METHOD FOR SYNTHESIZING URSODEOXYCHOLIC ACID USING BA AS RAW MATERIAL

Abstract

The present invention discloses a synthesis method of ursodeoxycholic acid by using the plant-derived compound BA as a raw material to synthesize ursodeoxycholic acid through the steps of ethylene glycol or neopentyl glycol protection, oxidation, Wittig reaction, deprotection, reduction and hydrolysis, etc. The raw materials used for the synthesis of ursodeoxycholic acid in the present invention are cheap and easy to get, the synthesis steps are easy to operate, the yield is high, the reaction is environmentally friendly, and the industrial production is convenient.

Claims

1. A method for the synthesis of ursodeoxycholic acid by using BA as a raw material, wherein, the said method comprises the following steps: (a) in the first solvent, BA shown in formula (1) is protected by ethylene glycol to obtain the compound of formula (2); (b) in the second solvent, the compound of formula (2) is oxidized to obtain the compound of formula (3); (c) in the third solvent, the compound of formula (3) undergoes Wittig reaction to obtain the compound of formula (6); (d) in the fourth solvent, the compound of formula (6) is oxidized to obtain the compound of formula (7); (e) in the fifth solvent, the compound of formula (7) undergoes hydrolysis reaction under the action of acid and deprotection of ethylene glycol, to obtain the compound of formula (8); (f) in the sixth solvent, under the action of catalyst and hydrogen under pressure, the compound in formula (8) is heated with alkali and subjected to reduction and hydrolysis reaction, to obtain ursodeoxycholic acid shown in formula (9); or, the said method comprises the following steps: (g) in the seventh solvent, BA shown in formula (1) is oxidized to obtain the compound of formula (4); (h) in the eighth solvent, the compound formula (4) undergoes Wittig reaction to obtain the compound formula (5); (i) in the ninth solvent, the compound of formula (5) is protected by ethylene glycol or neopentyl glycol to obtain the compound of formula (6); (d) in the fourth solvent, the compound of formula (6) is oxidized to obtain the compound of formula (7); (e) in the fifth solvent, the compound of formula (7) undergoes hydrolysis reaction under the action of acid and deprotection of ethylene glycol or neopentyl glycol, to obtain the compound of formula (8); (f) in the sixth solvent, under the action of catalyst and hydrogen under pressure, the compound of formula (8) is heated with alkali and subjected to reduction and hydrolysis reaction, to obtain the ursodeoxycholic acid as shown in formula (9); wherein, the reaction process of the said method is shown in the route (A): ##STR00034## in the said route (A), R is an alkyl group; R.sub.1 is ##STR00035##

2. The method of claim 1, wherein, R is a C1˜C20 alkyl group; R.sub.1 is ##STR00036##

3. The method of claim 1, wherein, in step (a), the said ethylene glycol protection reaction refers to: BA shown in formula (1), ethylene glycol and p-toluenesulfonic acid are dissolved in the first solvent and subjected to ethylene glycol protection reaction, to obtain the compound of formula (2); wherein, the molar ratio of BA shown in formula (1), ethylene glycol and p-toluenesulfonic acid is 1:(1-50):(0.01-1); and/or, the said first solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran or hexane; and/or, the said ethylene glycol protection reaction temperature is 80˜130° C.; and/or, the said ethylene glycol protection reaction time is 2˜36 h.

4. The method of claim 1, wherein, in step (a), the said ethylene glycol protection reaction refers to: BA shown in formula (1), ethylene glycol, p-toluenesulfonic acid and triethyl orthoformate are dissolved in the first solvent and subjected to ethylene glycol protection reaction, to obtain the compound of formula (2); wherein, the molar ratio of BA shown in formula (1), ethylene glycol, p-toluenesulfonic acid and triethyl orthoformate is 1:(1-50):(0.01-1):(1-20); and/or, the said first solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran or hexane; and/or, the said ethylene glycol protection reaction temperature is 0˜50° C.; and/or, the said ethylene glycol protection reaction time is 2˜36 h.

5. The method of claim 1, wherein, in step (b), the said oxidation reaction refers to: the compound of formula (2), TEMPO, sodium bicarbonate, tetrabutylammonium bromide and oxidant are dissolved in the second solvent and subjected to oxidation reaction, to obtain the compound of formula (3); wherein, the molar ratio of the compound of formula (2), TEMPO, sodium bicarbonate, tetrabutylammonium bromide and oxidant is 1:(0-1):(0-20):(0-1):(1-5); and/or, the said oxidation reaction is performed under the action of oxidant, wherein, the said oxidant is selected from one or more of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or 2-iodoylbenzoic acid (IBX); and/or, the said second solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide or water; and/or, the said oxidation reaction temperature is 0˜30° C.; and/or, the said oxidation reaction time is 2˜8 h.

6. The method of claim 1, wherein, in step (c), the said Wittig reaction refers to: the compound of formula (3) and ethyl (triphenylphosphoranylidene)acetate are dissolved in the third solvent and subjected to Wittig reaction, to obtain the compound of formula (6); wherein, the molar ratio of the compound of formula (3) and ethyl (triphenylphosphoranylidene)acetate is 1:(1˜5); and/or, the said third solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran or hexane; and/or, the said Wittig reaction temperature is 80˜130° C.; and/or, the said Wittig reaction time is 2˜8 h.

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

8. The method of claim 1, wherein, in step (g), the said oxidation reaction refers to: BA shown in formula (1), TEMPO, sodium bicarbonate, tetrabutylammonium bromide and an oxidant are dissolved in the seventh solvent and subjected to oxidation reaction, to obtain the compound of formula (4); wherein, the molar ratio of the compound of formula (1), TEMPO, sodium bicarbonate, tetrabutylammonium bromide and the oxidant is 1:(0-1):(0-20):(0-1):(1-5); and/or, the said oxidation reaction is performed under the action of oxidant, wherein, the said oxidant is selected from one or more of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), 2-iodoylbenzoic acid (IBX); and/or, the said seventh solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide or water; and/or, the said oxidation reaction temperature is 0˜30° C.; and/or, the said oxidation reaction time is 2˜8 h.

9. The method of claim 1, wherein, in step (h), the said Wittig reaction refers to: the compound of formula (4) and methyl (triphenylphosphoranylidene)acetate or ethyl (triphenylphosphoranylidene)acetate or propyl 2-(triphenylphosphoranylidene)acetate are dissolved in the eighth solvent and subjected to Wittig reaction, to obtain the compound of formula (5); wherein, the molar ratio of the compound of formula (4), methyl (triphenylphosphoranylidene)acetate or ethyl (triphenylphosphoranylidene)acetate or propyl 2-(triphenylphosphoranylidene)acetate is 1:(1-5); and/or, the said eighth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran or hexane; and/or, the said Wittig reaction temperature is 80˜130° C.; and/or, the said Wittig reaction time is 2˜8 h.

10. The method of claim 1, wherein, in step (h), the said Wittig reaction refers to: the compound of formula (4), sodium hydride and methyl phosphonoacetate diethyl ester or triethyl phosphonoacetate or propyl phosphonoacetate diethyl ester are dissolved in the eighth solvent and subjected to the Wittig reaction, to obtain the compound of formula (5); wherein said the eighth solvent is selected from one or more of the benzene, toluene, ethyl acetate, tetrahydrofuran or hexane; and/or, the molar ratio of the compound of formula (4), sodium hydride, methyl phosphonoacetate diethyl ester or triethyl phosphonoacetate or propyl phosphonoacetate diethyl ester is 1:(1˜5):(1˜5); and/or, said Wittig reaction temperature is 0˜30° C.; and/or, said Wittig reaction time is 2˜8 h.

