Synthesis method of plant-derived deoxycholic acid

Abstract

The application discloses a synthetic method of plant-derived deoxycholic acid, which comprises the following steps: taking plant-derived 9-OH-BA as raw material, and synthesizing the deoxycholic acid through side chain oxidation reaction, Wittig or Wittig-Horner reaction, dehydration reaction, hydrogenation reduction reaction, esterification reaction, C ring oxidation reaction, carbonyl reduction reaction and hydrolysis reaction. In view of the safety problem existing in the preparation of traditional animal-derived deoxycholic acid, the deoxycholic acid is synthesized by using plant-derived 9-OH-BA, so that the risk of pathogenic bacteria and virus infection is avoided, the safety of clinical use is improved, the synthetic yield is high, the environment is friendly, and the method is suitable for industrialized production and application.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic chemical synthesis, and relates to a method for synthesizing deoxycholic acid from plant-derived 9,21-dihydroxy-20-methyl-pregn-4-ene-3-ketone 9-OH-BA as raw material. BACKGROUND

[0002] Deoxycholic acid is a free bile acid derived from cholic acid by losing one oxygen atom, and is a natural substance in the human body. It has the effects of promoting bile secretion and helping to decompose fat in clinic. Commercial deoxycholic acid is mainly used for: 1. biochemical, bacteriological and enzymatic research; 2. lipase accelerator and anion remover; 3. double chin lipolysis needle. At present, most of the deoxycholic acid is obtained from pig, cow, sheep or chicken, duck bile. Research has found that animal-derived products may carry animal pathogens or other harmful factors, especially with the occurrence of mad cow disease (prion disease), sheep anthrax, swine streptococcus, avian influenza and other infections, people pay more and more attention to the safety of drugs. Therefore, in order to ensure the health and safety of people, it is urgent to develop a synthesis method of deoxycholic acid based on plant-derived raw materials.

[0003]

[0004] The reported chemical synthesis of deoxycholic acid based on plant-derived raw materials mainly includes the following methods:

[0005] (1) Deoxycholic acid is synthesized from hydrocortisone as raw material through 17 steps with a total molar yield of 4.7% (WO2012 / 021133 A9), as shown in Scheme 1. This route uses a relatively expensive catalyst PtO2, and the price of hydrocortisone raw material is relatively high. The reaction steps are long, and the total yield is low, which is not suitable for industrial production.

[0006]

[0007] (2) Deoxycholic acid is synthesized from 9α-hydroxyandrostenedione 9α-OH-4AD as raw material through 12 steps with a total molar yield of 22% (CN 106146593 B, as shown in Scheme 2). In this route, the step of generating C ring 12-position carbonyl group by oxidation reaction needs to be oxidized by TBHP first, and then oxidized by PCC again. The C ring double bond reduction step needs to be recycled three times, which is complicated and not suitable for industrial production.

[0008]

[0009] (3) Using sitosterol, stigmasterol, camphor sterol or cholesterol as raw material, compound (1) obtained by fermentation of Mycobacterium fortuitum as raw material, deoxycholic acid was synthesized by 12-step reaction with a total molar yield of 12.8% (WO 2019 / 081586 A1, as shown in Scheme 3). The total yield of this route is low, the raw material is not easy to obtain, the yield of C-ring oxidation reaction to generate carbonyl group is low, the purification is difficult, and it is not suitable for industrial production.

[0010]

[0011] At present, the chemical synthesis process of deoxycholic acid based on plant source raw materials has been reported, which has the disadvantages of long route, difficult raw materials, high raw material price, complex reaction operation, low product yield and the like. Therefore, it has important economic value and social significance to develop a more safe and efficient synthesis method of deoxycholic acid based on plant source raw materials. SUMMARY

[0012] In order to solve the problems existing in the prior art, the purpose of the present application is to provide a synthesis method of plant source deoxycholic acid. The present application uses plant source 9,21-dihydroxy-20-methyl-pregn-4-ene-3-ketone 9-OH-BA as raw material, and synthesizes the deoxycholic acid through side chain oxidation reaction, Wittig or Wittig-Horner reaction, dehydration reaction, A ring and side chain double bond hydrogenation reduction reaction, esterification reaction, C ring oxidation reaction, C ring double bond hydrogenation reduction reaction, C ring carbonyl reduction reaction, hydrolysis reaction steps; or through side chain oxidation reaction, Wittig or Wittig-Horner reaction, dehydration reaction, A ring double bond and side chain double bond hydrogenation reduction reaction, A ring carbonyl reduction reaction, esterification reaction, C ring oxidation reaction, C ring double bond hydrogenation reduction reaction, C ring carbonyl reduction reaction, hydrolysis reaction step; or through side chain oxidation reaction, Wittig or Wittig-Horner reaction, dehydration reaction, C ring oxidation reaction, A ring and side chain double bond hydrogenation reduction reaction, esterification reaction, C ring double bond hydrogenation reduction reaction, C ring carbonyl reduction reaction, hydrolysis reaction step; or through side chain oxidation reaction, Wittig or Wittig-Horner reaction, A ring double bond and side chain double bond hydrogenation reduction reaction, dehydration reaction, A ring carbonyl reduction reaction, esterification reaction, C ring oxidation reaction, C ring double bond hydrogenation reduction reaction, C ring carbonyl reduction reaction, hydrolysis reaction step. The starting material for synthesizing deoxycholic acid in the present application is safe, the method for synthesizing deoxycholic acid is simple in operation, high in yield, good in purity, environment-friendly, and convenient for industrial production.

[0013] In the synthetic method of the present application, the starting material 9,21-dihydroxy-20-methylpregn-4-ene-3-one 9-OH-BA includes but is not limited to being obtained by biofermentation of phytosterols or being obtained by a chemical synthesis method.

[0014] The present application provides a method for synthesizing deoxycholic acid using plant-derived 9,21-dihydroxy-20-methylpregn-4-ene-3-one 9-OH-BA as a starting material, and the reaction process of the method includes but is not limited to four synthetic methods as shown in Route (A):

[0015]

[0016] The synthetic routes are as follows:

[0017]

[0018]

[0019]

[0020] wherein R is selected from alkyl, and R1 is selected from alkyl, aryl, substituted aryl, etc.

[0021] Preferably, R is selected from one or more of C1-C10 straight-chain alkyl and branched-chain alkyl; and R1 is selected from C1-C10 straight-chain alkyl, C1-C10 branched-chain alkyl, phenyl p-methoxyphenyl o-methoxyphenyl 2,4-dimethoxyphenyl p-trifluoromethylphenyl , or the like.

[0022] Further preferably, R is selected from one or both of methyl and ethyl; and R1 is selected from p-methoxyphenyl

[0023] The synthetic method of the present application includes the following steps:

[0024] Step (a), the compound of formula (1) is subjected to a side chain oxidation reaction in a first solvent to obtain a compound of formula (2);

[0025] Step (b), the compound of formula (2) is subjected to a Wittig or Wittig-Horner reaction in a second solvent to obtain a compound of formula (3);

[0026] Step (c), the compound of formula (3) is subjected to a dehydration reaction in a third solvent to obtain a compound of formula (4);

[0027] Step (d), hydrogenation reduction of the double bond of the A ring and the side chain of the compound of formula (4) in a fourth solvent to obtain a compound of formula (5);

[0028] Step (g), esterification of the compound of formula (5) in a seventh solvent to obtain a compound of formula (7);

[0029] Step (h), epoxidation of the compound of formula (7) in an eighth solvent to obtain a compound of formula (8);

[0030] Step (l), hydrogenation reduction of the double bond of the C ring of the compound of formula (8) in a twelfth solvent to obtain a compound of formula (11);

[0031] Step (m), carbonyl reduction of the compound of formula (11) in a thirteenth solvent to obtain a compound of formula (12);

[0032] Step (n), hydrolysis of the compound of formula (12) in a fourteenth solvent to obtain a target product deoxycholic acid of formula (13).

[0033] Or, the synthetic method of the application comprises the following steps:

[0034] Step (a), side chain oxidation of the compound of formula (1) in a first solvent to obtain a compound of formula (2);

[0035] Step (b), Wittig or Wittig-Horner reaction of the compound of formula (2) in a second solvent to obtain a compound of formula (3);

[0036] Step (c), dehydration of the compound of formula (3) in a third solvent to obtain a compound of formula (4);

[0037] Step (e), hydrogenation reduction of the double bond of the A ring and the side chain of the compound of formula (4) in a fifth solvent to obtain a compound of formula (6);

[0038] Step (f), carbonyl reduction of the compound of formula (6) in a sixth solvent to obtain a compound of formula (5);

[0039] Step (g), esterification of the compound of formula (5) in a seventh solvent to obtain a compound of formula (7);

[0040] Step (h), epoxidation of the compound of formula (7) in an eighth solvent to obtain a compound of formula (8);

[0041] Step (l), hydrogenation reduction of the double bond of the C ring of the compound of formula (8) in a twelfth solvent to obtain a compound of formula (11);

[0042] Step (m), the compound of formula (11) is subjected to a C-ring carbonyl reduction reaction in a thirteenth solvent to obtain a compound of formula (12);

[0043] Step (n), the compound of formula (12) is subjected to a hydrolysis reaction in a fourteenth solvent to obtain a target product deoxycholic acid of formula (13).

[0044] Or, the synthetic method of the application comprises the following steps:

[0045] Step (a), the compound of formula (1) is subjected to a side chain oxidation reaction in a first solvent to obtain a compound of formula (2);

[0046] Step (b), the compound of formula (2) is subjected to a Wittig or Wittig-Horner reaction in a second solvent to obtain a compound of formula (3);

[0047] Step (c), the compound of formula (3) is subjected to a dehydration reaction in a third solvent to obtain a compound of formula (4);

[0048] Step (i), the compound of formula (4) is subjected to a C-ring oxidation reaction in a ninth solvent to obtain a compound of formula (9);

[0049] Step (j), the compound of formula (9) is subjected to an A-ring and side chain double bond hydrogenation reduction reaction in a tenth solvent to obtain a compound of formula (10);

[0050] Step (k), the compound of formula (10) is subjected to an esterification reaction in an eleventh solvent to obtain a compound of formula (8);

[0051] Step (l), the compound of formula (8) is subjected to a C-ring double bond hydrogenation reduction reaction in a twelfth solvent to obtain a compound of formula (11);

[0052] Step (m), the compound of formula (11) is subjected to a C-ring carbonyl reduction reaction in a thirteenth solvent to obtain a compound of formula (12);

[0053] Step (n), the compound of formula (12) is subjected to a hydrolysis reaction in a fourteenth solvent to obtain a target product deoxycholic acid of formula (13).

[0054] Or, the synthetic method of the application comprises the following steps:

[0055] Step (a), the compound of formula (1) is subjected to a side chain oxidation reaction in a first solvent to obtain a compound of formula (2);

[0056] Step (b), the compound of formula (2) is subjected to a Wittig or Wittig-Horner reaction in a second solvent to obtain a compound of formula (3);

[0057] Step (o), in a fifteenth solvent, the compound of formula (3) is subjected to a hydrogenation reduction reaction via the double bond of ring A and the double bond of the side chain to obtain a compound of formula (14);

[0058] Step (p), in a sixteenth solvent, the compound of formula (14) is subjected to a dehydration reaction to obtain a compound of formula (6);

[0059] Step (f), in a sixth solvent, the compound of formula (6) is subjected to a carbonyl reduction reaction of ring A to obtain a compound of formula (5);

[0060] Step (g), in a seventh solvent, the compound of formula (5) is subjected to an esterification reaction to obtain a compound of formula (7);

[0061] Step (h), in an eighth solvent, the compound of formula (7) is subjected to an oxidation reaction of ring C to obtain a compound of formula (8);

[0062] Step (l), in a twelfth solvent, the compound of formula (8) is subjected to a hydrogenation reduction reaction via the double bond of ring C to obtain a compound of formula (11);

[0063] Step (m), in a thirteenth solvent, the compound of formula (11) is subjected to a carbonyl reduction reaction of ring C to obtain a compound of formula (12);

[0064] Step (n), in a fourteenth solvent, the compound of formula (12) is subjected to a hydrolysis reaction to obtain a target product deoxycholic acid of formula (13).

[0065] Specifically, in step (a), the side chain oxidation reaction is specifically: in a first solvent, the compound of formula (1) is subjected to a side chain oxidation reaction with 2,2,6,6-tetramethylpiperidine oxide TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and an oxidizing agent to obtain a compound of formula (2).

[0066] The molar ratio of the compound of formula (1), TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and the oxidizing agent is 1: (0-1): (0-20): (0-1): (1-5); preferably, 1: 0.01: 1.35: 0.1: 1.15.

[0067] The side chain oxidation reaction is carried out under the action of an oxidizing agent, and the oxidizing agent is selected from one or more of N-chlorosuccinimide NCS, N-bromosuccinimide NBS, 2-iodoxybenzoic acid IBX, pyridine dichromate PDC, etc.; preferably, N-chlorosuccinimide NCS.

[0068] The first solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide, water, etc.; preferably, a mixed solvent of dichloromethane and water (volume ratio V / V = 5 / 2).

[0069] The temperature of the side chain oxidation reaction is 0-30℃; preferably, 0℃.

[0070] The time of the side chain oxidation reaction is 3-8h; preferably, 6h.

[0071] In a specific embodiment, the synthesis step of the compound of formula (2) comprises: dissolving the compound of formula (1) in a first solvent, then adding TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and an oxidant, and performing a side chain oxidation reaction to obtain the compound of formula (2).

[0072] In step (b) of the present application, the Wittig reaction specifically refers to: in a second solvent, the compound of formula (2) and methoxymethylidene triphenyl phosphonium or ethoxymethylidene triphenyl phosphonium or propoxymethylidene triphenyl phosphonium perform a Wittig reaction to obtain the compound of formula (3).

[0073] The molar ratio of the compound of formula (2), methoxymethylidene triphenyl phosphonium or ethoxymethylidene triphenyl phosphonium or propoxymethylidene triphenyl phosphonium is 1:(1-5); preferably, 1:1.5.

[0074] The second solvent is one or more of xylene, toluene, benzene, tetrahydrofuran, heptane, hexane, etc.; preferably, toluene.

[0075] The temperature of the Wittig reaction is 80-130℃; preferably, 110℃.

[0076] The time of the Wittig reaction is 2-8h; preferably, 4h.

[0077] In a specific embodiment, the synthesis step of the compound of formula (3) comprises: dissolving the compound of formula (2) in a second solvent, then adding methoxymethylidene triphenyl phosphonium or ethoxymethylidene triphenyl phosphonium or propoxymethylidene triphenyl phosphonium, and performing a Wittig reaction to obtain the compound of formula (3).

[0078] Alternatively, in step (b) of the present application, the Wittig-Horner reaction specifically refers to: in a second solvent, the compound of formula (2) and a base, methyl phosphonoacetate diethyl ester or triethyl phosphonoacetate or propyl phosphonoacetate diethyl ester perform a Wittig-Horner reaction to obtain the compound of formula (3).

[0079] The molar ratio of the compound of formula (2), the base, methyl phosphonoacetate diethyl ester or triethyl phosphonoacetate or propyl phosphonoacetate diethyl ester is 1:(1-5):(1-5); preferably, 1:1.5:1.5.

[0080] The second solvent is selected from one or more of xylene, toluene, benzene, tetrahydrofuran, heptane, hexane, and the like; preferably, tetrahydrofuran.

[0081] The base is selected from one or more of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, lithium hydride, and the like; preferably, sodium hydride.

[0082] The temperature of the Wittig-Horner reaction is 0-30℃; preferably, 0℃.

[0083] The time of the Wittig-Horner reaction is 2-8h; preferably, 4h.

[0084] In a specific embodiment, the synthesis step of the compound of formula (3) comprises: adding a base into a third solvent, stirring, then adding methyl diethyl phosphonoacetate or triethyl phosphonoacetate or propyl diethyl phosphonoacetate, the compound of formula (2), and performing a Wittig-Horner reaction to obtain the compound of formula (3).

[0085] In step (c) of the present application, the dehydration reaction specifically refers to: in a third solvent, the compound of formula (3) and acetic anhydride, acid perform a dehydration reaction to obtain the compound of formula (4).

[0086] The molar ratio of the compound of formula (3), acetic anhydride, and acid is 1:(0-8):(0.01-4); preferably, 1:0:0.9.

[0087] The acid is selected from one or more of p-methylbenzenesulfonic acid, sulfuric acid, boron trifluoride-acetic acid complex, and the like; preferably, sulfuric acid.

[0088] The third solvent is selected from one or more of dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane, water, acetic acid, and the like; preferably, dichloromethane.

[0089] The temperature of the dehydration reaction is -40℃-80℃; preferably, 0℃.

[0090] The time of the dehydration reaction is 0.5-10h; preferably, 1h.

[0091] In a specific embodiment, the synthesis step of the compound of formula (4) comprises: dissolving the compound of formula (3) in a third solvent, then adding an acid, and performing a dehydration reaction to obtain the compound of formula (4).

[0092] In step (d) of the present application, the hydrogenation reduction of the A ring and the side chain double bond specifically refers to: in a fourth solvent, the compound of formula (4) and Raney nickel, H2 perform a hydrogenation reduction reaction to obtain the compound of formula (5).

[0093] The mass ratio of the compound of formula (4) to Raney nickel is 1:(0.05-2); preferably, 1:1.

[0094] The fourth solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyltetrahydrofuran, isopropanol, methyl tert-butyl ether, toluene, etc.; preferably, tetrahydrofuran.

[0095] The H2 pressure of the hydrogenation reduction reaction of the A ring and the side chain double bond is 1-60 atm; preferably, 40 atm.

[0096] The temperature of the hydrogenation reduction reaction of the A ring and the side chain double bond is 20-120℃; preferably, 80℃.

[0097] The time of the hydrogenation reduction reaction of the A ring and the side chain double bond is 1-12 h, preferably, 3 h.

[0098] In a specific embodiment, the synthesis step of the compound of formula (5) comprises: dissolving the compound of formula (4) in a fourth solvent, adding Raney nickel, and carrying out a hydrogenation reduction reaction with H2 to obtain the compound of formula (5).

[0099] In step (e) of the present application, the hydrogenation reduction reaction of the A ring double bond and the side chain double bond is specifically: in a fifth solvent, the compound of formula (4) is subjected to a hydrogenation reduction reaction with palladium / carbon (Pd / C), a base, and H2 to obtain the compound of formula (6).

[0100] The molar ratio of the compound of formula (4) to the base is 1:(0.01-5); preferably, 1:0.05.

[0101] The mass ratio of the compound of formula (4) to Pd / C is 1:(0.02-0.3); preferably, 1:0.05.

[0102] The fifth solvent is selected from one or more of methanol, ethanol, propanol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, etc.; preferably, a mixed solution of dichloromethane and methanol (volume ratio V / V=20 / 1).

[0103] The base is selected from one or more of sodium carbonate, sodium bicarbonate, aqueous ammonia, 4-methoxypyridine, pyridine, 4-dimethylaminopyridine, etc.; preferably, pyridine.

[0104] The H2 pressure of the hydrogenation reduction reaction of the A ring double bond and the side chain double bond is 1-40 atm; preferably, 1 atm.

[0105] The temperature of the hydrogenation reduction reaction of the double bond of the A ring and the side chain double bond is 0-40 DEG C; preferably, 25 DEG C.

[0106] The time of the hydrogenation reduction reaction of the double bond of the A ring and the side chain double bond is 1-48 h; preferably, 12 h.

[0107] In a specific embodiment, the synthesis step of the compound of formula (6) comprises: dissolving the compound of formula (4) in a fifth solvent, adding palladium-carbon, a base, and H2 to carry out a hydrogenation reduction reaction to obtain the compound of formula (6).

[0108] In step (f) of the present application, the carbonyl reduction reaction of the A ring is specifically: in a sixth solvent, the compound of formula (6) and cerium chloride heptahydrate and a reducing agent are subjected to a carbonyl reduction reaction of the A ring to obtain the compound of formula (5).

[0109] The molar ratio of the compound of formula (6), cerium chloride heptahydrate, and the reducing agent is 1:(0-2):(1-5); preferably, 1:1.1:2.

[0110] The sixth solvent is selected from one or more of methanol, ethyl acetate, dichloromethane, tetrahydrofuran, ethanol, water, etc.; preferably, a mixed solution of methanol and tetrahydrofuran (volume ratio V / V=1 / 7).

[0111] The reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium tri-t-butoxyaluminum hydride, etc.; preferably, potassium borohydride.

[0112] The temperature of the carbonyl reduction reaction of the A ring is -40-30 DEG C; preferably, -10 DEG C.

[0113] The time of the carbonyl reduction reaction of the A ring is 0.1-8 h; preferably, 5 h.

[0114] In a specific embodiment, the synthesis step of the compound of formula (5) comprises: dissolving the compound of formula (6) in a sixth solvent, sequentially adding cerium chloride heptahydrate and a reducing agent to carry out a carbonyl reduction reaction of the A ring to obtain the compound of formula (5).

[0115] In step (g) of the present application, when the hydroxyl protection reagent is an acid anhydride, the esterification reaction is specifically: in a seventh solvent, the compound of formula (5) and the hydroxyl protection reagent and a base are subjected to an esterification reaction to obtain the compound of formula (7).

[0116] The seventh solvent is selected from one or more of ethyl acetate, dichloromethane, trichloromethane, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; preferably, dichloromethane.

[0117] The base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine (DMAP), and the like; preferably, DMAP.

[0118] The molar ratio of the compound of formula (5), the hydroxyl protection reagent, and the base is 1: (1-4): (0.05-5); preferably, 1:2:0.2.

