium hydroxide aqueous solution; the solvent is preferably one of isopropyl acetate, n-butyl acetate, isobutyl acetate and ethyl acetate; the oxidant is preferably one of sodium hypochlorite solution and calcium hypochlorite.

[0008] As a preferred technical solution of the present application, in the step S3, intermediate II is oxidized to obtain compound III, comprising adding intermediate II, a buffer solution and an auxiliary agent to an organic solvent, controlling the reaction temperature at 10-30°C, and adding an oxidant in batches to react to obtain compound I; wherein the buffer solution is preferably one of sodium dihydrogen phosphate, potassium dihydrogen phosphate, and glacial acetic acid solution; the auxiliary agent is preferably 2-methyl-2-butene olefin, and the solvent is preferably one of tert-butanol, acetone, dichloromethane and acetonitrile; the oxidant is preferably sodium chlorite.

[0009] As a preferred technical solution of the present application, in the step P1, seal cholic acid is subjected to a one-pot multifunctional oxidation to obtain compound III, comprising adding seal cholic acid and a buffer solution to an organic solvent, adding a catalyst, controlling the reaction temperature to 0-10°C, and adding an oxidant in batches to react to obtain compound III; wherein the buffer solution is preferably one of sodium dihydrogen phosphate, potassium dihydrogen phosphate and glacial acetic acid; the solvent is preferably one of butyl acetate, isopropyl acetate and ethyl acetate, and the catalyst is preferably one of sodium bromide, lithium bromide and potassium bromide; the oxidant is preferably one of sodium hypochlorite solution and calcium hypochlorite.

[0010] As a preferred technical solution of the present application, the S4 and compound I in step P2 are subjected to a reduction reaction to obtain 24-norursodeoxycholic acid; the process comprises adding compound III, an organic base, and a catalyst into an organic solvent, controlling the temperature at 40-80° C. and the pressure at 20-50 kg under a hydrogen atmosphere, reacting for 3-10 hours, and hydrogenating compound I to obtain compound 24-norursodeoxycholic acid.

[0011] As a preferred technical solution of the present application, the organic base is preferably one of potassium tert-butoxide and sodium tert-butoxide; the catalyst is preferably one of Raney nickel and palladium carbon; the solvent is preferably one of isopropanol, tert-butanol, and ethanol.

[0012] Beneficial effects: Compared with the prior art, the present invention provides a method for synthesizing 24-norursodeoxycholic acid, which has the following beneficial effects: the method for synthesizing 24-norursodeoxycholic acid takes seal cholic acid as a starting material, performs two-step oxidation with sodium hypochlorite or other oxidants, and performs two-step oxidation with sodium chlorite and hydrogenation reduction to obtain 24-norursodeoxycholic acid, or performs one-pot oxidation with sodium hypochlorite or other oxidants, and performs two-step hydrogenation reduction to obtain 24-norursodeoxycholic acid. The raw materials of the route are easily available, the reaction conditions are mild, and the route is suitable for industrial production. The entire method for synthesizing 24-norursodeoxycholic acid has a simple structure, is easy to operate, and has a better effect than the traditional method. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The present invention is a schematic diagram of the overall structure of a method for synthesizing 24-norursodeoxycholic acid.

[0014] Figure 2 The present invention is a schematic structural diagram of route 1 in a method for synthesizing 24-norsoursodeoxycholic acid.

[0015] Figure 3 The present invention is a schematic structural diagram of route 2 in a method for synthesizing 24-norursodeoxycholic acid. DETAILED DESCRIPTION

[0016] The technical scheme of the present invention will be clearly and completely described below in conjunction with the accompanying drawings and specific embodiments, but it will be understood by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work are within the scope of protection of the present invention. If specific conditions are not specified in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not specified in the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0017] In the description of the present invention, it should be noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., indicating the orientation or positional relationship, are based on the orientation or positional relationship shown in the drawings, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as limiting the present invention. In addition, the terms "first", "second", and "third" are used for descriptive purposes only, and cannot be understood as indicating or implying relative importance.