11. The method of claim 1, wherein, in step (i), the said ethylene glycol or neopentyl glycol protection reaction refers to: the compound of formula (5), ethylene glycol or neopentyl glycol and p-toluenesulfonic acid are dissolved in the ninth solvent and subjected to ethylene glycol or neopentyl glycol protection reaction, to obtain the compound of formula (6); wherein, the molar ratio of the compound of formula (5), ethylene glycol or neopentyl glycol and p-toluenesulfonic acid is 1:(1-50):(0.01-1); and/or, the said ninth solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran or hexane; and/or, the said ethylene glycol or neopentyl glycol protection reaction temperature is 80˜130° C.; and/or, the said ethylene glycol or neopentyl glycol protection reaction time is 2˜36 h.

12. The method of claim 1, wherein, in step (i), the said ethylene glycol or neopentyl glycol protection reaction refers to: the compound of formula (5), ethylene glycol or neopentyl glycol, p-toluenesulfonic acid and triethyl orthoformate are dissolved in the ninth solvent and subjected to ethylene glycol protection reaction, to obtain the compound of formula (6); wherein, the molar ratio of the compound of formula (5), ethylene glycol or neopentyl glycol, p-toluenesulfonic acid and triethyl orthoformate is 1:(1-50):(0.01-1):(1-20); and/or, the said ninth solvent is selected from one or more of benzene, toluene, ethyl acetate ester, tetrahydrofuran or hexane; and/or, the ethylene glycol or neopentyl glycol protection reaction temperature is 0˜50° C.; and/or, the ethylene glycol or neopentyl glycol protection reaction time is 2˜36 h.

13. The method of claim 1, wherein, in step (d), the said oxidation reaction refers to: the compound of formula (6), an oxidant, N-hydroxyphthalimide and acetic acid are dissolved in the fourth solvent and subjected to oxidation reaction, to obtain the compound of formula (7); wherein, the molar ratio of the compound of formula (6), the oxidant, N-hydroxyphthalimide (NHPI) and acetic acid is 1:(1-5):(1˜5):(0˜5); and/or, wherein, the said oxidant is selected from one or more of Na.sub.2Cr.sub.2O.sub.7, K.sub.2Cr.sub.2O.sub.7, PDC or BPO; and/or, the said fourth solvent is selected from one or more of toluene, acetone, acetonitrile, water, dichloromethane, N,N-dimethylformamide, ethyl acetate, tert-butanol or N-methylpyrrolidone; and/or, the said oxidation reaction temperature is 0˜50° C.; and/or, the said oxidation reaction time is 10˜48 h.

14. The method of claim 1, wherein, in step (e), the said ethylene glycol or neopentyl glycol deprotection reaction refers to: the compound of formula (7) and acid are dissolved in the fifth solvent and subjected to ethylene glycol or neopentyl glycol deprotection reaction, to obtain the compound of formula (8); wherein, the molar ratio of the compound of formula (7) and the acid is 1:(1˜50); and/or, the said fifth solvent is selected from one or more of tetrahydrofuran, ethyl acetate, methanol, dichloromethane, ether, water, toluene or acetone; and/or, the said acid is selected from one or more of concentrated sulfuric acid, concentrated hydrochloric acid or p-toluenesulfonic acid; and/or, the said hydrolysis reaction temperature is 0˜50° C.; and/or, the said hydrolysis reaction time is 1˜10 h.

15. The method of claim 1, wherein, in step (f), the molar ratio of the compound of formula (8) and the base is 1:(1˜5); and/or, the mass ratio of the compound of formula (8) and Raney nickel is 1:(0.1˜5); and/or, the said sixth solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, tert-butanol, methanol or ethanol; and/or, the said base is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide or potassium hydroxide; the said catalyst is selected from one or more of Raney nickel; and/or, the said hydrolysis and reduction reaction temperature is 20˜100° C.; and/or, the said hydrolysis and reduction reaction time is 24˜72 h; and/or, the said reaction is carried out under the condition of hydrogen pressurization, and the said pressure range of the hydrogen is 0.1˜10 MPa.

16. Compounds have the structures shown in formula (6′), formula (6″), formula (7′), formula (7″) or formula (8) respectively: ##STR00037## wherein R is an alkyl group.

17. The compound of claim 16, wherein R is a C1˜C20 alkyl group.

Description

DESCRIPTION OF DRAWINGS

[0106] FIG. 1 shows the TLC detection results of the compound of formula (10) oxidized by PDC in Comparative Example 1.

[0107] FIG. 2 shows the TLC detection results of the compound of formula (11) oxidized by PDC in Comparative Example 1.

[0108] FIG. 3 shows the results of TLC detection of the compound of formula (8) reduced by Pd/C—H.sub.2 in Comparative Example 2.

[0109] FIG. 4 shows the results of TLC detection of the compound of formula (8) reduced by NaBH.sub.4 in Comparative Example 2.

PREFERRED EMBODIMENTS OF THE INVENTION

[0110] The following examples are given to further illustrate the specific solutions of the present invention. The process, conditions, reagents and experimental methods of the implementation of the present invention are all general knowledge and common knowledge in the field except for the contents specially mentioned below, and the present invention has no special limitation.

Example 1 Preparation of the Compound of Formula (2)

[0111] BA (10.0 g, 30.26 mmol), p-toluenesulfonic acid (57 mg, 0.30 mmol), ethylene glycol (16.8 mL, 302.60 mmol), triethyl orthoformate (15.1 mL, 90.78 mmol) and 150 mL of tetrahydrofuran were added in sequence to a 250 mL single-necked flask and reacted for 8 h at room temperature. After the reaction was completed, the resulting mixture was concentrated under reduced pressure, added with 100 mL of water, extracted with ethyl acetate (60 mL×3), washed with water (50 mL×2), washed with saturated sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (2) (5.0 g, white solid) with a molar yield of 44%.

[0112] BA (10.0 g, 30.26 mmol), p-toluenesulfonic acid (57 mg, 0.30 mmol), ethylene glycol (16.8 mL, 302.60 mmol) and 300 mL of benzene were added in sequence to a 250 mL single-necked flask, and reacted under reflux for 24 h. After the reaction was completed and cooled, 20 mL of saturated sodium bicarbonate solution was added and stirred for 10 min, concentrated under reduced pressure, added with 100 mL of water, extracted with ethyl acetate (60 mL×3), washed with water (50 mL×2), washed with saturated with sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (2) (10.0 g, white solid) with a molar yield of 88%. mp: 175-177° C. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 5.36-5.32 (m, 1H), 3.97-3.90 (m, 4H), 3.63 (dd, J=10.5, 3.2 Hz, 1H), 3.35 (dd, J=10.5, 6.9 Hz, 1H), 2.58-2.53 (m, 1H), 2.11 (dd, J=14.2, 2.9 Hz, 1H), 2.03-1.91 (m, 2H), 1.85-1.72 (m, 3H), 1.69-1.58 (m, 3H), 1.57-1.49 (m, 2H), 1.49-1.39 (m, 2H), 1.36-1.27 (m, 3H), 1.22-1.15 (m, 2H), 1.12-1.07 (m, 1H), 1.04 (d, J=6.7 Hz, 3H), 1.02 (s, 3H), 1.00-0.97 (m, 1H), 0.70 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) δ 140.26, 122.25, 109.60, 68.12, 64.55, 64.34, 56.59, 52.52, 49.79, 42.55, 41.91, 39.74, 38.90, 36.73, 36.45, 32.04, 31.84, 31.19, 27.85, 24.51, 21.16, 19.00, 16.89, 12.07. HRMS (ESI): calcd for C.sub.24H.sub.38NaO.sub.3 [M+Na].sup.+, 397.2713, found 397.2704.

