Method for preparing ursodeoxycholic acid intermediate

Abstract

A method for preparing a key intermediate 7K of ursodeoxycholic acid (UDCA). The key intermediate 7K of UDCA is prepared from BA by means of eight steps of reaction below: first subjecting the raw material BA to sulfonylation and then to alkylation with a malonic diester so as to construct a 21-position side chain, in which steps, sulfonylation and alkylation proceed readily, the conditions are mild, and there are few by-products and impurities; and then subjecting same to ketal protection, oxidation, hydrolysis, hydrogenation, hydrolysis and decarboxylation.

Description

Preparation method of ursodeoxycholic acid intermediate TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemical synthesis / medicinal synthesis, and relates to a synthesis method of a key intermediate 7K of ursodeoxycholic acid (UDCA), in particular to a method for synthesizing 7K from BA (21-hydroxy-20-methylpregn-4-ene-3-one) as a raw material. BACKGROUND

[0002] There are mainly two sources of ursodeoxycholic acid (UDCA), namely animal bile extraction and artificial synthesis, but the resource of animal bile extraction is limited and difficult to meet the medical needs, so it mainly depends on artificial synthesis.

[0003] There are mainly two methods for artificial synthesis of ursodeoxycholic acid: one is to use animal-derived starting materials for semi-synthesis, such as using pig deoxycholic acid (HDCA), goose deoxycholic acid (CDCA), cholic acid (CA) and the like as starting materials, which can obtain ursodeoxycholic acid through multi-step chemical transformation, but these animal-derived starting materials may contain animal proteins, which may cause certain safety risks for human use, and the ursodeoxycholic acid prepared from animal-derived starting materials has complex impurities and is difficult to purify, so it is difficult to obtain high-purity ursodeoxycholic acid. The other is to use plant-derived starting materials for semi-synthesis, such as using BA (21-hydroxy-20-methylpregn-4-ene-3-one) as a starting material, and then through a key intermediate 7K, and then through chemical reduction or enzymatic reduction, it is a more commonly used method for preparing ursodeoxycholic acid.

[0004] Patents CN116836213 and CN111072744 disclose a method for preparing ursodeoxycholic acid or a key intermediate 7K from BA as a starting material, which is oxidized to introduce a 21-position side chain through condensation / Wittig reaction, and then prepared through multi-step reaction, but the synthesis process requires strict conditions of no water and no oxygen:

[0005] Patent CN115181150 discloses a method for preparing ursodeoxycholic acid from BA as a starting material, which is sulfonated to form a 21-position side chain through a bromoacetaldehyde derivative Grignard reagent alkylation reaction, and then prepared through multi-step reaction. The reaction process includes Grignard reaction, which requires not only no water and no oxygen, but also the Grignard reagent is difficult to prepare:

[0006] Patents CN109415407 and WO2023081657 disclose a method for preparing obeticholic acid and the like from BA as a raw material, which is brominated to form a 21-position side chain through diethyl malonate alkylation, and then prepared through multi-step reaction. The reaction is difficult because bromine is not easily substituted:

[0007] Therefore, it is still necessary to further explore a synthetic method with mild reaction conditions, simple operation and suitable for industrial production. SUMMARY

[0008] Therefore, the application provides a preparation method of a key intermediate 7K of ursodeoxycholic acid.

[0009] The technical scheme of the application is implemented as follows:

[0010] The application provides a preparation method of a key intermediate of ursodeoxycholic acid, and the key intermediate of ursodeoxycholic acid is 7K, as shown in formula (I).

[0011] The preparation method of the ursodeoxycholic acid intermediate comprises the following steps:

[0012] wherein R = CH3, -CH2CH3;

[0013] (a) sulfonating formula (II) to obtain a sulfonate of formula (III);

[0014] (b) the sulfonate of formula (III) is subjected to an alkylation reaction to obtain a double ester of formula (IV);

[0015] (c) the double ester of formula (IV) is subjected to a ketalization reaction to obtain a ketal of formula (V);

[0016] (d) the ketal of formula (V) is subjected to an oxidation reaction to obtain a ketal oxide of formula (VI);

[0017] (e) the ketal oxide of formula (VI) is subjected to a hydrolysis reaction to obtain a 3,7-diketone of formula (VII);

[0018] (f) the 3,7-diketone of formula (VII) is subjected to a hydrogenation reduction reaction to obtain a 7K double ester of formula (VIII);

[0019] (g) the 7K double ester of formula (VIII) is subjected to a hydrolysis reaction to obtain a 7K double carboxylic acid of formula (IX);

[0020] (h) the 7K double carboxylic acid of formula (IX) is subjected to a decarboxylation reaction to obtain 7K of formula (I).

[0021] Specifically, in step (a), BA (formula (II), 21-hydroxy-20-methylpregn-4-ene-3-one) is used as a starting material, and a sulfonate of formula (III) is obtained through a sulfonation reaction.