[0018] In the description of the present invention, it should be noted that, unless otherwise clearly specified and limited, the terms "installed", "connected", and "connected" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection, or it can be indirectly connected through an intermediate medium, or it can be the internal communication of two components. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0019] like Figure 1-3 As shown, a method for synthesizing 24-demethylursodeoxycholic acid includes route 1 and route 2, wherein route 1 includes the following steps: S1: The first step of oxidation: oxidation of seal bile acid (PCA) to obtain intermediate I; S2: The second oxidation step: Intermediate I is further oxidized to obtain intermediate II; S3: The third oxidation step: Intermediate II is further oxidized to obtain intermediate III; S4: Reduction reaction: Compound III is subjected to reduction reaction to obtain 24-demethylursodeoxycholic acid; Route 2 includes the following steps: P1: One-pot oxidation: PCA is directly oxidized to give compound III; P2: Reduction reaction: Compound III is subjected to reduction reaction to obtain 24-demethylursodeoxycholic acid.

[0020] The method uses seal cholic acid as a starting material, undergoes two-step oxidation reaction with sodium hypochlorite or other oxidants, and then undergoes two-step oxidation reaction with sodium chlorite and hydrogenation reduction to obtain 24-norursodeoxycholic acid, or undergoes one-pot oxidation of seal cholic acid with sodium hypochlorite or other oxidants, and then undergoes two-step hydrogenation reduction reaction to obtain 24-norursodeoxycholic acid. The raw materials of the route are easily available, the reaction conditions are mild, and the method is suitable for industrial production.

[0021] Furthermore, in step S1, seal bile acid is oxidized to obtain compound I, comprising adding seal bile acid and an acidic substance to an organic solvent, adding a catalyst, controlling the reaction temperature to -10~10°C, and adding an oxidant in batches to react to obtain compound I; wherein the acid is preferably one of glacial acetic acid, citric acid and hydrochloric acid; the solvent is preferably one of methanol, ethanol, isopropanol and tert-butanol, and the catalyst is preferably one of sodium bromide, lithium bromide and potassium bromide; and the oxidant is preferably one of sodium hypochlorite solution and calcium hypochlorite.

[0022] Furthermore, in step S2, intermediate I is oxidized to obtain compound II, comprising adding intermediate I and alkali solution to an organic solvent, controlling the reaction temperature to 30-60° C., and adding an oxidant in batches to react to obtain compound II; wherein the alkali solution is preferably one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and lithium hydroxide aqueous solution; the solvent is preferably one of isopropyl acetate, n-butyl acetate, isobutyl acetate and ethyl acetate; and the oxidant is preferably one of sodium hypochlorite solution and calcium hypochlorite.

[0023] Furthermore, in step S3, intermediate II is oxidized to obtain compound III, which comprises adding intermediate II, a buffer solution and an auxiliary agent to an organic solvent, controlling the reaction temperature at 10-30° C., and adding an oxidant in batches to react to obtain compound I; wherein the buffer solution is preferably one of sodium dihydrogen phosphate, potassium dihydrogen phosphate, and glacial acetic acid solution; the auxiliary agent is preferably 2-methyl-2-butene olefin, and the solvent is preferably one of tert-butanol, acetone, dichloromethane and acetonitrile; and the oxidant is preferably sodium chlorite.

[0024] Furthermore, in step P1, seal cholic acid is subjected to a one-pot multifunctional oxidation to obtain compound III, comprising adding seal cholic acid and a buffer solution to an organic solvent, adding a catalyst, controlling the reaction temperature to 0-10°C, and adding an oxidant in batches to react to obtain compound III; wherein the buffer solution is preferably one of sodium dihydrogen phosphate, potassium dihydrogen phosphate and glacial acetic acid; the solvent is preferably one of butyl acetate, isopropyl acetate and ethyl acetate, and the catalyst is preferably one of sodium bromide, lithium bromide and potassium bromide; and the oxidant is preferably one of sodium hypochlorite solution and calcium hypochlorite.

[0025] Further, the compound I in step S4 and P2 is subjected to a reduction reaction to obtain 24-norsoursodeoxycholic acid; the process comprises adding compound III, an organic base, and a catalyst into an organic solvent, controlling the temperature at 40-80° C. and the pressure at 20-50 kg under a hydrogen atmosphere for 3-10 hours, and hydrogenating compound I to obtain compound 24-norsoursodeoxycholic acid.

[0026] Furthermore, the organic base is preferably one of potassium tert-butoxide and sodium tert-butoxide; the catalyst is preferably one of Raney nickel and palladium on carbon; and the solvent is preferably one of isopropanol, tert-butanol and ethanol.

