WO2023207268A1 - Synthesis method of plant-derived deoxycholic acid - Google Patents

Synthesis method of plant-derived deoxycholic acid Download PDF

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WO2023207268A1
WO2023207268A1 PCT/CN2023/076722 CN2023076722W WO2023207268A1 WO 2023207268 A1 WO2023207268 A1 WO 2023207268A1 CN 2023076722 W CN2023076722 W CN 2023076722W WO 2023207268 A1 WO2023207268 A1 WO 2023207268A1
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formula
compound
reaction
solvent
ring
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PCT/CN2023/076722
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French (fr)
Chinese (zh)
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李晨晨
仇文卫
李洁
闻欣怡
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上海科骊科生物技术有限公司
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Publication of WO2023207268A1 publication Critical patent/WO2023207268A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C07J7/009—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by only one oxygen atom doubly bound
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • the invention belongs to the technical field of organic chemical synthesis and relates to a method for synthesizing deoxycholic acid using plant source 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA as raw material.
  • Deoxycholic acid is a free bile acid derived from cholic acid that loses an oxygen atom. It is a naturally occurring substance in the human body. It can clinically promote bile secretion and help break down fat.
  • Commercial deoxycholic acid is mainly used for: 1. Biochemical, bacteriological and enzymatic research; 2. Lipase accelerator and anion remover; 3. "Double chin" lipolysis injection.
  • deoxycholic acid (trade name Kybella) was approved by the U.S. Food and Drug Administration (FDA) as a drug for injectable lipolysis due to its excellent safety and effectiveness, making it the first of its kind to treat "double chin" The first injectable product approved for cosmetic use.
  • FDA U.S. Food and Drug Administration
  • deoxycholic acid can accurately destroy the cell membrane of adipocytes, lyse the adipocytes, and the outflowing fat is cleared by macrophages; whereas tissue cells such as skin and muscle contain a large amount of protein on their cell membrane surfaces. It will be broken down, thus having the effect of removing "double chin".
  • deoxycholic acid is extracted from the bile of pigs, cattle, sheep or chickens and ducks. Studies have found that animal-derived products are likely to carry animal pathogens or other harmful factors, especially with the rise of mad cow disease (caused by the Nguyen virus) and sheep anthrax.
  • deoxycholic acid (WO 2012/021133 A9) was synthesized with a total molar yield of 4.7% through 17 steps of reaction, as shown in Scheme 1.
  • This route uses the more expensive catalyst PtO 2 , and the price of hydrocortisone raw materials is relatively high, the reaction steps are long, and the overall yield is low, so it is not suitable for industrial production.
  • deoxycholic acid (CN 106146593 B, as shown in Scheme 2) was synthesized through 12 steps of reaction with a total molar yield of 22%.
  • This route generates the 12-position carbonyl group of the C ring through an oxidation reaction.
  • the step needs to be oxidized by TBHP first, and then oxidized by PCC. Only two oxidations can obtain compound (10), and the step of reducing the double bond of the C ring needs to be cycled three times, which is cumbersome and unnecessary. Suitable for industrial production.
  • the object of the present invention is to provide a synthesis method of plant-derived deoxycholic acid.
  • the invention uses plant source 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA as raw material, and undergoes side chain oxidation reaction, Wittig or Wittig-Horner reaction, dehydration reaction, A ring and side chain double bond hydrogenation reduction reaction, esterification reaction, C epoxidation reaction, C ring double bond hydrogenation reduction reaction, C ring carbonyl reduction reaction, hydrolysis reaction steps to synthesize the deoxycholic acid; 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 epoxidation reaction, C ring double bond hydrogenation reduction reaction, C The deoxycholic acid is synthesized through ring carbonyl reduction reaction and hydrolysis reaction
  • the raw material 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA includes but is not limited to It is obtained through biological fermentation of phytosterols or by chemical synthesis.
  • the invention provides a method for synthesizing deoxycholic acid using plant source 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA as raw material.
  • the reaction process of the method includes: Not limited to the four synthesis methods shown in route (A):
  • the synthetic routes are:
  • R is selected from alkyl
  • R 1 is selected from alkyl, aryl, substituted aryl, etc.
  • R is selected from one or more of C1-C10 linear alkyl and branched chain alkyl;
  • R 1 is selected from C1-C10 linear alkyl, C1-C10 branched alkyl, phenyl p-Methoxyphenyl o-Methoxyphenyl 2,4-dimethoxyphenyl p-trifluoromethylphenyl of one or more.
