7-KETOLITHOCHOLIC ACID INTERMEDIATE, SYNTHESIS METHOD THEREFOR, AND APPLICATION THEREOF

Abstract

A synthesis method for a 7-ketolithocholic acid is prepared from a new intermediate I-1. According to the method, phytosterol degradation product bisnoralcohol is used as a starting material, and the 7-ketolithocholic acid or the intermediate thereof is obtained by means of an oxidation reaction, a Knoevenagel reaction (or wittig reaction), hydrogenation, a ketal protection reaction, an allylic oxidation reaction, ketal removal protection, and the hydrogenation.

Claims

1. A method for preparing a compound of formula I, comprising subjecting a compound I-1 to a hydrogenation reaction in the presence of a catalyst to obtain the compound of formula I, ##STR00042## wherein R.sub.1 is H or alkyl.

2. The method according to claim 1, wherein the catalyst is selected from a Raney Ni catalyst, a Pd/C catalyst, a Pt/C catalyst or a Ru/C catalyst.

3. The method according to claim 1, wherein when R.sub.1 in the compound of formula I is alkyl, the method further comprises: hydrolyzing the compound of formula I in which R.sub.1 is alkyl to obtain the compound of formula I with R.sub.1 as H, ##STR00043##

4. An intermediate compound I-1 or I-2 shown below: ##STR00044## wherein R.sub.1 is defined in claim 1 and R.sub.2 is alkyl.

5. A method for preparing a compound I-1, comprising: ##STR00045## wherein R.sub.1 is defined in claim 1 and R.sub.2 is alkyl, h) subjecting a compound I-3 to an allylic oxidation reaction to obtain a compound I-2; and i) subjecting the compound I-2 to a de-protection of ethylene glycol to obtain the compound I-1 with R.sub.1 as alkyl; or subjecting the compound I-2 to a de-protection of ethylene glycol and a hydrolysis reaction to obtain the compound I-1 with R.sub.1 as H.

6. The method according to claim 5, wherein in step h), the reaction is performed in the presence of an oxidant and a catalyst.

7. The method according to claim 5, wherein in step i), the de-protection of ethylene glycol is performed in the presence of an acid, wherein the acid is selected from at least one of concentrated sulfuric acid, concentrated hydrochloric acid and p-toluenesulfonic acid; and the hydrolysis reaction is performed under an alkaline condition.

8. The method according to claim 5, wherein a method for preparing the compound I-3 comprises the following Method I or Method II, wherein Method I comprises: ##STR00046## wherein R.sub.2 is defined in claim 5; b) subjecting a compound I-8 and monoalkyl malonate ##STR00047## to a Knoevenagel condensation to obtain a compound I-7; or subjecting the compound I-8 and ##STR00048## wherein R.sub.3 and R.sub.4 are C.sub.1-6 alkyl to a wittig reaction to obtain the compound I-7; d) subjecting the compound I-7 to a protection of ethylene glycol to obtain a compound I-5; and f) subjecting the compound I-5 to a reduction reaction to obtain the compound I-3; and Method II comprises: ##STR00049## wherein R.sub.2 is defined in claim 5; c) subjecting the compound I-8 and ##STR00050## wherein R.sub.5 and R.sub.6 are C.sub.1-6 alkyl, or R.sub.5 and R.sub.6 together with the carbon atom to which they are connected form a C.sub.3-8 cycloalkyl, to a Knoevenagel condensation to obtain a compound I-6; e) reacting the compound I-6 with R.sub.2OH to obtain a compound I-4; and g) subjecting the compound I-4 to a protection of ethylene glycol to obtain a compound I-3.

9. The method according to claim 8, wherein the Knoevenagel condensation of step b) is performed in the presence of a catalyst, wherein the catalyst is DMAP; step d) is performed in the presence of a catalyst, wherein the catalyst is a catalyst A and/or a catalyst B, wherein the catalyst A is selected from p-toluenesulfonic acid or concentrated sulfuric acid, and the catalyst B is selected from trimethyl orthoformate, triethyl orthoformate or trimethyl orthoacetate; and step f) is performed in the presence of a catalyst, wherein the catalyst is Pd/C.