[0022] In the dichloromethane solution, the BA and p-toluenesulfonyl chloride undergo a sulfonylation reaction with 4-dimethylaminopyridine as an acylation reaction catalyst and triethylamine as an acid-binding agent; after water separation, extraction and concentration, and methanol beating, the sulfonyl compound is obtained;

[0023] In some embodiments, the molar ratio of BA, triethylamine and p-toluenesulfonyl chloride in step (a) is 1:(2-2.5):(1-1.5);

[0024] In some embodiments, the volume of dichloromethane is 5-10 times the mass of BA;

[0025] In some embodiments, the molar ratio of 4-dimethylaminopyridine to BA in step (a) is (0.08-0.1):1.

[0026] Specifically, the sulfonyl compound of formula (III) in step (b) undergoes an alkylation reaction to obtain a double ester compound of formula (IV):

[0027] The sulfonyl compound and diethyl malonate or dimethyl malonate undergo an alkylation reaction with DMF as the reaction solvent, potassium carbonate as the base, and TBAB as the phase transfer catalyst; after water separation, the double ester compound crude product is obtained, and then purified by ethanol beating to obtain the double ester compound;

[0028] In some embodiments, the molar ratio of the sulfonyl compound and diethyl malonate or dimethyl malonate in step (b) is 1:(2.5-3.5);

[0029] In some embodiments, the volume of DMF is 8-12 times the mass of the sulfonyl compound;

[0030] In some embodiments, the molar ratio of the sulfonyl compound, potassium carbonate and TBAB is 1:(2.5-3):(0.09-0.1).

[0031] Specifically, the double ester compound of formula (IV) in step (c) undergoes a ketal reaction to obtain a ketal compound of formula (V):

[0032] The double ester compound undergoes a ketal reaction with ethylene glycol as the reaction solvent and ketal reagent, triethyl orthoformate as the dehydrating agent, and p-toluenesulfonic acid as the catalyst; after water separation, the ketal compound crude product is obtained, and then purified by ethanol beating to obtain the ketal compound;

[0033] In some embodiments, the molar ratio of the double ester compound and p-toluenesulfonic acid is 1:(0.04-0.05);

[0034] In some embodiments, the ratio of the double ester compound, ethylene glycol and triethyl orthoformate is 1g:(1.8-2.2)mL:(1-1.2)mL;

[0035] Specifically, in step (d), the ketal of formula (V) is subjected to an oxidation reaction to obtain a ketal oxide of formula (VI):

[0036] The ketal is subjected to an oxidation reaction at the 7-position in acetone as a solvent, PDC as an oxidant, and NHPI as a catalyst; the reaction solution is subjected to post-treatment, recrystallized in ethanol to obtain the ketal oxide.

[0037] In some embodiments, the molar ratio of the ketal to PDC (MW = 376.21) and NHPI (MW 163.13) is 1: (1.1-1.5): (1.3-1.7);

[0038] In some embodiments, the volume of acetone is 5-10 times the mass of the ketal;

[0039] Specifically, in step (e), the ketal oxide of formula (VI) is subjected to an acidic hydrolysis to obtain a 3,7-diketone of formula (VII):

[0040] The ketal oxide is subjected to a hydrolysis of the 3-position ketal in a mixed solvent of tetrahydrofuran and water under hydrochloric acid conditions; neutralization, layering, extraction, concentration, and petroleum ether beating purification are performed to obtain the 3,7-diketone;

[0041] In some embodiments, the ratio of the ketal oxide, tetrahydrofuran, water, and hydrochloric acid is 1 g: 9 mL: 1 mL: 1 mL.

[0042] Specifically, in step (f), the 3,7-diketone of formula (VII) is subjected to a hydrogenation reaction to obtain a 7K double ester of formula (VIII):

[0043] The 3,7-diketone is subjected to a hydrogenation reduction reaction in tetrahydrofuran solution with Raney Ni as a catalyst in a hydrogen atmosphere at normal pressure; the catalyst is removed by filtration, and the reaction solution is directly concentrated to obtain the 7K double ester, which is directly used in the next alkaline hydrolysis reaction.

[0044] In some embodiments, the mass ratio of the 3,7-diketone to Raney Ni is 1: 2-3;

[0045] In some embodiments, the volume (in ml) of tetrahydrofuran is 15-20 times the mass (in g) of the 3,7-diketone.

[0046] Specifically, in step (g), the 7K double ester of formula (VIII) is subjected to an alkaline hydrolysis reaction to obtain a 7K double carboxylic acid of formula (IX):

[0047] The 7K double ester is subjected to a hydrolysis with a potassium hydroxide aqueous solution in methanol solution; neutralization with hydrochloric acid and water precipitation are performed to obtain the 7K double carboxylic acid;

[0048] In some embodiments, the molar concentration of the added potassium hydroxide is 10 mol / L, and the mass ratio of the 7K double ester and the potassium hydroxide is 1:(0.35-0.4).