[0027] Synthesis of Compound I Series Embodiment 1:

[0028] Seal cholic acid (PCA) (50g, 0.122mol), acetic acid aqueous solution (200mL, 30%) and sodium bromide (2.5g) were added to 500mL of methanol in sequence and cooled to -10-0℃. Under stirring, 150mL of sodium hypochlorite solution (active chlorine ≥5.0%) was added dropwise to the above reaction solution, and the temperature was controlled at -10~10℃. After the addition was completed, the mixture was kept warm and stirred for 1~2h. After the reaction was completed, 200mL of saturated sodium sulfite solution was added dropwise at 0~10℃ to quench the reaction. Methanol was removed by concentration under reduced pressure, and the residue was extracted with DCM (200mL, 100mL, 100mL). The organic phases were combined and washed once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 48.2g of color-like solid compound I with an HPLC purity of 93.5% and a yield of 97.3%. Embodiment 2:

[0029] Seal cholic acid (PCA) (50g, 0.122mol), sodium dihydrogen phosphate aqueous solution (500mL, 15%) and potassium bromide (2.5g) were added to 500mL of tert-butanol in sequence and cooled to -10-0℃. Under stirring, calcium hypochlorite (26.2g, 0.183mol) was added to the above reaction solution in batches, and the temperature was controlled at -10~10℃. After the addition was completed, the mixture was kept warm and stirred for 1~2h. After the reaction was completed, 200mL of saturated sodium sulfite solution was added dropwise at 0~10℃ to quench the reaction. The tert-butanol was removed by concentration under reduced pressure, and the residue was extracted with DCM (200mL, 100mL, 100mL). The organic phases were combined and washed once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 45.3g of color-like solid compound I with an HPLC purity of 91.7% and a yield of 91.5%.

[0030] Synthesis of Compound II Series Embodiment 3:

[0031] The intermediate I (45 g, 0.111 mol) and 200 mL of 10% sodium hydroxide solution were added to 500 mL of isopropyl acetate at one time, and the temperature was raised to 30-40°C. 300 mL of sodium hypochlorite solution (active chlorine ≥ 5.0%) was added dropwise to the above reaction solution under stirring. After the addition was completed, the temperature was controlled at 40-60°C for reaction. After the reaction was completed, the temperature was cooled to room temperature, and 100 mL of sodium sulfite solution was added to quench the reaction. The organic phase was separated, and the aqueous phase was extracted once with 200 mL of isopropyl acetate. The organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 35.9 g of color-like solid compound II with HPLC purity of 95.4% and a yield of 89.8%. Embodiment 4:

[0032] The intermediate I (45 g, 0.111 mol) and 300 mL of 5% lithium hydroxide solution were added to 500 mL of n-butyl acetate at one time, and the temperature was raised to 30-40 °C. Calcium hypochlorite (49.2 g, 0.275 mol) was added to the above reaction solution in batches under stirring, and the temperature was controlled at 40-60 °C for reaction. After the reaction was completed, the temperature was cooled to room temperature, and 100 mL of sodium sulfite solution was added to quench the reaction. The mother liquor was filtered to separate the organic phase, and the aqueous phase was extracted once with 200 mL of isopropyl acetate. The organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 36.5 g of color-like solid compound II with HPLC purity of 97.2% and a yield of 91.3%.

[0033] Synthesis of Compound III Series Embodiment 5:

[0034] Intermediate II (35 g, 0.0972 mol), 180 mL of 10% sodium dihydrogen phosphate solution and 150 g of 2-methyl-2-butene were added to 180 mL of tert-butanol in sequence, and the temperature was controlled at 10-30 °C. Sodium chlorite (80%, 22.6 g, 0.20 mol) was added to the above reaction solution in batches under stirring, and the temperature was controlled at 10-30 °C for reaction. After the reaction was completed, 100 mL of sodium sulfite solution was added to quench the reaction, and most of the organic solvent was removed by concentration under reduced pressure. The residue was extracted with dichloromethane (200 mL, 100 mL, 100 mL) to separate the organic phase, washed once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product which was recrystallized with anhydrous ethanol to obtain 30.8 g of a color-like solid compound III with an HPLC purity of 96.6% and a yield of 84.5%.