10. The method according to claim 8, wherein step e) is performed in the presence of a catalyst, wherein the catalyst is selected from at least one of concentrated sulfuric acid, p-toluenesulfonic acid and hydrochloric acid; and step g) is performed in the presence of a catalyst, wherein the catalyst is a catalyst A and/or a catalyst B, wherein the catalyst A is selected from p-toluenesulfonic acid or concentrated sulfuric acid, and the catalyst B is selected from trimethyl orthoformate, triethyl orthoformate or trimethyl orthoacetate.

11. The method according to claim 1, wherein alkyl is C.sub.1-6 alkyl.

12. The method according to claim 1, wherein alkyl is methyl, ethyl, n-propyl or tert-butyl.

13. The method according to claim 1, wherein the reaction is performed in the presence of a solvent, wherein the solvent is selected from an amide solvent.

14. The method according to claim 13, wherein the solvent is selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, formamide, N-methylpyrrolidone, N-methylformamide, N-methylacetamide and N,N-dimethylpropyleneurea.

15. The method according to claim 6, wherein, step h) is performed under the following reaction system of h1 or h2, wherein h1: the oxidant is oxygen or air, and the catalyst is a reaction system of N-hydroxyphthalimide (NHPI) and cobalt acetate; and a free radical initiator may further be added to the above system; and h2: the oxidant is tert-butyl hydroperoxide (TBHP) and the catalyst is a reaction system of manganese (III) acetate, manganese (III) acetate dihydrate or cuprous iodide (CuI).

16. The method according to claim 15, wherein the free radical initiator is benzoyl peroxide.

17. The method according to claim 7, wherein the hydrolysis reaction is performed in the presence of sodium hydroxide and/or potassium hydroxide.

Description

DETAILED DESCRIPTION

[0058] The technical solutions of the present invention will be further described in detail below in conjunction with specific examples. It should be understood that the following examples only exemplarily illustrate and explain the present invention and should not be construed as limiting the protection scope of the present invention. All the techniques realized on the basis of the above-mentioned contents of the present invention are covered in the protection scope of the present invention.

[0059] Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially-available, or may be prepared by known methods.

Example 1 Synthesis of A8

##STR00018##

[0060] NaBr (3.2 g, 31.06 mmol), TEMPO (1 g, 6.4 mmol) and NaHCO.sub.3 (30.6 g, 364 mmol) were added to a mixture of DCM (600 mL) and water (100 mL) containing BA (100 g, 303 mmol). The reaction solution was cooled to 0-5 C. and 10% NaClO solution (115 g, 155 mmol) was dropwise added while stirring. After the dropwise addition is completed, stirring was continued for 30 min. The reaction was quenched with 5 g of Na.sub.2SO.sub.3 and then stirred for 30 min. The reaction solution was stood and subjected to a liquid separation. The lower layer was washed once with saturated NaHCO.sub.3, dried and concentrated under reduced pressure to obtain 90 g of a white solid A8 with the yield of 90.5% and the purity of 90% by HPLC.

Example 2 Synthesis of A8

##STR00019##

[0061] After BA (33 g, 100 mmol) and DCM (100 mL) were added to a reaction flask and dissolved with stirring, hydrochloric acid (3.7%, 2 mmol, 2 g), TEMPO (0.31 g, 2 mmol) and sodium bromate (5 g, 35 mmol) were added. The mixture was reacted at 25 C. for 16 h while stirring, then water (100 mL) was added, and the mixture was subjected to a liquid separation. The organic phase was washed with an aqueous saturated sodium bicarbonate solution (100 mL) and a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to remove the solvent. The residue was subjected to column chromatography on silica gel (n-hexane:EtOAc=10:1) to obtain 28.2 g of A8 with the yield of 86% and the purity of 96% by HPLC.