[0049] Specifically, the 7K double carboxylic acid in step (h) is subjected to decarboxylation to obtain 7K of formula (I):

[0050] In the DMSO solution, an aqueous sodium chloride solution is added, and the 7K double carboxylic acid is subjected to high-temperature decarboxylation to obtain 7K by water extraction;

[0051] In some embodiments, the volume of DMSO is 5-10 times the mass of the 7K double carboxylic acid.

[0052] In some embodiments, the mass ratio of the 7K double carboxylic acid and the sodium chloride is 1:(0.5-1).

[0053] The present application also provides a compound, the structure of the compound comprises formula (V-1), formula (VI-1), formula (VII-1), formula (VIII-1), formula (V-2), formula (VI-2), formula (VII-2), formula (VIII-2) or formula (IX) respectively: BRIEF DESCRIPTION OF DRAWINGS

[0054] Figure 1 is the nuclear magnetic resonance hydrogen spectrum (H-NMR) of the ketal prepared in step (c) of Example 1;

[0055] Figure 2 is the nuclear magnetic resonance hydrogen spectrum (H-NMR) of the ketal oxide prepared in step (d) of Example 1;

[0056] Figure 3 is the nuclear magnetic resonance hydrogen spectrum (H-NMR) of the 3,7-biketone prepared in step (e) of Example 1;

[0057] Figure 4 is the nuclear magnetic resonance hydrogen spectrum (H-NMR) of the 7K double carboxylic acid prepared in step (g) of Example 1;

[0058] Figure 5 is the nuclear magnetic resonance hydrogen spectrum (H-NMR) of 7K prepared in step (h) of Example 1. DETAILED DESCRIPTION

[0059] EXAMPLE

[0060] HPLC Method 1:

[0061] Chromatographic column: InfinityLab Poroshell 120 EC-C18 (4.6x150mm, 4.6 Micron), Agilent.

[0062] Mobile phase: water and acetonitrile gradient

[0063] Flow rate: 1 ml / min

[0064] Detector: UV detector (VWD), signal polarity: positive; dual wavelength 210 nm & 254 nm

[0065] Column oven temperature: 29.9 °C

[0066] Injection volume: 20 ul

[0067] Collection time: 30 min

[0068] Preparation solvent: acetonitrile (1 mg / ml);

[0069] Data processing: 0.05% or less not integral

[0070] HPLC Method 2:

[0071] Column: InfinityLab Poroshell 120 EC-C18 (4.6 x 150 mm, 4.6 Micron), Agilent.

[0072] Mobile phase: acetonitrile: formic acid in water (0.4%) = 50:50

[0073] Flow rate: 0.8 ml / min

[0074] Detector: refractive index detector (RID), signal polarity: positive

[0075] Detector temperature: 35 °C

[0076] Column oven temperature: 35 °C

[0077] Injection volume: 20 ul

[0078] Collection time: 70 min

[0079] Example 1:

[0080] Step (a) sulfonylation reaction - preparation of sulfonyl of formula (III)

[0081] In a 3L reaction flask, 1L of dichloromethane and 200g of BA were added and stirred to dissolve and clarify, 6.4g of 4-dimethylaminopyridine, 200ml of triethylamine were added in turn, 150g of p-toluenesulfonyl chloride was slowly added in 400ml of dichloromethane, after the addition was completed, the reaction liquid was warmed to reflux reaction for 4-5h, until TLC (PE:EA = 3:1, UV 254nm coloration) showed that the raw material was completely converted.

[0082] The reaction solution was poured into 1 L of water, stirred, and allowed to separate into layers. The organic phase was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. 200 ml of methanol was added, and the mixture was stirred for 1-2 h while being cooled to 0-5°C. The mixture was filtered, and the filter cake was dried under reduced pressure at 40-50°C to obtain 271 g of white sulfonate, in a yield of 91.1%, and the purity was 98.52% as determined by HPLC Method 1 (254 nm).

[0083] Step (b) alkylation reaction - preparation of diester of formula (IV) (R = -CH2CH3)

[0084] In a 5 L reaction flask, 270 g of sulfonate was dissolved in 2.7 L of DMF under nitrogen protection. 230 g of potassium carbonate, 18 g of TBAB, and 270 g of diethyl malonate were added. The mixture was stirred at 50-60°C for 10 h until TLC (PE:EA = 2:1, visualized by ultraviolet 254 nm) showed that the starting material was completely converted.

[0085] The reaction solution was slowly poured into 2700 ml of water, and the crude diester was obtained by filtration. 540 ml of ethanol was added to the crude product, and the mixture was stirred for 30 min. The mixture was filtered, and the filter cake was dried under reduced pressure at 40-50°C to obtain 225 g of white diester, in a yield of 85.4%, and the purity was 92.20% as determined by HPLC Method 1 (254 nm).