##STR00014##

Example 2 Preparation of the Compound of Formula (3)

[0113] The compound of formula (2) (5.0 g, 13.35 mmol), IBX (7.5 g, 26.70 mmol), 50 mL of THF and 50 mL of DMSO were added in sequence to a 250 mL single-necked flask and reacted for 5 h at room temperature. After the completion of the reaction was detected by TLC, the resulting mixture was added with water, filtered with suction, extracted with dichloromethane (50 mL×3), washed with water (50 mL×2), washed with saturated sodium bicarbonate solution (50 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (3) (4.9 g, white solid) with a molar yield of 98%.

[0114] The compound of formula (2) (10.1 g, 26.96 mmol), TEMPO (42 mg, 0.27 mmol), 100 mL of dichloromethane, a solution of sodium bicarbonate (3.1 g, 36.40 mmol) and tetrabutyl ammonium bromide (870 mg, 2.70 mmol) in water (40 mL), and NCS (4.1 g, 31.00 mmol) were added in sequence to a 500 mL single-neck flask and reacted for 5 h at 0° C. After the completion of reaction was detected by TLC, the resulting mixture was added with sodium thiosulfate pentahydrate solution (1.3 g sodium thiosulfate pentahydrate in 25 mL water), stirred at 5-10° C. for 20 min, separated, and extracted with dichloromethane (50 mL×3), added with 120 mL of 1% sodium hydroxide solution, stirred for 30 min and the layers were separated. The aqueous phase was back-extracted once with dichloromethane (50 mL), washed with water, and concentrated under reduced pressure to obtain the compound of formula (3) (9.6 g, pale yellow solid) with a molar yield of 95%. mp: 168-171° C. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 9.56 (d, J=3.3 Hz, 1H), 5.36-5.31 (m, 1H), 3.97-3.90 (m, 4H), 2.58-2.53 (m, 1H), 2.39-2.31 (m, 1H), 2.11 (dd, J=14.2, 2.9 Hz, 1H), 2.00-1.93 (m, 2H), 1.91-1.82 (m, 1H), 1.81-1.73 (m, 2H), 1.68-1.62 (m, 3H), 1.59-1.53 (m, 1H), 1.52-1.44 (m, 3H), 1.40-1.29 (m, 2H), 1.28-1.15 (m, 2H), 1.12 (d, J=6.8 Hz, 3H), 1.11-1.03 (m, 2H), 1.02 (s, 3H), 0.72 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) δ 205.20, 140.26, 122.10, 109.54, 64.56, 64.35, 56.11, 51.08, 49.79, 49.61, 43.09, 41.90, 39.58, 36.74, 36.45, 32.01, 31.80, 31.19, 27.16, 24.78, 21.10, 19.00, 13.59, 12.37. HRMS (ESI): calcd for C.sub.24H.sub.36NaO.sub.3 [M+Na].sup.+, 395.2557, found 395.2542.

##STR00015##

Example 3 Preparation of the Compound of Formula (6′)

[0115] The compound of formula (3) (1.0 g, 2.68 mmol), methyl (triphenylphosphoranylidene)acetate (1.7 g, 5.36 mmol) and 15 mL of toluene were added in sequence to a 100 mL single-necked flask and reacted under reflux for 4 h. After the completion of the reaction was detected by TLC, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (6′-A) (1.13 g, white solid) with a molar yield of 98%.

[0116] Sodium hydride (161 mg, 4.02 mmol) and 10 mL of tetrahydrofuran were added in a 100 mL single-necked flask, stirred for 15 min, then added in sequence with trimethyl phosphonoacetate (0.65 mL, 4.02 mmol), the compound of formula (3) (1.0 g, 2.68 g mmol) and reacted for 4 h at 0° C. After the completion of the reaction was detected by TLC, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (6′-A) (1.12 g, white solid) with a molar yield of 97%. mp: 161-162° C. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.83 (dd, J=15.6, 9.0 Hz, 1H), 5.73 (d, J=15.6 Hz, 1H), 5.36-5.30 (m, 1H), 3.97-3.90 (m, 4H), 3.71 (s, 3H), 2.62-2.51 (m, 1H), 2.31-2.23 (m, 1H), 2.13-2.08 (m, 1H), 2.01-1.91 (m, 2H), 1.81-1.64 (m, 5H), 1.63-1.51 (m, 3H), 1.51-1.41 (m, 2H), 1.36-1.29 (m, 1H), 1.27-1.20 (m, 3H), 1.08 (d, J=6.6 Hz, 3H), 1.04 (dd, J=11.0, 4.0 Hz, 2H), 1.02 (s, 3H), 0.71 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) δ 167.61, 155.18, 140.24, 122.20, 118.65, 109.57, 64.56, 64.35, 56.62, 54.98, 51.49, 49.77, 42.80, 41.90, 39.88, 39.71, 36.75, 36.45, 32.02, 31.80, 31.19, 28.22, 24.42, 21.13, 19.37, 19.00, 12.25.

##STR00016##

[0117] The compound of formula (3) (9.6 g, 25.77 mmol), ethyl (triphenylphosphoranylidene)acetate (18.0 g, 51.54 mmol) and 150 mL of toluene were added in sequence to a 500 mL single-necked flask and reacted under reflux for 4 h. After the completion of the reaction was detected by TLC, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (6′-B) (11.2 g, white solid) with a molar yield of 98%.

[0118] Sodium hydride (805 mg, 20.13 mmol) and 50 mL of tetrahydrofuran were added in a 250 mL single-necked flask, stirred for 15 min, then added with triethyl phosphonoacetate (4.0 mL, 20.13 mmol), the compound of formula (3) (5.0 g, 13.42 mmol) and reacted for 4 h at 0° C. After the completion of the reaction was detected by TLC, the resulting mixture was concentrated under reduced pressure, slurried with methanol, to obtain the compound of formula (6′-B) (5.65 g, white solid) with a molar yield of 95%. mp: 122-124° C. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.82 (dd, J=15.6, 8.9 Hz, 1H), 5.72 (d, J=15.6 Hz, 1H), 5.39-5.28 (m, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.97-3.90 (m, 4H), 2.58-2.53 (m, 1H), 2.26 (d, J=6.7 Hz, 1H), 2.11 (dd, J=14.2, 2.9 Hz, 1H), 2.00-1.92 (m, 2H), 1.81-1.73 (m, 2H), 1.72-1.61 (m, 3H), 1.60-1.52 (m, 2H), 1.51-1.41 (m, 2H), 1.37-1.30 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.25-1.18 (m, 3H), 1.08 (d, J=6.7 Hz, 3H), 1.04-1.06 (m, 2H), 1.02 (s, 3H), 1.00-0.97 (m, 1H), 0.71 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) δ 167.20, 154.84, 140.24, 122.20, 119.07, 109.57, 64.56, 64.35, 60.22, 56.63, 55.01, 49.78, 42.79, 41.91, 39.85, 39.72, 36.75, 36.45, 32.02, 31.80, 31.20, 28.25, 24.42, 21.14, 19.38, 19.00, 14.42, 12.24. HRMS(ESI): calcd for C.sub.28H.sub.42NaO.sub.4 [M+Na].sup.+, 465.2975, found 465.2990.