Example 3 Synthesis of A7

##STR00020##

[0062] A8 (65.6 g, 200.00 mmol) prepared in Example 2 and monoethyl malonate (39.6 g, 300.00 mmol) were added to a 1 L three-necked flask containing 500 mL of DMF, stirred well, and DMAP (2.44 g, 20 mmol) was added at 25 C. and the reaction was stirred for 16 h. When TLC monitored that the reaction of A8 was complete, 500 mL of methyl tert-butyl ether was added. The organic phase was successively washed with aqueous saturated NaHCO.sub.3 solution (500 mL) and a saturated sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 90 g of a white solid A7 with the yield of 90.5% and the purity of 98% by HPLC.

Example 4 Synthesis of A7

##STR00021##

[0063] 40.9 g of triethyl phosphonoacetate and 400 mL of THE were added to a 1 L three-necked flask. The temperature was controlled to 0-5 C., 6.7 g of 60% NaH was added in batches with stirring, and a large amount of gas was released. After stirring for 1 h, 300 mL of the previously prepared THF solution containing 49.8 g of A8 prepared in Example 2 was dropwise added to the above system using a 500 mL pressure equalizing funnel. After the dropwise addition was completed, the stirring was continued for 2 h. The reaction was quenched by adding 20 g of ammonium chloride in 200 mL of water. After stirring for 1 h, liquid separation was performed. The aqueous phase was extracted once with 200 mL of EA, and the organic phases were combined, dried and concentrated under reduced pressure to obtain 55 g of a crude product. The crude product was slurried with 80 mL of petroleum ether and filtered to obtain 55 g of a off-white solid A7 with the yield of 91% and the purity of 95% by HPLC.

Example 5 Synthesis of A5

##STR00022##

[0064] 50 g of A7 prepared in Example 3, 50 g of ethylene glycol, 600 mL of DCM, 28 g of triethyl orthoformate and 0.5 g of p-toluenesulfonic acid were added to a 1 L three-necked flask under protection of N.sub.2, and stirred at 25 C. for 10 h. When TLC showed the reaction was complete, 1 mL of triethylamine was added and stirred for 30 min. The reaction solution was washed with 100 mL of water, subjected to liquid separation, dried and concentrated to obtain 55 g of an A5 crude product. The crude product was refluxed and slurried with 150 mL of petroleum ether to obtain 48.5 g of A5 with the yield of 87.3% and the purity of 97% by HPLC.

Example 6 Synthesis of A3

##STR00023##

[0065] 2.01 g of A5 prepared in Example 5 and 0.1 g of 5% palladium carbon were added to 20 mL of ethyl acetate, and stirred at 25 C. under a pressure of 0.2 MPa hydrogen for 1 h. The reaction solution was filtered and concentrated under reduced pressure to obtain 1.95 g of a white solid A3 with the yield of 97% and the purity of 97% by HPLC.

Example 7 Synthesis of A6

##STR00024##

[0066] A8 (258 g, 789 mmol, 1.0 eq) prepared in Example 2, Meldrum's acid (136 g, 947 mmol, 1.2 eq) and a mixed solution of formic acid and triethylamine (formic acid/triethylamine=5:2, 1,000 mL) were added to a reaction flask. The reaction mixture was heated at 110 C. for 16 h. When TLC monitored that A8 was reacted completely, the reaction product was poured into ice water (1,000 mL), then adjusted to pH 10 with 1 N NaOH, and washed with ethyl acetate (200 mL2). The aqueous phase was adjusted to pH 2 with 1 N HCl, and extracted with ethyl acetate (200 mL3). The organic phases were combined to obtain 288 g of a crude product which was refined with acetone to obtain 270 g of the product with the yield of 91.8% and the purity of 96% by HPLC.