[0119] The temperature of the esterification reaction is 0-50℃; preferably, 25℃.

[0120] The time of the esterification reaction is 2-24h, preferably, 8h.

[0121] In step (g) of the present application, when the hydroxyl protection reagent is acyl chloride, the esterification reaction is specifically: the compound of formula (5) is subjected to esterification reaction with the hydroxyl protection reagent and the base in a seventh solvent to obtain the compound of formula (7).

[0122] The seventh solvent is selected from one or more of ethyl acetate, dichloromethane, trichloromethane, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, and the like; preferably, dichloromethane.

[0123] The base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine (DMAP), and the like; preferably, a mixed base of triethylamine and DMAP; further preferably, the molar ratio of triethylamine and DMAP is 10 / 1.

[0124] The molar ratio of the compound of formula (5), the hydroxyl protection reagent, and the base is 1: (1-4): (0.05-5); preferably, 1:2:2.2.

[0125] The temperature of the esterification reaction is 0-50℃; preferably, 25℃.

[0126] The time of the esterification reaction is 2-24h, preferably, 8h.

[0127] In a specific embodiment, the synthesis of the compound of formula (7) comprises: dissolving the compound of formula (5) in the seventh solvent, adding the base and the hydroxyl protection reagent, and subjecting to esterification reaction to obtain the compound of formula (7).

[0128] In step (h) of the present application, the C-ring epoxidation reaction is specifically: the compound of formula (7) is subjected to C-ring epoxidation reaction with N-hydroxyphthalimide (NHPI) and an oxidizing agent in an eighth solvent to obtain the compound of formula (8).

[0129] The eighth solvent is selected from one or more of toluene, acetone, water, dichloromethane, N,N-dimethylformamide, ethyl acetate, N-methyl pyrrolidone, acetic acid, etc.; preferably, acetic acid.

[0130] The molar ratio of the compound of formula (7), the oxidizing agent and N-hydroxyphthalimide is 1:(1-5):(0-5); preferably, 1:4:0.

[0131] The oxidizing agent is selected from one or more of Na2Cr2O7, K2Cr2O7, pyridine dichromate PDC, benzoyl peroxide BPO, CrO3, etc.; preferably, CrO3.

[0132] The temperature of the C-epoxidation reaction is 0-50℃; preferably, 35℃.

[0133] The time of the C-epoxidation reaction is 10-48h; preferably, 12h.

[0134] In a specific embodiment, the synthesis of the compound of formula (8) comprises: dissolving the compound of formula (7) in an eighth solvent, adding N-hydroxyphthalimide NHPI and an oxidizing agent, and performing a C-epoxidation reaction to obtain the compound of formula (8).

[0135] In step (i) of the present application, the C-epoxidation reaction is specifically: in a ninth solvent, the compound of formula (4) reacts with N-hydroxyphthalimide NHPI and an oxidizing agent to obtain the compound of formula (9).

[0136] The ninth solvent is selected from one or more of toluene, acetone, water, dichloromethane, N,N-dimethylformamide, ethyl acetate, N-methyl pyrrolidone, acetic acid, etc.; preferably, acetone / water.

[0137] The molar ratio of the compound of formula (4), the oxidizing agent and N-hydroxyphthalimide is 1:(1-10):(0-5); preferably, 1:3:1.

[0138] The oxidizing agent is selected from one or more of Na2Cr2O7, K2Cr2O7, pyridine dichromate PDC, benzoyl peroxide BPO, CrO3, etc.; preferably, PDC.

[0139] The temperature of the C-epoxidation reaction is 0-50℃; preferably, 45℃.

[0140] The time of the C-epoxidation reaction is 10-48h; preferably, 12h.

[0141] In an embodiment, the synthesis step of the compound of formula (9) comprises: dissolving the compound of formula (4) in a ninth solvent, adding N-hydroxyphthalimide and an oxidant, and performing a C-ring epoxidation reaction to obtain the compound of formula (9).

[0142] In step (j) of the present application, the hydrogenation reduction reaction of the A ring and the side chain double bond is specifically: in a tenth solvent, the compound of formula (9) is subjected to a hydrogenation reduction reaction with Raney nickel and H2 to obtain the compound of formula (10).

[0143] Preferably, the mass ratio of the compound of formula (9) to Raney nickel is 1:1.

[0144] Preferably, the tenth solvent is tetrahydrofuran.

[0145] Preferably, the hydrogenation reduction reaction of the A ring and the side chain double bond is performed at a H2 pressure of 40 atm.

[0146] Preferably, the hydrogenation reduction reaction of the A ring and the side chain double bond is performed at a temperature of 90°C.

[0147] Preferably, the hydrogenation reduction reaction of the A ring and the side chain double bond is performed for 3 h.

[0148] In an embodiment, the synthesis step of the compound of formula (10) comprises: dissolving the compound of formula (9) in the tenth solvent, and adding Raney nickel to perform a hydrogenation reduction reaction at a certain H2 pressure to obtain the compound of formula (10).

[0149] In step (k) of the present application, when the hydroxyl protection reagent is an acid anhydride, the esterification reaction is specifically: in an eleventh solvent, the compound of formula (10) is subjected to an esterification reaction with a hydroxyl protection reagent and a base to obtain the compound of formula (8).

[0150] Preferably, the eleventh solvent is dichloromethane.

[0151] Preferably, the base is DMAP.

[0152] The molar ratio of the compound of formula (10), the hydroxyl protection reagent and the base is 1: (1-4): (0.05-5); preferably, 1:2:0.2.

[0153] The temperature of the reaction is 0-50℃; preferably, 25℃.

[0154] The time of the esterification reaction is 2-24h, preferably, 8h.

[0155] In step (k) of the present application, when the hydroxyl protection reagent is acyl chloride, the esterification reaction is specifically: the compound of formula (10) is subjected to esterification reaction with the hydroxyl protection reagent and the base in the eleventh solvent to obtain the compound of formula (8).

[0156] The eleventh solvent is selected from one or more of ethyl acetate, dichloromethane, trichloromethane, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran and the like; preferably, dichloromethane.

[0157] The base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine (DMAP) and the like; preferably, a mixed base of triethylamine and DMAP; further preferably, the molar ratio of triethylamine and DMAP is 10 / 1.

[0158] The molar ratio of the compound of formula (10), the hydroxyl protection reagent and the base is 1: (1-4): (0.05-5); preferably, 1:2:2.2.

[0159] The temperature of the reaction is 0-50℃; preferably, 25℃.

[0160] The time of the esterification reaction is 2-24h, preferably, 8h.

[0161] In a specific embodiment, the synthesis of the compound of formula (8) comprises: the compound of formula (10) is dissolved in the eleventh solvent, the hydroxyl protection reagent and the base are added, and esterification reaction is carried out to obtain the compound of formula (8).

[0162] In step (l) of the present application, the C ring double bond reduction reaction is specifically: the compound of formula (8) is subjected to C ring double bond reduction reaction with the catalyst and H2 in the twelfth solvent to obtain the compound of formula (11).

[0163] The mass ratio of the compound of formula (8) and the catalyst is 1: (0.05-2); preferably, 1:0.2.

[0164] The catalyst is selected from one or more of Raney nickel, palladium on carbon, platinum oxide and palladium hydroxide; preferably, palladium on carbon.

[0165] The twelfth solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyltetrahydrofuran, isopropanol, methyl tert-butyl ether, toluene, xylene, etc.; preferably, 1,4-dioxane.

[0166] The H2 pressure of the C-ring double bond reduction reaction is 20-60 atm; preferably, 40 atm.

[0167] The temperature of the C-ring double bond reduction reaction is 70-120℃; preferably, 110℃.

[0168] The time of the C-ring double bond reduction reaction is 8-72 h; preferably, 48 h.

[0169] In a specific embodiment, the synthesis step of the compound of formula (11) comprises: dissolving the compound of formula (8) in the twelfth solvent, adding a catalyst, and performing a C-ring double bond reduction reaction under a certain H2 pressure to obtain the compound of formula (11).

[0170] In step (m) of the present application, the C-ring carbonyl reduction reaction is specifically: in a thirteenth solvent, the compound of formula (11) and a reducing agent perform a C-ring carbonyl reduction reaction to obtain the compound of formula (12).

[0171] The molar ratio of the compound of formula (11) to the reducing agent is 1:(1-5); preferably, 1:1.5.

[0172] The thirteenth solvent is selected from one or more of ethanol, methanol, ethyl acetate, dichloromethane, tetrahydrofuran, etc.; preferably, tetrahydrofuran.

[0173] The reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium tri-tert-butoxyaluminum hydride, etc.; preferably, lithium tri-tert-butoxyaluminum hydride.

[0174] The temperature of the C-ring carbonyl reduction reaction is -10-30℃; preferably, 0℃.

[0175] The time of the C-ring carbonyl reduction reaction is 0.5-24 h; preferably, 12 h.

[0176] In a specific embodiment, the synthesis step of the compound of formula (12) comprises: dissolving the compound of formula (11) in the thirteenth solvent, adding the reducing agent in batches, and performing a C-ring carbonyl reduction reaction to obtain the compound of formula (12).

[0177] In step (n) of the present application, the hydrolysis reaction is specifically: the compound of formula (12) is dissolved in a fourteenth solvent, and a base is added to generate a hydrolysis reaction to obtain deoxycholic acid.

[0178] Preferably, the molar ratio of the compound of formula (12) to the base is 1:2.

[0179] Preferably, the fourteenth solvent is a mixed solution of tetrahydrofuran and methanol (v / v = 1:1).

[0180] Preferably, the base is lithium hydroxide monohydrate.

[0181] Preferably, the temperature of the hydrolysis reaction is 25°C.

[0182] Preferably, the time of the hydrolysis reaction is 12h.

[0183] In a specific embodiment, the synthesis steps of deoxycholic acid include: the compound of formula (12) is dissolved in a fourteenth solvent, a base is added, a hydrolysis reaction occurs, and deoxycholic acid is obtained.

[0184] In step (o) of the present application, the hydrogenation reduction reaction of the A ring double bond and the side chain double bond is specifically: the compound of formula (3) is dissolved in the fifteenth solvent, and under the action of Pd / C, a base and hydrogen, a hydrogenation reduction reaction occurs to obtain a compound of formula (14).

[0185] Preferably, the molar ratio of the compound of formula (3) to the base is 1:0.01.

[0186] Preferably, the mass ratio of the compound of formula (3) to Pd / C is 1:0.05.

[0187] Preferably, the fifteenth solvent is N,N-dimethylformamide.

[0188] Preferably, the base is pyridine.

[0189] The H2 pressure of the hydrogenation reduction reaction of the double bond of the A ring and the side chain double bond is 1-40 atm; preferably, 4 atm.

[0190] The temperature of the hydrogenation reduction reaction of the double bond of the A ring and the side chain double bond is 0-40℃; preferably, 25℃.

[0191] The time of the hydrogenation reduction reaction of the double bond of the A ring and the side chain double bond is 1-48 h; preferably, 12 h.

[0192] In a specific embodiment, the synthesis step of the compound of formula (14) comprises: dissolving the compound of formula (3) in a fifteenth solvent, and under the action of Pd / C, a base and hydrogen, a hydrogenation reduction reaction occurs to obtain the compound of formula (14).

[0193] In step (p) of the present application, the dehydration reaction is specifically that the compound of formula (14), acetic anhydride and an acid undergo a dehydration reaction in a sixteenth solvent to obtain the compound of formula (6).

[0194] The molar ratio of the compound of formula (14), acetic anhydride and the acid is 1:(0-8):(0.01-4); preferably, 1:0:0.9.

[0195] The acid is selected from one or more of p-methylbenzenesulfonic acid, sulfuric acid and boron trifluoride acetic acid complex; preferably, sulfuric acid.

[0196] The sixteenth solvent is selected from one or more of dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane and water; preferably, dichloromethane.

[0197] The temperature of the dehydration reaction is -40℃-80℃; preferably, 0℃.

[0198] The time of the dehydration reaction is 0.5-10 h; preferably, 1 h.

[0199] In a specific embodiment, the synthesis step of the compound of formula (6) comprises: dissolving the compound of formula (14) in a sixteenth solvent, and under the action of acetic anhydride and an acid, a dehydration reaction occurs to obtain the compound of formula (6).

[0200] The present application also provides a new compound, and the structure of the compound is as follows:

[0201]

[0202]

[0203] The application further provides a preparation and synthesis method of the new compounds (2, 3, 4, 6, 7, 8, 9, 11, 12) and application of the new compounds (2, 3, 4, 6, 7, 8, 9, 11, 12) in preparation of deoxycholic acid synthesized by using 9,21-dihydroxy-20-methylpregn-4-ene-3-one 9-OH-BA as a plant source raw material.

[0204] The application has the following advantages: in the preparation method of the plant source deoxycholic acid, the raw material 9,21-dihydroxy-20-methylpregn-4-ene-3-one 9-OH-BA is a plant source raw material, so that the risk of pathogenic bacteria and virus infection of animal source raw materials is avoided; the synthesis steps are relatively short, the operation is simple, the yield is high, the side reaction is less, and the industrial production of deoxycholic acid is facilitated; and the problem of poor safety of the existing deoxycholic acid product is solved. BRIEF DESCRIPTION OF DRAWINGS

[0205] Figure 1 NMR spectrum of deoxycholic acid 1 H NMR and 13 C NMR). DETAILED DESCRIPTION

[0206] The application will be further described in combination with the following specific examples and drawings. The process, conditions, experimental methods and the like for implementing the application are the general knowledge and common sense in the art, and the application does not have special limitations.

[0207] In the following examples, the structure of the compound is determined by a nuclear magnetic resonance instrument and a high-resolution mass spectrometer; the reagent is mainly provided by Shanghai National Medicine Chemical Reagent Company; the product purification is mainly through beating, column chromatography; and the silica gel (200-300 mesh) is produced by Qingdao Marine Chemical Plant.

[0208] Example 1 Preparation of the compound of formula (2)

[0209]

[0210] A flask was charged with compound of formula (1) (5.19 g, 15 mmol), TEMPO (23.5 mg, 0.15 mmol), dichloromethane (40 mL), sodium bicarbonate (1.76 g, 21 mmol), NCS (2.31 g, 17.3 mmol), tetrabutylammonium bromide (0.484 g, 1.5 mmol) and water (16 mL) at 0 °C for 6 h. After TLC detection of the reaction was completed, sodium thiosulfate pentahydrate solution (1.13 g sodium thiosulfate pentahydrate / 23 mL water) was added, stirred at 5-10 °C for 20 min, separated, the aqueous phase was extracted with dichloromethane (60 mL x 2), the combined organic phase was washed with 1% sodium hydroxide solution (30 mL), separated, and the organic phase was concentrated under reduced pressure to obtain the compound of formula (2) (4.96 g, white solid, molar yield 95.9%). 1 H NMR (600 MHz, CDCI3) δ 9.58 (s, 1 H), 5.89 (s, 1 H), 2.50-2.44 (m, 4 H), 2.40-2.28 (m, 2 H), 1.99-1.91 (m, 2 H), 1.85-1.77 (m, 2 H), 1.71-1.56 (m, 7 H), 1.48-1.40 (m, 2 H), 1.35 (s, 3 H), 1.30-1.26 (m, 1 H), 1.16 (d, J = 6.9 Hz, 3 H), 0.79 (s, 3 H). 13 C NMR (150 MHz, CDCI3) δ 204.76, 199.03, 168.45, 126.98, 76.38, 50.69, 49.40, 48.68, 44.37, 42.84, 37.36, 34.73, 34.03, 31.73, 28.47, 26.95, 26.69, 25.37, 24.38, 19.89, 13.44, 11.48.

[0211] Preparation of compound of formula (3)

[0212] (1) Preparation of compound of formula (3-1)

[0213]

[0214] A flask was charged with sodium hydride (3.25 g, 81.25 mmol) and tetrahydrofuran (200 mL), stirred for 15 min, then methyl phosphonate diethyl ester (17.07 g, 81.25 mmol), compound of formula (2) (20 g, 58.05 mmol) were added at 0 °C for 4 h. After TLC detection of the reaction was completed, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (3-1) (21.03 g, white solid, molar yield 94.7%). 1HNMR (600 MHz, CDC13) δ 6.84 (dd, J = 15.5, 9.0 Hz, 1H), 5.88 (s, 1H), 5.77 (d, J = 15.6 Hz, 1H), 3.74 (s, 3H), 2.48 - 2.41 (m, 4H), 2.31 (d, J = 13.9 Hz, 2H), 1.97 - 1.89 (m, 1H), 1.87 - 1.83 (m, 1H), 1.79 - 1.71 (m, 3H), 1.62 - 1.47 (m, 5H), 1.36 - 1.26 (m, 7H), 1.11 (d, J = 6.7 Hz, 3H), 0.77 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 199.05, 168.68, 167.4, 154.60, 126.87, 118.79, 76.33, 54.62, 51.43, 49.19, 44.34, 42.56, 39.69, 37.36, 34.86, 34.04, 31.78, 28.46, 28.00, 26.71, 25.34, 24.05, 19.90, 19.22, 11.34.

[0215] (2) Preparation of the compound of formula (3-2)

[0216]

[0217] In a flask was added sodium hydride (805 mg, 20.13 mmol) and tetrahydrofuran (50 mL), after stirring for 15 min, triethyl phosphonoacetate (4.5 g, 20.13 mmol), compound of formula (2) (5.17 g, 15 mmol) were added successively, and the reaction was carried out at 0 °C for 4 h. After TLC detection of the completion of the reaction, it was concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (3-2) (5.98 g, white solid, molar yield 96%). 1 H NMR (600 MHz, CDC13) δ 6.83 (dd, J = 15.5, 9.0 Hz, 1H), 5.88 (s, 1H), 5.76 (d, J = 15.6 Hz, 1H), 4.21 - 4.18 (m, 2H), 2.48 - 2.41 (m, 4H), 2.31 (d, J = 13.9 Hz, 2H), 1.97 - 1.89 (m, 1H), 1.87 - 1.83 (m, 1H), 1.79 - 1.71 (m, 3H), 1.62 - 1.47 (m, 5H), 1.36 - 1.26 (m, 10H), 1.11 (d, J = 6.7 Hz, 3H), 0.77 (s, 3H). 13C NMR (150 MHz, CDC13) δ 199.08, 168.77, 167.05, 154.30, 126.83, 119.19, 76.33, 60.19, 54.64, 49.18, 44.34, 42.55, 39.66, 37.36, 34.85, 34.04, 31.78, 28.45, 28.02, 26.71, 25.34, 24.04, 19.89, 19.22, 14.28, 11.33.

[0218] Preparation of compound of formula (4) in Example 3

[0219] (1) Preparation of compound of formula (4-1)

[0220]

[0221] Into a flask was added dichloromethane (150 mL) and compound of formula (3-1) (15.66 g, 39.09 mmol), stirred to dissolve, slowly added concentrated sulfuric acid (1.9 mL), stirred at 0 °C for 1 h, stopped after TLC detection of complete reaction. Slowly poured into ice water (200 mL), stirred for 5 min, added saturated sodium carbonate solution to adjust pH to 7-8, separated, the water phase was extracted once with DCM (100 mL), combined organic phases, washed with water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (4-1) (14.1 g, white solid, molar yield 94.3%). 1 HNMR (600 MHz, CDC13) δ 6.86 (dd, J = 15.6, 9.0 Hz, 1H), 5.79-5.76 (m, 2H), 5.47 (d, J = 5.7 Hz, 1H), 3.74 (s, 3H), 2.59-2.46 (m, 3H), 2.38-2.00 (m, 8H), 1.80-1.76 (m, 2H), 1.37-1.22 (m, 7H), 1.11 (d, J = 6.5 Hz, 4H), 0.71 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 199.39, 170.07, 167.03, 154.33, 144.67, 123.92, 119.21, 118.84, 54.96, 54.94, 52.56, 41.67, 41.09, 40.92, 39.71, 37.32, 34.28, 33.77, 32.92, 32.16, 28.50, 26.14, 25.26, 18.84, 11.72.

[0222] (2) Preparation of compound of formula (4-2)

[0223]

[0224] Into a flask was added dichloromethane (40 mL) and the compound of formula (3-2) (4.15 g, 10 mmol), stirred to dissolve, and concentrated sulfuric acid (0.55 mL) was slowly added dropwise. After stirring at 10 °C for 3 h, the reaction was stopped after TLC detection showed that the reaction was complete. It was slowly poured into ice water (100 mL), stirred for 5 min, and a saturated sodium carbonate solution was added dropwise to adjust the pH to 7-8. Dichloromethane (30 mL*2) was added for extraction, and the combined organic phases were washed with water and saturated brine, respectively. After concentration under reduced pressure, column chromatography was used for purification to obtain the compound of formula (4-2) (3.79 g, white solid, molar yield 94.8%). 1 HNMR (600 MHz, CDC13) δ 6.85 (dd, J = 15.6, 8.9 Hz, 1H), 5.77 (d, J = 16.5 Hz, 2H), 5.48 (d, J = 5.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.57 - 2.46 (m, 3H), 2.36 - 2.01 (m, 8H), 1.80 - 1.76 (m, 2H), 1.37 - 1.24 (m, 10H), 1.11 (d, J = 6.5 Hz, 4H), 0.71 (s, 3H). 13 CNMR (150 MHz, CDC13) δ 199.39, 170.07, 167.03, 154.33, 144.67, 123.92, 119.21, 118.84, 60.18, 54.96, 52.56, 41.67, 41.09, 40.92, 39.71, 37.32, 34.28, 33.77, 32.92, 32.16, 28.50, 26.14, 25.26, 18.84, 14.29, 11.72.