[0086] Step (c) ketal reaction - preparation of ketal of formula (V) (R = -CH2CH3)

[0087] In a 3 L reaction flask, 800 ml of ethylene glycol, 420 ml of triethyl orthoformate, and 7.28 g of p-toluenesulfonic acid were added. 400 g of diester was added, and the mixture was reacted at 20-25°C for 10 h until TLC (developing agent: PE:EA = 3:1, visualized by vanillin) showed that the starting material was completely converted.

[0088] The reaction solution was poured into 800 ml of water, stirred for 1 h, and filtered to obtain the crude ketal. 800 ml of ethanol was added to the crude product, and the mixture was stirred at 50-60°C for 1 h. The mixture was cooled to 0-10°C and stirred for 1 h. The mixture was filtered, and the filter cake was dried under reduced pressure at 40-50°C to obtain 372 g of ketal, in a yield of 85%, and the purity was 92.67% as determined by HPLC Method 1 (210 nm), as shown in FIG. 1.

[0089] Step (d) oxidation reaction - preparation of ketal oxide of formula (VI) (R = -CH2CH3)

[0090] In a 3 L reaction flask, 2 L of acetone, 200 g of ketal, 200 g of PDC, and 100 g of NHPI were added under nitrogen protection. The mixture was stirred at 40-50°C for 4-5 h until TLC (PE:EA = 3:1, visualized by vanillin) showed that the starting material was completely converted.

[0091] The reaction solution was concentrated to dryness under reduced pressure, 2 L of ethyl acetate was added and stirred for 30 min, the mixture was filtered through diatomite, the filtrate was washed once with 2 L of 1.5 M aqueous sodium hydroxide solution and then once with 2 L of saturated brine, and the organic phase was concentrated to dryness under reduced pressure at 45-50°C.

[0092] To the concentrate was added 400 ml of ethanol, and the solution was warmed to reflux and then cooled to room temperature and stirred for 1 h, filtered, and the filter cake was dried under reduced pressure at 40-50°C to give 144 g of white ketal oxide, in a yield of 70%, with a purity of 97.47% as determined by HPLC Method 1 (254 nm), as shown in Figure 2.

[0093] Step (e) Acidic hydrolysis reaction - preparation of 3,7-biketone of formula (VII) (R = -CH2CH3)

[0094] In a 3 L reaction flask was added 900 ml of tetrahydrofuran, 100 ml of water and 100 g of ketal oxide, which was stirred to dissolve, 100 ml of hydrochloric acid was added, and the reaction was stirred at a temperature of 40-50°C for 4 h, until TLC (PE:EA = 2:1, visualized by ultraviolet light at 254 nm) showed that the starting material was completely converted.

[0095] The reaction solution was neutralized by adding 1000 ml of saturated aqueous sodium bicarbonate solution, and the layers were separated, the aqueous layer was extracted with 500 ml of ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, 300 ml of petroleum ether was added, stirred at room temperature for 1 h, filtered, and the filter cake was dried under reduced pressure at 40-50°C to give 82.5 g of white 3,7-biketone solid, in a yield of 92%, with a purity of 81.35% as determined by HPLC Method 1 (254 nm). The nuclear magnetic resonance spectrum of the product of step (e) is shown in Figure 3.

[0096] Step (f) Hydrogenation, hydrolysis reaction - preparation of 7K diester of formula (VIII)

[0097] In a 3 L reaction flask was added 1.6 L of tetrahydrofuran, 80 g of 3,7-biketone, which was stirred to dissolve, 200 g of Raney Ni was added, the reaction flask was purged with nitrogen 3 times and then with hydrogen 3 times, and then a slight positive pressure of hydrogen was maintained, and the reaction was stirred at room temperature for 24 h, until TLC (PE:EA = 2:1, visualized by phosphomolybdic acid) showed that the starting material was completely converted.

[0098] The catalyst was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 7K diester of formula (VIII).

[0099] Step (g) Hydrolysis reaction - preparation of 7K dicarboxylic acid

[0100] The 72g 7K bis-ester of the above formula (VIII) was dissolved in 560ml of methanol, 28g of potassium hydroxide in 48ml of water was slowly added, the temperature was raised to 50-60°C and the reaction was stirred for 2h until TLC (dichloromethane:methanol = 20:1, molybdenum phosphoric acid coloration) showed that the hydrolysis reaction was complete.

[0101] The reaction solution was cooled to room temperature, 1.2L of water was added, and the pH value was adjusted to 4-5 with 3M hydrochloric acid, a large amount of solid was precipitated, and the stirring was continued at room temperature for 2h, then filtered, and the filter cake was dried under reduced pressure at 40-50°C to obtain white 7K bis-carboxylic acid 70.4g, the yield of two steps of hydrogenation and hydrolysis was 93%, the purity was 90.49% detected by HPLC method 2, as shown in Figure 4.