##STR00017##

[0119] The compound of formula (3) (1.0 g, 2.68 mmol), propyl 2-(triphenylphosphoranylidene)acetate (1.85 g, 5.36 mmol) and 15 mL of toluene were added in sequence to a 100 mL single-necked flask and reacted under reflux for 4 h. After the completion of the reaction was detected by TLC, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v) to obtain the compound of formula (6′-C) (1.2 g, white solid) with a molar yield of 98%. mp: 108-110° C. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.82 (dd, J=15.6, 8.9 Hz, 1H), 5.73 (d, J=15.6 Hz, 1H), 5.40-5.30 (m, 1H), 4.07 (t, J=6.7 Hz, 2H), 3.97-3.89 (m, 4H), 2.55 (dd, J=14.2, 2.6 Hz, 1H), 2.30-2.23 (m, 1H), 2.11 (dd, J=14.2, 2.8 Hz, 1H), 2.01-1.92 (m, 2H), 1.81-1.73 (m, 2H), 1.70-1.62 (m, 5H), 1.60-1.52 (m, 2H), 1.50-1.41 (m, 2H), 1.36-1.18 (m, 5H), 1.08 (d, J=6.6 Hz, 3H), 1.06-1.04 (m, 1H), 1.02 (s, 3H), 1.01-0.97 (m, 1H), 0.95 (t, J=7.4 Hz, 3H), 0.71 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) δ 167.30, 154.82, 140.24, 122.20, 119.06, 109.57, 65.88, 64.56, 64.35, 56.63, 55.02, 49.78, 42.79, 41.91, 39.84, 39.72, 36.75, 36.45, 32.02, 31.80, 31.20, 28.24, 24.42, 22.18, 21.14, 19.37, 19.00, 12.24, 10.58.

##STR00018##

Example 4 Preparation of the Compound of Formula (4)

[0120] BA (5.0 g, 15.13 mmol), IBX (8.5 g, 30.26 mmol), 50 mL of THF and 50 mL of DMSO were added in sequence to a 250 mL single-neck flask and reacted for 5 h at room temperature. After the completion of the reaction was detected by TLC, the resulting mixture was added with water, filtered with suction, extracted with dichloromethane (50 mL×3), washed with water (50 mL×2), washed with saturated sodium bicarbonate solution (50 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (3) (4.9 g, white solid) with a molar yield of 98%.

[0121] BA (10.0 g, 30.26 mmol), TEMPO (47 mg, 0.30 mmol), 100 mL of dichloromethane, sodium bicarbonate (3.43 g, 40.85 mmol) and tetrabutyl ammonium bromide (977 mg, 3.03 mmol) in water (40 mL), NCS (4.65 g, 34.80 mmol) were added in sequence to a 500 mL single-necked flask to react for 5 h at 0° C. After the completion of the reaction was detected by TLC, the resulting mixture was added with sodium thiosulfate pentahydrate solution (1.5 g sodium thiosulfate pentahydrate/30 mL water), stirred for 20 min at 5-10° C., separated, extracted with dichloromethane (50 mL×3), added with 135 mL of 1% sodium hydroxide solution, stirred for 30 min, and separated. The aqueous phase was back-extracted once with dichloromethane (50 mL), washed with water, and concentrated under reduced pressure, to obtain the compound of formula (4) (9.5 g, pale yellow solid) with a molar yield of 95%. mp: 155-157° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.55 (s, 1H), 5.71 (s, 1H), 2.45-2.23 (m, 5H), 1.99 (t, J=13.7 Hz, 2H), 1.91-1.78 (m, 2H), 1.68 (t, J=10.2 Hz, 2H), 1.43 (m, 5H), 1.30-1.19 (m, 2H), 1.17 (s, 3H), 1.11 (d, J=5.5 Hz, 3H), 1.06-0.89 (m, 3H), 0.75 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 205.00, 199.65, 171.31, 123.99, 55.25, 53.84, 51.04, 49.54, 43.10, 39.39, 38.68, 35.80, 35.68, 34.06, 32.93, 32.05, 27.11, 24.64, 21.06, 17.48, 13.53, 12.44. HRMS(ESI): calcd for C.sub.22H.sub.32NaO.sub.2 [M+Na].sup.+, 351.2295, found 351.2292.

##STR00019##

Example 5 Preparation of the Compound of Formula (5)

[0122] The compound of formula (4) (1.0 g, 3.04 mmol), methyl (triphenylphosphoranylidene)acetate (1.92 g, 6.08 mmol) and 15 mL of toluene were added in sequence to a 100 mL single-necked flask and reacted under reflux for 4 h. After the completion of the reaction was detected by TLC, the resulting mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (5-A) (1.15 g, white solid) with a molar yield of 98%.

[0123] Sodium hydride (182 mg, 4.56 mmol) and 10 mL of tetrahydrofuran were added in sequence to a 100 mL single-necked flask, stirred for 15 min, and added in sequence with methyl phosphonoacetate diethyl ester (0.75 mL, 4.56 mmol) and the compound of formula (4) (1.0 g, 3.04 mmol), then reacted for 4 h at 0° C. After the completion of the reaction was detected by TLC, the resulting mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (5-A) (1.14 g, white solid) with a molar yield of 97%. mp: 142-144° C. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.81 (dd, J=15.6, 9.0 Hz, 1H), 5.73 (d, J=15.8 Hz, 1H), 5.71 (s, 1H), 3.70 (s, 3H), 2.43-2.23 (m, 5H), 2.04-1.97 (m, 2H), 1.82 (ddd, J=11.3, 6.5, 4.1 Hz, 1H), 1.69 (ddd, J=14.3, 9.1, 3.7 Hz, 2H), 1.60 (ddd, J=11.8, 5.8, 2.7 Hz, 1H), 1.53 (ddd, J=14.1, 6.9, 3.7 Hz, 2H), 1.50-1.38 (m, 1H), 1.28-1.19 (m, 3H), 1.17 (s, 3H), 1.15-1.09 (m, 1H), 1.07 (d, J=6.6 Hz, 3H), 1.05-0.97 (m, 2H), 0.96-0.88 (m, 1H), 0.73 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) δ 199.63, 171.43, 167.53, 154.86, 123.94, 118.80, 55.77, 54.97, 53.85, 51.51, 42.83, 39.81, 39.54, 38.69, 35.81, 35.70, 34.08, 32.98, 32.06, 28.17, 24.28, 21.10, 19.32, 17.49, 12.33.

##STR00020##

[0124] The compound of formula (4) (9.5 g, 28.92 mmol), ethyl (triphenylphosphoranylidene)acetate (20.2 g, 57.84 mmol) and 150 mL of toluene were added in sequence to a 500 mL single-necked flask and reacted under reflux for 4 h. After the completion of the reaction was detected by TLC, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (5-B) (11.3 g, white solid) with a molar yield of 98%.

[0125] Sodium hydride (913 mg, 22.83 mmol) and 50 mL of tetrahydrofuran were added to a 250 mL single-necked flask, stirred for 15 min, and added with triethyl phosphonoacetate (4.5 mL, 22.83 mmol) and the compound of formula (3) (5.0 g, 15.22 g) mmol), then reacted for 4 h at 0° C. After the completion of the reaction was detected by TLC, the resulting mixture was concentrated under reduced pressure and slurried with methanol, to obtain the compound of formula (5-B) (5.6 g, white solid) with a molar yield of 92%. mp: 160-162° C. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.81 (dd, J=15.3, 9.0 Hz, 1H), 5.71 (d, J=13.4 Hz, 2H), 4.24-4.09 (m, 2H), 2.45-2.21 (m, 5H), 2.00 (d, J=12.6 Hz, 2H), 1.80 (m, 1H), 1.76-1.33 (m, 7H), 1.26 (m, 6H), 1.17 (s, 3H), 1.08 (d, J=6.2 Hz, 3H), 1.05-0.86 (m, 3H), 0.73 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 199.70, 171.51, 167.16, 154.56, 123.94, 119.21, 60.27, 55.78, 54.98, 53.84, 42.82, 39.80, 39.54, 38.69, 35.80, 35.70, 34.08, 32.98, 32.06, 28.19, 24.28, 21.10, 19.31, 17.49, 14.40, 12.32. HRMS(ESI): calcd for C.sub.26H.sub.38NaO.sub.3 [M+Na].sup.+, 421.2713, found 421.2708.