  • R is selected from one or both of methyl and ethyl; R 1 is selected from p-methoxyphenyl
  • the synthesis method of the present invention includes the following steps:
  • Step (a) in the first solvent, the compound of formula (1) undergoes a side chain oxidation reaction to obtain the compound of formula (2);
  • Step (b) in the second solvent, the compound of formula (2) is subjected to Wittig or Wittig-Horner reaction to obtain the compound of formula (3);
  • Step (c) in a third solvent, the compound of formula (3) undergoes a dehydration reaction to obtain the compound of formula (4);
  • Step (d) in the fourth solvent, the compound of formula (4) is subjected to a hydrogenation reduction reaction of the A ring and the side chain double bond to obtain the compound of formula (5);
  • Step (1) in the twelfth solvent, the compound of formula (8) undergoes hydrogenation and reduction reaction of the C ring double bond to obtain the compound of formula (11) compound;
  • Step (m) in the thirteenth solvent, the compound of formula (11) is subjected to the C ring carbonyl reduction reaction to obtain the compound of formula (12);
  • the synthetic method of the present invention includes the following steps:
  • Step (a) in the first solvent, the compound of formula (1) undergoes a side chain oxidation reaction to obtain the compound of formula (2);
  • Step (b) in the second solvent, the compound of formula (2) is subjected to Wittig or Wittig-Horner reaction to obtain the compound of formula (3);
  • Step (c) in a third solvent, the compound of formula (3) undergoes a dehydration reaction to obtain the compound of formula (4);
  • Step (e) in the fifth solvent, the compound of formula (4) is subjected to a hydrogenation reduction reaction of the A ring double bond and the side chain double bond to obtain the compound of formula (6);
  • Step (1) in the twelfth solvent, the compound of formula (8) undergoes hydrogenation and reduction reaction of the C ring double bond to obtain the compound of formula (11);
  • Step (m) in the thirteenth solvent, the compound of formula (11) is subjected to the C ring carbonyl reduction reaction to obtain the compound of formula (12);
  • the synthetic method of the present invention includes the following steps:
  • Step (a) in the first solvent, the compound of formula (1) undergoes a side chain oxidation reaction to obtain the compound of formula (2);
  • Step (b) in the second solvent, the compound of formula (2) is subjected to Wittig or Wittig-Horner reaction to obtain the compound of formula (3);
  • Step (c) in a third solvent, the compound of formula (3) undergoes a dehydration reaction to obtain the compound of formula (4);
  • Step (i) in the ninth solvent, the compound of formula (4) is subjected to C epoxidation reaction to obtain the compound of formula (9);
  • Step (1) in the twelfth solvent, the compound of formula (8) undergoes hydrogenation and reduction reaction of the C ring double bond to obtain the compound of formula (11) compound;
  • Step (m) in the thirteenth solvent, the compound of formula (11) is subjected to the C ring carbonyl reduction reaction to obtain the compound of formula (12);
  • the synthetic method of the present invention includes the following steps:
  • Step (a) in the first solvent, the compound of formula (1) undergoes a side chain oxidation reaction to obtain the compound of formula (2);
  • Step (b) in the second solvent, the compound of formula (2) is subjected to Wittig or Wittig-Horner reaction to obtain the compound of formula (3);
  • Step (1) in the twelfth solvent, the compound of formula (8) undergoes hydrogenation and reduction reaction of the C ring double bond to obtain the compound of formula (11);
  • Step (m) in the thirteenth solvent, the compound of formula (11) is subjected to the C ring carbonyl reduction reaction to obtain the compound of formula (12);
  • step (a) the side chain oxidation reaction is: in the first solvent, the compound of formula (1) and 2,2,6,6-tetramethylpiperidine oxide TEMPO, sodium bicarbonate , tetrabutylammonium bromide and oxidant undergo side chain oxidation reaction to obtain the compound of formula (2).
  • the molar ratio of the compound of formula (1), TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and oxidant is 1: (0 ⁇ 1): (0 ⁇ 20): (0 ⁇ 1): (1 ⁇ 5 ); preferably, it is 1:0.01:1.35:0.1:1.15.
  • the side chain oxidation reaction is carried out under the action of an oxidant, and the oxidant is selected from N-chlorosuccinimide NCS, N-bromosuccinimide NBS, 2-iodoacylbenzoic acid IBX, dichromium One or more of the acid pyridinium salts PDC, etc.; preferably, it is N-chlorosuccinimide NCS.
  • the temperature of the side chain oxidation reaction is 0-30°C; preferably, it is 0°C.
  • the side chain oxidation reaction time is 3 to 8 hours; preferably, it is 6 hours.
  • the synthesis steps of the compound of formula (2) include: dissolving the compound of formula (1) in the first solvent, then adding TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and oxidizing agent to cause side chain oxidation Reaction to obtain the compound of formula (2).
  • step (b) of the present invention the Wittig reaction is specifically: in the second solvent, the compound of formula (2) and methoxyformylmethylenetriphenylphosphine or ethoxyformylmethylenetriphenylphosphine Or propoxyformyl methylene triphenylphosphine undergoes Wittig reaction to obtain the compound of formula (3).
  • the molar ratio of the compound of formula (2), methoxyformylmethylenetriphenylphosphine or ethoxyformylmethylenetriphenylphosphine or propoxyformylmethylenetriphenylphosphine is 1: ( 1 ⁇ 5); preferably, it is 1:1.5.
  • the second solvent is one or more of xylene, toluene, benzene, tetrahydrofuran, heptane, hexane, etc.; preferably, it is toluene.
  • the temperature of the Wittig reaction is 80-130°C; preferably, it is 110°C.
  • the Wittig reaction time is 2 to 8 hours; preferably, it is 4 hours.
  • the synthesis step of the compound of formula (3) includes: dissolving the compound of formula (2) in the second solvent, and then adding methoxyformylmethylenetriphenylphosphine or ethoxyformylmethylene Triphenylphosphine or propoxyformylmethylene triphenylphosphine undergoes Wittig reaction to obtain the compound of formula (3).
  • the Wittig-Horner reaction is specifically: in the second solvent, the compound of formula (2) and a base, diethyl methyl phosphonoacetate or triethyl phosphonoacetate or phosphine
  • the Wittig-Horner reaction occurs with diethyl propyl acylacetate to obtain the compound of formula (3).
  • the molar ratio of the compound of formula (2), base, methyl phosphonoacetate diethyl ester or phosphonoacetate triethyl ester or phosphonoacetate propyl diethyl ester is 1: (1 ⁇ 5): (1 ⁇ 5 ); preferably, it is 1:1.5:1.5.
  • the second solvent is selected from one or more of xylene, toluene, benzene, tetrahydrofuran, heptane, hexane, etc.; preferably, it is tetrahydrofuran.
  • the base is selected from one or more of sodium hydrogen, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, lithium hydride, etc.; preferably, it is sodium hydrogen.
  • the temperature of the Wittig-Horner reaction is 0-30°C; preferably, it is 0°C.
  • the Wittig-Horner reaction time is 2 to 8 hours; preferably, it is 4 hours.
  • the synthesis steps of the compound of formula (3) include: adding a base to the third solvent, stirring, and then adding methyl diethyl phosphonoacetate or triethyl phosphonoacetate or propyl phosphonoacetate.