[0102] Step (h) decarboxylation reaction-preparation of 7K of formula (I)

[0103] In a 3L reaction bottle, 600ml of DMSO and 60g of 7K bis-carboxylic acid were added and stirred to dissolve, 30g of sodium chloride and 36ml of water were added, the temperature was raised to 140-150°C and refluxed for 5h until TLC (dichloromethane:methanol = 20:1, molybdenum phosphoric acid coloration) showed that the raw material was completely converted.

[0104] The reaction solution was cooled to room temperature, poured into 3L of water, stirred for 1h, and the crude solid product was precipitated, then filtered. The wet filter cake was added with 60ml of methanol, stirred at room temperature for 1h, filtered, and the filter cake was dried under reduced pressure at 40-50°C to obtain white 7K 48g, the yield was 89.3%, the purity was 96.40% detected by HPLC method 2, as shown in Figure 5.

[0105] As can be seen, the purity of 7K prepared by this route is more than 95%, which is significantly higher than the purity of 88-90% of 7K obtained by the existing process route.

[0106] Example 2:

[0107] Step (a) sulfonylation reaction-preparation of sulfonyl of formula (III)

[0108] In a 3L reaction bottle, 1.4L of dichloromethane and 200g of BA were added and stirred to dissolve and clarify, 6.18g of 4-dimethylaminopyridine and 175.7ml of triethylamine were added in turn, 120.48g of p-toluenesulfonyl chloride in 400ml of dichloromethane was slowly added dropwise, after the addition was completed, the reaction solution was raised to reflux and reacted for 4-5h until TLC (PE:EA = 3:1, ultraviolet 254nm coloration) showed that the raw material was completely converted.

[0109] The reaction solution was poured into 1 L of water, stirred, and allowed to separate into layers. The organic phase was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. 200 ml of methanol was added, and stirred for 1-2 h while being cooled to 0-5°C. Filtration was performed, and the product was dried under reduced pressure at 40-50°C to obtain 256 g of white sulfonate with a yield of 88.3% and a purity of 97.28% as determined by HPLC method 1 (254 nm).

[0110] Step (b) alkylation reaction - preparation of diester of formula (IV) (R = -CH2CH3)

[0111] In a 5 L reaction flask, 250 g of sulfonate was dissolved in 2 L of DMF under nitrogen protection. 189.98 g of potassium carbonate, 15.95 g of TBAB, and 220.17 g of diethyl malonate were added. The temperature was raised to 50-60°C, and stirred for 10 h until TLC (PE:EA = 2:1, UV 254 nm) showed that the starting material was completely converted.

[0112] The reaction solution was slowly poured into 2000 ml of water, and filtration was performed to obtain the crude diester. 400 ml of ethanol was added to the crude product, stirred for 30 min, and filtration was performed. The product was dried under reduced pressure at 40-50°C to obtain 213 g of white diester with a yield of 84.3% and a purity of 91.78% as determined by HPLC method 1 (254 nm).

[0113] Step (c) ketal reaction - preparation of ketal of formula (V) (R = -CH2CH3)

[0114] In a 3 L reaction flask, 720 ml of ethylene glycol, 400 mL of triethyl orthoformate, and 5.97 g of p-toluenesulfonic acid were added. 400 g of diester was added, and the reaction was performed at 20-25°C for 10 h until TLC (developing agent: PE:EA = 3:1, vanillin) showed that the starting material was completely converted.

[0115] The reaction solution was poured into 800 ml of water, stirred for 1 h, and filtration was performed to obtain the crude ketal. 800 ml of ethanol was added to the crude product, stirred for 1 h at 50-60°C, cooled to 0-10°C, stirred for 1 h, and filtration was performed. The product was dried under reduced pressure at 40-50°C to obtain 365.7 g of ketal with a yield of 84.5% and a purity of 92.58% as determined by HPLC method 1 (210 nm).

[0116] Step (d) oxidation reaction - preparation of ketal oxide of formula (VI) (R = -CH2CH3)

[0117] In a 3 L reaction flask, 2 L of acetone, 200 g of ketal, 160.58 g of PDC, and 82.29 g of NHPI were added under nitrogen protection. The temperature was raised to 40-50°C, and stirred for 4-5 h until TLC (PE:EA = 3:1, vanillin) showed that the starting material was completely converted.

[0118] The reaction solution was concentrated to dryness under reduced pressure, 2 L of ethyl acetate was added and stirred for 30 min, the mixture was filtered through diatomite, the filtrate was washed once with 2 L of 1.5 M aqueous sodium hydroxide solution and once with 2 L of saturated brine, and the organic phase was concentrated to dryness under reduced pressure at 45-50°C.