##STR00021##

[0126] The compound of formula (4) (1.0 g, 3.04 mmol), propyl 2-(triphenylphosphoranylidene)acetate (2.1 g, 6.08 mmol) and 15 mL of toluene were added in sequence to a 100 mL single-neck flask and reacted under reflux for 4 h. After the completion of the reaction was detected by TLC, the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (5-C) (1.23 g, white solid) with a molar yield of 98%. mp: 144-146° C. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.81 (dd, J=15.6, 8.9 Hz, 1H), 5.73 (d, J=16.3 Hz, 1H), 5.71 (s, 1H), 4.06 (t, J=6.7 Hz, 2H), 2.44-2.22 (m, 5H), 2.03-1.97 (m, 2H), 1.85-1.78 (m, 1H), 1.74-1.64 (m, 4H), 1.63-1.57 (m, 1H), 1.57-1.50 (m, 2H), 1.48-1.39 (m, 1H), 1.29-1.20 (m, 3H), 1.17 (s, 3H), 1.15-1.09 (m, 1H), 1.08 (d, J=6.6 Hz, 3H), 1.06-0.97 (m, 2H), 0.94 (t, J=7.4 Hz, 3H), 0.93-0.89 (m, 1H), 0.74 (s, 3H).

##STR00022##

Example 6 Preparation of the Compound of Formula (6′-B)

[0127] The compound of formula (5-B) (5.0 g, 12.54 mmol), p-toluenesulfonic acid (25 mg, 0.13 mmol), ethylene glycol (7.0 mL, 125.40 mmol), triethyl orthoformate Ester (6.3 mL, 37.62 mmol) and 150 mL of tetrahydrofuran were added in sequence to a 250 mL single-necked flask and reacted for 8 h at room temperature. After the reaction was completed, the resulting mixture was concentrated under reduced pressure, added with 100 mL of water, extracted with ethyl acetate (60 mL×3), washed with water (50 mL×2), washed with saturated sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (6′-B) (3.0 g, white solid) with a molar yield of 54%.

[0128] The compound of formula (5-B) (5.0 g, 12.54 mmol), p-toluenesulfonic acid (25 mg, 0.13 mmol), ethylene glycol (7.0 mL, 125.40 mmol) and 150 mL of toluene were added in sequence to a 250 mL single-necked flask and reacted under reflux for 24 h. After the reaction was completed and cooled, the resulting mixture was added with 20 mL of saturated sodium bicarbonate solution, stirred for 10 min, concentrated under reduced pressure, then added with 100 mL of water, extracted with ethyl acetate (50 mL×3), washed with water (50 mL×2), washed with saturated with sodium chloride solution (50 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (6′-B) (4.9 g, white solid)) with a molar yield is 88%. mp: 122-124° C. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.82 (dd, J=15.6, 8.9 Hz, 1H), 5.72 (d, J=15.6 Hz, 1H), 5.39-5.28 (m, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.97-3.90 (m, 4H), 2.58-2.53 (m, 1H), 2.26 (d, J=6.7 Hz, 1H), 2.11 (dd, J=14.2, 2.9 Hz, 1H), 2.00-1.92 (m, 2H), 1.81-1.73 (m, 2H), 1.72-1.61 (m, 3H), 1.60-1.52 (m, 2H), 1.51-1.41 (m, 2H), 1.37-1.30 (m, 1H), 1.27 (t, J=7.1 Hz, 3H), 1.25-1.18 (m, 3H), 1.08 (d, J=6.7 Hz, 3H), 1.04-1.06 (m, 2H), 1.02 (s, 3H), 1.00-0.97 (m, 1H), 0.71 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) δ 167.20, 154.84, 140.24, 122.20, 119.07, 109.57, 64.56, 64.35, 60.22, 56.63, 55.01, 49.78, 42.79, 41.91, 39.85, 39.72, 36.75, 36.45, 32.02, 31.80, 31.20, 28.25, 24.42, 21.14, 19.38, 19.00, 14.42, 12.24. HRMS(ESI): calcd for C.sub.28H.sub.42NaO.sub.4 [M+Na].sup.+, 465.2975, found 465.2990.

##STR00023##

Example 7 Preparation of the Compound of Formula (6″-B)

[0129] The compound of formula (5-B) (10.0 g, 25.09 mmol), neopentyl glycol (6.33 g, 60.7 mmol), p-toluenesulfonic acid monohydrate (215 mg, 1.13 mmol) and toluene (25 mL) were added in sequence to a 100 mL single-necked flask, and triethyl orthoformate (7.5 mL, 45.16 mmol) was added dropwise, then reacted for 2 h at room temperature. After the completion of the reaction was detected by TLC, 30 mL of saturated NaHCO.sub.3 was added to the reaction solution, stirred for 10 min, added with 100 mL of water, extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with saturated brine (50 mL), dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain a pale yellow solid. The pale yellow solid was added to 25 mL of ethanol, slurried for 12 h at room temperature and suction filtered, to obtain compound 6″-B (9 g, white solid) with a molar yield of 74%. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.83 (dd, J=15.6, 8.9 Hz, 1H), 5.73 (d, J=15.6 Hz, 1H), 5.41-5.16 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.49 (m, 4H), 2.56 (dd, J=14.3, 2.8 Hz, 1H), 2.37-2.13 (m, 3H), 2.03-1.85 (m, 2H), 1.67 (dd, J=21.0, 8.2 Hz, 2H), 1.57-1.38 (m, 8H), 1.34-1.15 (m, 7H), 1.08 (t, J=7.7 Hz, 3H), 1.04-0.94 (m, 7H), 0.91 (s, 3H), 0.71 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) δ 167.11, 154.75, 139.61, 122.07, 118.93, 98.40, 70.21, 69.88, 60.11, 56.51, 54.89, 49.60, 42.67, 39.97, 39.74, 39.60, 36.88, 34.97, 31.89, 31.69, 30.12, 28.13, 27.66, 24.29, 22.79, 22.65, 20.98, 19.24, 19.05, 14.29, 12.11.

##STR00024##

Example 8 Preparation of the Compound of Formula (7′-B)

[0130] For the preparation of the compound of formula (7-B), the present invention tested various oxidation reaction conditions (as shown in Table 1), and obtained the best oxidation reaction conditions (as shown in Table 1, Entry 23).