[0035] 1H-NMR (400MHz, CD3OD) δ0.76 (s, 3H), δ0.99 (S, 3H), 1.02-1.06 (m, 3H), 1.27-1.32 (m, 7H), 1.45-1.51 (m, 6H), 1.62-1.66 (m, 3H), 1.84-1.89 (m, 6H), 1.98-2.05 (m, 1H), 2.43-2.46 (m, 1H) 3.50-3.53 (m, 2H). Embodiment 6:

[0036] Intermediate II (35 g, 0.0972 mol), 200 mL of 20% acetic acid aqueous solution and 150 g of 2-methyl-2-butene were added to 200 mL of acetone in sequence, and the temperature was controlled at 10-30 °C. Sodium chlorite (80%, 22.6 g, 0.20 mol) was added to the above reaction solution in batches under stirring, and the temperature was controlled at 10-30 °C for reaction. After the reaction was completed, 100 mL of sodium sulfite solution was added to quench the reaction, and most of the organic solvent was removed by concentration under reduced pressure. The residue was extracted with dichloromethane (200 mL, 100 mL, 100 mL) to separate the organic phase, washed once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product which was recrystallized with anhydrous ethanol to obtain 29.6 g of a color-like solid compound III with an HPLC purity of 95.8% and a yield of 81.1%. Embodiment 7:

[0037] Seal cholic acid (PCA) (50g, 0.122mol), 300mL sodium dihydrogen phosphate aqueous solution and sodium bromide (0.2g, 0.002mol) were added to 500mL of isopropyl acetate in sequence and cooled to 0-5°C. Under stirring, 500mL of sodium hypochlorite solution (active chlorine ≥5.0%) was added dropwise to the above reaction solution, and the temperature was controlled not to exceed 10°C. After the addition was completed, it was stirred at 0-10°C for 5-10h. After the reaction was completed, 100mL of saturated sodium sulfite was added dropwise at 0-10°C to quench the reaction. After static separation, the organic phase was separated, and the aqueous phase was extracted with isopropyl acetate (200mL×2). After the organic phases were combined, they were washed with water, dried over anhydrous sodium sulfate, and the crude product after reduced pressure concentration was recrystallized twice with anhydrous ethanol to obtain 28.3g of white solid compound III, HPLC=94.1%, and the yield was 61.7%. Embodiment 8:

[0038] Seal cholic acid (PCA) (50g, 0.122mol), 300mL of 20% acetic acid aqueous solution and potassium bromide (0.25g, 0.002mol) were added to 500mL of n-butyl acetate in sequence and cooled to 0-5°C. Calcium hypochlorite (87.2g, 0.61mol) was added to the above reaction solution in batches under stirring, and the temperature was controlled not to exceed 10°C. After the addition was completed, it was stirred at 0-10°C for 5-10h. After the reaction was completed, 100mL of saturated sodium sulfite was added dropwise at 0-10°C to quench the reaction. After static separation, the organic phase was separated, and the aqueous phase was extracted with n-butyl acetate (200mL×2). The organic phases were combined and washed with water, dried over anhydrous sodium sulfate, and the crude product after reduced pressure concentration was recrystallized twice with anhydrous ethanol to obtain 25.8g of white solid compound III, HPLC=93.8%, yield 56.2%.

[0039] Synthesis of Compound 24-Demethylursodeoxycholic Acid Embodiment 9:

[0040] 500 mL of isopropanol, compound I (50 g, 0.133 mol), potassium tert-butoxide (17.9 g, 0.159 mol) and Raney nickel (2.5 g) were added to a 1 L autoclave in sequence. After the autoclave was sealed, nitrogen and hydrogen were replaced three times, and the reaction was stirred at 50-60 ° C and a pressure of 20-25 kg for 6-8 hours. After the reaction was completed, the temperature was cooled to room temperature, the catalyst was filtered off, and about 100 mL of 5% dilute hydrochloric acid was added to acidify to a pH of 4-5. The isopropanol was removed by concentration under reduced pressure, and the residue was extracted with dichloromethane (500 mL, 200 mL, 200 mL). The polar phases were combined and concentrated under reduced pressure to remove most of the solvent. Isopropyl acetate was added for recrystallization to obtain 42.4 g of white solid 24-demethylursodeoxycholic acid with a yield of 84.2% and a purity of 98.6%.

[0041] 1H-NMR (400MHz, CD3OD): δ (ppm) 0.75 (s, 3H), 0.97 (s, 3H), 1.00-1.03 (m, 3H), 1.24-1.31 (m, 7H), 1.44-1.50 (m, 6H), 1.61-1 .64(m, 3H), 1.83-1.88(m, 6H), 1.95-2.03(m, 1H), 2.41-2.45(m, 1H), 3.48-3.51(m, 2H).

[0042] In summary, the preparation method of the present invention uses the readily available bis-decanoic acid alcohol as the starting raw material, the raw material is readily available, the reaction conditions are mild, and it is suitable for industrial production.