  • the ester diethyl ester and the compound of formula (2) undergo Wittig-Horner reaction to obtain the compound of formula (3).
  • step (c) of the present invention the dehydration reaction is specifically: in the third solvent, the compound of formula (3) undergoes a dehydration reaction with acetic anhydride and acid to obtain the compound of formula (4).
  • the molar ratio of the compound of formula (3), acetic anhydride, and acid is 1: (0-8): (0.01-4); preferably, it is 1:0:0.9.
  • the acid is selected from one or more of p-toluenesulfonic acid, sulfuric acid, boron trifluoride acetic acid complex, etc.; preferably, it is sulfuric acid.
  • the third solvent is selected from one or more of dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane, water, acetic acid, etc.; preferably, it is dichloromethane.
  • the temperature of the dehydration reaction is -40°C to 80°C; preferably, it is 0°C.
  • the dehydration reaction time is 0.5 to 10 h; preferably, it is 1 h.
  • the synthesis step of the compound of formula (4) includes: dissolving the compound of formula (3) in a third solvent, and then adding acid to cause a dehydration reaction to obtain the compound of formula (4).
  • step (d) of the present invention the hydrogenation reduction of the A ring and side chain double bonds is specifically: in the fourth solvent, the compound of formula (4) undergoes a hydrogenation reduction reaction with Raney nickel and H 2 to obtain formula (5) compound.
  • the mass ratio of the compound of formula (4) to Raney nickel is 1: (0.05-2); preferably, it is 1:1.
  • the fourth solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyltetrahydrofuran, isopropyl alcohol, methyl tert-butyl ether, toluene, etc. ; Preferably, it is tetrahydrofuran.
  • the H 2 pressure of the hydrogenation and reduction reaction of the A ring and side chain double bonds is 1-60 atm; preferably, it is 40 atm.
  • the temperature of the hydrogenation reduction reaction of the A ring and side chain double bonds is 20-120°C; preferably, it is 80°C.
  • the time for the hydrogenation and reduction reaction of the A ring and side chain double bonds is 1 to 12 hours, preferably 3 hours.
  • the synthesis steps of the compound of formula (5) include: dissolving the compound of formula (4) in a fourth solvent, adding Raney nickel, and performing a hydrogenation reduction reaction with H 2 to obtain the compound of formula (5).
  • step (e) of the present invention the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is specifically: in the fifth solvent, the compound of formula (4) and palladium/carbon (Pd/C), alkali, H 2 A hydrogenation reduction reaction occurs to obtain the compound of formula (6).
  • the molar ratio of the compound of formula (4) and the base is 1: (0.01-5); preferably, it is 1:0.05.
  • the mass ratio of the compound of formula (4) and Pd/C is 1: (0.02-0.3); preferably, it is 1:0.05.
  • the base is selected from one or more of sodium carbonate, sodium bicarbonate, ammonia, 4-methoxypyridine, pyridine, 4-dimethylaminopyridine, etc.; preferably, it is pyridine.
  • the H 2 pressure of the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is 1 to 40 atm; preferably, it is 1 atm.
  • the temperature of the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is 0-40°C; preferably, it is 25°C.
  • the hydrogenation and reduction reaction time of the A ring double bond and the side chain double bond is 1 to 48 hours; preferably, it is 12 hours.
  • the synthesis steps of the compound of formula (6) include: dissolving the compound of formula (4) in the fifth solvent, adding palladium carbon, alkali, and H 2 to perform a hydrogenation reduction reaction to obtain the compound of formula (6).
  • step (f) of the present invention the A ring carbonyl reduction reaction is specifically: in the sixth solvent, the A ring carbonyl reduction reaction occurs between the compound of formula (6), cerium trichloride heptahydrate and a reducing agent to obtain formula (5 ) compound.
  • the molar ratio of the compound of formula (6), cerium trichloride heptahydrate, and the reducing agent is 1: (0-2): (1-5); preferably, it is 1:1.1:2.
  • the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium tri-tert-butoxyaluminum hydride, etc.; preferably, it is potassium borohydride.
  • the temperature of the A ring carbonyl reduction reaction is -40 ⁇ 30°C; preferably, it is -10°C.
  • the time for the reduction reaction of the carbonyl group of the A ring is 0.1 to 8 hours; preferably, it is 5 hours.
  • the synthesis steps of the compound of formula (5) include: dissolving the compound of formula (6) in the sixth solvent, adding cerium trichloride heptahydrate and a reducing agent in sequence, and reducing the A ring carbonyl group to obtain Compounds of formula (5).
  • step (g) of the present invention when the hydroxyl protecting reagent is an acid anhydride, the esterification reaction is specifically: in the seventh solvent, the compound of formula (5) undergoes an esterification reaction with the hydroxyl protecting reagent and a base to obtain formula (7) compound.
  • the seventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; preferably Ground, is methylene chloride.
  • the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine, DMAP, etc.; preferably, it is DMAP.
  • the molar ratio of the compound of formula (5), hydroxyl protecting reagent and base is 1:(1 ⁇ 4):(0.05 ⁇ 5); preferably, it is 1:2:0.2.
  • the temperature of the esterification reaction is 0-50°C; preferably, it is 25°C.
  • the time of the esterification reaction is 2 to 24 hours, preferably 8 hours.
  • step (g) of the present invention when the hydroxyl protecting reagent is an acid chloride, the esterification reaction is specifically: in the seventh solvent, the compound of formula (5) undergoes an esterification reaction with the hydroxyl protecting reagent and a base to obtain formula (7) compound.
  • the seventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; preferably Ground, is methylene chloride.
  • the base is selected from triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine DMAP, etc.
  • the base is selected from triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine DMAP, etc.
  • the molar ratio of the compound of formula (5), hydroxyl protecting reagent, and base is 1:(1-4):(0.05-5); preferably, it is 1:2:2.2.
  • the temperature of the esterification reaction is 0-50°C; preferably, it is 25°C.