[0225] Preparation of the compound of formula (14)

[0226] (1) Preparation of the compound of formula (14-1)

[0227]

[0228] Into a flask was added N,N-dimethylformamide (10 mL), the compound of formula (3-1) (401 mg, 1 mmol), stirred to dissolve, and pyridine (1 mg, 0.01 mmol) and 10% Pd / C (20 mg) were added. After three times of hydrogen replacement, the reaction was carried out at 25 °C for 12 h under a hydrogen pressure of 4 atm. After TLC detection showed that the reaction was complete, the Pd / C was filtered off, and the filtrate was concentrated under reduced pressure, dried, and purified by column chromatography to obtain the compound of formula (14-1) (350 mg, white solid, molar yield 86.4%). 1H NMR (500 MHz, CDC13) δ 3.68 (s, 3H), 2.39 - 2.33 (m, 1H), 2.26 - 2.22 (m, 1H), 2.07 - 2.02 (m, 1H), 1.88 - 1.84 (m, 2H), 1.80 - 1.67 (m, 6H), 1.60 - 1.50 (m, 6H), 1.47 - 1.38 (m, 3H), 1.33 - 1.22 (m, 7H), 0.96 (s, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.66 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 211.77, 174.84, 95.70, 80.17, 55.41, 51.47, 48.50, 42.07, 38.83, 37.42, 35.33, 34.90, 32.04, 31.27, 30.98, 29.71, 28.60, 28.10, 27.36, 23.99, 21.32, 20.27, 18.27, 14.26, 11.05.

[0229] (2) Preparation of the compound of formula (14-2)

[0230]

[0231] In a flask was added N,N-dimethylformamide (10 mL), the compound of formula (3-2) (414 mg, 1 mmol), stirred to dissolve, added pyridine (1 mg, 0.01 mmol), 10% Pd / C (21 mg), replaced with hydrogen three times, hydrogen pressure 4 atm, reacted at 25°C for 12 h. After TLC monitoring reaction was completed, Pd / C was filtered off, the filtrate was concentrated under reduced pressure, dried, and purified by column chromatography to obtain the compound of formula (14-2) (347 mg, white solid, molar yield 82.8%). 1 H NMR (500 MHz, CDC13) δ 3.68 (s, 3H), 2.39 - 2.33 (m, 1H), 2.26 - 2.22 (m, 1H), 2.07 - 2.02 (m, 1H), 1.88 - 1.84 (m, 2H), 1.80 - 1.67 (m, 6H), 1.60 - 1.50 (m, 6H), 1.47 - 1.38 (m, 3H), 1.33 - 1.22 (m, 7H), 0.96 (s, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.66 (s, 3H). 13C NMR (150 MHz, CDC13) δ 213.70, 174.72, 139.37, 119.65, 56.07, 53.27, 51.52, 44.68, 43.80, 41.93, 41.04, 38.82, 38.30, 37.49, 36.32, 35.24, 31.06, 30.95, 28.92, 28.27, 26.50, 26.44, 25.25, 17.94, 11.70.

[0232] Example Five Preparation of the compound of formula (6)

[0233] (1) Preparation of the compound of formula (6-1)

[0234]

[0235] Into a flask was added a mixture solvent of dichloromethane and methanol (105 mL, v / v = 20 / 1), the compound of formula (4-1) (3.83 g, 10 mmol), stirred to dissolve, added pyridine (40 mg, 0.5 mmol), 10% Pd / C (192 mg), replaced with hydrogen three times, hydrogen pressure 1 atm, reacted at 25°C for 12 h. After TLC monitoring reaction was completed, Pd / C was filtered off, the filtrate was concentrated under reduced pressure, dried, and purified by column chromatography to obtain the compound of formula (6-1) (3.37 g, white solid, molar yield 87.9%). 1 HNMR (500 MHz, CDC13) δ 5.50 (d, J = 5.4 Hz, 1H), 3.67 (s, 3H), 2.59-2.52 (m, 1H), 2.43-2.18 (m, 5H), 2.06-1.99 (m, 3H), 1.96-1.88 (m, 3H), 1.85-1.78 (m, 2H), 1.56-1.45 (m, 2H), 1.38-1.29 (m, 4H), 1.22-1.15 (m, 5H), 1.14 (s, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.62 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 213.70, 174.72, 139.37, 119.65, 56.07, 53.27, 51.52, 44.68, 43.80, 41.93, 41.04, 38.82, 38.30, 37.49, 36.32, 35.24, 31.06, 30.95, 28.92, 28.27, 26.50, 26.44, 25.25, 17.94, 11.70.

[0236]

[0237] Into a flask was placed dichloromethane (8 mL) and the compound of formula (14-1) (404 mg, 1 mmol), stirred to dissolve, slowly added concentrated sulfuric acid (0.05 mL), stirred at 0 °C for 1 h, stopped after TLC detection of the reaction complete. Slowly poured into ice water (20 mL), stirred for 5 min, added saturated sodium carbonate solution to adjust the pH value to 7-8, separated, the aqueous phase was extracted once more with DCM (15 mL), combined organic phase, washed with water, saturated brine in turn, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (6-1) (368 mg, white solid, molar yield 95.1%). 1 HNMR (500 MHz, CDC13) δ 5.50 (d, J = 5.4 Hz, 1H), 3.67 (s, 3H), 2.59-2.52 (m, 1H), 2.43-2.18 (m, 5H), 2.06-1.99 (m, 3H), 1.96-1.88 (m, 3H), 1.85-1.78 (m, 2H), 1.56-1.45 (m, 2H), 1.38-1.29 (m, 4H), 1.22-1.15 (m, 5H), 1.14 (s, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.62 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 213.70, 174.72, 139.37, 119.65, 56.07, 53.27, 51.52, 44.68, 43.80, 41.93, 41.04, 38.82, 38.30, 37.49, 36.32, 35.24, 31.06, 30.95, 28.92, 28.27, 26.50, 26.44, 25.25, 17.94, 11.70.

[0238] (2) Preparation of the compound of formula (6-2)

[0239]

[0240] Into a flask was placed dichloromethane (8 mL) and the compound of formula (14-1) (404 mg, 1 mmol), stirred to dissolve, slowly added concentrated sulfuric acid (0.05 mL), stirred at 0 °C for 1 h, stopped after TLC detection of the reaction complete. Slowly poured into ice water (20 mL), stirred for 5 min, added saturated sodium carbonate solution to adjust the pH value to 7-8, separated, the aqueous phase was extracted once more with DCM (15 mL), combined organic phase, washed with water, saturated brine in turn, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (6-1) (368 mg, white solid, molar yield 95.1%). 1H NMR (500 MHz, CDC13) δ 5.50 (d, J = 5.4 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.59 - 2.52 (m, 1H), 2.43 - 2.18 (m, 5H), 2.06 - 1.99 (m, 3H), 1.96 - 1.88 (m, 3H), 1.85 - 1.78 (m, 2H), 1.56 - 1.45 (m, 2H), 1.38 - 1.26 (m, 12H), 1.15 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.63 (s, 3H).

[0241] Example Six Preparation of the compound of formula (5)

[0242] (1) Preparation of the compound of formula (5-1)

[0243]

[0244] Into a reaction kettle was added tetrahydrofuran (8 mL), the compound of formula (4-1) (765 mg, 2 mmol), the solution was stirred, Raney Ni (770 mg) was added, and the reaction was carried out at 90 °C under 4 MPa H2for 3 h. After TLC detection showed that the reaction was complete, the reaction was stopped. The above reaction solution was filtered to remove the Raney Ni, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (5-1) (535 mg, white solid, molar yield 70%). 1 H NMR (500 MHz, CDC13) δ 5.38 - 5.30 (m, 1H), 3.69 (s, 3H), 3.68 - 3.62 (m, 1H), 2.40 - 2.35 (m, 1H), 2.28 - 2.21 (m, 1H), 2.16 - 2.12 (m, 1H), 2.07 - 2.02 (m, 2H), 2.00 - 1.88 (m, 3H), 1.87 - 1.81 (m, 1H), 1.77 - 1.69 (m, 2H), 1.65 - 1.60 (m, 1H), 1.54 - 1.45 (m, 5H), 1.35 - 1.28 (m, 3H), 1.20 - 1.14 (m, 3H), 1.07 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.59 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.91, 140.19, 119.61, 72.41, 56.18, 53.44, 51.63, 42.18, 42.09, 41.05, 38.66, 38.09, 36.70, 35.87, 35.39, 31.98, 31.21, 31.11, 29.75, 28.42, 27.07, 25.46, 18.06, 11.76.

[0245] (2) Preparation of the compound of formula (5-1)

[0246]

[0247] A flask was charged with a mixture solvent of tetrahydrofuran and methanol (40 mL, v / v = 7 / 1), the compound of formula (6-1) (3.86 g, 10 mmol) and CeCl3.7H2O (3.18 g, 11 mmol), and KBH4 (1.08 g, 20 mmol) was added, and the reaction was carried out at -10 °C for 5 h. After TLC monitoring showed that the reaction was completed, the reaction was quenched by adding acetone (4 mL). The solution was concentrated under reduced pressure, extracted with ethyl acetate (60 mL) / water (60 mL), and the organic phase was washed with water and saturated NaCl solution in turn, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (5-1) (3.4 g, white solid, molar yield 88.1%). 1 H NMR (500 MHz, CDCl3) δ 5.38-5.30 (m, 1H), 3.69 (s, 3H), 3.68-3.62 (m, 1H), 2.40-2.35 (m, 1H), 2.28-2.21 (m, 1H), 2.16-2.12 (m, 1H), 2.07-2.02 (m, 2H), 2.00-1.88 (m, 3H), 1.87-1.81 (m, 1H), 1.77-1.69 (m, 2H), 1.65-1.60 (m, 1H), 1.54-1.45 (m, 5H), 1.35-1.28 (m, 3H), 1.20-1.14 (m, 3H), 1.07 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.59 (s, 3H).13C NMR (150 MHz, CDCl3) δ 174.91, 140.19, 119.61, 72.41, 56.18, 53.44, 51.63, 42.18, 42.09, 41.05, 38.66, 38.09, 36.70, 35.87, 35.39, 31.98, 31.21, 31.11, 29.75, 28.42, 27.07, 25.46, 18.06, 11.76.

[0248] (3) Preparation of the compound of formula (5-2)

[0249]

[0250] Into a reaction kettle was added tetrahydrofuran (8 mL), a compound of formula (4-2) (793 mg, 2 mmol), and the solution was stirred. Raney Ni (795 mg) was added, and the reaction was carried out at 80 °C under 4 MPa of H2for 3 h. After TLC detection showed that the reaction was complete, the reaction was stopped. The above reaction liquid was filtered to remove the Raney Ni, concentrated under reduced pressure, and purified by column chromatography to obtain a compound of formula (5-2) (572 mg, white solid, molar yield 71.1%). 1 H NMR (600 MHz, CDCl3) δ 5.35-5.29 (m, 1H), 4.15-4.08 (m, 2H), 3.67-3.61 (m, 1H), 2.37-2.31 (m, 1H), 2.24-2.18 (m, 1H), 2.14-2.10 (m, 1H), 2.06-2.00 (m, 2H), 1.99-1.85 (m, 3H), 1.83-1.77 (m, 1H), 1.75-1.67 (m, 2H), 1.62-1.58 (m, 1H), 1.53-1.42 (m, 6H), 1.36-1.27 (m, 4H), 1.26-1.23 (m, 3H), 1.21-1.07 (m, 4H), 1.05 (s, 3H), 0.91 (d, J = 5.3 Hz, 3H), 0.57 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 174.33, 140.06, 119.49, 72.28, 60.18, 56.07, 53.32, 42.06, 41.97, 40.93, 38.53, 37.97, 36.58, 35.75, 35.24, 31.86, 31.34, 30.98, 29.61, 28.27, 26.94, 25.33, 17.93, 14.26, 11.62.

[0251] Example Seven Preparation of a compound of formula (7)

[0252] (1) Preparation of a compound of formula (7-1)

[0253]

[0254] To the flask was added dichloromethane (8 mL), compound of formula (5-1) (500 mg, 1.28 mmol), stirred to dissolve, DMAP (31.5 mg, 0.26 mmol) and acetic anhydride (263 mg, 2.56 mmol) were added, the reaction was carried out at 25 °C for 8 h, after TLC monitoring reaction was complete, saturated ammonium chloride (1 mL) was added to quench the reaction, dichloromethane (20 mL) and water (20 mL) were added to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (7-1) (white solid 536 mg, molar yield 97.4%). 1 HNMR (600 MHz, CDC13) δ 5.35 - 5.32 (m, 1H), 4.82 - 4.71 (m, 1H), 3.69 (s, 3H), 2.40 - 2.35 (m, 1H), 2.28 - 2.26 (m, 1H), 2.18 - 2.06 (m, 3H), 2.03 (s, 3H), 1.98 - 1.80 (m, 4H), 1.77 - 1.71 (m, 2H), 1.66 - 1.59 (m, 3H), 1.56 - 1.50 (m, 3H), 1.48 - 1.42 (m, 1H), 1.40 - 1.19 (m, 7H), 1.08 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.60 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 174.90, 170.81, 140.07, 119.70, 74.99, 56.23, 53.43, 51.64, 42.16, 41.92, 41.06, 38.70, 36.64, 35.53, 35.39, 33.97, 31.22, 31.12, 29.73, 28.41, 27.98, 26.99, 26.89, 25.44, 22.33, 18.07, 11.77.

[0255] (2) Preparation of compound of formula (7-2)

[0256]

[0257] Into a flask was placed dichloromethane (40 mL), compound of formula (5-1) (3.88 g, 10 mmol), stirred to dissolve, added triethylamine (2.02 g, 20 mmol), DMAP (0.25 g, 2 mmol) and p-methoxybenzoyl chloride (3.4 g, 20 mmol), reacted at 25 °C for 8 h, after TLC monitoring reaction was complete, added saturated ammonium chloride (5 mL) to quench the reaction, added dichloromethane (50 mL) and water (40 mL) to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (7-2) (white solid 4.88 g, molar yield 93.5%). 1 H NMR (600 MHz, CDC13) δ 8.01 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 5.44 - 5.30 (m, 1H), 5.04 - 4.89 (m, 1H), 3.87 (s, 3H), 3.69 (s, 3H), 2.40 - 2.36 (m, 1H), 2.28 - 2.23 (m, 1H), 2.16 - 2.11 (m, 3H), 2.06 - 1.96 (m, 2H), 1.94 - 1.89 (m, 1H), 1.87 - 1.83 (m, 2H), 1.77 - 1.72 (m, 2H), 1.64 (d, J = 5.5 Hz, 3H), 1.62 (s, 1H), 1.52 - 1.42 (m, 1H), 1.41 - 1.29 (m, 5H), 1.25 - 1.14 (m, 3H), 1.11 (s, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.61 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.75, 165.92, 163.15, 140.07, 131.53, 123.42, 119.53, 113.45, 75.07, 56.09, 55.41, 53.28, 51.50, 42.03, 41.86, 40.95, 38.64, 36.54, 35.48, 35.25, 34.02, 31.07, 31.00, 29.65, 28.29, 28.04, 26.91, 26.81, 25.31, 17.96, 11.66.

[0258] (3) Preparation of compound of formula (7-3)

[0259]

[0260] Into a flask was placed dichloromethane (40 mL), compound of formula (5-2) (4.02 g, 10 mmol), stirred to dissolve, triethylamine (2.02 g, 20 mmol), DMAP (0.246 g, 2 mmol) and p-methoxybenzoyl chloride (3.41 g, 20 mmol) were added, and the reaction was allowed to proceed at 25 °C for 8 h. After the reaction was completed as monitored by TLC, saturated ammonium chloride (5 mL) was added to quench the reaction, dichloromethane (50 mL) and water (40 mL) were added to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain compound of formula (7-3) (white solid 4.98 g, 93% molar yield). 1 H NMR (600 MHz, CDC13) δ 8.01 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 5.45 - 5.35 (m, 1H), 5.01 - 4.91 (m, 1H), 4.20 - 4.08 (m, 2H), 3.87 (s, 3H), 2.39 - 2.35 (m, 1H), 2.27 - 2.22 (m, 1H), 2.20 - 2.10 (m, 3H), 2.07 - 1.95 (m, 2H), 1.94 - 1.90 (m, 1H), 1.87 - 1.83 (m, 2H), 1.77 - 1.73 (m, 2H), 1.64 (d, J = 5.6 Hz, 4H), 1.48 - 1.45 (m, 1H), 1.39 - 1.32 (m, 5H), 1.28 (t, J = 7.1 Hz, 3H), 1.24 - 1.14 (m, 3H), 1.11 (s, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.62 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.34, 165.94, 163.15, 140.08, 131.53, 123.44, 119.54, 113.46, 75.10, 60.20, 56.13, 55.41, 53.30, 42.05, 41.88, 40.96, 38.65, 36.56, 35.49, 35.25, 34.03, 31.36, 31.01, 29.65, 28.29, 28.05, 26.91, 26.82, 25.31, 17.97, 14.27, 11.66.

[0261] (4) Preparation of compound of formula (7-4)

[0262]

[0263] Into a flask was placed dichloromethane (8 mL), compound of formula (5-1) (500 mg, 1.28 mmol), stirred to dissolve, DMAP (32 mg, 0.26 mmol) and benzoic anhydride (583 mg, 2.56 mmol) were added, and the reaction was allowed to proceed at 25 °C for 8 h. After the reaction was completed as monitored by TLC, saturated ammonium chloride (1 mL) was added to quench the reaction, dichloromethane (30 mL) and water (20 mL) were added to extract, the organic phase was washed with water, saturated brine, and concentrated under reduced pressure. Purification by column chromatography gave compound of formula (7-4) (white solid 601 mg, 95.3% molar yield). 1 H NMR (500 MHz, CDC13) δ 8.06 (dd, J = 8.1, 1.5 Hz, 2H), 7.60 - 7.52 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 5.39 - 5.37 (m, 1H), 5.08 - 4.97 (m, 1H), 3.69 (s, 3H), 2.42 - 2.36 (m, 1H), 2.27 (dd, J = 9.8, 6.3 Hz, 1H), 2.17 - 2.12 (m, 2H), 2.04 - 1.99 (m, 2H), 1.84 - 1.82 (m, 3H), 1.79 - 1.73 (m, 2H), 1.68 - 1.57 (m, 5H), 1.48 - 1.42 (m, 1H), 1.39 - 1.29 (m, 5H), 1.25 - 1.15 (m, 3H), 1.12 (s, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.62 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 174.78, 166.18, 140.03, 132.66, 130.96, 129.54, 128.24, 119.57, 75.45, 56.09, 53.28, 51.51, 42.03, 41.86, 40.95, 38.64, 36.53, 35.46, 35.26, 33.96, 31.08, 31.00, 29.65, 28.29, 27.98, 26.90, 26.80, 25.31, 17.96, 11.66.

[0264] (5) Preparation of compound of formula (7-5)

[0265]

[0266] Into a flask was placed dichloromethane (8 mL), compound of formula (5-1) (500 mg, 1.28 mmol), stirred to dissolve, DMAP (32 mg, 0.26 mmol), triethylamine (261 mg, 2.56 mmol) and 4-trifluoromethylbenzoyl chloride (534 mg, 2.56 mmol), 25 °C for 8 h, TLC monitoring reaction complete, saturated ammonium chloride (1 mL) was added to quench the reaction, dichloromethane (30 mL) and water (30 mL) were added to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (7-5) (white solid 677 mg, molar yield 94.4%). 1 HNMR (500 MHz, CDC13) δ 8.17 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 5.45 - 5.35 (m, 1H), 5.03 (q, J = 7.7, 6.0 Hz, 1H), 3.69 (s, 3H), 2.42 - 2.36 (m, 1H), 2.29 - 2.22 (m, 1H), 2.18 - 2.10 (m, 2H), 2.08 - 1.96 (m, 2H), 1.94 - 1.73 (m, 5H), 1.71 - 1.56 (m, 5H), 1.49 - 1.44 (m, 1H), 1.41 - 1.28 (m, 5H), 1.25 - 1.14 (m, 3H), 1.12 (s, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.62 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 174.76, 164.93, 139.97, 134.16, 129.95, 125.29, 125.25, 119.65, 76.18, 56.11, 53.28, 51.51, 42.02, 41.85, 40.95, 38.63, 36.52, 35.39, 35.25, 33.88, 31.07, 30.99, 29.61, 28.28, 27.92, 26.88, 26.77, 25.30, 17.96, 11.66.

[0267] (6) Preparation of compound of formula (7-6)

[0268]

[0269] In a flask was added dichloromethane (8 mL), compound of formula (5-1) (500 mg, 1.28 mmol), stirred to dissolve, added DMAP (32 mg, 0.26 mmol), triethylamine (261 mg, 2.56 mmol) and 2,4-dimethoxybenzoyl chloride (514 mg, 2.56 mmol), reacted at 40 °C for 6 h, after TLC monitoring reaction was complete, added saturated ammonium chloride (2 mL) to quench the reaction, added dichloromethane (30 mL) and water (30 mL) to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (7-6) (white solid 636 mg, molar yield 90%). 1 HNMR (500 MHz, CDC13) δ 7.82 (d, J = 9.3 Hz, 1H), 6.48 (dd, J = 4.6, 2.4 Hz, 2H), 5.36 (dd, J = 5.2, 2.6 Hz, 1H), 5.00 - 4.92 (m, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.68 (s, 3H), 2.40 - 2.35 (m, 1H), 2.28 - 2.22 (m, 1H), 2.18 - 1.94 (m, 5H), 1.92 - 1.80 (m, 3H), 1.75 - 1.71 (m, 2H), 1.67 - 1.58 (m, 5H), 1.50 - 1.43 (m, 1H), 1.38 - 1.26 (m, 5H), 1.22 - 1.12 (m, 2H), 1.10 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.60 (s, 3H).