Example 8 Synthesis of A4

##STR00025##

[0067] A6 prepared in Example 7 (100 g, 270 mmol), ethanol (300 mL) and hydrochloric acid (20 mL, 37.5%) were added to a reaction flask and stirred at 25 C. for 16 h. When TLC monitored that A6 was reacted completely, the reaction product was concentrated under reduced pressure to remove excess ethanol and diluted with ethyl acetate (300 mL). The organic phase was successively washed with water (300 mL), an aqueous saturated sodium bicarbonate solution (300 mL) and an aqueous saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 100 g of A4 with the yield of 93% and the purity of 96% by HPLC. ESI-MS [M+H].sup.+ 445.33.

Example 9 Synthesis of A4

##STR00026##

[0068] A6 prepared in Example 7 (74.4 g, 200 mmol), ethanol (200 mL) and concentrated sulfuric acid (5 mL) were added to a reaction flask and reacted for 24 h under refluxing and stirring. When TLC monitored that A6 was reacted completely, the reaction product was concentrated under reduced pressure to remove excess ethanol, and diluted with dichloromethane (200 mL). The organic phase was successively washed with water (200 mL), an aqueous saturated sodium bicarbonate solution (200 mL) and an aqueous saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 73.6 g of A4 with the yield of 92% and the purity of 97% by HPLC. ESI-MS [M+H].sup.+ 445.33.

Example 10 Synthesis of A3

##STR00027##

[0069] A4 (50 g, 125 mmol) prepared in Example 9, ethylene glycol (50 g, 806 mmol), DCM (600 mL), triethyl orthoformate (28 g, 189 mmol) and p-toluenesulfonic acid (0.5 g, 2.6 mmol) were added to a 1 L three-necked flask under protection of N.sub.2, and stirred at 25 C. for 10 h. When TLC showed the reaction was completed, 1 mL of triethylamine was added and stirred for 30 min. The reaction solution was washed with 100 mL of water and subjected to liquid separation. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 58 g of an A3 crude product. The crude product was refluxed and slurried with 150 mL of petroleum ether to obtain 51.8 g of A3 with the yield of 95% and the purity of 95% by HPLC. ESI-MS [M+H].sup.+ 444.35. .sup.1H-NMR (CDCl.sub.3, 400 MHz) (ppm): 5.36-5.34 (m, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.98-3.91 (m, 4H), 2.58-2.54 (m, 1H), 2.38-2.30 (m, 1H), 2.13-2.09 (m, 1H), 2.00-1.92 (m, 2H), 1.89-1.73 (m, 4H), 1.67-1.60 (m, 3H), 1.49-1.40 (m, 4H), 1.36-1.30 (m, 2H), 1.25 (t, J=7.2 Hz, 3H), 1.20-1.06 (m, 4H), 1.02 (s, 3H), 0.92 (d, J=6.4 Hz, 3H), 0.68 (s, 3H).

Example 11 Synthesis of A3

##STR00028##

[0070] A4 (50 g, 125 mmol) prepared in Example 9, ethylene glycol (150 mL, 2,702 mmol), 90 g of trimethyl orthoacetate (90 g, 750 mmol) and p-toluenesulfonic acid (5 g, 26 mmol) were added to a reaction flask under protection of inert gas, and reacted at 25 C. for 2 h to precipitate a large amount of a solid. Methanol (100 mL) was added to disperse, the pH was adjusted to 7-8 with triethylamine, and the reaction solution was filtered and dried to obtain 50.2 g of a compound A3 with the yield of 92% and the purity of 98% by HPLC. ESI-MS [M+H].sup.+ 444.35.