  • the time of the esterification reaction is 2 to 24 hours, preferably 8 hours.
  • the synthesis steps of the compound of formula (7) include: dissolving the compound of formula (5) in a seventh solvent, adding a base and a hydroxyl protecting reagent, and performing an esterification reaction to obtain the compound of formula (7).
  • step (h) of the present invention the C epoxidation reaction is specifically: in the eighth solvent, the C epoxidation reaction occurs between the compound of formula (7), N-hydroxyphthalimide NHPI and an oxidant, Compounds of formula (8) are obtained.
  • the eighth solvent is selected from one or more of toluene, acetone, water, methylene chloride, N,N-dimethylformamide, ethyl acetate, N-methylpyrrolidone, acetic acid, etc.; preferably The ground is acetic acid.
  • the molar ratio of the compound of formula (7), oxidizing agent and N-hydroxyphthalimide is 1: (1-5): (0 ⁇ 5); preferably, it is 1:4:0.
  • the oxidizing agent is selected from one or more of Na 2 Cr 2 O 7 , K 2 Cr 2 O 7 , pyridinium dichromate PDC, benzoyl peroxide BPO, CrO 3, etc.; preferably, it is CrO 3 .
  • the temperature of the C epoxidation reaction is 0-50°C; preferably, it is 35°C.
  • the time of the C epoxidation reaction is 10 to 48 hours; preferably, it is 12 hours.
  • the synthesis steps of the compound of formula (8) include: dissolving the compound of formula (7) in the eighth solvent, adding N-hydroxyphthalimide NHPI and an oxidant, and causing C epoxidation Reaction to obtain the compound of formula (8).
  • step (i) of the present invention the C epoxidation reaction is specifically: in the ninth solvent, the compound of formula (4) undergoes a C epoxidation reaction with N-hydroxyphthalimide NHPI and an oxidant, Compounds of formula (9) are obtained.
  • the ninth solvent is selected from one or more of toluene, acetone, water, methylene chloride, N,N-dimethylformamide, ethyl acetate, N-methylpyrrolidone, acetic acid, etc.; preferably Ground is acetone/water.
  • the molar ratio of the compound of formula (4), oxidizing agent and N-hydroxyphthalimide is 1: (1-10): (0 ⁇ 5); preferably, it is 1:3:1.
  • the oxidizing agent is selected from one or more of Na 2 Cr 2 O 7 , K 2 Cr 2 O 7 , pyridinium dichromate PDC, benzoyl peroxide BPO, CrO 3, etc.; preferably, it is PDC.
  • the temperature of the C epoxidation reaction is 0-50°C; preferably, it is 45°C.
  • the time of the C epoxidation reaction is 10 to 48 hours; preferably, it is 12 hours.
  • the synthesis step of the compound of formula (9) includes: dissolving the compound of formula (4) in the ninth solvent In, add N-hydroxyphthalimide and oxidant, C epoxidation reaction occurs, and the compound of formula (9) is obtained.
  • step (j) of the present invention the hydrogenation reduction reaction of the A ring and the side chain double bond is specifically: in the tenth solvent, the compound of formula (9) undergoes a hydrogenation reduction reaction with Raney nickel and H 2 to obtain formula (10 ) compound.
  • the mass ratio of the compound of formula (9) to Raney nickel is 1: (0.05-2); preferably, it is 1:1.
  • the tenth solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyltetrahydrofuran, isopropyl alcohol, methyl tert-butyl ether, toluene, etc. ; Preferably, it is tetrahydrofuran.
  • the H 2 pressure of the hydrogenation and reduction reaction of the A ring and side chain double bonds is 1-60 atm; preferably, it is 40 atm.
  • the temperature of the hydrogenation reduction reaction of the A ring and side chain double bonds is 20-120°C; preferably, it is 90°C.
  • the time for the hydrogenation and reduction reaction of the A ring and side chain double bonds is 1 to 12 hours; preferably, it is 3 hours.
  • the synthesis steps of the compound of formula (10) include: dissolving the compound of formula (9) in the tenth solvent, adding Raney nickel, and performing a hydrogenation reduction reaction under a certain H pressure to obtain the formula (10) Compounds.
  • step (k) of the present invention when the hydroxyl protecting reagent is an acid anhydride, the esterification reaction is specifically: in the eleventh solvent, the compound of formula (10) undergoes an esterification reaction with the hydroxyl protecting reagent and a base to obtain the formula ( 8) Compounds.
  • the eleventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; Preferably, it is methylene chloride.
  • the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine, DMAP, etc.; preferably, it is DMAP.
  • the molar ratio of the compound of formula (10), hydroxyl protecting reagent, and base is 1:(1-4):(0.05-5); preferably, it is 1:2:0.2.
  • the temperature of the reaction is 0-50°C; preferably, it is 25°C.
  • the time of the esterification reaction is 2 to 24 hours, preferably 8 hours.
  • step (k) of the present invention when the hydroxyl protecting reagent is an acid chloride, the esterification reaction is specifically: in the eleventh solvent, the compound of formula (10) undergoes an esterification reaction with the hydroxyl protecting reagent and a base to obtain the formula ( 8) Compounds.
  • the eleventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; Preferably, it is methylene chloride.
  • the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine DMAP, etc.; preferably, it is a mixture of triethylamine and DMAP Base; further preferably, the molar ratio of triethylamine and DMAP is 10/1.
  • the molar ratio of the compound of formula (10), hydroxyl protecting reagent and base is 1:(1 ⁇ 4):(0.05 ⁇ 5); preferably, it is 1:2:2.2.
  • the temperature of the reaction is 0-50°C; preferably, it is 25°C.
  • the time of the esterification reaction is 2 to 24 hours, preferably 8 hours.
  • the synthesis steps of the compound of formula (8) include: dissolving the compound of formula (10) in the eleventh solvent, adding a hydroxyl protecting reagent and a base, and causing an esterification reaction to obtain the compound of formula (8) .