[0270] 13 C NMR (125 MHz, CDC13) δ 174.79, 165.08, 163.95, 161.28, 140.07, 133.47, 119.48, 113.21, 104.42, 98.97, 74.83, 56.07, 55.99, 55.46, 53.29, 51.51, 42.04, 41.89, 40.93, 38.66, 36.54, 35.52, 35.26, 33.98, 31.08, 30.98, 29.64, 28.29, 28.00, 26.91, 26.82, 25.31, 17.94, 11.64.

[0271] (7) Preparation of compound of formula (7-7)

[0272]

[0273] Into a flask was placed dichloromethane (8 mL), a compound of formula (5-1) (500 mg, 1.28 mmol), stirred to dissolve, DMAP (32 mg, 0.26 mmol), triethylamine (261 mg, 2.56 mmol) and 2-methoxybenzoyl chloride (437 mg, 2.56 mmol), and reacted at 25 °C for 8 h, after TLC monitoring of the reaction completion, saturated ammonium chloride (2 mL) was added to quench the reaction, dichloromethane (30 mL) and water (30 mL) were added to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain a compound of formula (7-7) (white solid 614 mg, molar yield 92%). 1 H NMR (500 MHz, CDC13) δ 7.75 (dd, J = 7.8, 1.8 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.01 - 6.94 (m, 2H), 5.40 - 5.33 (m, 1H), 5.02 - 4.98 (m, 1H), 3.90 (s, 3H), 3.68 (s, 3H), 2.41 - 2.35 (m, 1H), 2.28 - 2.21 (m, 1H), 2.18 - 2.05 (m, 3H), 2.03 - 1.94 (m, 2H), 1.92 - 1.79 (m, 3H), 1.78 - 1.68 (m, 3H), 1.64 (t, J = 8.0 Hz, 3H), 1.48 - 1.42 (m, 1H), 1.39 - 1.28 (m, 5H), 1.22 - 1.12 (m, 3H), 1.10 (s, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.60 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.74, 165.77, 158.95, 140.01, 133.05, 131.21, 121.12, 120.08, 119.54, 112.07, 75.28, 56.08, 56.01, 53.29, 51.48, 42.05, 41.91, 40.94, 38.64, 36.54, 35.50, 35.25, 33.91, 31.08, 30.98, 29.62, 28.28, 27.94, 26.90, 26.81, 25.31, 17.94, 11.64.

[0274] (8) Preparation of a compound of formula (7-8)

[0275]

[0276] Into a flask was placed dichloromethane (8 mL), compound of formula (5-2) (515 mg, 1.28 mmol), stirred to dissolve, DMAP (32 mg, 0.26 mmol), triethylamine (392 mg, 3.87 mmol) and 4-trifluoromethylbenzoyl chloride (534 mg, 2.56 mmol), 25 °C for 8 h, TLC monitored the reaction was complete, added saturated ammonium chloride (1 mL) to quench the reaction, dichloromethane (30 mL) and water (30 mL) were added to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (7-8). 1 HNMR (600 MHz, CDC13) δ 8.14 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 5.43 - 5.33 (m, 1H), 5.03 - 4.99 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 2.37 - 2.32 (m, 1H), 2.24 - 2.17 (m, 1H), 2.18 - 2.08 (m, 3H), 2.06 - 1.95 (m, 2H), 1.92 - 1.79 (m, 3H), 1.76 - 1.71 (m, 2H), 1.67 - 1.62 (m, 4H), 1.49 - 1.42 (m, 1H), 1.37 - 1.30 (m, 5H), 1.25 (t, J = 7.1 Hz, 3H), 1.22 - 1.12 (m, 3H), 1.10 (s, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.59 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.31, 164.92, 139.97, 134.30, 134.18, 134.08, 129.94, 125.30, 125.27, 125.25, 119.66, 76.19, 60.20, 56.14, 53.30, 42.04, 41.86, 40.96, 38.63, 36.54, 35.40, 35.23, 33.89, 31.35, 30.99, 29.61, 28.27, 27.93, 26.89, 26.78, 25.30, 17.97, 14.26, 11.65.

[0277] (9) Preparation of compound of formula (7-9)

[0278]

[0279] To the flask was added dichloromethane (8 mL), compound of formula (5-2) (515 mg, 1.28 mmol), stirred to dissolve, added DMAP (33 mg, 0.27 mmol), triethylamine (390 mg, 3.85 mmol) and 2,4-dimethoxybenzoyl chloride (642 mg, 3.2 mmol), reacted at 40 °C for 8 h, after TLC monitoring reaction was complete, added saturated ammonium chloride (2 mL) to quench the reaction, added dichloromethane (30 mL) and water (30 mL) to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (7-9). 1 H NMR (500 MHz, CDC13) δ 7.82 (d, J = 9.3 Hz, 1H), 6.49 - 6.46 (m, 2H), 5.38 - 5.32 (m, 1H), 4.95 (t, J = 7.4 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.39 - 2.33 (m, 1H), 2.27 - 2.20 (m, 1H), 2.16 - 1.79 (m, 8H), 1.77 - 1.72 (m, 3H), 1.63 (t, J = 8.0 Hz, 3H), 1.50 - 1.44 (m, 1H), 1.33 - 1.25 (m, 8H), 1.22 - 1.12 (m, 3H), 1.09 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.60 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 174.78, 165.07, 163.96, 161.29, 140.08, 133.48, 119.49, 113.22, 104.43, 98.98, 74.19, 60.19, 56.08, 55.99, 55.46, 53.29, 51.52, 42.04, 41.89, 40.94, 38.67, 36.55, 35.52, 35.26, 33.98, 31.08, 30.98, 29.64, 28.29, 28.00, 26.92, 26.83, 25.31, 17.94, 11.64.

[0280] (10) Preparation of compound of formula (7-10)

[0281]

[0282] Into a flask was placed dichloromethane (8 mL), compound of formula (5-2) (515 mg, 1.28 mmol), stirred to dissolve, DMAP (33 mg, 0.27 mmol), triethylamine (385 mg, 3.81 mmol) and 2-methoxybenzoyl chloride (655 mg, 3.84 mmol), 45 °C for 8 h, TLC monitored the reaction was complete, added saturated ammonium chloride (2 mL) to quench the reaction, dichloromethane (30 mL) and water (30 mL) were added to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (7-10). 1 HNMR (600 MHz, CDC13) δ 7.75 (dd, J = 7.9, 1.9 Hz, 1H), 7.47 - 7.44 (m, 1H), 6.99 - 6.96 (m, 2H), 5.41 - 5.34 (m, 1H), 5.05 - 4.98 (m, 1H), 4.16 - 4.12 (m, 2H), 3.91 (s, 3H), 2.39 - 2.34 (m, 1H), 2.27 - 2.21 (m, 1H), 2.17 - 2.05 (m, 3H), 2.03 - 1.94 (m, 2H), 1.93 - 1.87 (m, 2H), 1.85 - 1.81 (m, 1H), 1.77 - 1.71 (m, 2H), 1.68 - 1.64 (m, 3H), 1.49 - 1.44 (m, 1H), 1.41 - 1.30 (m, 6H), 1.28 (d, J = 7.2 Hz, 3H), 1.22 - 1.12 (m, 3H), 1.11 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.61 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.76, 165.78, 158.94, 140.02, 133.07, 131.20, 121.13, 120.09, 119.55, 112.09, 74.17, 60.18, 56.08, 56.02, 53.29, 51.48, 42.05, 41.91, 40.94, 38.64, 36.54, 35.50, 35.25, 33.91, 31.08, 30.98, 29.62, 28.28, 27.94, 26.90, 26.81, 25.31, 17.94, 11.64.

[0283] (11) Preparation of compound of formula (7-11)

[0284]

[0285] Into a flask was added dichloromethane (8 mL), compound of formula (5-2) (515 mg, 1.28 mmol), stirred to dissolve, DMAP (32 mg, 0.26 mmol) and benzoic anhydride (583 mg, 2.56 mmol) were added, and the reaction was allowed to proceed at 25 °C for 8 h, TLC monitoring showed that the reaction was complete, saturated ammonium chloride (1 mL) was added to quench the reaction, dichloromethane (30 mL) and water (20 mL) were added to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain compound of formula (7-11) (white solid 605 mg, molar yield 93.4%). 1 HNMR (600 MHz, CDC13) δ 8.10 - 8.03 (m, 2H), 7.58 - 7.53 (m, 1H), 7.44 (t, J = 7.8 Hz, 2H), 5.42 - 5.35 (m, 1H), 5.06 - 4.97 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.40 - 2.34 (m, 1H), 2.27 - 2.21 (m, 1H), 2.20 - 2.11 (m, 3H), 2.07 - 1.96 (m, 2H), 1.94 - 1.82 (m, 3H), 1.79 - 1.73 (m, 2H), 1.69 - 1.61 (m, 4H), 1.49 - 1.45 (m, 1H), 1.39 - 1.32 (m, 5H), 1.28 (t, J = 7.1 Hz, 3H), 1.24 - 1.13 (m, 3H), 1.12 (s, 3H), 0.95 (d, J = 6.6 Hz, 3H), 0.62 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.33, 166.17, 140.03, 132.66, 130.97, 129.54, 128.24, 119.58, 75.44, 60.20, 56.12, 53.29, 42.04, 41.87, 40.95, 38.65, 36.54, 35.46, 35.24, 33.96, 31.35, 31.00, 29.65, 28.29, 27.99, 26.90, 26.81, 25.31, 17.97, 14.28, 11.66.

[0286] Example Eight Preparation of compound of formula (9)

[0287] (1) Preparation of compound of formula (9-1)

[0288]

[0289] Into a flask was added acetone / water (100 mL, v / v = 9:1), compound of formula (4-1) (3.82 g, 10 mmol), stirred to dissolve, added PDC (11.3 g, 30 mmol) and NHPI (1.63 g, 10 mmol), stirred at 45 °C for 12 h, stopped after TLC detection of complete reaction. Added ethyl acetate (120 mL) and water (100 mL) to the reaction solution, extracted, organic phase was washed with water, saturated brine successively, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (9-1) (1.97 g, white solid, molar yield 49.7%). 1 H NMR (600 MHz, CDC13) δ 6.94 (dd, J = 15.6, 9.2 Hz, 1H), 5.89 - 5.77 (m, 3H), 3.72 (s, 3H), 2.66 - 2.41 (m, 6H), 2.18 - 2.01 (m, 4H), 1.88 - 1.83 (m, 2H), 1.75 - 1.70 (m, 2H), 1.50 - 1.44 (m, 5H), 1.27 - 1.23 (m, 2H), 1.17 (dd, J = 6.9, 1.4 Hz, 3H), 0.96 (s, 3H). 13 CNMR (150 MHz, CDC13) δ 204.46, 198.16, 167.35, 166.55, 154.18, 125.20, 122.14, 119.62, 52.66, 52.17, 51.43, 46.87, 41.59, 39.29, 38.56, 33.95, 33.32, 32.19, 30.98, 26.52, 26.25, 23.98, 20.90, 11.46.

[0290] Into a flask was added acetic acid (20 mL), chromium trioxide (4 g, 40 mmol), stirred to dissolve, added compound of formula (4-1) (3.82 g, 10 mmol), stirred at 45 °C for 12 h, stopped after TLC detection of complete reaction. Added ethyl acetate (60 mL) and water (60 mL) to the reaction solution, extracted, organic phase was washed with saturated NaHC03 aqueous solution, water, saturated brine successively, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (9-1) (1.9 g, white solid, molar yield 47.9%). 1H NMR (600 MHz, CDCI3) δ 6.94 (dd, J = 15.6, 9.2 Hz, 1 H), 5.89 - 5.77 (m, 3 H), 3.72 (s, 3 H), 2.66 - 2.41 (m, 6 H), 2.18 - 2.01 (m, 4 H), 1.88 - 1.83 (m, 2 H), 1.75 - 1.70 (m, 2 H), 1.50 - 1.44 (m, 5 H), 1.27 - 1.23 (m, 2 H), 1.17 (dd, J = 6.9, 1.4 Hz, 3 H), 0.96 (s, 3 H). 13 C NMR (150 MHz, CDCI3) δ 204.46, 198.16, 167.35, 166.55, 154.18, 125.20, 122.14, 119.62, 52.66, 52.17, 51.43, 46.87, 41.59, 39.29, 38.56, 33.95, 33.32, 32.19, 30.98, 26.52, 26.25, 23.98, 20.90, 11.46.

[0291] (2) Preparation of compound of formula (9-2)

[0292]

[0293] In a flask was added acetic acid (20 mL), chromium trioxide (4 g, 40 mmol), stirred to dissolve, added compound of formula (4-2) (3.96 g, 10 mmol), stirred at 40 °C for 20 h, stopped after TLC detection of complete reaction. Added ethyl acetate (60 mL) and water (60 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHC03aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (9-2) (2.25 g, white solid, molar yield 54.8%). 1 H NMR (600 MHz, CDCI3) δ 6.94 (dd, J = 15.6, 9.2 Hz, 1 H), 5.89 - 5.77 (m, 3 H), 3.72 (s, 3 H), 2.66 - 2.41 (m, 6 H), 2.18 - 2.01 (m, 4 H), 1.88 - 1.83 (m, 2 H), 1.75 - 1.70 (m, 2 H), 1.50 - 1.44 (m, 5 H), 1.27 - 1.23 (m, 2 H), 1.17 (dd, J = 6.9, 1.4 Hz, 3 H), 0.96 (s, 3 H). 13C NMR (150 MHz, CDC13) δ 204.46, 198.16, 166.97, 166.53, 153.86, 125.20, 122.14, 120.03, 60.19, 52.66, 52.17, 46.87, 41.59, 39.29, 38.56, 33.95, 33.32, 32.19, 30.98, 26.52, 26.25, 23.98, 20.90, 14.28, 11.46.

[0294] Preparation of compound of formula (10)

[0295] (1) Preparation of compound of formula (10-1)

[0296]

[0297] Into a reaction kettle was added tetrahydrofuran (8 mL), compound of formula (9-1) (793 mg, 2 mmol), stirred to dissolve, added Raney Ni (794 mg), reacted at 90 °C, 4 MPa H2for 3 h, stopped after TLC detection of complete reaction. The above reaction solution was filtered to remove Raney Ni, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (10-1) (540 mg, white solid, molar yield 67%). 1 HNMR (600 MHz, CDC13) δ 5.67 (d, J = 2.3 Hz, 1H), 3.63 (s, 3H), 3.62-3.56 (m, 1H), 2.40-2.30 (m, 2H), 2.25-1.98 (m, 3H), 1.92-1.64 (m, 7H), 1.59-1.50 (m, 2H), 1.48-1.19 (m, 9H), 1.15 (s, 3H), 0.98 (d, 3H, J = 6.6 Hz), 0.87 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 205.04, 174.61, 164.29, 123.49, 71.37, 53.34, 52.89, 51.33, 47.12, 41.87, 39.82, 37.94, 37.75, 35.16, 35.26, 31.64, 31.36, 30.50, 29.67, 27.25, 26.46, 26.22, 24.08, 19.34, 10.62.

[0298] (2) Preparation of compound of formula (10-2)

[0299]

[0300] Into a flask was placed tetrahydrofuran (8 mL), a compound of formula (9-2) (821 mg, 2 mmol), stirred to dissolve, Raney Ni (821 mg) was added, and the reaction was carried out at 85°C under 4 MPa of H2for 4 h. After TLC detection showed that the reaction was complete, the reaction was stopped. The above reaction solution was filtered to remove the Raney Ni, concentrated under reduced pressure, and purified by column chromatography to obtain a compound of formula (10-2) (530 mg, white solid, molar yield 64.6%). 1 HNMR (600 MHz, CDC13) δ 5.74 (d, J = 2.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.69-3.66 (m, 1H), 2.49-2.45 (m, 1H), 2.41-2.31 (m, 2H), 2.13-2.05 (m, 3H), 2.00-1.95 (m, 1H), 1.92-1.87 (m, 2H), 1.84-1.73 (m, 4H), 1.67-1.57 (m, 2H), 1.52-1.39 (m, 6H), 1.35-1.27 (m, 5H), 1.21 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.93 (s, 3H).

[0301] Example Ten Preparation of a compound of formula (8)

[0302] (1) Preparation of a compound of formula (8-1)

[0303]

[0304] Into a flask was placed ethyl acetate (40 mL), a compound of formula (10-1) (4.02 g, 10 mmol), stirred to dissolve, DMAP (246 mg, 2 mmol) and acetic anhydride (2.04 g, 20 mmol) were added, and the reaction was carried out at 25°C for 8 h. After TLC detection showed that the reaction was complete, water (40 mL) was added to quench the reaction, and ethyl acetate (50 mL) was added to extract. The organic phase was washed with water and saturated brine, concentrated under reduced pressure, and a compound of formula (8-1) was obtained (white solid 4.35 g, molar yield 97.8%). 1HNMR (600 MHz, CDC13) δ 5.73 (d, J = 2.3 Hz, 1H), 4.83 - 4.66 (m, 1H), 3.69 (s, 3H), 2.42 - 2.39 (m, 2H), 2.34 - 2.24 (m, 1H), 2.14 - 2.07 (m, 2H), 2.02 (s, 3H), 1.98 (s, 1H), 1.91 - 1.86 (m, 2H), 1.84 - 1.71 (m, 5H), 1.59 (d, J = 11.0 Hz, 1H), 1.49 - 1.27 (m, 9H), 1.22 (s, 3H), 1.04 (d, J = 6.5 Hz, 3H), 0.93 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 205.16, 174.74, 170.67, 164.03, 123.72, 73.82, 53.53, 53.09, 51.49, 47.29, 41.85, 39.98, 37.85, 35.32, 35.07, 34.04, 31.51, 30.66, 29.78, 27.68, 27.41, 26.54, 26.21, 24.23, 21.38, 19.49, 10.75.

[0305] (2) Preparation of the compound of formula (8-2)

[0306]

[0307] In a flask was added dichloromethane (40 mL), compound of formula (10-1) (4.02 g, 10 mmol), stirred to dissolve, added triethylamine (2.02 g, 20 mmol), DMAP (246 mg, 2 mmol) and p-methoxybenzoyl chloride (2.56 g, 15 mmol), reacted at 25 °C for 8 h, after TLC monitoring reaction was complete, saturated ammonium chloride (5 mL) was added to quench the reaction, dichloromethane (100 mL) and water (80 mL) were added to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (8-2) (white solid 5.1 g, molar yield 94.9%). 1H NMR (500 MHz, CDCI3) δ 7.99 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 5.78 (d, J = 2.3 Hz, 1H), 5.01 - 4.96 (m, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 2.44 - 2.40 (m, 2H), 2.35 - 2.25 (m, 1H), 2.19 - 2.08 (m, 2H), 2.01 - 1.72 (m, 11H), 1.51 - 1.37 (m, 7H), 1.25 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.95 (s, 3H). 13 C NMR (150 MHz, CDCI3) δ 205.36, 174.76, 165.86, 164.27, 163.27, 131.58, 123.73, 123.06, 113.52, 73.98, 55.43, 53.53, 53.11, 51.50, 47.31, 41.91, 40.06, 37.88, 35.31, 35.16, 34.23, 31.51, 30.67, 29.80, 27.87, 27.39, 26.58, 26.23, 24.23, 19.52, 10.76.

[0308] (3) Preparation of the compound of formula (8-2)

[0309]

[0310] In a flask was added acetic acid (20 mL), chromium trioxide (4 g, 40 mmol), stirred to dissolve, added the compound of formula (7-2) (5.22 g, 10 mmol), stirred at 35°C for 12 h, stopped after TLC detection of complete reaction. Added ethyl acetate (90 mL) and water (100 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHC03aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (8-2) (4.95 g, white solid, molar yield 92.3%). 1H NMR (500 MHz, CDC13) δ 7.99 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 5.78 (d, J = 2.3 Hz, 1H), 5.01 - 4.96 (m, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 2.44 - 2.40 (m, 2H), 2.35 - 2.25 (m, 1H), 2.19 - 2.08 (m, 2H), 2.01 - 1.72 (m, 11H), 1.51 - 1.37 (m, 7H), 1.25 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.95 (s, 3H). 13 CNMR (150 MHz, CDC13) δ 205.36, 174.76, 165.86, 164.27, 163.27, 131.58, 123.73, 123.06, 113.52, 73.98, 55.43, 53.53, 53.11, 51.50, 47.31, 41.91, 40.06, 37.88, 35.31, 35.16, 34.23, 31.51, 30.67, 29.80, 27.87, 27.39, 26.58, 26.23, 24.23, 19.52, 10.76.