Example 12 Synthesis of A3

##STR00029##

[0071] A4 (50 g, 125 mmol) prepared in Example 9, ethylene glycol (39 g, 625 mmol), p-toluenesulfonic acid (5 g, 26 mmol) and toluene (200 mL) were added in a reaction flask under protection of inert gas, and the reaction mixture was reacted for 24 h while heating, refluxing and separating water. The reaction mixture was cooled to 25 C. and successively washed with water (200 mL), an aqueous saturated sodium bicarbonate solution (200 mL) and an aqueous saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate and concentrated to obtain 57 g of an A3 crude product. The crude product was refluxed and slurried with 150 mL of petroleum ether to obtain 46.3 g of A3 with the yield of 85% and the purity of 90% by HPLC. ESI-MS [M+H].sup.+ 444.35.

Example 13 Synthesis of A2

##STR00030##

[0072] The compound A3 prepared in Example 11 (44.4 g, 100 mmol), N-hydroxyphthalimide (NHPI) (1.63 g, 10 mmol), benzoyl peroxide (2.4 g, 10 mmol), cobalt acetate (88 mg, 0.5 mmol) and cyclohexanone (200 mL) were added to a reaction flask. The reaction mixture was stirred at 25 C. for 10 min, heated to 60 C., and reacted while blowing air. After the reaction was completed, the reaction solution was concentrated to remove cyclohexanone, then dichloromethane was added, and the reaction solution was filtered to remove the catalyst. Triethylamine (10 g, 100 mmol) and acetic anhydride (10 g, 100 mmol) were added, and the mixture was reacted at 25 C. for 10 h. After the reaction was complete, the reaction solution was quenched with ethanol, and concentrated. After ethanol was added, the product was obtained and dried to give 30 g of a compound A2 with the yield of 65.8% and the purity of 95% by HPLC. ESI-MS [M+H].sup.+ 459.35. .sup.1H-NMR (CDCl.sub.3, 400 MHz) (ppm): 5.67 (s, 1H), 4.12 (brs, 2H), 3.97 (brs, 4H), 2.70-2.66 (m, 1H), 2.45-2.22 (m, 5H), 2.00-1.75 (m, 6H), 1.59-1.11 (m, 17H), 0.94 (s, 3H), 0.69 (s, 3H).

Example 14 Synthesis of A2

##STR00031##

[0073] A3 (100 g, 270 mmol) prepared in Example 11, ethyl acetate (200 mL), TBHP (270 mL, 1,350 mmol, 5.0 M n-decane solution), 3 A molecular sieve (20 g) and manganese (III) acetate dihydrate (740 mg, 27 mmol) were added to a reaction flask and reacted at 25 C. for 48 h. The reaction system was diluted with methyl tert-butyl ether (200 mL) and filtered through celite. The filtrate was concentrated under reduced pressure to remove the solvent and purified by column chromatography (n-hexane:EtOAc=5:1) to obtain 110 g of a product with the yield of 90% and the purity of 98% by HPLC. ESI-MS [M+H].sup.+ 459.35.

Example 15 Synthesis of A2

##STR00032##

[0074] A3 (44 g, 100 mmol) prepared in Example 11, TBHP (120 mL, 600 mmol, 5.0 M n-decane solution), cuprous iodide (0.19 g, 1 mmol) and acetonitrile (200 mL) were added to a reaction flask, and reacted at 50 C. for 20 h. The reaction system was filtered through celite. The filtrate was concentrated under reduced pressure to remove the solvent and purified by column chromatography (n-hexane:EtOAc=5:1) to obtain 38 g of a product with the yield of 83% and the purity of 96% by HPLC. ESI-MS [M+H].sup.+ 459.35.