  • step (l) of the present invention the C-ring double bond reduction reaction is specifically: in the twelfth solvent, the C-ring double bond reduction reaction occurs between the compound of formula (8) and the catalyst and H 2 to obtain the compound of formula (11) .
  • the mass ratio of the compound of formula (8) to the catalyst is 1: (0.05-2); preferably, it is 1:0.2.
  • the catalyst is selected from one or more of Raney nickel, palladium on carbon, platinum oxide, and palladium hydroxide; preferably, it is palladium on carbon.
  • the twelfth solvent is selected from tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyltetrahydrofuran, isopropyl alcohol, methyl tert-butyl ether, toluene, xylene, etc.
  • 1,4-dioxane 1,4-dioxane.
  • the H 2 pressure of the C ring double bond reduction reaction is 20-60 atm; preferably, it is 40 atm.
  • the temperature of the C ring double bond reduction reaction is 70-120°C; preferably, it is 110°C.
  • the time of the C ring double bond reduction reaction is 8 to 72 hours; preferably, it is 48 hours.
  • the synthesis steps of the compound of formula (11) include: dissolving the compound of formula (8) in a twelfth solvent, adding a catalyst, and performing a C ring double bond reduction reaction under a certain H 2 pressure to obtain Compound of formula (11).
  • step (m) of the present invention the C ring carbonyl reduction reaction is specifically: in the thirteenth solvent, the C ring carbonyl reduction reaction occurs between the compound of formula (11) and the reducing agent to obtain the compound of formula (12).
  • the molar ratio of the compound of formula (11) to the reducing agent is 1: (1-5); preferably, it is 1:1.5.
  • the thirteenth solvent is selected from one or more of ethanol, methanol, ethyl acetate, methylene chloride, tetrahydrofuran, etc.; preferably, it is tetrahydrofuran.
  • the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium tri-tert-butoxyaluminum hydride, etc.; preferably, it is lithium tri-tert-butoxyaluminum hydride.
  • the temperature of the C ring carbonyl reduction reaction is -10 ⁇ 30°C; preferably, it is 0°C.
  • the time for the C ring carbonyl reduction reaction is 0.5 to 24 hours; preferably, it is 12 hours.
  • the synthesis steps of the compound of formula (12) include: dissolving the compound of formula (11) in the thirteenth solvent, adding a reducing agent in batches, and causing a C ring carbonyl reduction reaction to obtain the compound of formula (12) .
  • step (n) of the present invention the hydrolysis reaction is specifically: in the fourteenth solvent, the compound of formula (12) undergoes a hydrolysis reaction with a base to obtain deoxycholic acid.
  • the molar ratio of the compound of formula (12) and the base is 1: (1-5); preferably, it is 1:2.
  • the base is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium hydroxide monohydrate, etc.; Preferably, it is lithium hydroxide monohydrate.
  • the temperature of the hydrolysis reaction is 20-80°C; preferably, it is 25°C.
  • the hydrolysis reaction time is 3 to 24 hours; preferably, it is 12 hours.
  • the synthesis step of deoxycholic acid includes: dissolving the compound of formula (12) in a fourteenth solvent, adding a base, and causing a hydrolysis reaction to obtain deoxycholic acid.
  • step (o) of the present invention the hydrogenation and 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, in Pd/C, alkali and hydrogen Under the action of , a hydrogenation reduction reaction occurs to obtain the compound of formula (14).
  • the molar ratio of the compound of formula (3) and the base is 1: (0-5); preferably, it is 1:0.01.
  • the mass ratio of the compound of formula (3) and Pd/C is 1: (0.02-0.3); preferably, it is 1:0.05.
  • the fifteenth solvent is selected from one or more of methanol, ethanol, propanol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, N,N-dimethylformamide; preferably, N,N-dimethylformamide.
  • the base is selected from one or more of sodium carbonate, sodium bicarbonate, ammonia, 4-methoxypyridine, pyridine, and 4-dimethylaminopyridine; preferably, it is pyridine.
  • the H 2 pressure of the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is 1 to 40 atm; preferably, it is 4 atm.
  • the temperature of the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is 0-40°C; preferably, it is 25°C.
  • the hydrogenation and reduction reaction time of the A ring double bond and the side chain double bond is 1 to 48 hours; preferably, it is 12 hours.
  • the synthesis steps of the compound of formula (14) include: dissolving the compound of formula (3) in the fifteenth solvent, and performing a hydrogenation reduction reaction under the action of Pd/C, alkali and hydrogen to obtain the formula (14) Compounds.
  • step (p) of the present invention the dehydration reaction is specifically: the compound of formula (14), acetic anhydride, and acid undergo a dehydration reaction in the sixteenth solvent to obtain the compound of formula (6).
  • the molar ratio of the compound of formula (14), acetic anhydride, and acid is 1: (0-8): (0.01-4); preferably, it is 1:0:0.9.
  • the acid is selected from one or more of p-toluenesulfonic acid, sulfuric acid, and boron trifluoride acetic acid complex; preferably, it is sulfuric acid.
  • the sixteenth solvent is selected from one or more of dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane, and water; preferably, it is dichloromethane.
  • the temperature of the dehydration reaction is -40°C to 80°C; preferably, it is 0°C.
  • the dehydration reaction time is 0.5 to 10 h; preferably, it is 1 h.
  • the synthesis steps of the compound of formula (6) include: dissolving the compound of formula (14) in the sixteenth solvent, and dehydration reaction occurs under the action of acetic anhydride and acid to obtain the compound of formula (6) .
  • the present invention also provides new compounds, the structures of which are as follows:
  • the invention also provides preparation and synthesis methods of the above new compounds (2, 3, 4, 6, 7, 8, 9, 11, 12), as well as the new compounds (2, 3, 4, 6, 7, 8, 9, 11, 12) Application in the preparation of deoxycholic acid using 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA as a plant source raw material.