[0311] (4) Preparation of the compound of formula (8-3)

[0312]

[0313] Into a flask was added dichloromethane (40 mL), the compound of formula (10-2) (4.17 g, 10 mmol), stirred to dissolve, added triethylamine (2.02 g, 20 mmol), DMAP (0.123 g, 1 mmol) and p-methoxybenzoyl chloride (2.56 g, 15 mmol), reacted at 25°C for 8 h, after TLC monitoring of the reaction completion, added saturated ammonium chloride (5 mL) to quench the reaction, added dichloromethane (80 mL) and water (100 mL) to extract, the organic phase was washed with water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (8-3) (white solid 5.28 g, molar yield 95.8%). 1H NMR (500 MHz, CDCI3) δ 7.99 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 5.78 (d, J = 2.3 Hz, 1H), 5.01 - 4.96 (m, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.44 - 2.40 (m, 2H), 2.35 - 2.25 (m, 1H), 2.19 - 2.08 (m, 2H), 2.01 - 1.72 (m, 11H), 1.51 - 1.37 (m, 7H), 1.27 (t, J = 7.1 Hz, 3H), 1.25 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.95 (s, 3H). 13 C NMR (150 MHz, CDCI3) δ 205.29, 174.31, 165.85, 164.19, 163.28, 131.57, 123.75, 123.09, 113.52, 73.98, 60.18, 55.42, 53.55, 53.12, 47.35, 41.93, 40.05, 37.89, 35.31, 35.17, 34.24, 31.79, 30.68, 29.79, 27.87, 27.39, 26.58, 26.24, 24.23, 19.52, 14.26, 10.75.

[0314] (5) Preparation of the compound of formula (8-3)

[0315]

[0316] In a flask was added acetic acid (10 mL), chromium trioxide (2 g, 20 mmol), stirred to dissolve, added the compound of formula (7-3) (2.68 g, 5 mmol), stirred at 35°C for 12 h, stopped after TLC detection of complete reaction. Added ethyl acetate (70 mL) and water (80 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHC03aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (8-3) (2.48 g, white solid, molar yield 90.1 %). 1H NMR (500 MHz, CDCI3) δ 7.99 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 5.78 (d, J = 2.3 Hz, 1 H), 5.01 - 4.96 (m, 1 H), 4.14 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.44 - 2.40 (m, 2H), 2.35 - 2.25 (m, 1 H), 2.19 - 2.08 (m, 2H), 2.01 - 1.72 (m, 1 1 H), 1.51 - 1.37 (m, 7H), 1.27 (t, J = 7.1 Hz, 3H), 1.25 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.95 (s, 3H). 13 C NMR (150 MHz, CDCI3) δ 205.29, 174.31, 165.85, 164.19, 163.28, 131.57, 123.75, 123.09, 113.52, 73.98, 60.18, 55.42, 53.55, 53.12, 47.35, 41.93, 40.05, 37.89, 35.31, 35.17, 34.24, 31.79, 30.68, 29.79, 27.87, 27.39, 26.58, 26.24, 24.23, 19.52, 14.26, 10.75.

[0317] (6) Preparation of the compound of formula (8-4)

[0318]

[0319] In a flask was added acetic acid (10 mL), chromium trioxide (1.5 g, 15 mmol), stirred to dissolve, added the compound of formula (7-4) (2.46 g, 5 mmol), stirred at 35°C for 12 h, stopped after TLC detection of complete reaction. Added ethyl acetate (40 mL) and water (50 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHC03aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (8-4) (2.2 g, white solid, molar yield 87%). 1HNMR (500 MHz, CDC13) δ 8.09 - 8.01 (m, 2H), 7.55 (d, J = 7.5 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 5.78 (d, J = 2.3 Hz, 1H), 5.05 - 4.99 (m, 1H), 3.69 (s, 3H), 2.46 - 2.39 (m, 2H), 2.31 - 2.27 (m, 1H), 2.19 - 2.12 (m, 2H), 1.97 - 1.87 (m, 4H), 1.86 - 1.74 (m, 6H), 1.56 - 1.37 (m, 6H), 1.27 (d, J = 13.6 Hz, 5H), 1.05 (d, J = 6.6 Hz, 3H), 0.95 (s, 3H). 13 C NMR (125 MHz, CDC13) δ 205.32, 174.77, 166.10, 164.17, 132.82, 130.61, 129.56, 128.29, 123.76, 74.34, 53.52, 53.12, 51.51, 47.30, 41.90, 40.05, 37.87, 35.31, 35.13, 34.16, 31.51, 30.66, 29.80, 27.81, 27.39, 26.57, 26.23, 24.23, 19.52, 10.77.

[0320] (7) Preparation of the compound of formula (8-5)

[0321]

[0322] In a flask was added acetic acid (15 mL), chromium trioxide (2.5 g, 25 mmol), stirred to dissolve, added the compound of formula (7-5) (2.8 g, 5 mmol), stirred at 40 °C for 8 h, stopped the reaction after TLC detection of complete reaction. Added ethyl acetate (50 mL) and water (70 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHC03aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (8-5) (2.49 g, white solid, molar yield 86.7%). 1HNMR (600 MHz, CDC13) δ 8.14 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 5.78 (s, 1H), 5.04 (t, J = 5.0 Hz, 1H), 3.69 (s, 3H), 2.45 - 2.40 (m, 2H), 2.31 (d, J = 7.9 Hz, 1H), 2.22 - 2.11 (m, 2H), 2.03 - 1.87 (m, 4H), 1.86 - 1.74 (m, 6H), 1.57 - 1.39 (m, 6H), 1.26 (d, J = 8.8 Hz, 5H), 1.05 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 2.8 Hz, 3H). 13 C NMR (150 MHz, CDC13) δ 205.30, 174.74, 164.85, 163.96, 134.43, 134.22, 133.83, 129.97, 125.34, 125.31, 123.80, 75.06, 53.56, 53.14, 51.50, 47.31, 41.89, 40.00, 37.86, 35.31, 35.07, 34.07, 31.49, 30.66, 29.74, 27.75, 27.39, 26.56, 26.20, 24.23, 19.51, 10.74.

[0323] (8) Preparation of the compound of formula (8-6)

[0324]

[0325] Into a flask was added acetic acid (10 mL), chromium trioxide (2 g, 20 mmol), stirred to dissolve, added the compound of formula (7-6) (2.76 g, 5 mmol), stirred at 30°C for 16 h, stopped after TLC detection of complete reaction. Added ethyl acetate (60 mL) and water (70 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHC03aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (8-6) (2.04 g, white solid, molar yield 72.1%). 1H NMR (500 MHz, CDC13) δ 7.85 - 7.75 (m, 1H), 6.49 - 6.47 (m, 2H), 5.76 (d, J = 2.3 Hz, 1H), 5.03 - 4.89 (m, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.67 (s, 3H), 2.43 - 2.38 (m, 2H), 2.33 - 2.25 (m, 1H), 2.17 - 2.07 (m, 2H), 1.98 - 1.86 (m, 4H), 1.80 - 1.70 (m, 5H), 1.48 - 1.37 (m, 6H), 1.29 - 1.26 (m, 3H), 1.23 (s, 3H), 1.03 (d, J = 6.5 Hz, 3H), 0.96 - 0.90 (m, 3H). 13 C NMR (125 MHz, CDC13) δ 205.33, 174.75, 164.94, 164.35, 164.12, 161.40, 133.67, 123.68, 112.71, 104.41, 98.96, 73.68, 55.96, 55.48, 53.50, 53.08, 51.49, 47.28, 41.94, 40.08, 37.89, 35.31, 35.19, 34.22, 31.50, 30.66, 29.80, 29.70, 27.85, 27.41, 26.59, 26.25, 24.22, 19.50, 10.76.

[0326] (9) Preparation of the compound of formula (8-7)

[0327]

[0328] In a flask was added acetic acid (10 mL), chromium trioxide (2 g, 20 mmol), stirred to dissolve, added the compound of formula (7-7) (2.62 g, 5 mmol), stirred at 35°C for 12 h, stopped after TLC detection of complete reaction. Added ethyl acetate (60 mL) and water (80 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHC03aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (8-7) (2.01 g, white solid, molar yield 75%). 1H NMR (500 MHz, CDC13) δ 7.75 (dd, J = 7.9, 1.9 Hz, 1H), 7.48 - 7.44 (m, 1H), 6.99 - 6.96 (m, 2H), 5.77 (d, J = 2.3 Hz, 1H), 5.07 - 4.95 (m, 1H), 3.90 (s, 3H), 3.68 (s, 3H), 2.42 - 2.39 (m, 2H), 2.33 - 2.27 (m, 1H), 2.19 - 2.09 (m, 2H), 2.00 - 1.93 (m, 2H), 1.91 - 1.85 (m, 2H), 1.82 - 1.71 (m, 5H), 1.55 - 1.36 (m, 7H), 1.31 - 1.27 (m, 2H), 1.24 (s, 3H), 1.04 (d, J = 6.5 Hz, 3H), 0.94 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 205.20, 174.73, 165.65, 164.18, 159.10, 133.28, 131.41, 123.72, 120.63, 120.10, 112.04, 74.17, 56.00, 53.50, 53.09, 51.46, 47.31, 41.97, 40.07, 37.90, 35.32, 35.18, 34.15, 31.51, 30.67, 29.80, 27.81, 27.39, 26.58, 26.26, 24.23, 19.50, 10.76.

[0329] (10) Preparation of the compound of formula (8-8)

[0330]

[0331] In a flask was added acetic acid (10 mL), chromium trioxide (2 g, 20 mmol), stirred to dissolve, added the compound of formula (7-8) (2.87 g, 5 mmol), stirred at 40 °C for 18 h, stopped the reaction after TLC detection of complete reaction. Added ethyl acetate (50 mL) and water (70 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHC03aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (8-8) (2.5 g, white solid, molar yield 85%). 1H NMR (600 MHz, CDCI3) δ 8.14 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 5.78 (d, J = 2.4 Hz, 1H), 5.07 - 5.02 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 2.45 - 2.39 (m, 2H), 2.32 - 2.26 (m, 1H), 2.22 - 2.11 (m, 2H), 2.03 - 1.87 (m, 4H), 1.84 - 1.74 (m, 5H), 1.58 - 1.38 (m, 7H), 1.34 - 1.22 (m, 8H), 1.05 (d, J = 6.6 Hz, 3H), 0.95 (s, 3H). 13 C NMR (150 MHz, CDCI3) δ 205.26, 174.28, 164.84, 163.91, 134.44, 134.22, 133.85, 129.97, 125.36, 125.33, 125.31, 125.28, 123.80, 75.06, 60.19, 53.57, 53.15, 47.35, 41.90, 40.00, 37.87, 35.30, 35.07, 34.08, 31.77, 30.66, 29.74, 27.76, 27.39, 26.56, 26.21, 24.23, 19.51, 14.26, 10.73.

[0332] (11) Preparation of compound of formula (8-9)

[0333]

[0334] In a flask was added acetic acid (3 mL), chromium trioxide (500 mg, 5 mmol), stirred to dissolve, added compound of formula (7-9) (567 mg, 1 mmol), stirred at 30°C for 16 h, stopped after TLC detection of complete reaction. Added ethyl acetate (15 mL) and water (30 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHC03aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain compound of formula (8-9) (424 mg, white solid, molar yield 73%). 1H NMR (500 MHz, CDC13) δ 7.85 - 7.78 (m, 1H), 6.49 - 6.46 (m, 2H), 5.76 (s, 1H), 4.96 (m, 1H), 4.13 (d, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.43 - 2.37 (m, 2H), 2.32 - 2.26 (m, 1H), 2.16 - 2.07 (m, 2H), 1.99 - 1.65 (m, 8H), 1.52 - 1.38 (m, 7H), 1.34 - 1.20 (m, 9H), 1.03 (d, J = 6.5 Hz, 3H), 0.95 - 0.91 (m, 3H).

[0335] (12) Preparation of the compound of formula (8-10)

[0336]

[0337] In a flask was added acetic acid (12 mL), chromium trioxide (2.3 g, 23 mmol), stirred to dissolve, added the compound of formula (7-10) (2.69 g, 5 mmol), stirred at 25 °C for 16 h, stopped after TLC detection of complete reaction. Added ethyl acetate (60 mL) and water (80 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHC03aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (8-10) (2.03 g, white solid, molar yield 73.8%). 1 H NMR (500 MHz, CDC13) δ 7.85 - 7.78 (m, 1H), 6.49 - 6.46 (m, 2H), 5.76 (s, 1H), 4.96 (m, 1H), 4.13 (d, J = 7.1 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.43 - 2.37 (m, 2H), 2.32 - 2.26 (m, 1H), 2.16 - 2.07 (m, 2H), 1.99 - 1.65 (m, 8H), 1.52 - 1.38 (m, 7H), 1.34 - 1.20 (m, 9H), 1.03 (d, J = 6.5 Hz, 3H), 0.95 - 0.91 (m, 3H). 13C NMR (150 MHz, CDC13) δ 205.22, 174.31, 165.65, 164.16, 159.09, 133.29, 131.41, 123.72, 120.60, 120.10, 112.03, 60.18, 55.99, 53.51, 53.09, 47.31, 41.96, 40.06, 37.90, 35.31, 35.17, 34.15, 31.79, 30.67, 29.80, 27.80, 27.41, 26.58, 26.26, 24.23, 19.51, 14.26, 10.75.

[0338] (13) Preparation of the compound of formula (8-11)

[0339]

[0340] In a flask was added acetic acid (3 mL), chromium trioxide (400 mg, 4 mmol), stirred to dissolve, added the compound of formula (7-11) (506 mg, 1 mmol), stirred at 35°C for 12 h, stopped after TLC detection of the reaction completion. Added ethyl acetate (20 mL) and water (20 mL) to the reaction solution, extracted with organic phase, successively washed with saturated NaHCO3 aqueous solution, water, saturated brine, concentrated under reduced pressure, purified by column chromatography to obtain the compound of formula (8-11) (457 mg, white solid, molar yield 87.8%). 1 H NMR (500 MHz, CDC13) δ 8.07 - 8.01 (m, 2H), 7.59 - 7.52 (m, 1H), 7.44 (t, J = 7.8 Hz, 2H), 5.78 (d, J = 2.3 Hz, 1H), 5.04 - 5.00 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.44 - 2.38 (m, 2H), 2.32 - 2.26 (m, 1H), 2.20 - 2.09 (m, 2H), 2.01 - 1.84 (m, 4H), 1.83 - 1.71 (m, 6H), 1.57 - 1.33 (m, 7H), 1.30 - 1.24 (m, 7H), 1.05 (d, J = 6.6 Hz, 3H), 0.95 (s, 3H). 13C NMR (125 MHz, CDC13) δ 205.25, 174.29, 166.08, 164.09, 132.79, 130.64, 129.56, 128.27, 123.77, 74.34, 60.18, 53.54, 53.12, 47.35, 41.92, 40.04, 37.89, 35.31, 35.14, 34.17, 31.79, 30.67, 29.79, 27.83, 27.39, 26.58, 26.24, 24.24, 19.52, 14.26, 10.75.

[0341] Example XI Preparation of compound of formula (11)

[0342] (1) Preparation of compound of formula (11-1)

[0343]

[0344] A reaction kettle was charged with compound of formula (8-1) (889 mg, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (178 mg, 20% w.t.), nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4 MPa, the reaction system was heated to 110 °C, stirred for 48 h, HPLC monitoring showed that the raw material was completely reacted, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the system temperature was controlled at 25 °C, pyridine chlorochromate (862 mg, 4 mmol) was added, and stirring was continued for 4 h, then filtered, the filtrate was washed with water, the organic phases were combined and concentrated under reduced pressure, and column chromatography was used for purification to obtain compound of formula (11-1) (535 mg, white solid, molar yield 60.5%). 1 HNMR (600 MHz, CDC13) δ 4.77-4.67 (m, 1H), 3.69 (s, 3H), 2.50 (t, J = 12.4 Hz, 1H), 2.42-2.39 (m, 1H), 2.33-2.25 (m, 1H), 2.08-2.02 (m, 5H), 1.98-1.82 (m, 5H), 1.76-1.70 (m, 3H), 1.61-1.53 (m, 3H), 1.44-1.27 (m, 8H), 1.17-1.09 (m, 2H), 1.04 (d, J = 2.6 Hz, 6H), 0.87 (d, J = 6.7 Hz, 3H). 13C NMR (150 MHz, CDC13) δ 214.72, 174.69, 170.67, 73.73, 58.66, 57.52, 51.49, 46.48, 44.06, 41.36, 38.11, 35.67, 35.64, 35.37, 34.95, 32.15, 31.32, 30.52, 27.53, 26.95, 26.36, 26.01, 24.35, 22.76, 21.42, 18.59, 11.70.

[0345] (2) Preparation of the compound of formula (11-2)

[0346]

[0347] A reaction kettle was charged with the compound of formula (8-2) (1.07 g, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (214 mg, 20% w.t.), nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4 MPa, the reaction system was heated to 110°C, stirred for 48 h, HPLC monitoring showed that the raw material was completely reacted, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the system temperature was controlled at 25°C, pyridine chlorochromate (862.7 mg, 4 mmol) was added, stirring was continued for 4 h, filtration was performed, the filtrate was washed with water, the organic phases were combined, the organic phase was concentrated under reduced pressure, column chromatography purification was performed, to obtain the compound of formula (11-2) (964 mg, white solid, molar yield 90.1%). 1 H NMR (500 MHz, CDC13) δ 8.00 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 4.97 - 4.92 (m, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 2.53 (t, J = 12.6 Hz, 1H), 2.44 - 2.37 (m, 1H), 2.31 - 2.23 (m, 1H), 2.13 - 2.03 (m, 2H), 1.99 - 1.92 (m, 2H), 1.87 - 1.82 (m, 3H), 1.78 - 1.69 (m, 3H), 1.59 - 1.52 (m, 2H), 1.38 - 1.26 (m, 9H), 1.23 - 1.13 m, 2H), 1.06 (d, J = 10.5 Hz, 6H), 0.88 (d, J = 6.5 Hz, 3H). 13C NMR (150 MHz, CDC13) δ 214.98, 174.36, 165.96, 163.34, 131.65, 123.27, 113.62, 74.26, 58.82, 57.67, 55.53, 46.61, 44.25, 41.52, 38.27, 35.80, 35.74, 35.54, 35.14, 32.43, 31.70, 30.64, 27.64, 27.08, 26.65, 26.15, 24.46, 22.88, 18.72, 14.37, 11.80.

[0348] (3) Preparation of the compound of formula (11-3)

[0349]

[0350] Into a reaction kettle, compound of formula (8-3) (1.11 g, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (223 mg, 20% w.t.) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4 MPa, the reaction system was heated to 110°C, stirred for 55 h, HPLC monitoring showed that the raw material was completely reacted, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the system temperature was controlled at 25°C, pyridine chlorochromate (862.8 mg, 4 mmol) was added, and stirring was continued for 4 h, then filtered, the filtrate was washed with water, the organic phases were combined and concentrated under reduced pressure, and column chromatography purification was performed to obtain the compound of formula (11-3) (983 mg, white solid, molar yield 88.9%). 1 H NMR (500 MHz, CDC13) δ 8.00 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 4.97 - 4.92 (m, 1H), 3.88 (s, 3H), 4.14 (q, J = 7.2 Hz, 2H), 2.53 (t, J = 12.6 Hz, 1H), 2.44 - 2.37 (m, 1H), 2.31 - 2.23 (m, 1H), 2.13 - 2.03 (m, 2H), 1.99 - 1.92 (m, 2H), 1.87 - 1.82 (m, 3H), 1.78 - 1.69 (m, 3H), 1.59 - 1.52 (m, 2H), 1.38 - 1.26 (m, 12H), 1.23 - 1.13 (m, 2H), 1.06 (d, J = 10.5 Hz, 6H), 0.88 (d, J = 6.5 Hz, 3H). 13C NMR (150 MHz, CDC13) δ 214.88, 174.26, 165.86, 163.24, 131.55, 123.17, 113.52, 73.92, 60.19, 58.71, 57.57, 55.43, 46.51, 44.15, 41.42, 38.17, 35.70, 35.64, 35.44, 35.04, 32.33, 31.60, 30.54, 27.54, 26.98, 26.54, 26.04, 24.36, 22.78, 18.62, 14.27, 11.70.

[0351] Into a reaction kettle, compound of formula (8-3) (1.11 g, 2 mmol), toluene (10 mL) and 10% Pd / C (333 mg, 30% w.t.) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4.5 MPa, the reaction system was heated to 110°C, stirred for 40 h, HPLC monitoring of the complete reaction of raw materials, the reaction was stopped. Filtered to recover Pd / C, the filtrate was removed under reduced pressure after the solvent was dissolved in ethyl acetate (10 mL), the temperature of the system was controlled at 25°C, pyridine chlorochromate (862.5 mg, 4 mmol) was added, and stirring was continued for 4 h, filtered, the filtrate was washed with water, the organic phases were combined, the organic phase was concentrated under reduced pressure, and column chromatography was used for purification to obtain compound of formula (11-3) (969 mg, white solid, molar yield 88.1%).

[0352] Into a reaction kettle, compound of formula (8-3) (1.11 g, 2 mmol), toluene (10 mL) and 10% Pd / C (333 mg, 30% w.t.) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4.5 MPa, the reaction system was heated to 110°C, stirred for 40 h, HPLC monitoring of the complete reaction of raw materials, the reaction was stopped. Filtered to recover Pd / C, the filtrate was removed under reduced pressure after the solvent was dissolved in ethyl acetate (10 mL), the temperature of the system was controlled at 25°C, pyridine chlorochromate (862.5 mg, 4 mmol) was added, and stirring was continued for 4 h, filtered, the filtrate was washed with water, the organic phases were combined, the organic phase was concentrated under reduced pressure, and column chromatography was used for purification to obtain compound of formula (11-3) (969 mg, white solid, molar yield 88.1%).