[0119] To the concentrate was added 400 ml of ethanol, and the solution was warmed to reflux and then cooled to room temperature and stirred for 1 h, filtered, and the filter cake was dried under reduced pressure at 40-50°C to give white ketal oxide 131 g in 68% yield, and the purity was 97.56% as determined by HPLC Method 1 (254 nm).

[0120] Step (e) Acidic hydrolysis reaction - preparation of 3,7-biketone (R = -CH2CH3) of formula (VII)

[0121] In a 3 L reaction flask was added 900 ml of tetrahydrofuran, 100 ml of water and 100 g of ketal oxide, and stirred to dissolve, 100 ml of hydrochloric acid was added, and the reaction was stirred at 40-50°C for 4 h until TLC (PE:EA = 2:1, UV 254 nm) showed that the starting material was completely converted.

[0122] The reaction solution was neutralized by adding 1000 ml of saturated aqueous sodium bicarbonate solution, and the layers were separated, the aqueous layer was extracted with 500 ml of ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure, 300 ml of petroleum ether was added, stirred at room temperature for 1 h, filtered, and the filter cake was dried under reduced pressure at 40-50°C to give white 3,7-biketone solid 82.9 g in 92.7% yield, and the purity was 81.34% as determined by HPLC Method 1 (254 nm).

[0123] Step (f) Hydrogenation, hydrolysis reaction - preparation of 7K diester of formula (VIII)

[0124] In a 3 L reaction flask was added 1.4 L of tetrahydrofuran, 80 g of 3,7-biketone, and stirred to dissolve, 160 g of Raney Ni was added, the reaction flask was replaced with nitrogen 3 times, and then replaced with hydrogen 3 times, and then a slightly positive pressure of hydrogen atmosphere was maintained, and the reaction was stirred at room temperature for 24 h until TLC (PE:EA = 2:1, phosphomolybdic acid) showed that the starting material was completely converted.

[0125] The catalyst was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 7K diester of formula (VIII).

[0126] Step (g) Hydrolysis reaction - preparation of 7K dicarboxylic acid

[0127] The above 70 g of 7K bis-ester of formula (VIII) was dissolved in 560 ml of methanol, 28 g of potassium hydroxide in 48 ml of water was slowly added, the temperature was raised to 50-60 °C and the reaction was stirred for 2 h until TLC (dichloromethane:methanol = 20:1, molybdenum phosphoric acid coloration) showed that the hydrolysis reaction was complete.

[0128] The reaction solution was cooled to room temperature, 1.2 L of water was added, and the pH was adjusted to 4-5 with 3 M hydrochloric acid. A large amount of solid precipitated, and stirring was continued at room temperature for 2 h. Filtration was performed, and the filter cake was dried under reduced pressure at 40-50 °C to obtain white 7K bis-carboxylic acid 68.8 g, with a two-step yield of hydrogenation and hydrolysis of 92.4%. The purity was 90.12% as detected by HPLC method 2.

[0129] Step (h) decarboxylation reaction - preparation of 7K of formula (I)

[0130] In a 3 L reaction flask, 600 ml of DMSO and 60 g of 7K bis-carboxylic acid were added and stirred to dissolve. 45 g of sodium chloride and 54 ml of water were added, the temperature was raised to 140-150 °C and refluxed for 5 h until TLC (dichloromethane:methanol = 20:1, molybdenum phosphoric acid coloration) showed that the starting material was completely converted.

[0131] The reaction solution was cooled to room temperature, poured into 3 L of water, stirred for 1 h, and the crude solid product precipitated. The filter cake was added to 60 ml of methanol and stirred at room temperature for 1 h. Filtration was performed, and the filter cake was dried under reduced pressure at 40-50 °C to obtain white 7K 47.8 g, with a yield of 89.2%. The purity was 96.51% as detected by HPLC method 2.

[0132] Example 3:

[0133] Step (a) sulfonylation reaction - preparation of sulfonylated compound of formula (III)

[0134] In a 3 L reaction flask, 2 L of dichloromethane and 200 g of BA were added and stirred to dissolve. 7.72 g of 4-dimethylaminopyridine, 219.6 ml of triethylamine, and 180.72 g of p-toluenesulfonyl chloride in 400 ml of dichloromethane were added in sequence, and the reaction solution was heated to reflux for 4-5 h until TLC (PE:EA = 3:1, ultraviolet 254 nm coloration) showed that the starting material was completely converted.

[0135] The reaction solution was poured into 1 L of water, stirred, and allowed to separate into layers. The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, 200 ml of methanol was added, the temperature was lowered to 0-5 °C, and stirring was performed for 1-2 h. Filtration was performed, and the filter cake was dried under reduced pressure at 40-50 °C to obtain white sulfonylated compound 283 g, with a yield of 89.7%. The purity was 98.34% as detected by HPLC method 1 (254 nm).