  • the beneficial effects of the present invention include: in the preparation method of plant-derived deoxycholic acid of the present invention, the raw material 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA is of plant origin.
  • the raw materials avoid the risk of pathogenic bacteria and virus infection that may exist in animal-derived raw materials; and the synthesis steps are relatively short, easy to operate, high yield, and few side reactions, which facilitates the industrial production of deoxycholic acid; it solves the existing problems The problem of poor safety of deoxycholic acid products.
  • the structure of the compound was determined with a nuclear magnetic resonance instrument and a high-resolution mass spectrometer; the reagents were mainly provided by Shanghai Sinopharm Chemical Reagent Company; the product was purified mainly through pulping and column chromatography; silica gel (200-300 mesh) was provided by Qingdao Ocean Chemical Plant Production.
  • dichloromethane (8mL), compound of formula (5-1) (500mg, 1.28mmol) to the flask, stir to dissolve, add DMAP (32mg, 0.26mmol), triethylamine (261mg, 2.56mmol) and 4- Trifluoromethylbenzoyl chloride (534 mg, 2.56 mmol) was reacted at 25°C for 8 hours. After TLC monitoring of the reaction was complete, saturated ammonium chloride (1 mL) was added to quench the reaction, and dichloromethane (30 mL) and water (30 mL) were added for extraction.
  • Patented route and method (WO 2012/021133)
  • This patent uses the compound of formula (7-1) as the raw material (the 3-position hydroxyl group is protected by an acetyl group), uses acetic acid as the solvent, and undergoes an oxidation reaction under the action of CrO 3. The reaction is carried out at 60°C for 36 hours. The raw material is completely converted. The literature reaction yield is 60.5%.
  • the present invention has discovered through many experiments that the acetyl group at position 3 of the compound of formula (7-1) is replaced with p-methoxybenzoyl group, that is, p-methoxybenzoyl chloride and the 3-position group of the compound of formula (5-1) are used.
  • the compound of formula (7-2) is obtained by reacting the hydroxyl group at the position.
  • the compound of formula (7-2) undergoes oxidation reaction under the action of CrO 3 in acetic acid solvent. After reaction at 35°C for 12 hours, the raw material is completely converted and the product yield can reach 92.3%. (See Example 10-(3)), and the reaction temperature is low and the reaction time is short, which is more conducive to industrial production.
  • the present invention has shown through many tests that the selection of the 3-position hydroxyl protecting group has an important influence on the oxidation reaction of the C ring; when the 3-position hydroxyl protecting group is an aromatic acyl group, it is consistent with the 3-position hydroxyl protection in the patented route (WO 2012/021133).
  • the aromatic acyl protecting group at the 3-position is more conducive to the oxidation reaction at the ⁇ position of the C-ring double bond, with a higher yield and shorter time.
  • Patented route and method (CN 106146593 B)
  • This patent uses the compound of formula (7-4) as raw material (the 3-position hydroxyl group is protected with benzoyl group), uses acetonitrile as the solvent, and undergoes an oxidation reaction under the action of copper iodide and tert-butyl hydrogen peroxide TBHP at 50°C After reacting for 24 hours, the raw materials were completely converted to obtain a mixture of the compound of formula (8-4) and the formula (15-4); then the mixture was oxidized with PCC, and the compound of formula (15-4) was converted into the compound of formula (8-4). Finally, the molar yield of the compound of formula (8-4) was 71%.
  • the present invention uses the compound of formula (7-4) as the raw material, acetic acid as the solvent, and an oxidation reaction occurs under the action of CrO 3. After the reaction at 35°C for 12 hours, the raw material is completely converted, and the product molar yield can reach 87% (see Example 10- (6)); In addition, when the substituent of the 3-position hydroxyl group in the A ring is p-methoxybenzoyl, the molar yield of the oxidation reaction can reach more than 92% (see Example 9-(3)).
  • the oxidation method discovered through many experiments in the present invention has higher oxidant efficiency, high yield, simple operation, short reaction time, and is more conducive to industrial production.
  • This document uses the compound of formula (1) as the raw material, ethyl acetate as the solvent, reacts at 30°C under the action of 10% Pd/CH 2 (1 atm), and purifies by column chromatography to obtain the formula with a molar yield of 75.8%.
  • (2) Compounds We tried this literature method, using the compound of formula (10-1) as raw material, 10% Pd/C as the catalyst, and hydrogenation reduction reaction at 30°C for 24 hours. The target compound of formula (14-1) was not detected in the reaction solution. In subsequent experiments, we increased the reaction temperature and hydrogen pressure, and tried to use Raney Ni-H 2 or 10% Pd/CH 2 to hydrogenate the C ring carbonyl group and double bond.
  • the main product in the reaction solution was the compound of formula (13) (including the formula (13-1) and formula (13-2) compounds), there are a small amount of formula (14) compounds (including formula (14-1) and formula (14-2) compounds); and these four compounds have similar polarities and are relatively Difficult to isolate and purify.
  • formula (13) including the formula (13-1) and formula (13-2) compounds
  • formula (14) compounds including formula (14-1) and formula (14-2) compounds
  • the present invention protects the 3-position hydroxyl group, hydrogenates and reduces the C ring carbonyl group and double bond, and then oxidizes the target compound to obtain a high yield and easy separation and purification.
  • the compound of formula (8-2) is used as a raw material (that is, 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 a raw material, and 1,4-bis Oxyhexanes were used as solvents, and the reaction was carried out at 110°C for 24 hours under the action of 10% Pd/CH 2.
  • the reaction solution was oxidized by PCC to obtain the compound of formula (11-2), the product of the hydrogenation reduction of the C-ring double bond, with a molar yield of 90.1 % (see Example 11-(2)).
  • the present invention first protects the hydroxyl group of the A ring with acetyl, p-methoxybenzoyl and other protecting groups, and then attempts to hydrogenate and reduce the carbonyl group and double bond of the C ring. After screening different 3-position hydroxyl substituents, catalysts, solvents, temperatures, hydrogen pressure and other conditions, the target compound was finally obtained with a higher yield.