[0353] (4) Preparation of compound of formula (11-4)

[0354]

[0355] Into a reaction kettle, a compound of formula (8-4) (1.01 g, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (200 mg, 20% w.t.) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4 MPa, the reaction system was heated to 105°C, stirred for 50 h, HPLC monitoring showed that the raw material was completely reacted, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the system temperature was controlled at 25°C, pyridine chlorochromate (862 mg, 4 mmol) was added, and stirring was continued for 4 h, then filtered, the filtrate was washed with water, the organic phases were combined and concentrated under reduced pressure, and column chromatography was used for purification to obtain a compound of formula (11-4) (857 mg, white solid, molar yield 84%). 1 HNMR (600 MHz, CDC13) δ 8.04 (d, J = 7.5 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.5 Hz, 2H), 4.98 (d, J = 11.8 Hz, 1H), 3.68 (s, 3H), 2.52 (t, J = 12.4 Hz, 1H), 2.45-2.36 (m, 1H), 2.30-2.25 (m, 1H), 2.16-2.02 (m, 2H), 1.98-1.91 (m, 3H), 1.85 (t, J = 10.8 Hz, 4H), 1.75 (d, J = 16.4 Hz, 3H), 1.66-1.51 (m, 3H), 1.48-1.25 (m, 6H), 1.22-1.11 (m, 2H), 1.05 (d, J = 14.7 Hz, 6H), 0.87 (d, J = 6.5 Hz, 3H). 13 C NMR (150 MHz, CDC13) δ 214.79, 174.66, 166.08, 132.78, 130.73, 129.54, 128.29, 74.28, 58.69, 57.55, 51.50, 46.48, 44.13, 41.41, 38.16, 35.69, 35.63, 35.43, 35.01, 32.26, 31.31, 30.53, 27.54, 26.97, 26.50, 26.03, 24.35, 22.78, 18.61, 11.70.

[0356] (5) Preparation of a compound of formula (11-5)

[0357]

[0358] Into a reaction kettle, a compound of formula (8-5) (1.15 g, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (345 mg, 30% w.t.) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4 MPa, the reaction system was heated to 110°C, stirred for 24 h, HPLC monitoring showed that the raw material was completely reacted, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the system temperature was controlled at 25°C, pyridine chlorochromate (862 mg, 4 mmol) was added, and stirring was continued for 4 h, then filtered, the filtrate was washed with water, the organic phases were combined and concentrated under reduced pressure, and column chromatography was used for purification to obtain a compound of formula (11-5) (990 mg, white solid, molar yield 86.1%). 1 H NMR (600 MHz, CDCI3) δ 8.14 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 5.02-4.97 (m, 1H), 3.67 (s, 3H), 2.53 (t, J = 12.6 Hz, 1H), 2.43-2.38 (m, 1H), 2.30-2.25 (m, 1H), 2.10-2.04 (m, 2H), 1.99-1.90 (m, 3H), 1.90-1.81 (m, 4H), 1.80-1.69 (m, 3H), 1.67-1.52 (m, 3H), 1.46-1.26 (m, 6H), 1.22-1.10 (m, 2H), 1.07 (s, 3H), 1.05 (s, 3H), 0.87 (d, J = 6.6 Hz, 3H). 13 C NMR (150 MHz, CDCI3) δ 214.78, 174.65, 164.83, 134.38, 134.16, 133.94, 129.94, 125.36, 125.34, 125.31, 125.29, 124.58, 122.77, 75.01, 58.72, 57.57, 51.48, 46.49, 44.15, 41.40, 38.15, 35.67, 35.62, 35.40, 34.94, 32.17, 31.29, 30.52, 27.52, 26.93, 26.42, 26.02, 24.34, 22.74, 18.59, 11.69.

[0359] (6) Preparation of a compound of formula (11-6)

[0360]

[0361] Into a reaction kettle, a compound of formula (8-6) (1.13 g, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (283 mg, 25% w.t.) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4 MPa, the reaction system was heated to 110°C, stirred for 48 h, HPLC monitoring showed that the raw material was completely reacted, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the system temperature was controlled at 25°C, pyridine chlorochromate (863 mg, 4 mmol) was added, and stirring was continued for 4 h, then filtered, the filtrate was washed with water, the organic phases were combined and concentrated under reduced pressure, and column chromatography was used for purification to obtain a compound of formula (11-6) (820 mg, white solid, molar yield 72.5%). 1 H NMR (600 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 9.1 Hz, 2H), 4.96-4.90 (m, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.68 (s, 3H), 2.51 (t, J = 12.6 Hz, 1H), 2.44-2.39 (m, 1H), 2.30-2.25 (m, 1H), 2.13-2.02 (m, 2H), 1.97-1.90 (m, 3H), 1.87-1.79 (m, 4H), 1.77-1.71 (m, 3H), 1.62 (d, J = 13.7 Hz, 1H), 1.58-1.50 (m, 2H), 1.43-1.27 (m, 6H), 1.21-1.12 (m, 2H), 1.05 (d, J = 11.0 Hz, 6H), 0.87 (d, J = 6.6 Hz, 3H). 13 C NMR (150 MHz, CDCl3) δ 214.94, 174.71, 165.04, 164.09, 161.37, 133.62, 112.91, 104.43, 99.02, 73.63, 58.70, 57.55, 55.98, 55.48, 51.49, 46.47, 44.13, 41.45, 38.16, 35.70, 35.64, 35.46, 35.08, 32.32, 31.32, 30.53, 27.54, 27.00, 26.53, 26.05, 24.35, 22.77, 18.60, 11.70.

[0362] (7) Preparation of a compound of formula (11-7)

[0363]

[0364] Into a reaction kettle, a compound of formula (8-7) (1.07 g, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (268 mg, 25% w.t.) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4.5 MPa, the reaction system was heated to 110°C, stirred for 24 h, HPLC monitoring showed that the raw material was completely reacted, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the system temperature was controlled at 25°C, pyridine chlorochromate (862 mg, 4 mmol) was added, and stirring was continued for 4 h, then filtered, the filtrate was washed with water, the organic phases were combined and concentrated under reduced pressure, and column chromatography was used for purification to obtain a compound of formula (11-7) (803 mg, white solid, molar yield 75.1%). 1 HNMR (500 MHz, CDC13) δ 7.76 (dd, J = 8.0, 1.8 Hz, 1H), 7.49 - 7.43 (m, 1H), 6.99 (t, J = 7.3 Hz, 2H), 5.00 - 4.95 (m, 1H), 3.91 (s, 3H), 3.68 (s, 3H), 2.51 (t, J = 12.6 Hz, 1H), 2.44 - 2.38 (m, 1H), 2.31 - 2.24 (m, 1H), 2.10 - 2.03 (m, 2H), 1.99 - 1.81 (m, 7H), 1.78 - 1.70 (m, 3H), 1.65 - 1.52 (m, 2H), 1.44 - 1.26 (m, 7H), 1.22 (d, J = 3.5 Hz, 2H), 1.05 (d, J = 11.9 Hz, 6H), 0.87 (d, J = 6.6 Hz, 3H). 13 C NMR (125 MHz, CDC13) δ 214.80, 174.68, 165.72, 159.06, 133.23, 131.37, 120.76, 120.11, 112.05, 74.1, 58.67, 57.54, 56.01, 51.48, 46.47, 44.10, 41.46, 38.14, 35.70, 35.64, 35.45, 35.05, 32.24, 31.32, 30.52, 27.53, 26.99, 26.47, 26.04, 24.35, 22.77, 18.59, 11.70.

[0365] (8) Preparation of a compound of formula (11-8)

[0366]

[0367] Into a reaction kettle, a compound of formula (8-8) (1.18 g, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (354 mg, 30% w.t.) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4 MPa, the reaction system was heated to 110°C, stirred for 48 h, HPLC monitoring showed that the raw material was completely reacted, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the system temperature was controlled at 25°C, pyridine chlorochromate (862 mg, 4 mmol) was added, and stirring was continued for 4 h, then filtered, the filtrate was washed with water, the organic phases were combined and concentrated under reduced pressure, and column chromatography was used for purification to obtain a compound of formula (11-8) (1 g, white solid, molar yield 85.3%). 1 HNMR (600 MHz, CDCI3) δ 8.15 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 5.03-4.97 (m, 1H), 4.16-4.12 (m, 2H), 2.53 (t, J = 12.6 Hz, 1H), 2.42-2.37 (m, 1H), 2.29-2.23 (m, 1H), 2.10-2.04 (m, 2H), 2.00-1.90 (m, 3H), 1.89-1.82 (m, 4H), 1.79-1.70 (m, 3H), 1.67-1.54 (m, 3H), 1.47-1.29 (m, 6H), 1.23 (t, J = 7.1 Hz, 3H), 1.23-1.13 (m, 2H), 1.08 (s, 3H), 1.05 (s, 3H), 0.88 (d, J = 6.6 Hz, 3H). 13 C NMR (150 MHz, CDCI3) δ 214.79, 174.23, 164.84, 134.39, 134.17, 133.94, 129.94, 125.36, 125.34, 125.31, 125.29, 124.58, 122.77, 75.02, 60.19, 58.73, 57.58, 46.52, 44.15, 41.40, 38.15, 35.69, 35.62, 35.41, 34.95, 32.17, 31.58, 30.53, 27.52, 26.94, 26.43, 26.02, 24.35, 22.74, 18.61, 14.26, 11.69.

[0368] (9) Preparation of a compound of formula (11-9)

[0369]

[0370] Into a reaction flask was added compound of formula (8-9) (1.16 g, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (290 mg, 25% w.t.), nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4.5 MPa, the reaction system was heated to 110 °C, stirred for 50 h, HPLC monitoring of the complete reaction of raw materials, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the temperature of the system was controlled at 25 °C, pyridine chlorochromate (863 mg, 4 mmol) was added, and stirring was continued for 4 h, filtered, the filtrate was washed with water, the organic phases were combined, the organic phase was concentrated under reduced pressure, and column chromatography purification was performed to obtain compound of formula (11-9) (812 mg, white solid, molar yield 70%). 1 HNMR (600 MHz, CDC13) δ 7.83 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 9.0 Hz, 2H), 4.96 - 4.91 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 2.52 (t, J = 12.6 Hz, 1H), 2.41 - 2.37 (m, 1H), 2.29 - 2.22 (m, 1H), 2.12 - 2.05 (m, 3H), 1.99 - 1.92 (m, 2H), 1.89 - 1.81 (m, 4H), 1.77 - 1.71 (m, 3H), 1.64 - 1.52 (m, 3H), 1.46 - 1.12 (m, 11H), 1.06 (s, 3H), 1.05 (s, 3H), 0.90 (d, J = 8.9 Hz, 3H). 13 C NMR (150 MHz, CDC13) δ 214.85, 174.29, 165.47, 164.09, 161.38, 133.63, 112.92, 104.43, 99.02, 73.64, 60.20, 58.71, 57.56, 55.99, 55.48, 46.50, 44.13, 41.45, 38.16, 35.71, 35.64, 35.46, 35.08, 32.32, 31.61, 30.54, 29.71, 27.54, 27.00, 26.53, 26.06, 24.36, 22.78, 18.61, 11.70.

[0371] (10) Preparation of compound of formula (11-10)

[0372]

[0373] Into a reaction kettle, a compound of formula (8-10) (1.10 g, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (220 mg, 20% w.t.) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4.5 MPa, the reaction system was heated to 100 °C, stirred for 40 h, HPLC monitoring showed that the raw material was completely reacted, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the system temperature was controlled at 25 °C, pyridine chlorochromate (862 mg, 4 mmol) was added, and stirring was continued for 4 h, then filtered, the filtrate was washed with water, the organic phases were combined and concentrated under reduced pressure, and column chromatography was used for purification to obtain a compound of formula (11-10) (838 mg, white solid, molar yield 76.2%). 1 HNMR (500 MHz, CDC13) δ 7.75 (dd, J = 7.9, 1.9 Hz, 1H), 7.47 - 7.44 (m, 1H), 6.98 (t, J = 7.3 Hz, 2H), 5.01 - 4.91 (m, 1H), 4.12 (t, J = 7.1 Hz, 2H), 3.90 (s, 3H), 2.51 (t, J = 12.5 Hz, 1H), 2.42 - 2.36 (m, 1H), 2.28 - 2.22 (m, 1H), 2.13 - 2.01 (m, 2H), 1.98 - 1.89 (m, 3H), 1.88 - 1.80 (m, 4H), 1.76 - 1.71 (m, 3H), 1.62 (dd, J = 13.3, 4.7 Hz, 1H), 1.58 - 1.51 (m, 2H), 1.44 - 1.24 (m, 10H), 1.23 - 1.11 (m, 2H), 1.05 (d, J = 11.8 Hz, 6H), 0.87 (d, J = 6.6 Hz, 3H). 13 C NMR (125 MHz, CDC13) δ 214.78, 174.24, 165.72, 159.05, 133.23, 131.36, 120.76, 120.10, 112.05, 74.10, 60.17, 58.67, 57.53, 56.00, 46.49, 44.09, 41.45, 38.14, 35.69, 35.62, 35.44, 35.04, 32.23, 31.59, 30.52, 27.53, 26.99, 26.47, 26.04, 24.35, 22.76, 18.60, 14.26, 11.69.

[0374] (11) Preparation of a compound of formula (11-11)

[0375]

[0376] Into a reaction kettle, a compound of formula (8-11) (1.04 g, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd / C (208 mg, 20% w.t.) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4.0 MPa, the reaction system was heated to 110°C, stirred for 48 h, HPLC monitoring showed that the raw material was completely reacted, the reaction was stopped. The Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, then dissolved in ethyl acetate (10 mL), the system temperature was controlled at 25°C, pyridine chlorochromate (862 mg, 4 mmol) was added, and stirring was continued for 4 h, then filtered, the filtrate was washed with water, the organic phases were combined and concentrated under reduced pressure, and column chromatography was used for purification to obtain a compound of formula (11-11) (864 mg, white solid, molar yield 83.1%). 1 H NMR (600 MHz, CDCI3) δ 8.03 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 5.07-4.90 (m, 1H), 4.14 (q, J = 7.3 Hz, 2H), 2.52 (t, J = 12.5 Hz, 1H), 2.40-2.36 (m, 1H), 2.28-2.24 (m, 1H), 2.13-2.02 (m, 2H), 1.96-1.91 (m, 3H), 1.87-1.80 (m, 4H), 1.76-1.70 (m, 3H), 1.64-1.53 (m, 3H), 1.46-1.23 (m, 9H), 1.21-1.12 (m, 2H), 1.05 (d, J = 14.5 Hz, 6H), 0.87 (d, J = 6.5 Hz, 3H). 13 C NMR (150 MHz, CDCI3) δ 214.80, 174.23, 166.08, 132.77, 130.72, 129.54, 128.29, 74.28, 60.18, 58.69, 57.56, 46.50, 44.13, 41.41, 38.16, 35.69, 35.62, 35.43, 35.01, 32.26, 31.59, 30.53, 27.53, 26.97, 26.49, 26.03, 24.35, 22.78, 18.62, 14.27, 11.70.

[0377] Example Twelve Preparation of a compound of formula (12)

[0378] (1) Preparation of a compound of formula (12-1)

[0379]

[0380] A flask was charged with compound of formula (11-1) (4.46 g, 10 mmol), tetrahydrofuran (45 mL), and stirred to dissolve. At 0 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution (15 mL, 15 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitoring that the starting material was consumed, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, combined organic phase, and washed with water, saturated sodium chloride successively. The organic phase was concentrated under reduced pressure and purified by column chromatography to give compound of formula (12-1) (4.0 g, white solid, molar yield 89.7%). 1 HNMR (600 MHz, CDC13) δ 4.76-4.65 (m, 1H), 3.98 (t, J = 2.5 Hz, 1H), 3.66 (s, 3H), 2.39-2.34 (m, 1H), 2.26-2.21 (m, 1H), 2.01 (d, J = 1.7 Hz, 3H), 1.87-1.80 (m, 5H), 1.69 (t, J = 9.6 Hz, 2H), 1.62-1.38 (m, 10H), 1.28-1.24 (m, 2H), 1.14-1.02 (m, 3H), 0.97 (d, J = 6.1 Hz, 3H), 0.91 (d, J = 1.5 Hz, 3H), 0.68 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.67, 170.68, 74.27, 73.07, 51.49, 48.26, 47.31, 46.49, 41.84, 35.97, 35.08, 34.87, 34.11, 33.62, 32.14, 31.04, 30.89, 28.71, 27.43, 26.95, 26.48, 26.01, 23.60, 23.11, 21.45, 17.31, 12.73.

[0381] (2) Preparation of compound of formula (12-2)

[0382]

[0383] A flask was charged with compound of formula (11-2) (2.69 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. At 0 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution (7.5 mL, 7.5 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitoring that the starting material was consumed, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, combined organic phase, and washed with water, saturated sodium chloride successively. The organic phase was concentrated under reduced pressure and purified by column chromatography to give compound of formula (12-2) (2.42 g, white solid, molar yield 90%).1 HNMR (600 MHz, CDC13) δ 8.01 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.98 - 4.93 (m, 1H), 4.03 (t, J = 3.0 Hz, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 2.42 - 2.37 (m, 1H), 2.31 - 2.24 (m, 1H), 2.00 (q, J = 12.5 Hz, 1H), 1.94 - 1.79 (m, 6H), 1.76 - 1.53 (m, 8H), 1.49 - 1.36 (m, 4H), 1.34 - 1.28 (m, 2H), 1.21 - 1.07 (m, 3H), 1.00 (d, J = 6.3 Hz, 3H), 0.97 (s, 3H), 0.72 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.73, 165.96, 163.18, 131.56, 123.33, 113.48, 74.50, 73.23, 55.42, 51.53, 48.36, 47.39, 46.52, 41.95, 36.02, 35.08, 34.96, 34.20, 33.75, 32.37, 31.05, 30.92, 28.77, 27.44, 27.00, 26.72, 26.05, 23.61, 23.17, 17.37, 12.76.

[0384] A flask was charged with compound of formula (11-2) (2.69 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. Potassium borohydride (0.54 g, 10 mmol) was added at 0 °C, and stirring was continued for 12 h. After the reaction was completed as monitored by TLC, the reaction was stopped. The reaction was quenched by dropwise addition of acetone, concentrated under reduced pressure, extracted with ethyl acetate, separated, and the organic phase was washed with water and saturated sodium chloride successively. The organic phase was concentrated under reduced pressure and purified by column chromatography to give compound of formula (12-2) (2.3 g, white solid, 85.5% molar yield). 1H NMR (600 MHz, CDC13) δ 8.01 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.98 - 4.93 (m, 1H), 4.03 (t, J = 3.0 Hz, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 2.42 - 2.37 (m, 1H), 2.31 - 2.24 (m, 1H), 2.00 (q, J = 12.5 Hz, 1H), 1.94 - 1.79 (m, 6H), 1.76 - 1.53 (m, 8H), 1.49 - 1.36 (m, 4H), 1.34 - 1.28 (m, 2H), 1.21 - 1.07 (m, 3H), 1.00 (d, J = 6.3 Hz, 3H), 0.97 (s, 3H), 0.72 (s, 3H). 13 CNMR (150 MHz, CDC13) δ 174.73, 165.96, 163.18, 131.56, 123.33, 113.48, 74.50, 73.23, 55.42, 51.53, 48.36, 47.39, 46.52, 41.95, 36.02, 35.08, 34.96, 34.20, 33.75, 32.37, 31.05, 30.92, 28.77, 27.44, 27.00, 26.72, 26.05, 23.61, 23.17, 17.37, 12.76.

[0385] A flask was charged with compound of formula (11-2) (2.69 g, 5 mmol), a mixture solution of tetrahydrofuran (15 mL) and methanol (10 mL), and the solution was stirred to dissolve. A 1 mol / L solution of lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran (10 mL, 10 mmol) was added dropwise at 5 °C, and stirring was continued for 12 h. After TLC monitoring showed that the reaction was complete, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, and the organic phase was separated and washed with water and saturated sodium chloride successively. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain compound of formula (12-2) (2.34 g, white solid, molar yield 86.9%). 1HNMR (600 MHz, CDC13) δ 8.01 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.98 - 4.93 (m, 1H), 4.03 (t, J = 3.0 Hz, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 2.42 - 2.37 (m, 1H), 2.31 - 2.24 (m, 1H), 2.00 (q, J = 12.5 Hz, 1H), 1.94 - 1.79 (m, 6H), 1.76 - 1.53 (m, 8H), 1.49 - 1.36 (m, 4H), 1.34 - 1.28 (m, 2H), 1.21 - 1.07 (m, 3H), 1.00 (d, J = 6.3 Hz, 3H), 0.97 (s, 3H), 0.72 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.73, 165.96, 163.18, 131.56, 123.33, 113.48, 74.50, 73.23, 55.42, 51.53, 48.36, 47.39, 46.52, 41.95, 36.02, 35.08, 34.96, 34.20, 33.75, 32.37, 31.05, 30.92, 28.77, 27.44, 27.00, 26.72, 26.05, 23.61, 23.17, 17.37, 12.76.

[0386] (3) Preparation of the compound of formula (12-3)

[0387]

[0388] A flask was charged with the compound of formula (11-3) (2.76 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. At 0 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution (7.5 mL, 7.5 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitoring showed that the starting material was completely consumed, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, and the organic phase was combined. The organic phase was washed with water and saturated sodium chloride successively, concentrated under reduced pressure, and purified by column chromatography to give the compound of formula (12-3) (2.5 g, white solid, molar yield 90.6%). 1HNMR (600 MHz, CDC13) δ 8.02 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 4.98 - 4.94 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 4.08 - 4.00 (m, 1H), 3.88 (s, 3H), 2.40 - 2.35 (m, 1H), 2.27 - 2.22 (m, 1H), 2.01 (q, J = 12.5 Hz, 1H), 1.94 - 1.80 (m, 6H), 1.75 - 1.54 (m, 9H), 1.49 - 1.42 (m, 3H), 1.42 - 1.34 (m, 1H), 1.34 - 1.25 (m, 5H), 1.21 - 1.07 (m, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.97 (s, 3H), 0.72 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.27, 165.94, 163.18, 131.56, 123.35, 113.49, 74.49, 73.23, 60.23, 55.43, 48.37, 47.45, 46.53, 41.96, 36.03, 35.06, 34.97, 34.20, 33.76, 32.38, 31.34, 30.92, 28.77, 27.45, 27.01, 26.73, 26.05, 23.61, 23.18, 17.39, 14.28, 12.77.