TABLE-US-00001 TABLE 1 Oxidation of the compound of formula (6′-B)..sup.a Reaction Temper- ature Yield Entry Solvent Oxidant (° C.) (%)  1 Toluene Na.sub.2Cr.sub.2O.sub.7/NHPI 25 N.sup.b  2 Toluene Na.sub.2Cr.sub.2O.sub.7/NHPI/AcOH 25 54  3 Toluene K.sub.2Cr.sub.2O.sub.7/NHPI/AcOH 25 52  4 Toluene PDC/NHPI 25 66  5 Toluene PDC/TBHP 25 43  6 Toluene BPO/NHPI 25 42  7 Acetone Na.sub.2Cr.sub.2O.sub.7/NHPI 25 N.sup.b  8 Acetone Na.sub.2Cr.sub.2O.sub.7/NHPI/AcOH 25 62  9 Acetone K.sub.2Cr.sub.2O.sub.7/NHPI/AcOH 25 61 10 Acetone PDC/NHPI 25 72 11 Acetone PDC/TBHP 25 59 12 Acetone BPO/NHPI 25 51 13 N,N-Dimethylformamide PDC/NHPI 25 38 14 tert-Butanol PDC/NHPI 25 N.sup.b 15 Ethyl acetate PDC/NHPI 25 N.sup.b 16 Acetonitrile PDC/NHPI 25 70 17 N-Methylpyrrolidone PDC/NHPI 25 N.sup.b 18 Dichloromethane PDC/NHPI 25 68 19 Acetonitrile/Water PDC/NHPI 25 77 (4:1, v/v) 20 Acetonitrile/Water PDC/NHPI 25 79 (9:1, v/v) 21 Acetonitrile/Water PDC/NHPI 25 79 (14:1, v/v) 22 Acetone/Water (4:1, v/v) PDC/NHPI 25 80 23 Acetone/Water (9:1, v/v) PDC/NHPI 25 85 24 Acetone/Water (14:1, v/v) PDC/NHPI 25 82 25 Acetone/Water (9:1, v/v) PDC/NHPI  0 65 26 Acetone/Water (9:1, v/v) PDC/NHPI 50 73
a. All reaction times were 20 h, oxidant/compound 6′-B=1.1:1 (mol:mol).
b. No react.

[0131] It can be seen from Table 1 that the optimal reaction conditions were obtained by screening and optimizing the solvent, oxidant and reaction temperature, namely, the optimal reaction solvent was acetone/water (9:1), the optimal oxidant was PDC, and the optimal reaction temperature was at 25° C., and the reaction yield reached 85%.

[0132] Some of the Examples are as Follows:

[0133] The compound of formula (6′-B) (1.0 g, 2.26 mmol), 20 mL of acetone, NHPI (400 mg, 2.49 mmol), and PDC (940 mg, 2.49 mmol) were added in sequence to a 250 mL single-necked flask and reacted at room temperature for 20 h. After the completion of the reaction was detected by TLC, the resulting mixture was suction filtered with diatomite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (7′-B) (743 mg, white solid)), the molar yield was 72%.

[0134] The compound of formula (6′-B) (1.0 g, 2.26 mmol), 20 mL of acetonitrile, NHPI (400 mg, 2.49 mmol), and PDC (940 mg, 2.49 mmol) were added in sequence to a 250 mL single-necked flask and reacted at room temperature for 20 h. After the completion of the reaction was detected by TLC, the resulting mixture was suction filtered with diatomite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (7′-B) (722 mg, white solid) with a molar yield of 70%.

[0135] The compound of formula (6′-B) (1.0 g, 2.26 mmol), 20 mL of acetone, NHPI (400 mg, 2.49 mmol), Na.sub.2Cr.sub.2O.sub.7.2H.sub.2O (742 mg, 2.49 mmol), AcOH (0.4 mL, 6.78 mmol) and reacted for 20 h at room temperature. After the completion of the reaction was detected by TLC, the resulting mixture was suction filtered with diatomite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (7′-B) (640 mg, white solid)) with a molar yield of 62%.

[0136] The compound of formula (6′-B) (5.0 g, 11.30 mmol), 90 mL of acetone, 10 mL of water, NHPI (2.0 g, 12.43 mmol), PDC (4.7 g, 12.43 mmol) were added in sequence to a 250 mL single-necked flask and reacted for 20 hours at room temperature. After the completion of the reaction was detected by TLC, the resulting mixture was suction filtered with diatomite. The filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (7′-B) (4.4 g, white solid)) with a molar yield of 85%. mp: 139-141° C. .sup.1H NMR (500 MHz, CDCl.sub.3) δ 6.82 (dd, J=15.6, 9.0 Hz, 1H), 5.72 (d, J=15.6 Hz, 1H), 5.65 (d, J=1.7 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.98-3.90 (m, 4H), 2.66 (dd, J=14.7, 1.8 Hz, 1H), 2.44-2.36 (m, 1H), 2.34-2.18 (m, 3H), 2.02-1.95 (m, 1H), 1.89-1.83 (m, 2H), 1.78-1.71 (m, 2H), 1.64-1.52 (m, 3H), 1.52-1.43 (m, 1H), 1.27 (m, 8H), 1.19 (s, 3H), 1.08 (d, J=6.6 Hz, 3H), 0.70 (s, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3) δ 201.52, 167.11, 164.66, 154.53, 126.73, 119.23, 108.98, 64.70, 64.62, 60.24, 53.82, 50.01, 49.65, 45.41, 43.58, 41.84, 39.59, 38.65, 38.35, 35.73, 31.16, 28.34, 26.44, 21.25, 19.58, 17.08, 14.40, 12.40. HRMS(ESI): calcd for C.sub.28H.sub.40NaO.sub.5 [M+Na].sup.+, 479.2768, found 479.2770.

##STR00025##

Example 9 Preparation of the Compound of Formula (7″-B)

[0137] The compound of formula (6″-B) (2.1 g, 4.21 mmol), 33.5 mL of acetone, 3.7 mL of H.sub.2O, NHPI (1.38 g, 8.42 mmol) and PDC (3.17 g, 8.42 mmol) were added in sequence to a 250 mL single-necked flask and reacted at room temperature for 24 h. Post-processing: after the completion of the reaction was detected by TLC, the solvent was removed, then added with DCM (50 mL), stirred and dissolved, suction filtered with diatomite. The filter cake was washed with DCM (20 mL*3), and the filtrate was concentrated under reduced pressure, to obtain a light brown solid. The above crude product was added to ethanol (5 mL+0.05 mL TEA), slurried for 12 h at room temperature, and filtered with suction, to obtain compound 7″-B (1.5 g, light yellow solid) with a molar yield of 70%. .sup.1H NMR (600 MHz, CDCl.sub.3) δ 6.83 (dd, J=15.6, 9.0 Hz, 1H), 5.70 (dd, J=24.9, 8.5 Hz, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.65-3.50 (m, 2H), 3.41 (q, J=11.5 Hz, 2H), 2.83 (dd, J=14.8, 3.0 Hz, 1H), 2.50-2.33 (m, 2H), 2.25 (m, 3H), 1.98 (d, J=12.9 Hz, 1H), 1.81-1.69 (m, 3H), 1.68-1.52 (m, 4H), 1.47-1.31 (m, 3H), 1.25 (m, 7H), 1.18 (s, 3H), 1.17 (d, J=12.9 Hz, 1H), 1.08 (d, J=6.6 Hz, 3H), 0.95 (d, J=11.1 Hz, 6H), 0.70 (s, 3H). .sup.13C NMR (151 MHz, CDCl.sub.3) δ 201.59, 167.05, 164.52, 154.47, 126.81, 119.12, 98.07, 70.39, 70.01, 60.15, 53.73, 49.89, 49.60, 45.37, 43.49, 39.50, 39.28, 38.54, 38.52, 34.44, 30.08, 28.42, 28.25, 26.33, 22.62, 21.13, 19.46, 17.12, 14.29, 12.28.

##STR00026##

Example 10 Preparation of the Compound of Formula (8)

[0138] The compound of formula (7′-B) (4.4 g, 9.64 mmol), 45 mL of tetrahydrofuran, 5 mL of water, and 2 mL of concentrated sulfuric acid were added in sequence to a 100 mL single-necked flask, and stirred at room temperature for 4 h after the dripping was completed. After the completion of the reaction was detected by TLC, the resulting mixture was added with 80 mL of a saturated sodium bicarbonate solution to quench the reaction, extracted with ethyl acetate (30 mL*3), washed with saturated sodium chloride solution (30 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=3/1, v/v), to obtain the compound of formula (8) (3.9 g, white solid) with a molar yield of 98%.