[0136] Step (b) alkylation reaction - preparation of bis-ester of formula (IV) (R = -CH2CH3)

[0137] In a 5L reaction flask, 260g of the sulfonyl compound was dissolved in 3.12L of DMF, 237.1g of potassium carbonate, 18.43g of TBAB, and 320.57g of diethyl malonate were added, and the mixture was stirred at 50-60°C for 10h until TLC (PE:EA=2:1, UV 254nm) showed that the starting material was completely converted.

[0138] The reaction solution was slowly poured into 3120ml of water, and the diester crude product was obtained by filtration. 624ml of ethanol was added to the crude product, and the mixture was stirred for 30min, filtered, and dried under reduced pressure at 40-50°C to obtain 240g of white diester product with a yield of 89.8%, and a purity of 92.60% detected by HPLC method 1 (254nm).

[0139] Step (c) ketal reaction - preparation of ketal of formula (V) (R = -CH2CH3)

[0140] In a 3L reaction flask, 880ml of ethylene glycol, 480ml of triethyl orthoformate, and 7.47g of p-toluenesulfonic acid were added, and the mixture was stirred at 20-25°C for 10h until TLC (developing agent: PE:EA=3:1, vanillin) showed that the starting material was completely converted.

[0141] The reaction solution was poured into 800ml of water, stirred for 1h, filtered, and the ketal crude product was obtained. 800ml of ethanol was added to the crude product, stirred at 50-60°C for 1h, cooled to 0-10°C, stirred for 1h, filtered, and dried under reduced pressure at 40-50°C to obtain 379g of ketal with a yield of 86.1% and a purity of 92.71% detected by HPLC method 1 (210nm).

[0142] Step (d) oxidation reaction - preparation of ketal oxide of formula (VI) (R = -CH2CH3)

[0143] Under nitrogen protection, 2L of acetone, 200g of ketal, 218.98g of PDC, and 107.61g of NHPI were added to a 3L reaction flask, and the mixture was stirred at 40-50°C for 4-5h until TLC (PE:EA=3:1, vanillin) showed that the starting material was completely converted.

[0144] The reaction solution was concentrated to dryness under reduced pressure, 2L of ethyl acetate was added and stirred for 30min, the mixture was filtered through diatomite, the filtrate was washed once with 2L of 1.5M sodium hydroxide aqueous solution and once with 2L of saturated brine, and the organic phase was concentrated to dryness under reduced pressure at 45-50°C.

[0145] To the concentrate, 400 ml of ethanol was added, warmed to reflux to dissolve, cooled to room temperature and stirred for 1 h, filtered, and the filter cake was dried at 40-50 °C under reduced pressure to give the white ketal oxide 149 g in 73% yield, HPLC Method 1 (254 nm) purity: 97.51%.

[0146] Step (e) Acid hydrolysis reaction - preparation of 3,7-biketals (R = -CH2CH3) of formula (VII)

[0147] In a 3 L reaction flask, 900 ml of tetrahydrofuran, 100 ml of water and 100 g of ketal oxide were added, stirred to dissolve, 100 ml of hydrochloric acid was added, warmed to 40-50 °C and stirred to react for 4 h until TLC (PE:EA = 2:1, UV 254 nm) showed that the starting material was completely converted.

[0148] The reaction solution was neutralized by adding 1000 ml of saturated sodium bicarbonate aqueous solution, separated into layers, the aqueous layer was extracted with 500 ml of ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, 300 ml of petroleum ether was added, stirred at room temperature for 1 h, filtered, and the filter cake was dried at 40-50 °C under reduced pressure to give white 3,7-biketals solid 82.2 g in 91.6% yield, HPLC Method 1 (254 nm) purity: 81.29%.

[0149] Step (f) Hydrogenation, hydrolysis reaction - preparation of 7K diester of formula (VIII)

[0150] In a 3 L reaction flask, 1.2 L of tetrahydrofuran, 80 g of 3,7-biketals were added, stirred to dissolve, 240 g of Raney Ni was added, the air in the reaction flask was replaced with nitrogen 3 times, then replaced with hydrogen 3 times, and then a slight positive pressure of hydrogen atmosphere was maintained, stirred to react at room temperature for 24 h until TLC (PE:EA = 2:1, phosphomolybdic acid) showed that the starting material was completely converted.

[0151] The catalyst was filtered, and the filtrate was concentrated to dryness under reduced pressure to give 7K diester of formula (VIII).

[0152] Step (g) Hydrolysis reaction - preparation of 7K dicarboxylic acid

[0153] 80 g of 7K diester of formula (VIII) above was dissolved in 560 ml of methanol, 28 g of potassium hydroxide in 48 ml of water was slowly added, warmed to 50-60 °C and stirred to react for 2 h until TLC (dichloromethane:methanol = 20:1, phosphomolybdic acid) showed that the hydrolysis reaction was complete.