Example 16 Synthesis of A1

##STR00033##

[0075] Water (40 mL) and THF (100 mL) were added to a 1 L single-neck flask, concentrated sulfuric acid (4 g, 40.8 mmol) was added while stirring at 0 C., stirring was performed for 10 min, then A2 (12 g, 26.2 mmol) prepared in Example 14 was added, the cold bath was removed, and stirring was performed overnight at 25 C. After adding water (100 mL), NaHCO.sub.3 (10 g, 119 mmol) was added in batches to control the pH of 7-8. Then the reaction system was extracted twice with 200 mL of EtOAc. The organic phases were combined and concentrated under reduced pressure to obtain a crude product as a yellow oil. The crude product was purified by column chromatography (n-hexane:EtOAc=3:1) to obtain 9.97 g of a solid A1 with the yield of 92% and the purity of 95% by HPLC. ESI-MS [M+H].sup.+ 415.30.

Example 17 Synthesis of A1

##STR00034##

[0076] A2 prepared in Example 14 (54 g, 118 mmol) and p-toluenesulfonic acid monohydrate (5.2 g, 27.4 mmol) were added to a 1 L reaction flask containing 200 mL of toluene and 50 mL of water, stirred at 50 C. for 1 h, and cooled to 25 C. The reaction was quenched by adding NaHCO.sub.3 (10 g, 119 mmol). The reaction solution was stood for liquid separation and the aqueous phase was extracted once with toluene (100 mL). The organic phases were combined and concentrated under reduced pressure to obtain a crude product as a yellow oil. The crude product was purified by column chromatography (n-hexane:EtOAc=3:1) to obtain 46.8 g of a light yellow solid A1 with the yield of 96% and the purity of 98% by HPLC. ESI-MS: [M+H].sup.+ 415.30

[0077] .sup.1H-NMR (DMSO-d6, 400 MHz) (ppm): 10.25 (brs, 1H), 5.29-5.28 (m, 2H), 4.03 (q, J=7.2 Hz, 2H), 2.41-2.12 (m, 6H), 1.98-1.66 (m, 4H), 1.11-1.53 (m, 10H), 1.17 (t, J=7.2 Hz, 3H), 1.05 (s, 3H), 0.91 (d, J=6 Hz, 3H), 0.66 (s, 3H).

Example 18 Synthesis of A

##STR00035##

[0078] A1 (3.2 g, 7.73 mmol) prepared in Example 17 was dissolved in N,N-dimethylformamide (DMF) (32 mL) and then 0.32 g of Raney nickel was added. The reaction mixture was hydrogenated at 25 C. under 0.1 MPa hydrogen for 12 h. After the hydrogenation was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain 3.3 g of a crude product A. The crude product was refined with acetone to obtain 2.84 g of a white solid A with the yield of 88% and the purity of 98% by HPLC. ESI-MS [M+H].sup.+ 419.30. [0079] .sup.1H-NMR (DMSO-d6, 400 MHz) (ppm): 4.48 (d, J=4.8 Hz, 1H), 4.04 (q, J=6.8 Hz, 2H), 2.90 (dd, J=6 Hz, 12 Hz, 1H), 2.47-2.41 (m, 1H), 2.36-2.27 (m, 1H), 2.22-2.15 (m, 1H), 2.09-2.02 (m, 1H), 1.94-1.90 (m, 1H), 1.85-1.76 (m, 2H), 1.73-1.64 (m, 4H), 1.50-1.45 (m, 2H), 1.39-1.30 (m, 4H), 1.27-1.21 (m, 2H), 1.17 (t, J=6.8 Hz, 3H), 1.14 (s, 3H), 1.11-1.01 (m, 5H), 0.96-0.77 (m, 2H), 0.88 (d, J=6.4 Hz, 3H), 0.61 (s, 3H).

Example 19 Synthesis of A

##STR00036##

[0080] A1 (3.2 g, 7.73 mmol) prepared in Example 17 was dissolved in N,N-dimethylacetamide (32 mL) and then 0.32 g of Raney nickel was added. The reaction mixture was hydrogenated at 25 C. under 0.1 MPa hydrogen for 12 h. After the hydrogenation was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain 3.4 g of a crude product A. The crude product was refined with acetone to obtain 2.74 g of a white solid A with the yield of 85% and the purity of 98% by HPLC. ESI-MS [M+H].sup.+ 419.30.