##STR00027##

[0139] The compound of formula (7″-B) (5.70 g, 11.1 mmol), 51 mL of THF, and 5.8 mL of H.sub.2O were added in sequence to a 100 mL single-necked flask, and 2.3 mL of concentrated sulfuric acid was added dropwise in an ice bath, then stirred for 12 h at room temperature after the dripping was completed. After the completion of the reaction was detected by TLC, the resulting mixture was added with 80 mL of a saturated sodium bicarbonate solution to quench, extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with saturated brine (35 mL), dried with anhydrous sodium sulfate, and concentrated under reduced pressure, to obtain a khaki solid. The solid was added to 16 mL of a mixed solution of petroleum ether and ethyl acetate (PE:EA=3:1), slurried for 12 h at room temperature, and suction filtration, to obtain compound 8 (3.7 g, white solid) with a molar yield of 81%. mp: 167-169° C. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.22 (s, 1H), 6.74 (dd, J=15.4, 9.0 Hz, 1H), 5.78 (d, J=15.5 Hz, 1H), 5.29 (s, 1H), 5.27 (s, 1H), 4.09 (dd, J=13.2, 6.4 Hz, 2H), 2.37-2.13 (m, 5H), 1.94-1.85 (m, 2H), 1.58-1.42 (m, 4H), 1.34-1.25 (m, 3H), 1.20 (m, 6H), 1.05 (d, J=7.0 Hz, 6H), 0.69 (s, 3H). .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ 198.89, 165.98, 165.30, 164.15, 154.50, 118.79, 117.65, 99.83, 59.69, 53.03, 50.42, 48.87, 44.90, 43.47, 38.80, 38.27, 35.45, 32.49, 27.95, 26.30, 25.43, 21.04, 19.19, 16.91, 14.17, 12.09. HRMS(ESI): calcd for C.sub.26H.sub.36NaO.sub.4 [M+Na].sup.+, 435.2506, found 435.2501.

##STR00028##

Example 11 Preparation of the Compound of Formula (9)

[0140] For the preparation of the compound of formula (9), the present invention tested various reduction and hydrolysis reaction conditions (as shown in Table 2), and obtained the optimal reduction and hydrolysis reaction conditions (as shown in Table 2, Entry 12).

TABLE-US-00002 TABLE 2 Reduction and hydrolysis of the compound of formula (8)..sup.a Reaction temperature Yield Entry Solvent Base (° C.) (%)  1 Isopropyl alcohol Potassium tert-butoxide 60 38  2 n-Butanol Potassium tert-butoxide 60 35  3 tert-Butanol Potassium tert-butoxide 60 36  4 Tetrahydrofuran Potassium tert-butoxide 60 N.sup.c  5 Isopropyl alcohol Potassium tert-butoxide 40 33  6 Isopropyl alcohol Potassium tert-butoxide 90 61  7 Isopropyl alcohol Sodium methoxide 90 44  8 Isopropyl alcohol Sodium ethoxide 90 43  9 Isopropyl alcohol Sodium tert-butoxide 90 72 10 Tetrahydrofuran/ Sodium tert-butoxide 90 81 Isopropanol (1:1, v/v) 11 1,4-dioxane/Isopropyl Sodium tert-butoxide 90 70 Alcohol (1:1, v/v) 12 2- Sodium tert-butoxide 90 87 Methyltetrahydrofuran/ Isopropanol (1:1, v/v) 13.sup.b Isopropyl Sodium tert-butoxide 90 60 alcohol 14.sup.b Tetrahydrofuran. Sodium tert-butoxide 90 65 Isopropanol (1:1, v/v) 15.sup.b 2- Sodium tert-butoxide 90 68 Methyltetrahydrofuran/ Isopropanol (1:1, v/v) .sup.aAll reaction times were 48 h, Raney-Ni/Compound 8 = 1:1 (m:m); .sup.bSolvent and base are added together (the rest are added separately); .sup.cNo UDCA.

[0141] It can be seen from Table 2 that the optimal reaction conditions were obtained by screening and optimizing the solvent, base and reaction temperature, namely, the optimal reaction solvent was 2-methyltetrahydrofuran/isopropanol (1:1, v/v), the optimal base is sodium tert-butoxide, the optimal reaction temperature is 90° C., and the reaction yield reaches 87%.

[0142] Some of the Examples are as Follows:

[0143] The compound of formula (8) (1.0 g, 2.42 mmol), 20 mL of isopropanol, 1.0 g of Raney Ni, H.sub.2 (4.0 MPa) were added in sequence to an autoclave and reacted for 24 hours at 90° C., then added with potassium tert-butoxide (543 mg, 4.84 mmol) and reacted for 24 hours at 90° C. After the completion of the reaction was detected by TLC, the resulting mixture was added with acetic acid to adjust the pH to 5, suction filtered with diatomite. The filtrate was concentrated under reduced pressure, dissolved in ethyl acetate (30 mL), washed with water and saturated sodium chloride solution in turn, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (DCM/MeOH=20/1, v/v), to obtain ursodeoxycholic acid (580 mg, white solid) with a molar yield of 61%.

[0144] The compound of formula (8) (1.0 g, 2.42 mmol), 20 mL of isopropanol, 1.0 g of Raney Ni, H.sub.2 (4.0 MPa), sodium tert-butoxide (465 mg, 4.84 mmol) were added in sequence to an autoclave and reacted for 48 hours at 90° C. After the completion of the reaction was detected by TLC, the resulting mixture was added with acetic acid, adjusted the pH to 5, suction filtered with diatomite. The filtrate was concentrated under reduced pressure, dissolved in ethyl acetate (30 mL), washed with water and saturated sodium chloride solution in turn, dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (DCM/MeOH=20/1, v/v), to obtain ursodeoxycholic acid (571 mg, white solid) with a molar yield of 60%.

[0145] The compound of formula (8) (1.0 g, 2.42 mmol), 20 mL of isopropanol, 1.0 g of Raney Ni, H.sub.2 (4.0 MPa) were added in sequence to an autoclave and reacted for 24 hours at 90° C., then added with sodium tert-butoxide (465 mg, 4.84 mmol) and reacted for 24 hours at 90° C. After the completion of the reaction was detected by TLC, the resulting mixture was added with acetic acid to adjust the pH to 5, suction filtered with diatomite. The filtrate was concentrated under reduced pressure, dissolved in ethyl acetate (30 mL), washed with water and saturated sodium chloride solution in turn, dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (DCM/MeOH=20/1, v/v), to obtain ursodeoxycholic acid (685 mg, white solid) with a molar yield of 72%.

[0146] The compound of formula (8) (1.0 g, 2.42 mmol), 20 mL of 2-methyltetrahydrofuran, 1.0 g of Raney Ni, H.sub.2 (4.0 MPa), 20 mL of isopropanol, and sodium tert-butoxide (465 mg, 4.84 mmol), and reacted for 48 hours at 90° C. After the completion of the reaction was detected by TLC, the resulting mixture was added with acetic acid to adjust the pH to 5, suction filtered with diatomite. The filtrate was concentrated under reduced pressure, dissolved in ethyl acetate (30 mL), washed with water and saturated sodium chloride solution in turn, dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (DCM/MeOH=20/1, v/v), to obtain ursodeoxycholic acid (646 mg, white solid) with a molar yield of 68%.