[0043] It should be noted that, in this article, relational terms such as first and second (number one, number two), etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "including one..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0044] The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.

Claims

1. A method for synthesizing 24-norursodeoxycholic acid, comprising route 1 and route 2, characterized in that: The route 1 comprises the following steps: S1: The first step of oxidation: oxidation of seal bile acid (PCA) to obtain intermediate I; S2: The second oxidation step: Intermediate I is further oxidized to obtain intermediate II; S3: The third oxidation step: Intermediate II is further oxidized to obtain intermediate III; S4: Reduction reaction: Compound III is subjected to reduction reaction to obtain 24-demethylursodeoxycholic acid; The route 2 includes the following steps: P1: One-pot oxidation: PCA is directly oxidized to give compound III; P2: Reduction reaction: Compound III is subjected to reduction reaction to obtain 24-demethylursodeoxycholic acid.

2. A method for synthesizing 24-norursodeoxycholic acid according to claim 1, characterized in that: In step S1, phocolic acid is oxidized to obtain compound I, which comprises adding phocolic acid and an acidic substance into an organic solvent, adding a catalyst, controlling the reaction temperature to -10 to 10°C, and adding an oxidant in batches to react to obtain compound I; wherein the acid is preferably one of glacial acetic acid, citric acid and hydrochloric acid; the solvent is preferably one of methanol, ethanol, isopropanol and tert-butanol, and the catalyst is preferably one of sodium bromide, lithium bromide and potassium bromide; and the oxidant is preferably one of sodium hypochlorite solution and calcium hypochlorite.

3. A method for synthesizing 24-norursodeoxycholic acid according to claim 1, characterized in that: In the step S2, intermediate I is oxidized to obtain compound II, comprising adding intermediate I and alkali solution to an organic solvent, controlling the reaction temperature to 30-60° C., and adding an oxidant in batches to react to obtain compound II; wherein the alkali solution is preferably one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution and lithium hydroxide aqueous solution; the solvent is preferably one of isopropyl acetate, n-butyl acetate, isobutyl acetate and ethyl acetate; and the oxidant is preferably one of sodium hypochlorite solution and calcium hypochlorite.

4. A method for synthesizing 24-norursodeoxycholic acid according to claim 1, characterized in that: In the step S3, intermediate II is oxidized to obtain compound III, which comprises adding intermediate II, a buffer solution and an auxiliary agent into an organic solvent, controlling the reaction temperature at 10-30° C., and adding an oxidant in batches to react to obtain compound I; wherein the buffer solution is preferably one of sodium dihydrogen phosphate, potassium dihydrogen phosphate, and glacial acetic acid solution; the auxiliary agent is preferably 2-methyl-2-butene olefin; the solvent is preferably one of tert-butyl alcohol, acetone, dichloromethane and acetonitrile; and the oxidant is preferably sodium chlorite.

5. A method for synthesizing 24-norursodeoxycholic acid according to claim 1, characterized in that: In step P1, the compound III is obtained by one-pot multifunctional oxidation of cholic acid, which comprises adding cholic acid and a buffer solution to an organic solvent, adding a catalyst, controlling the reaction temperature to 0-10° C., and adding an oxidant in batches to react to obtain the compound III; wherein the buffer solution is preferably one of sodium dihydrogen phosphate, potassium dihydrogen phosphate and glacial acetic acid; the solvent is preferably one of butyl acetate, isopropyl acetate and ethyl acetate, and the catalyst is preferably one of sodium bromide, lithium bromide and potassium bromide; and the oxidant is preferably one of sodium hypochlorite solution and calcium hypochlorite.

6. A method for synthesizing 24-norursodeoxycholic acid according to claim 1, characterized in that: The S4 and P2 steps combine compound I to undergo a reduction reaction to obtain 24-norursodeoxycholic acid; the step comprises adding compound III, an organic base, and a catalyst into an organic solvent, controlling the temperature at 40-80° C. and the pressure at 20-50 kg under a hydrogen atmosphere for 3-10 hours, and hydrogenating compound I to obtain compound 24-norursodeoxycholic acid.

7. A method for synthesizing 24-norursodeoxycholic acid according to claim 6, characterized in that: The organic base is preferably one of potassium tert-butoxide and sodium tert-butoxide; the catalyst is preferably one of Raney nickel and palladium carbon; the solvent is preferably one of isopropanol, tert-butanol and ethanol.

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