[0389] (4) Preparation of the compound of formula (12-4)

[0390]

[0391] A flask was charged with the compound of formula (11-4) (2.55 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. At 0 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution (7.5 mL, 7.5 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitoring showed that the starting material was completely consumed, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, and the organic phase was washed with water and saturated sodium chloride successively. The organic phase was concentrated under reduced pressure and purified by column chromatography to give the compound of formula (12-4) (2.3 g, white solid, molar yield 90.2%). 1HNMR (600 MHz, CDC13) δ 8.06 (dd, J = 8.1, 1.5 Hz, 2H), 7.59 - 7.54 (m, 1H), 7.45 (t, J = 7.7 Hz, 2H), 5.01 - 4.97 (m, 1H), 4.04 (d, J = 3.0 Hz, 1H), 3.69 (s, 3H), 2.42 - 2.37 (m, 1H), 2.29 - 2.23 (m, 1H), 2.03 (q, J = 12.5 Hz, 1H), 1.95 - 1.80 (m, 6H), 1.76 - 1.67 (m, 2H), 1.64 - 1.59 (m, 2H), 1.59 - 1.55 (m, 3H), 1.50 - 1.36 (m, 5H), 1.34 - 1.28 (m, 2H), 1.22 - 1.08 (m, 3H), 1.03 - 0.92 (m, 6H), 0.72 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.70, 166.18, 132.70, 130.89, 129.56, 128.26, 74.86, 73.21, 51.52, 48.36, 47.40, 46.52, 41.95, 36.02, 35.07, 34.94, 34.20, 33.76, 32.31, 31.05, 30.92, 28.79, 27.44, 27.00, 26.67, 26.04, 23.61, 23.17, 17.37, 12.77.

[0392] (5) Preparation of the compound of formula (12-5)

[0393]

[0394] A flask was charged with the compound of formula (11-5) (2.89 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. At 0 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution (10 mL, 10 mmol) was added dropwise, and stirring was continued for 15 h. After TLC monitoring showed that the starting material was completely consumed, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, and the organic phase was washed with water and saturated sodium chloride successively. The organic phase was concentrated under reduced pressure and purified by column chromatography to give the compound of formula (12-5) (2.57 g, white solid, molar yield 88.9%). 1HNMR (600 MHz, CDC13) δ 8.17 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 5.04 - 4.99 (m, 1H), 4.04 (d, J = 3.0 Hz, 1H), 3.68 (s, 3H), 2.42 - 2.36 (m, 1H), 2.28 - 2.23 (m, 1H), 2.04 (q, J = 12.5 Hz, 1H), 1.96 - 1.80 (m, 6H), 1.72 (q, J = 9.5 Hz, 2H), 1.67 - 1.61 (m, 3H), 1.61 - 1.54 (m, 3H), 1.51 - 1.42 (m, 4H), 1.38 - 1.27 (m, 1H), 1.35 - 1.25 (m, 3H), 1.20 - 1.09 (m, 3H), 1.04 - 0.94 (m, 6H), 0.72 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.68, 164.92, 134.32, 134.09, 129.96, 125.31, 125.28, 124.60, 122.80, 75.60, 73.20, 51.53, 48.37, 47.42, 46.53, 41.94, 36.01, 35.05, 34.88, 34.18, 33.77, 32.22, 31.04, 30.90, 28.76, 27.43, 26.96, 26.61, 26.02, 23.59, 23.14, 17.38, 12.76.

[0395] (6) Preparation of compound of formula (12-6)

[0396]

[0397] A flask was charged with compound of formula (11-6) (2.85 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. At 0 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution (10 mL, 10 mmol) was added dropwise, and stirring was continued for 15 h. After TLC monitoring showed that the starting material was completely consumed, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, and the organic phase was combined. The organic phase was washed with water and saturated sodium chloride successively, concentrated under reduced pressure, and purified by column chromatography to give compound of formula (12-6) (2.59 g, white solid, molar yield 90.8%). 1HNMR (600 MHz, CDC13) δ 7.84 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 8.3 Hz, 2H), 4.96 - 4.92 (m, 1H), 4.02 (d, J = 3.0 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.68 (s, 3H), 2.41 - 2.36 (m, 1H), 2.28 - 2.23 (m, 1H), 1.98 (q, J = 12.5 Hz, 1H), 1.92 - 1.78 (m, 6H), 1.74 - 1.55 (m, 8H), 1.47 - 1.35 (m, 4H), 1.33 - 1.25 (m, 3H), 1.18 - 1.06 (m, 3H), 0.99 (d, J = 6.3 Hz, 3H), 0.96 (s, 3H), 0.71 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.72, 165.06, 164.01, 161.33, 133.59, 113.09, 104.39, 99.01, 73.20, 55.98, 55.48, 51.52, 48.32, 47.36, 46.50, 41.98, 36.03, 35.08, 35.00, 34.22, 33.72, 32.35, 31.06, 30.91, 28.77, 27.44, 27.03, 26.71, 26.06, 23.62, 23.16, 17.34, 12.75.

[0398] (7) Preparation of the compound of formula (12-7)

[0399]

[0400] A flask was charged with the compound of formula (11-7) (2.69 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. At 0 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution (7.5 mL, 7.5 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitoring showed that the starting material was completely consumed, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, and the organic phase was washed with water and saturated sodium chloride successively. The organic phase was concentrated under reduced pressure and purified by column chromatography to give the compound of formula (12-7) (2.3 g, white solid, molar yield 85.6%). 1HNMR (600 MHz, CDC13) δ 7.79-7.76 (m, 1H), 7.49-7.45 (m, 1H), 7.02-6.97 (m, 2H), 5.01-4.96 (m, 1H), 4.01 (s, 1H), 3.91 (s, 3H), 3.68 (s, 3H), 2.41-2.36 (m, 1H), 2.28-2.23 (m, 1H), 2.00 (q, J = 12.5 Hz, 1H), 1.91-1.81 (m, 6H), 1.71 (d, J = 9.7 Hz, 2H), 1.64-1.58 (m, 3H), 1.55 (q, J = 5.1, 4.0 Hz, 2H), 1.47-1.39 (m, 4H), 1.33-1.25 (m, 3H), 1.17-1.08 (m, 4H), 0.99 (d, J = 6.3 Hz, 3H), 0.96 (s, 3H), 0.71 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.71, 165.75, 159.02, 133.15, 131.34, 120.95, 120.09, 112.03, 74.68, 73.17, 56.01, 51.52, 48.30, 47.37, 46.51, 41.98, 36.03, 35.08, 34.98, 34.22, 33.71, 32.28, 31.06, 30.91, 28.76, 27.44, 27.02, 26.64, 26.06, 23.62, 23.16, 17.34, 12.76.

[0401] (8) Preparation of the compound of formula (12-8)

[0402]

[0403] A flask was charged with the compound of formula (11-8) (2.95 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. At 5 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution (10 mL, 10 mmol) was added dropwise, and stirring was continued for 10 h. After TLC monitoring showed that the starting material was completely reacted, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, and the organic phase was washed with water and saturated sodium chloride successively. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (12-8) (2.69 g, white solid, molar yield 91.2%). 1H NMR (600 MHz, CDC13) δ 8.17 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 5.04 - 4.99 (m, 1H), 4.17 - 4.12 (m, 2H), 4.04 (t, J = 3.0 Hz, 1H), 2.40 - 2.35 (m, 1H), 2.27 - 2.22 (m, 1H), 2.06 - 1.99 (m, 1H), 1.93 - 1.83 (m, 6H), 1.75 - 1.69 (m, 2H), 1.66 - 1.56 (m, 6H), 1.49 - 1.46 (m, 2H), 1.41 - 1.34 (m, 1H), 1.34 - 1.25 (m, 6H), 1.18 - 1.10 (m, 3H), 1.00 (d, J = 6.5 Hz, 3H), 0.98 (s, 3H), 0.72 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.25, 164.93, 134.32, 134.10, 129.97, 125.33, 125.31, 125.28, 75.61, 73.20, 60.23, 48.36, 47.47, 46.54, 41.94, 36.01, 35.04, 34.88, 34.19, 33.77, 32.23, 31.32, 30.90, 28.74, 27.43, 26.97, 26.61, 26.03, 23.59, 23.14, 17.39, 14.26, 12.76.

[0404] (9) Preparation of compound of formula (12-9)

[0405]

[0406] A flask was charged with compound of formula (11-9) (2.91 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. At 0 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution (10 mL, 10 mmol) was added dropwise, and stirring was continued for 15 h. After TLC monitoring showed that the starting material was completely consumed, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, and the organic phase was washed with water and saturated sodium chloride successively. The organic phase was concentrated under reduced pressure and purified by column chromatography to give compound of formula (12-9) (2.56 g, white solid, molar yield 88%). 1HNMR (600 MHz, CDC13) δ 7.85 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 8.5 Hz, 2H), 4.97 - 4.92 (m, 1H), 4.20 - 4.10 (m, 2H), 4.02 (t, J = 3.0 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 2.40 - 2.35 (m, 1H), 2.27 - 2.22 (m, 1H), 1.98 (q, J = 12.5 Hz, 1H), 1.92 - 1.81 (m, 5H), 1.71 (t, J = 10.2 Hz, 2H), 1.65 - 1.54 (m, 4H), 1.49 - 1.33 (m, 5H), 1.34 - 1.25 (m, 7H), 1.19 - 1.09 (m, 3H), 1.00 (d, J = 6.4 Hz, 3H), 0.96 (s, 3H), 0.71 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.30, 165.07, 164.01, 161.34, 133.60, 113.11, 104.39, 99.02, 74.20, 73.23, 60.23, 55.98, 55.48, 48.33, 47.42, 46.52, 41.98, 36.04, 35.07, 35.01, 34.23, 33.73, 32.36, 31.35, 30.91, 29.71, 28.75, 27.44, 27.03, 26.71, 26.07, 23.62, 23.17, 17.36, 14.27, 12.75.

[0407] (10) Preparation of compound of formula (12-10)

[0408]

[0409] A flask was charged with compound of formula (11-10) (2.76 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. At 0 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride tetrahydrofuran solution (7.5 mL, 7.5 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitoring showed that the starting material was completely consumed, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, and the organic phase was washed with water and saturated sodium chloride successively, concentrated under reduced pressure, and purified by column chromatography to give compound of formula (12-10) (2.41 g, white solid, molar yield 87.3%). 1HNMR (600 MHz, CDC13) δ 7.79-7.75 (m, 1H), 7.49-7.43 (m, 1H), 7.00-6.95 (m, 2H), 4.99-4.96 (m, 1H), 4.15-4.11 (m, 2H), 4.00 (t, J = 3.0 Hz, 1H), 3.90 (s, 3H), 2.39-2.34 (m, 1H), 2.26-2.20 (m, 1H), 2.03-1.95 (m, 1H), 1.90-1.79 (m, 6H), 1.71 (dd, J = 11.6, 7.6 Hz, 2H), 1.62-1.53 (m, 6H), 1.47-1.41 (m, 3H), 1.39-1.34 (m, 1H), 1.32-1.24 (m, 5H), 1.19-1.07 (m, 3H), 0.99 (d, J = 6.4 Hz, 3H), 0.96 (s, 3H), 0.70 (s, 3H). 13 CNMR (150 MHz, CDC13) δ 174.28, 165.75, 159.01, 133.14, 131.33, 120.93, 120.08, 112.02, 74.69, 73.15, 60.21, 55.99, 48.28, 47.37, 46.50, 41.98, 36.03, 35.07, 34.98, 34.21, 33.70, 32.27, 31.33, 30.90, 28.74, 27.44, 27.02, 26.63, 26.06, 23.62, 23.15, 17.34, 14.27, 12.75.

[0410] (11) Preparation of compound of formula (12-11)

[0411]

[0412] A flask was charged with compound of formula (11-11) (2.61 g, 5 mmol), tetrahydrofuran (25 mL), and stirred to dissolve. At 0 °C, 1 mol / L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran (10 mL, 10 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitoring showed that the starting material was consumed, the reaction was stopped. The reaction was quenched by dropwise addition of 1 mol / L hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, separated, and the organic phase was washed with water and saturated sodium chloride successively. The organic phase was concentrated under reduced pressure and purified by column chromatography to give compound of formula (12-11) (2.37 g, white solid, molar yield 90.4%). 1H NMR (600 MHz, CDC13) δ 8.07 (d, J = 7.7 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.02 - 4.98 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 4.04 (d, J = 2.9 Hz, 1H), 2.41 - 2.36 (m, 1H), 2.27 - 2.22 (m, 1H), 2.03 (q, J = 12.5 Hz, 1H), 1.96 - 1.80 (m, 6H), 1.76 - 1.68 (m, 2H), 1.66 - 1.56 (m, 6H), 1.50 - 1.43 (m, 3H), 1.41 - 1.36 (m, 1H), 1.34 - 1.25 (m, 5H), 1.22 - 1.09 (m, 3H), 1.03 - 0.91 (m, 6H), 0.72 (s, 3H). 13 C NMR (150 MHz, CDC13) δ 174.28, 166.06, 132.70, 130.89, 129.57, 128.26, 74.86, 73.23, 60.23, 48.36, 47.46, 46.54, 41.95, 36.03, 35.06, 34.94, 34.21, 33.76, 32.31, 31.34, 30.91, 28.76, 27.44, 27.00, 26.68, 26.05, 23.61, 23.17, 17.39, 14.27, 12.77.

[0413] Example Thirteen Preparation of Deoxycholic Acid

[0414] (1) Preparation of Deoxycholic Acid from Compound of Formula (12-1)

[0415]

[0416] A flask was charged with compound of formula (12-1) (2.24 g, 5 mmol), tetrahydrofuran (10 mL) and methanol (10 mL), stirred to dissolve, added LiOH.H2O (0.42 g, 10 mmol), stirred at 25 °C for 12 h. TLC monitored the reaction was completed, concentrated under reduced pressure, added water solution, dropwise added 1 mol / L hydrochloric acid to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried to obtain deoxycholic acid (1.85 g, white solid, molar yield 94.4%). 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 4.47 (d, J = 4.3 Hz, 1H), 4.22 (d, J = 4.1 Hz, 1H), 3.81 (d, J = 3.5 Hz, 1H), 3.39 (s, 1H), 2.28 - 2.21 (m, 1H), 2.15 - 2.08 (m, 1H), 1.85 - 1.74 (m, 4H), 1.70 - 1.60 (m, 3H), 1.59 - 1.46 (m, 3H), 1.41 - 1.28 (m, 8H), 1.25 - 1.18 (m, 3H), 1.09 - 0.99 (m, 2H), 0.93 (d, J = 6.5 Hz, 3H), 0.93 - 0.89 (m, 1H), 0.87 (s, 3H), 0.62 (s, 3H). 13 C NMR (125 MHz, DMSO-d6) δ 175.38, 71.46, 70.41, 47.91, 46.62, 46.46, 42.08, 36.76, 36.12, 35.62, 35.44, 34.27, 33.38, 31.29, 31.21, 30.70, 29.06, 27.65, 27.45, 26.57, 23.97, 23.54, 17.37, 12.89.

[0417] (2) Preparation of deoxycholic acid from compound of formula (12-2)

[0418]

[0419] A flask was charged with compound of formula (12-2) (2.7 g, 5 mmol), methanol (20 mL), stirred to dissolve, sodium hydroxide (0.60 g, 15 mmol) was added, stirred at 25 °C for 16 h. After TLC monitoring reaction was completed, concentrated under reduced pressure, added water to dissolve, added 1 mol / L hydrochloric acid dropwise to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried, purified by column chromatography to obtain deoxycholic acid (1.86 g, white solid, molar yield 94.9%).

[0420] (3) Preparation of deoxycholic acid from compound of formula (12-3)

[0421]

[0422] A flask was charged with compound of formula (12-3) (2.77 g, 5 mmol), tetrahydrofuran (10 mL) and methanol (10 mL), stirred to dissolve, added LiOH.H2O (0.42 g, 10 mmol), stirred at 25 °C for 12 h. TLC monitored the reaction was completed, concentrated under reduced pressure, added water to dissolve, added 1 mol / L hydrochloric acid dropwise to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried, purified by column chromatography to obtain deoxycholic acid (1.88 g, white solid, molar yield 95.9%).

[0423] (4) Preparation of deoxycholic acid from compound of formula (12-4)

[0424]

[0425] A flask was charged with compound of formula (12-4) (2.55 g, 5 mmol), dichloromethane (10 mL) and methanol (10 mL), stirred to dissolve, added LiOH.H2O (0.42 g, 10 mmol), stirred at 45 °C for 8 h. TLC monitored the reaction was completed, concentrated under reduced pressure, added water to dissolve, added 1 mol / L hydrochloric acid dropwise to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried, purified by column chromatography to obtain deoxycholic acid (1.86 g, white solid, molar yield 94.9%).

[0426] (5) Preparation of deoxycholic acid from compound of formula (12-5)

[0427]

[0428] A flask was charged with compound of formula (12-5) (2.89 g, 5 mmol), tetrahydrofuran (10 mL) and methanol (15 mL), stirred to dissolve, added LiOH.H2O (0.42 g, 10 mmol), stirred at 25 °C for 12 h. TLC monitored the reaction was completed, concentrated under reduced pressure, added water to dissolve, added 1 mol / L hydrochloric acid dropwise to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried, purified by column chromatography to obtain deoxycholic acid (1.87 g, white solid, molar yield 95.4%).

[0429] (6) Preparation of deoxycholic acid from compound of formula (12-6)

[0430]

[0431] A flask was charged with compound of formula (12-6) (2.86 g, 5 mmol), tetrahydrofuran (15 mL) and methanol (15 mL), stirred to dissolve, added LiOH.H2O (0.63 g, 15 mmol), stirred at 25 °C for 12 h. TLC monitored the reaction was completed, concentrated under reduced pressure, added water to dissolve, added 1 mol / L hydrochloric acid dropwise to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried, purified by column chromatography to obtain deoxycholic acid (1.84 g, white solid, molar yield 93.8%).

[0432] (7) Preparation of deoxycholic acid from compound of formula (12-7)

[0433]

[0434] A flask was charged with compound of formula (12-7) (2.71 g, 5 mmol), 2-methyltetrahydrofuran (10 mL) and methanol (15 mL), stirred to dissolve, added KOH (0.56 g, 10 mmol), stirred at 25 °C for 12 h. TLC monitored the reaction was completed, concentrated under reduced pressure, added water to dissolve, added 1 mol / L hydrochloric acid dropwise to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried, purified by column chromatography to obtain deoxycholic acid (1.86 g, white solid, molar yield 94.9%).

[0435] (8) Preparation of deoxycholic acid from compound of formula (12-8)

[0436]

[0437] A flask was charged with compound of formula (12-8) (2.96 g, 5 mmol), tetrahydrofuran (10 mL) and methanol (15 mL), stirred to dissolve, added LiOH.H2O (0.42 g, 10 mmol), stirred at 25 °C for 12 h. TLC monitored the reaction was completed, concentrated under reduced pressure, added water to dissolve, added 1 mol / L hydrochloric acid dropwise to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried, purified by column chromatography to obtain deoxycholic acid (1.86 g, white solid, molar yield 94.9%).

[0438] (9) Preparation of deoxycholic acid from compound of formula (12-9)

[0439]

[0440] A flask was charged with compound of formula (12-9) (2.92 g, 5 mmol), tetrahydrofuran (15 mL) and methanol (15 mL), stirred to dissolve, added LiOH.H2O (0.63 g, 15 mmol), stirred at 25 °C for 12 h. After TLC monitoring reaction was completed, concentrated under reduced pressure, added water to dissolve, added 1 mol / L hydrochloric acid dropwise to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried, purified by column chromatography to obtain deoxycholic acid (1.80 g, white solid, molar yield 91.8%).

[0441] (10) Preparation of deoxycholic acid from compound of formula (12-10)

[0442]

[0443] A flask was charged with compound of formula (12-10) (2.77 g, 5 mmol), dichloromethane (10 mL) and methanol (15 mL), stirred to dissolve, added LiOH.H2O (0.42 g, 10 mmol), stirred at 25 °C for 12 h. After TLC monitoring reaction was completed, concentrated under reduced pressure, added water to dissolve, added 1 mol / L hydrochloric acid dropwise to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried, purified by column chromatography to obtain deoxycholic acid (1.82 g, white solid, molar yield 92.8%).

[0444] (11) Preparation of deoxycholic acid from compound of formula (12-11)

[0445]

[0446] A flask was charged with compound of formula (12-11) (2.62 g, 5 mmol), dichloromethane (10 mL) and methanol (15 mL), stirred to dissolve, added potassium hydroxide (0.56 g, 10 mmol), stirred at 25 °C for 12 h. After TLC monitoring reaction was completed, concentrated under reduced pressure, added water to dissolve, added 1 mol / L hydrochloric acid dropwise to adjust pH to 3-4, a large amount of white solid precipitated, suction filtered, dried, purified by column chromatography to obtain deoxycholic acid (1.85 g, white solid, molar yield 94.4%).