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Abstract

Provided is a synthesis method for deoxycholic acid, which synthesizes deoxycholic acid from plant-derived 9-OH-BA as the starting material by means of steps of side chain oxidation reaction, Wittig or Wittig-Horner reaction, dehydration reaction, hydrogenation reaction, esterification reaction, C epoxidation reaction, carbonyl reduction reaction, hydrolysis reaction, and the like.

Description

一种植物源脱氧胆酸的合成方法A kind of synthesis method of plant-derived deoxycholic acid 技术领域Technical field
本发明属于有机化学合成技术领域，涉及一种以植物源9,21-二羟基-20-甲基孕甾-4-烯-3-酮9-OH-BA为原料合成脱氧胆酸的方法。The invention belongs to the technical field of organic chemical synthesis and relates to a method for synthesizing deoxycholic acid using plant source 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA as raw material.
背景技术Background technique
脱氧胆酸(Deoxycholic acid)是胆酸失去一个氧原子衍生而得的一种游离胆汁酸，是人体内天然存在的一种物质，临床上具有促进胆汁分泌、帮助分解脂肪等作用。商品化的脱氧胆酸主要用于：1、生化、细菌学和酶学研究；2、脂酶加速剂和阴离子去除剂；3、“双下巴”溶脂针。2015年，脱氧胆酸(商品名Kybella)因其出色的安全性和有效性，被美国食品药品管理局(FDA)批准作为用于注射溶脂的药物上市，治疗“双下巴”使其成为同类产品中首个获批用于美容的注射针剂。通过颏下区脂肪组织局部注射，脱氧胆酸能够精准破坏脂肪细胞的细胞膜，使脂肪细胞裂解，流出的脂肪被巨噬细胞清除；而皮肤和肌肉等组织细胞因为细胞膜表面含有大量蛋白质，则不会被裂解，从而起到去除“双下巴”的功效。目前，脱氧胆酸大部分从猪、牛、羊或鸡、鸭胆汁中提取所得，研究发现动物源产品很可能携带动物病原体或其它有害因子，尤其随着疯牛病(阮病毒引起)、羊炭疽病、猪链球菌、禽流感等感染事件的发生，使人们越来越重视药品的安全性。因此，为保证人们的健康和安全，迫切需要研发一种基于植物源原料的脱氧胆酸的合成方法。
Deoxycholic acid is a free bile acid derived from cholic acid that loses an oxygen atom. It is a naturally occurring substance in the human body. It can clinically promote bile secretion and help break down fat. Commercial deoxycholic acid is mainly used for: 1. Biochemical, bacteriological and enzymatic research; 2. Lipase accelerator and anion remover; 3. "Double chin" lipolysis injection. In 2015, deoxycholic acid (trade name Kybella) was approved by the U.S. Food and Drug Administration (FDA) as a drug for injectable lipolysis due to its excellent safety and effectiveness, making it the first of its kind to treat "double chin" The first injectable product approved for cosmetic use. Through local injection of adipose tissue in the submental area, deoxycholic acid can accurately destroy the cell membrane of adipocytes, lyse the adipocytes, and the outflowing fat is cleared by macrophages; whereas tissue cells such as skin and muscle contain a large amount of protein on their cell membrane surfaces. It will be broken down, thus having the effect of removing "double chin". At present, most deoxycholic acid is extracted from the bile of pigs, cattle, sheep or chickens and ducks. Studies have found that animal-derived products are likely to carry animal pathogens or other harmful factors, especially with the rise of mad cow disease (caused by the Nguyen virus) and sheep anthrax. The occurrence of infections such as Streptococcus suis and avian influenza has made people pay more and more attention to the safety of drugs. Therefore, in order to ensure people's health and safety, there is an urgent need to develop a synthesis method of deoxycholic acid based on plant-derived raw materials.
基于植物源原料的脱氧胆酸的化学合成报道主要有以下方法：Reports on the chemical synthesis of deoxycholic acid based on plant-derived raw materials mainly include the following methods:
(1)以氢化可的松为原料，经17步反应，以总摩尔收率4.7％合成了脱氧胆酸(WO 2012/021133 A9)，如Scheme 1所示。该路线使用了较昂贵的催化剂PtO2，并且氢化可的松原料价格相对较高，反应步骤长，总收率低，不适合工业化生产。
(1) Using hydrocortisone as raw material, deoxycholic acid (WO 2012/021133 A9) was synthesized with a total molar yield of 4.7% through 17 steps of reaction, as shown in Scheme 1. This route uses the more expensive catalyst PtO 2 , and the price of hydrocortisone raw materials is relatively high, the reaction steps are long, and the overall yield is low, so it is not suitable for industrial production.
(2)以9α-羟基雄烯二酮9α-OH-4AD为原料，经12步反应，以总摩尔收率22％合成了脱氧胆酸(CN 106146593 B，如Scheme 2所示)。该路线通过氧化反应生成C环12位-羰基步骤需要先经TBHP氧化，然后再经PCC氧化，两次氧化才能得到化合物(10)，并且还原C环双键步骤需要循环三次，操作繁琐，不适合工业化生产。
(2) Using 9α-hydroxyandrostenedione 9α-OH-4AD as raw material, deoxycholic acid (CN 106146593 B, as shown in Scheme 2) was synthesized through 12 steps of reaction with a total molar yield of 22%. This route generates the 12-position carbonyl group of the C ring through an oxidation reaction. The step needs to be oxidized by TBHP first, and then oxidized by PCC. Only two oxidations can obtain compound (10), and the step of reducing the double bond of the C ring needs to be cycled three times, which is cumbersome and unnecessary. Suitable for industrial production.