Example 20 Synthesis of A

##STR00037##

[0081] A1 (3.2 g, 7.73 mmol) prepared in Example 17 was dissolved in N-methylpyrrolidone (32 mL) and then 0.32 g of Raney nickel was added. The reaction mixture was hydrogenated at 25 C. under 0.1 MPa hydrogen for 12 h. After the hydrogenation was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain 3.0 g of a crude product A. The crude product was refined with acetone to obtain 2.52 g of a white solid A with the yield of 78.3% and the purity of 95% by HPLC. ESI-MS: [M+H].sup.+ 419.30.

Example 21 Synthesis of A

##STR00038##

[0082] A1 (3.2 g, 7.73 mmol) prepared in Example 17 was dissolved in N,N-dimethylformamide (32 mL) and then 0.32 g of 5% palladium carbon catalyst was added. The reaction mixture was hydrogenated at 25 C. under 0.1 MPa hydrogen for 12 h. After the hydrogenation was completed, the reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (n-hexane:EtOAc=3:1) to obtain 2.09 g of a white solid A with the yield of 65% and the purity of 91% by HPLC. ESI-MS [M+H].sup.+ 419.30.

Example 22 Synthesis of A

##STR00039##

[0083] A1 (3.2 g, 7.73 mmol) prepared in Example 17 was dissolved in N,N-dimethylformamide (32 mL) and then 0.32 g of 5% platinum carbon catalyst was added. The reaction mixture was hydrogenated at 25 C. under 0.1 MPa hydrogen for 12 h. After the hydrogenation was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (n-hexane:EtOAc=3:1) to obtain 1.70 g of a white solid A with the yield of 53% and the purity of 92% by HPLC. ESI-MS [M+H].sup.+ 419.30.

Example 23 Synthesis of A1-1

##STR00040##

[0084] A1 (5 g, 12.08 mmol) prepared in Example 17 was dissolved in THE (20 mL) and water (10 mL) and then 3 N of a NaOH aqueous solution (6 mL, 18 mmol) was added. The reaction mixture was reacted at 25 C. for 1 h. When TLC detected that the raw materials were reacted completely, the reaction mixture was cooled to an internal temperature of 0 C., and 3 N of a HCl aqueous solution (8 mL, 24 mmol) was dropwise added. The reaction solution was extracted with ethyl acetate (30 mL2). The organic phases were combined, washed with water (30 mL), a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and refined with acetone to obtain 4.38 g of a white solid A1-1 with the yield of 94% and the purity of 98% by HPLC. ESI-MS [M+H].sup.+ 387.30.

[0085] .sup.1H-NMR (CDCl, 400 MHz) (ppm): 5.72-5.68 (m, 1H), 3.49-3.41 (m, 1H), 3.10-3.02 (m, 1H), 2.61-2.11 (m, 7H), 2.10-1.63 (m, 9H), 1.49-1.22 (m, 5H), 1.23-1.02 (m, 3H), 0.72-0.71 (m, 3H).

Example 24 Synthesis of 7-LCA

##STR00041##

[0086] A1-1 (3 g, 7.77 mmol) prepared in Example 23 was dissolved in N,N-dimethylformamide (DMF) (30 mL) and then 0.3 g of Raney nickel was added. The reaction mixture was hydrogenated at 25 C. under 0.1 MPa hydrogen for 12 h. After the hydrogenation was completed, the reaction solution was filtered, concentrated under reduced pressure and refined with acetone to obtain 2.5 g of a white solid 7-LCA with the yield of 82% and the purity of 92% by HPLC. ESI-MS [M+H].sup.+ 391.30.

[0087] The foregoing exemplarily illustrates the implementation of the technical solutions of the present invention. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, and the like made by a person skilled in the art within the spirit and principle of the present invention shall fall within the protection scope of the claims of the present application.