[0447] Comparative Example One

[0448] Patent route and method: (WO 2012 / 021133)

[0449]

[0450] This patent takes compound of formula (7-1) as raw material (3-hydroxyl is protected by acetyl), acetic acid as solvent, and CrO3 as oxidant. The reaction is carried out at 60 °C for 36 h. The raw material is completely converted, and the literature reaction yield is 60.5%.

[0451] The oxidation reaction of compound of formula (7-1) was attempted according to the experimental method provided in the above patent (WO 2012 / 021133): using compound of formula (7-1) as raw material, acetic acid as solvent, under the action of CrO3, 60℃ for 24h, there was still a small amount of raw material left, the reaction time was extended to 36h, the raw material was basically completely converted, column chromatography separation, the molar yield of the obtained oxidation product compound of formula (8-1) was low, only 58%, and the reaction result was basically consistent with the literature.

[0452] The present application found through multiple experiments that the 3-acetyl group of compound of formula (7-1) was replaced with p-methoxybenzoyl, that is, p-methoxybenzoyl chloride was reacted with the 3-hydroxy group of compound of formula (5-1) to obtain compound of formula (7-2), which was subjected to oxidation reaction in acetic acid solvent under the action of CrO3, 35℃ for 12h, the raw material was completely converted, and the product yield could reach 92.3% (see Example Ten-(3)), and the reaction temperature was low, the reaction time was short, which was more conducive to industrial production. The present application shows through multiple experiments that the selection of the 3-hydroxy protecting group has an important influence on the oxidation reaction of the C ring; when the 3-hydroxy protecting group is selected as an aromatic acyl group, compared with the 3-hydroxy protecting group selected as an alkanoyl group such as acetyl group in the patent route (WO 2012 / 021133), the 3-aromatic acyl protecting group is more conducive to the oxidation reaction of the double bond at the α position of the C ring, and the yield is higher and the time is shorter.

[0453] Comparative Example Two

[0454] Patent route and method: (CN 106146593 B)

[0455]

[0456] The patent uses compound of formula (7-4) as raw material (3-hydroxy is protected with benzoyl), acetonitrile as solvent, and undergoes oxidation reaction under the action of cuprous iodide and tert-butyl hydroperoxide TBHP, 50℃ for 24h, the raw material is completely converted, to obtain a mixture of compound of formula (8-4) and compound of formula (15-4); then the mixture is oxidized with PCC, compound of formula (15-4) is converted into compound of formula (8-4), and finally the molar yield of compound of formula (8-4) is 71%.

[0457] The oxidation reaction of compound of formula (7-4) was attempted according to the experimental method provided in the above reference: using compound of formula (7-4) as raw material, acetonitrile as solvent, adding cuprous iodide and TBHP according to the amount in the patent, and reacting at 50 DEG C for 24 h, the raw material was basically completely converted; after post-treatment, PCC was added to the mixture again, and stirred at 25 DEG C for 4 h, compound of formula (15-4) was basically completely converted into compound of formula (8-4), and after post-treatment and column chromatography purification, the molar yield of compound of formula (8-4) obtained was 65%, which was basically consistent with the literature. It is shown that although the patent (CN 106146593 B) selects a similar benzoyl group to protect the hydroxyl group at position 3, the oxidation method is different from the present application, the oxidation reaction yield described in the patent is low, the reaction time is long, and the reaction is actually a two-step operation, which is relatively cumbersome and is not conducive to industrial production.

[0458] In the present application, compound of formula (7-4) is used as raw material, acetic acid is used as solvent, and oxidation reaction occurs under the action of CrO3, and the raw material is completely converted after reacting at 35 DEG C for 12 h, and the molar yield of the product can reach 87% (see Example Ten-(6)); in addition, when the substituent of the hydroxyl group at position 3 in ring A is p-methoxybenzoyl, the molar yield of the oxidation reaction can reach more than 92% (see Example Nine-(3)). The oxidation method found through repeated experiments in the present application has higher efficiency of oxidizing agent, high yield, simple operation, short reaction time, and is more conducive to industrial production.

[0459] Comparative Example Three

[0460] Literature route and method: (Journal of the American Chemical Society, 1977, 99 (23), 7686-7695)

[0461]

[0462] This document takes the compound of formula (1) as raw material, ethyl acetate as solvent, under the action of 10% Pd / C-H2(1 atm), 30℃ reaction, purification by column chromatography, to obtain the compound of formula (2) with a molar yield of 75.8%. We tried the method of this document, with the compound of formula (10-1) as raw material, 10% Pd / C as catalyst, hydrogenation reduction reaction at 30℃ for 24h, no target compound of formula (14-1) was detected in the reaction solution. In subsequent experiments, we increased the reaction temperature and hydrogen pressure, and tried to hydrogenate and reduce the C ring carbonyl and double bond with Raney Ni-H2 or 10% Pd / C-H2, and the main product in the obtained reaction solution was the compound of formula (13) (including compounds of formula (13-1) and formula (13-2)), and a small amount of compound of formula (14) (including compounds of formula (14-1) and formula (14-2)); and the four compounds are difficult to separate and purify due to their similar polarity. Experiments show that the strategy of directly hydrogenating and reducing the C ring carbonyl and double bond with the compound of formula (10-1) as raw material without protecting the 3-hydroxyl group is not feasible.

[0463] After protecting the 3-hydroxyl group, hydrogenating and reducing the C ring carbonyl and double bond, and then oxidizing, the yield of the obtained target compound is high and easy to separate and purify through multiple experiments. For example, taking the compound of formula (8-2) (i.e. the compound of formula (8-2) is obtained by reacting p-methoxybenzoyl chloride with the 3-hydroxyl group of the compound of formula (10-1)) as raw material, 1,4-dioxane as solvent, under the action of 10% Pd / C-H2 at 110℃ for 24h, the reaction solution is oxidized by PCC to obtain the product of hydrogenation reduction of the C ring double bond, the molar yield of the compound of formula (11-2) can reach 90.1% (see Example XI-(2)).

[0464]

[0465] Specific experimental steps:

[0466] In the reaction kettle, add the compound of formula (10-1) (402mg, 1mmol), 1,4-dioxane (8mL) and 10% Pd / C (126mg, 30% w.t.), carry out nitrogen replacement and hydrogen replacement in turn, maintain the system pressure at 4MPa, heat the reaction system to 110℃, stir for 24h, stop the reaction after HPLC monitoring that the raw material is completely reacted. Filter to recover Pd / C, concentrate the filtrate under reduced pressure, and purify by column chromatography to obtain the compound of formula (13) (including compounds of formula (13-1) and formula (13-2)) and the compound of formula (14) (including compounds of formula (14-1) and formula (14-2)). 1 HNMR judgment, the ratio of the compound of formula (13) (including compounds of formula (13-1) and formula (13-2)) and the compound of formula (14) (including compounds of formula (14-1) and formula (14-2)) in the product is about 4:1.

[0467] Into a reactor, a compound of formula (10-1) (402 mg, 1 mmol), 1,4-dioxane (8 mL) and Raney Ni (1 g) were added, nitrogen and hydrogen were replaced in sequence, the system pressure was maintained at 4 MPa, the reaction system was heated to 110°C, stirred for 24 h, after HPLC monitoring that the raw material was completely reacted, the reaction was stopped. Pd / C was recovered by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate=1:1) to obtain a compound of formula (10-2) (300 mg, 1 mmol). 1 HNMR determination showed that the ratio of the compound of formula (13) (including compounds of formula (13-1) and formula (13-2)) and the compound of formula (14) (including compounds of formula (14-1) and formula (14-2)) in the product was about 9:1.

[0468] This experiment shows that the strategy of directly hydrogenating and reducing the C ring carbonyl and double bond with the compound of formula (10-1) as the raw material is not feasible, and it is difficult to obtain methyl deoxycholate. Therefore, the acetyl, p-methoxybenzoyl and other protecting groups are used to protect the hydroxyl group of the A ring, and then the hydrogenation and reduction of the carbonyl and double bond of the C ring are attempted. After screening different 3-hydroxyl substituents, catalysts, solvents, temperatures and hydrogen pressures, the target compound is finally obtained in a high yield.

[0469] The protection scope of the present application is not limited to the above examples. Changes and advantages that can be thought of by those skilled in the art without departing from the spirit and scope of the present application are included in the present application, and are protected by the appended claims.

Claims

1. A method for synthesizing deoxycholic acid using plant-derived 9,21-dihydroxy-20-methyl-pregna-4-ene-3-one 9-OH-BA as a raw material, characterized by, The reaction process of the method is shown in route (A): The synthesis routes are as follows: wherein the A-D rings in the compound 1 are labeled as: wherein R is selected from the group consisting of C1-C10 linear and branched alkyl; R1is selected from the group consisting of C1-C10 linear alkyl, C1-C10 branched alkyl, phenyl p-methoxyphenyl o-methoxyphenyl 2,4-dimethoxyphenyl p-trifluoromethylphenyl The reaction steps in the method are as follows: Step a, in a first solvent, the compound of formula 1 is subjected to side chain oxidation reaction to obtain a compound of formula 2; Step b, in a second solvent, the compound of formula 2 is subjected to Wittig or Wittig-Horner reaction to obtain a compound of formula 3; Step c, in a third solvent, the compound of formula 3 is subjected to dehydration reaction to obtain a compound of formula 4; Step d, in a fourth solvent, the compound of formula 4 is subjected to hydrogenation reduction reaction of A ring double bond, A ring carbonyl and side chain double bond to obtain a compound of formula 5; Step e, in a fifth solvent, the compound of formula 4 is subjected to hydrogenation reduction reaction of A ring double bond and side chain double bond to obtain a compound of formula 6; Step f, in a sixth solvent, the compound of formula 6 is subjected to A ring carbonyl reduction reaction to obtain a compound of formula 5; Step g, in a seventh solvent, the compound of formula 5 is subjected to esterification reaction to obtain a compound of formula 7; Step h, in an eighth solvent, the compound of formula 7 is subjected to C ring oxidation reaction to obtain a compound of formula 8; The C ring oxidation reaction is that the compound of formula 7, N-hydroxyphthalimide NHPI and an oxidizing agent are subjected to C ring oxidation reaction in the eighth solvent to obtain the compound of formula 8; Wherein, the molar ratio of the compound of formula 7, the oxidizing agent and N-hydroxyphthalimide is 1:(1-5):(0-5); the oxidizing agent is selected from one or more of Na2Cr2O7, K2Cr2O7, pyridine dichromate PDC, benzoyl peroxide BPO and CrO3; the eighth solvent is selected from one or more of toluene, acetone, water, dichloromethane, N,N-dimethylformamide, ethyl acetate, N-methyl pyrrolidone and acetic acid; the temperature of the C ring oxidation reaction is 0-50℃; the time of the C ring oxidation reaction is 10-48h; Step i, in a ninth solvent, the compound of formula 4 is subjected to C ring oxidation reaction to obtain a compound of formula 9; Step j, in a tenth solvent, the compound of formula 9 is subjected to hydrogenation reduction reaction of A ring double bond, A ring carbonyl and side chain double bond to obtain a compound of formula 10; Step k, in an eleventh solvent, the compound of formula 10 is subjected to esterification reaction to obtain a compound of formula 8; Step l, in a twelfth solvent, the compound of formula 8 is subjected to C ring double bond hydrogenation reduction reaction to obtain a compound of formula 11; The C ring double bond hydrogenation reduction reaction is that the compound of formula 8, a catalyst and H2 are subjected to C ring double bond hydrogenation reduction reaction in the twelfth solvent to obtain the compound of formula 11; Wherein, the mass ratio of the compound of formula 8 and the catalyst is 1:(0.05-2); the catalyst is selected from one or more of Raney nickel, palladium on carbon, platinum oxide and palladium hydroxide; the twelfth solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyltetrahydrofuran, isopropanol, methyl tert-butyl ether, toluene and xylene; the H2 pressure of the double bond hydrogenation reduction reaction is 20-60atm; the temperature of the double bond hydrogenation reduction reaction is 70-120℃; the time of the double bond hydrogenation reduction reaction is 8-72h; Step m, the compound of formula 11 is subjected to a C-ring carbonyl reduction reaction in a thirteenth solvent to obtain a compound of formula 12; Step n, the compound of formula 12 is subjected to a hydrolysis reaction in a fourteenth solvent to obtain a compound of formula 13, i.e. deoxycholic acid; Step o, the compound of formula 3 is subjected to a hydrogenation reduction reaction of the A-ring double bond and the side chain double bond in a fifteenth solvent to obtain a compound of formula 14; Step p, the compound of formula 14 is subjected to a dehydration reaction in a sixteenth solvent to obtain a compound of formula 6.

2. The method of claim 1, wherein, In the step a, the side chain oxidation reaction is: in the first solvent, the compound shown in formula 1 is subjected to an oxidation reaction with 2,2,6,6-tetramethylpiperidine oxide TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and an oxidizing agent to obtain a compound of formula 2; Wherein, the molar ratio of the 9-OH-BA shown in formula 1, TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and the oxidizing agent is 1: (0-1): (0-20): (0-1): (1-5); the oxidizing agent is selected from one or more of N-chlorosuccinimide NCS, N-bromosuccinimide NBS, 2-iodoxybenzoic acid IBX, and pyridine dichromate PDC; the first solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide, and water; the temperature of the side chain oxidation reaction is 0-30℃; the time of the side chain oxidation reaction is 3-8h.

3. The method of claim 1, wherein, In the step b, the Wittig reaction is: the compound of formula 2, methoxycarbonylmethylidene triphenyl phosphonium or ethoxycarbonylmethylidene triphenyl phosphonium or propoxycarbonylmethylidene triphenyl phosphonium is added to the second solvent to undergo a Wittig reaction to obtain a compound of formula 3; Wherein, the molar ratio of the compound of formula 2, methoxycarbonylmethylidene triphenyl phosphonium or ethoxycarbonylmethylidene triphenyl phosphonium or propoxycarbonylmethylidene triphenyl phosphonium is 1: (1-5); the second solvent is selected from one or more of xylene, toluene, benzene, tetrahydrofuran, heptane, and hexane; the temperature of the Wittig reaction is 80-130℃; the time of the Wittig reaction is 2-8h.

4. The method of claim 1, wherein, In the step b, the Wittig-Horner reaction refers to: adding a base, methyl phosphonoacetate diethyl ester or triethyl phosphonoacetate or propyl phosphonoacetate diethyl ester, and the compound of formula 2 into the second solvent to undergo a Wittig-Horner reaction to obtain a compound of formula 3; Wherein, the second solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, hexane, heptane, and xylene; the base is selected from one or more of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, and lithium hydride; the molar ratio of the compound of formula 2, the base, methyl phosphonoacetate diethyl ester or triethyl phosphonoacetate or propyl phosphonoacetate diethyl ester is 1: (1-5): (1-5); the temperature of the Wittig-Horner reaction is 0-30℃; the time of the Wittig-Horner reaction is 2-8h.

5. The method of claim 1, wherein, In step c, the dehydration reaction is that the compound of formula 3, acetic anhydride and acid are subjected to a dehydration reaction in a third solvent to obtain a compound of formula 4. In step c, the dehydration reaction is that the compound of formula 3, acetic anhydride and acid are subjected to a dehydration reaction in a third solvent to obtain a compound of formula 4.

6. The method of claim 1, wherein, In step d, the reduction reaction is specifically that the compound of formula 4, Raney nickel and H2 are subjected to a hydrogenation reduction reaction in a fourth solvent to obtain a compound of formula 5. In step d, the reduction reaction is specifically that the compound of formula 4, Raney nickel and H2 are subjected to a hydrogenation reduction reaction in a fourth solvent to obtain a compound of formula 5.

7. The method of claim 1, wherein, In step e, the reduction reaction is specifically that the compound of formula 4, under the action of Pd / C and a base, is subjected to a hydrogenation reduction reaction with H2 in a fifth solvent to obtain a compound of formula 6. In step e, the reduction reaction is specifically that the compound of formula 4, under the action of Pd / C and a base, is subjected to a hydrogenation reduction reaction with H2 in a fifth solvent to obtain a compound of formula 6.

8. The method of claim 1, wherein, In step f, the A ring carbonyl reduction reaction is specifically that the compound of formula 6, cerium chloride heptahydrate and a reducing agent are added in a sixth solvent to obtain a compound of formula 5. In step f, the A ring carbonyl reduction reaction is specifically that the compound of formula 6, cerium chloride heptahydrate and a reducing agent are added in a sixth solvent to obtain a compound of formula 5.

9. The method of claim 1, wherein, In step g, the esterification reaction is that the compound of formula 5 and a hydroxyl protection reagent are subjected to an esterification reaction in a seventh solvent under the action of a base to obtain a compound of formula 7. The seventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran; the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine DMAP; the molar ratio of the compound of formula 5, the hydroxyl protection reagent, and the base is 1:(1-4):(0.05-5); the temperature of the esterification reaction is 0-50 DEG C; and the time of the esterification reaction is 2-24 h.

10. The method of claim 1, wherein, In the step i, the C ring oxidation reaction is that the compound of formula 4, N-hydroxyphthalimide NHPI, and an oxidizing agent are subjected to an oxidation reaction in a ninth solvent to obtain a compound of formula 9. The molar ratio of the compound of formula 4, the oxidizing agent, and N-hydroxyphthalimide NHPI is 1:(1-10):(0-5); the oxidizing agent is selected from one or more of Na2Cr2O7, K2Cr2O7, pyridine dichromate PDC, benzoyl peroxide BPO, and CrO3; the ninth solvent is selected from one or more of toluene, acetone, water, dichloromethane, N,N-dimethylformamide, ethyl acetate, N-methylpyrrolidone, and acetic acid; the temperature of the C ring oxidation reaction is 0-50 DEG C; and the time of the C ring oxidation reaction is 10-48 h.

11. The method of claim 1, wherein, In the step j, the reduction reaction is that the compound of formula 9, Raney nickel, and H2 are subjected to a hydrogenation reduction reaction in a tenth solvent to obtain a compound of formula 10. The mass ratio of the compound of formula 9 and Raney nickel is 1:(0.05-2); the tenth solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyltetrahydrofuran, isopropanol, methyl tert-butyl ether, and toluene; the H2 pressure is 1-60 atm; the reaction temperature is 20-120 DEG C; and the reaction time is 1-12 h.

12. The method of claim 1, wherein, In the step k, the esterification reaction is that the compound of formula 10 and a hydroxyl protection reagent are dissolved in an eleventh solvent, and an esterification reaction occurs under the action of a base to obtain a compound of formula 8. The eleventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran; the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, and 4-dimethylaminopyridine DMAP; the molar ratio of the compound of formula 8, the hydroxyl protection reagent, and the base is 1:(1-4):(0.05-5); the temperature of the esterification reaction is 0-50 DEG C; and the time of the esterification reaction is 2-24 h.

13. The method of claim 1, wherein, In the step m, the C ring carbonyl reduction reaction is that the compound of formula 11 is subjected to a C ring carbonyl reduction reaction in a thirteenth solvent by adding a reducing agent to obtain a compound of formula 12. The molar ratio of the compound of formula 11 to the reducing agent is 1:(1-5); the thirteenth solvent is selected from one or more of ethanol, methanol, ethyl acetate, dichloromethane, and tetrahydrofuran; the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, and lithium tri-t-butoxyhydroborate; the temperature of the C-ring carbonyl reduction reaction is -10-30°C; and the C-ring carbonyl reduction reaction time is 0.5-24 hours.

14. The method of claim 1, wherein, In step n, the hydrolysis reaction is that the compound of formula 12 is subjected to a hydrolysis reaction in the presence of a base in the fourteenth solvent to obtain deoxycholic acid. The molar ratio of the compound of formula 12 to the base is 1:(1-5); the fourteenth solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropanol, t-butanol, methanol, ethanol, dichloromethane, and water; the base is selected from one or more of sodium t-butoxide, potassium t-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, and lithium hydroxide monohydrate; the temperature of the hydrolysis reaction is 20-80°C; and the hydrolysis reaction time is 3-24 hours.

15. The method of claim 1, wherein, In step o, the reduction reaction is that the compound of formula 3 is subjected to a hydrogenation reduction reaction in the presence of Pd / C, a base, and hydrogen in the fifteenth solvent to obtain a compound of formula 14. The molar ratio of the compound of formula 3 to the base is 1:(0-5); the mass ratio of the compound of formula 3 to Pd / C is 1:(0.02-0.3); the fifteenth solvent is selected from one or more of methanol, ethanol, propanol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, and N,N-dimethylformamide; the base is selected from one or more of sodium carbonate, sodium bicarbonate, aqueous ammonia, 4-methoxy pyridine, pyridine, and 4-dimethylamino pyridine; the H2 pressure is 1-40 atm; the reaction temperature is 0-40°C; and the reaction time is 1-48 hours.

16. The method of claim 1, wherein, In step p, the dehydration reaction is that the compound of formula 14, acetic anhydride, and an acid are subjected to a dehydration reaction in the presence of the sixteenth solvent to obtain a compound of formula 6. The molar ratio of the compound of formula 14 to acetic anhydride to the acid is 1:(0-8):(0.01-4); the acid is selected from one or more of p-methylbenzenesulfonic acid, sulfuric acid, and boron trifluoride-acetic acid complex; the sixteenth solvent is selected from one or more of dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane, and water; the temperature of the dehydration reaction is -40°C-80°C; and the dehydration reaction time is 0.5-10 hours.

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