[0147] The compound of formula (8) (1.0 g, 2.42 mmol), 20 mL of 2-methyltetrahydrofuran, 1.0 g of Raney Ni, H.sub.2 (4.0 MPa) were added in sequence to an autoclave and reacted for 24 hours at 90° C., then added with 20 mL of isopropanol, sodium tert-butoxide (465 mg, 4.84 mmol) and reacted for 24 hours at 90° C. After the completion of the reaction was detected by TLC, the resulting mixture was added with acetic acid to adjust the pH to 5, suction filtered with diatomite. The filtrate was concentrated under reduced pressure, dissolved in ethyl acetate (30 mL), washed with water and saturated sodium chloride solution in turn, dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (DCM/MeOH=20/1, v/v), to obtain ursodeoxycholic acid (827 mg, white solid) with a molar yield of 87%.

[0148] The compound of formula (8) (1.0 g, 2.42 mmol), 20 mL of tetrahydrofuran, 1.0 g of Raney Ni, H.sub.2 (4.0 MPa), 20 mL of isopropanol and sodium tert-butoxide (465 mg, 4.84 mmol) were added in sequence to an autoclave and reacted for 48 hours at 90° C. After the completion of the reaction was detected by TLC, the resulting mixture was added with acetic acid to adjust the pH to 5, suction filtered with diatomite. The filtrate was concentrated under reduced pressure, dissolved in ethyl acetate (30 mL), washed with water and saturated sodium chloride solution in turn, dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (DCM/MeOH=20/1, v/v), to obtain ursodeoxycholic acid (618 mg, white solid) with a molar yield of 65%.

[0149] The compound of formula (8) (2.0 g, 4.85 mmol), 20 mL of tetrahydrofuran, 2.0 g of Raney Ni, H.sub.2 (4.0 MPa) were added in sequence to an autoclave and reacted for 24 hours at 90° C., then added with 20 mL of isopropanol and sodium tert-butoxide (932 mg, 9.70 mmol) and reacted for 24 hours at 90° C. After the completion of the reaction was detected by TLC, the resulting mixture was added with acetic acid to adjust the pH to 5, suction filtered with diatomite. The filtrate was concentrated under reduced pressure, dissolved in ethyl acetate (30 mL), washed with water and saturated sodium chloride solution in turn, dried with anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (DCM/MeOH=20/1, v/v), to obtain ursodeoxycholic acid (1.54 g, white solid) with a molar yield of 81%. mp: 200-202° C. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.94 (s, 1H), 4.46 (s, 1H), 3.88 (d, J=6.7 Hz, 1H), 3.35-3.24 (m, 2H), 2.26-2.19 (m, 1H), 2.13-2.05 (m, 1H), 1.95-1.81 (m, 2H), 1.78-1.63 (m, 4H), 1.51-1.42 (m, 3H), 1.41-1.28 (m, 7H), 1.23-1.08 (m, 6H), 1.05-0.91 (m, 2H), 0.88 (d, J=6.5 Hz, 6H), 0.61 (s, 3H). .sup.13C NMR (100 MHz, DMSO-d.sub.6) δ 174.93, 69.75, 69.46, 55.87, 54.70, 43.11, 43.02, 42.20, 39.94, 39.84, 39.73, 38.75, 37.75, 37.28, 34.88, 33.78, 30.78, 30.26, 28.21, 26.75, 23.34, 20.89, 18.32, 12.06. HRMS(ESI). calcd for C.sub.24H.sub.40NaO.sub.4 [M+Na].sup.+, 415.2819, found 415.2834.

##STR00029##

Comparative Example 1

[0150] By protecting the 3-position carbonyl group of the compound of formula (5-B), when synthesizing alkenyl ether and alkenyl ester structures (the structures are shown in formulas (10) and (11) respectively), the compounds of formula (10) and formula (11) obtained have poor stability and is easy to deteriorate; and when PDC and NHPI are used to further oxidize the compounds of formula (10) and formula (11) at the 7th position, the reaction results are complicated, and the target compound of formula (12) and formula (13) are not obtained by separation (the reaction formula is as follows).

##STR00030##

[0151] The compound of formula (5-B) (1.0 g, 2.51 mmol) and 20 mL of 1.5 M HCl/EtOH solution were added in sequence to a 100 mL single-necked flask and reacted for 4 h at room temperature. After completion of the reaction, the resulting mixture was concentrated under reduced pressure to obtain the compound of formula (10) (1.1 g, white solid), which was directly used in the next step.

[0152] The compound of formula (10) (1.1 g, 2.51 mmol), 18 mL of acetone, 2 mL of water, NHPI (444 mg, 2.76 mmol) and PDC (1.0 g, 2.76 mmol) were added in sequence to a 100 mL a single-necked flask and reacted for 20 h at room temperature. The TLC detection result is shown in FIG. 1 (PE/EA=3/1, v/v), the alkenyl ether compound has poor stability, the reaction result is complicated, and the compound of formula (12) is not obtained by isolation.

##STR00031##

[0153] The compound of formula (5-B) (1.0 g, 2.51 mmol), 10 mL of acetyl chloride and 10 mL of acetic anhydride were added in sequence to a 100 mL single-neck flask and reacted under reflux for 4 h. After completion of the reaction, the resulting mixture was concentrated under reduced pressure to obtain the compound of formula (11) (1.1 g, white solid), which was directly used in the next step.

[0154] The compound of formula (11) (1.1 g, 2.51 mmol), 18 mL of acetone, 2 mL of water, NHPI (444 mg, 2.76 mmol), and PDC (1.0 g, 2.76 mmol) were added in sequence to a 100 mL single-necked flask and reacted for 20 h at room temperature. The TLC detection results are shown in FIG. 2 (PE/EA=3/1, v/v), the alkene ester compound has poor stability, the reaction results are complicated, and the compound of formula (13) is not obtained by isolation.

[0155] From this comparative example 1, it can be seen that the compounds with alkenyl ether and alkenyl ester structures have poor stability and are easy to deteriorate. When using PDC and NHPI for 7th position oxidation, the reaction results are complicated, and the target compounds of formula (12) and formula (13) are not obtained by separation.

Comparative Example 2

[0156] When the compound (8) is reduced by Pd/C—H.sub.2, NaBH.sub.4, etc., the reaction result is complicated, and the target compounds of formula (14) and formula (15) are not obtained by separation (reaction formula is as follows).

##STR00032##

[0157] The compound of formula (8) (1.0 g, 2.42 mmol), 20 mL of methanol and 0.1 g of 10% Pd/C, H.sub.2 (4.0 MPa) were added in sequence to an autoclave, and reacted for 24 hours at 60° C. The TLC detection results are shown in FIG. 3 (PE/EA=1/1, v/v). When Pd/C—H.sub.2 is used to reduce compound (8), the reaction result is complicated, and the compound of formula (14) is not isolated.

##STR00033##

[0158] The compound of formula (8) (1.0 g, 2.42 mmol), 20 mL of methanol, and NaBH.sub.4 (458 mg, 12.10 mmol) were added in sequence to a 100 mL single-necked flask, stirred for 4 h at room temperature. The TLC detection results are shown in FIG. 4 (PE/EA=1/1, v/v). When compound (8) is reduced by NaBH.sub.4, the reaction result is complicated, and the compound of formula (15) is not obtained by separation.

[0159] It can be seen from this comparative example 2 that when Pd/C—H.sub.2, NaBH.sub.4, etc. are used for reduction, the reaction result is complicated, and the target compounds of formula (14) and formula (15) are not obtained by separation.

[0160] The protection of the invention is not limited to the above embodiments. Without departing from the spirit and scope of the idea of the invention, all changes and advantages that can be thought of by a person skilled in the field are included in the present invention and the scope of protection is the appended claim.