[0154] The reaction solution was cooled to room temperature, 1.2 L of water was added, and 3 M hydrochloric acid was used to adjust the pH to 4-5, a large amount of solid was precipitated, and the stirring was continued at room temperature for 2 h, then filtered, and the filter cake was dried under reduced pressure at 40-50°C to obtain white 7K dicarboxylic acid 74.7 g, with a two-step yield of 93.6% for hydrogenolysis and hydrolysis, and a purity of 89.99% detected by HPLC method 2.

[0155] Step (h) decarboxylation reaction to prepare 7K of formula (I)

[0156] In a 3 L reaction flask, 600 ml of DMSO and 60 g of 7K dicarboxylic acid were added and stirred to dissolve, 60 g of sodium chloride and 72 ml of water were added, and the temperature was raised to 140-150°C to reflux for 5 h until TLC (dichloromethane:methanol = 20:1, phosphomolybdic acid coloration) showed that the starting material was completely converted.

[0157] The reaction solution was cooled to room temperature, 1.2 L of water was added, and 3 M hydrochloric acid was used to adjust the pH to 4-5, a large amount of solid was precipitated, and the stirring was continued at room temperature for 2 h, then filtered, and the filter cake was dried under reduced pressure at 40-50°C to obtain white 7K dicarboxylic acid 74.7 g, with a two-step yield of 93.6% for hydrogenolysis and hydrolysis, and a purity of 89.99% detected by HPLC method 2. The above only describes the preferred embodiments of the present application and is not intended to limit the present application, and any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A process for the preparation of an Ursodeoxycholic acid intermediate, wherein, The intermediate is 7K, which has the structural formula: The preparation method comprises the following steps: wherein R = CH3, -CH2CH3; (a) sulfonating the compound of formula (II) to obtain a sulfonate of formula (III); (b) alkylating the sulfonate of formula (III) to obtain a diester of formula (IV); (c) ketalizing the diester of formula (IV) to obtain a ketal of formula (V); (d) oxidizing the ketal of formula (V) to obtain a ketal oxidate of formula (VI); (e) hydrolyzing the ketal oxidate of formula (VI) to obtain a 3,7-diketone of formula (VII); (f) hydrogenating the 3,7-diketone of formula (VII) to obtain a 7K diester of formula (VIII); (g) hydrolyzing the 7K diester of formula (VIII) to obtain a 7K dicarboxylic acid of formula (IX); (h) decarboxylating the 7K dicarboxylic acid of formula (IX) to obtain 7K of formula (I).

2. The method of making according to claim 1, wherein: In step (a), the compound of formula (II) is BA, and the sulfonating reaction of BA and p-toluenesulfonyl chloride in dichloromethane solution is catalyzed by 4-dimethylaminopyridine as an acylation catalyst and triethylamine as an acid-binding agent to obtain a sulfonate of formula (III).

3. The method of making according to claim 1, wherein: In step B, the sulfonate of formula (III) and diethyl malonate or dimethyl malonate are alkylated in DMF as a reaction solvent, with potassium carbonate aqueous solution as a base and TBAB as a phase transfer catalyst to obtain a diester of formula (IV).

4. The method of making according to claim 1, wherein: In step (c), the diester of formula (IV) is ketalized in ethylene glycol as a reaction solvent, with triethyl orthoformate as a dehydrating agent and p-toluenesulfonic acid as a catalyst to obtain a ketal of formula (V).

5. The method of making according to claim 1, wherein: In step (d), the ketal of formula (V) is oxidized in acetone as a solvent, with PDC as an oxidizing agent and NHPI as a catalyst to obtain a ketal oxidate of formula (VI).

6. The method of making according to claim 1, wherein: In step (e), the ketal oxidate of formula (VI) is hydrolyzed in a mixed solvent of tetrahydrofuran and water under hydrochloric acid conditions to obtain a 3,7-diketone of formula (VII).

7. The method of making according to claim 1, wherein: In step (f), the 3,7-diketone of formula (VII) is hydrogenated in tetrahydrofuran solution with Raney Ni as a catalyst in a hydrogen atmosphere at normal pressure to obtain a 7K diester of formula (VIII).

8. The method of making according to claim 1, wherein: In step (g), the 7K diester of formula (VIII) is hydrolyzed in methanol solution with potassium hydroxide aqueous solution to obtain a 7K dicarboxylic acid of formula (IX).

9. The method of making according to claim 1, wherein: In step (h), the 7K dicarboxylic acid of formula (IX) is decarboxylated to obtain 7K of formula (I).

10. A compound, wherein, The structure of the compound includes as shown in formula (V-1), formula (VI-1), formula (VII-1), formula (VIII-1), formula (V-2), formula (VI-2), formula (VII-2), formula (VIII-2) or formula (IX):

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