(3)以谷甾醇、豆甾醇、樟脑甾醇或胆固醇为原料，经Mycobacterium fortuitum发酵所得的化合物(1)为原料，经12步反应，以总摩尔收率12.8％合成了脱氧胆酸(WO 2019/081586  A1，如Scheme 3所示)。该路线总收率偏低，原料不易得，C环氧化反应生成羰基的收率较低，纯化困难，不适合工业化生产。
(3) Using sitosterol, stigmasterol, camphorsterol or cholesterol as raw materials, compound (1) obtained by fermentation of Mycobacterium fortuitum was used as raw material, and deoxycholic acid was synthesized with a total molar yield of 12.8% through 12 steps of reaction (WO 2019 /081586 A1, as shown in Scheme 3). The overall yield of this route is low, raw materials are not easy to obtain, the yield of carbonyl generated by C epoxidation reaction is low, and purification is difficult, so it is not suitable for industrial production.
目前已经报道基于植物源原料的脱氧胆酸化学合成工艺，路线长、原料不易的、原料价格高、反应操作复杂、产品收率低等不足。因此，研发一种基于植物源原料的、更加安全、高效的脱氧胆酸合成方法具有重要的经济价值和社会意义。At present, the chemical synthesis process of deoxycholic acid based on plant-derived raw materials has been reported, which has shortcomings such as long route, difficult raw materials, high raw material prices, complex reaction operations, and low product yield. Therefore, developing a safer and more efficient deoxycholic acid synthesis method based on plant-derived raw materials has important economic value and social significance.
发明内容Contents of the invention
为了解决现有技术存在的不足，本发明的目的是提供一种植物源脱氧胆酸的合成方法。本发明以植物源9,21-二羟基-20-甲基孕甾-4-烯-3-酮9-OH-BA为原料，经侧链氧化反应、Wittig或Wittig-Horner反应、脱水反应、A环及侧链双键氢化还原反应、酯化反应、C环氧化反应、C环双键氢化还原反应、C环羰基还原反应、水解反应步骤合成所述脱氧胆酸；或经侧链氧化反应、Wittig或Wittig-Horner反应、脱水反应、A环双键及侧链双键氢化还原反应、A环羰基还原反应、酯化反应、C环氧化反应、C环双键氢化还原反应、C环羰基还原反应、水解反应步骤合成所述脱氧胆酸；或经侧链氧化反应、Wittig或Wittig-Horner反应、脱水反应、C环氧化反应、A环及侧链双键氢化还原反应、酯化反应、C环双键氢化还原反应、C环羰基还原反应、水解反应步骤合成所述脱氧胆酸；或经侧链氧化反应、Wittig或Wittig-Horner反应、A环双键和侧链双键氢化还原反应、脱水反应、A环羰基还原反应、酯化反应、C环氧化反应、C环双键氢化还原反应、C环羰基还原反应、水解反应步骤合成所述脱氧胆酸。本发明合成脱氧胆酸选择的起始原料安全，合成脱氧胆酸的方法操作简单、收率高、纯度好、环境友好，便于工业化生产。In order to solve the shortcomings of the existing technology, the object of the present invention is to provide a synthesis method of plant-derived deoxycholic acid. The invention uses plant source 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA as raw material, and undergoes side chain oxidation reaction, Wittig or Wittig-Horner reaction, dehydration reaction, A ring and side chain double bond hydrogenation reduction reaction, esterification reaction, C epoxidation reaction, C ring double bond hydrogenation reduction reaction, C ring carbonyl reduction reaction, hydrolysis reaction steps to synthesize the deoxycholic acid; 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 epoxidation reaction, C ring double bond hydrogenation reduction reaction, C The deoxycholic acid is synthesized through ring carbonyl reduction reaction and hydrolysis reaction steps; or through side chain oxidation reaction, Wittig or Wittig-Horner reaction, dehydration reaction, C epoxidation reaction, A ring and side chain double bond hydrogenation reduction reaction, and ester synthesis reaction, C ring double bond hydrogenation reduction reaction, C ring carbonyl reduction reaction, and hydrolysis reaction steps to synthesize the deoxycholic acid; or through side chain oxidation reaction, Wittig or Wittig-Horner reaction, A ring double bond and side chain double bond The deoxycholic acid is synthesized through the steps of hydrogenation reduction reaction, dehydration reaction, A ring carbonyl reduction reaction, esterification reaction, C epoxidation reaction, C ring double bond hydrogenation reduction reaction, C ring carbonyl reduction reaction, and hydrolysis reaction. The starting raw materials selected for synthesizing deoxycholic acid in the present invention are safe, and the method for synthesizing deoxycholic acid is simple to operate, has high yield, good purity, is environmentally friendly, and is convenient for industrial production.
本发明合成方法中，所述原料9,21-二羟基-20-甲基孕甾-4-烯-3-酮9-OH-BA包括但不限 于通过植物甾醇经生物发酵得到，或由化学合成方法得到。In the synthesis method of the present invention, the raw material 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA includes but is not limited to It is obtained through biological fermentation of phytosterols or by chemical synthesis.
本发明提供的以植物源9,21-二羟基-20-甲基孕甾-4-烯-3-酮9-OH-BA为原料合脱氧胆酸的方法，所述方法的反应过程包括但不限于如路线(A)所示的四种合成方法：
The invention provides a method for synthesizing deoxycholic acid using plant source 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA as raw material. The reaction process of the method includes: Not limited to the four synthesis methods shown in route (A):
合成路线分别为：


The synthetic routes are:


其中，R选自烷基，R1选自烷基、芳基、取代的芳基等。Among them, R is selected from alkyl, and R 1 is selected from alkyl, aryl, substituted aryl, etc.
优选地，R选自C1-C10直链烷基及支链烷基中的一种或多种；R1选自C1-C10直链烷基、C1-C10支链烷基、苯基对甲氧基苯基邻甲氧基苯基2,4-二甲氧基苯基对三氟甲基苯基的一种或多种。Preferably, R is selected from one or more of C1-C10 linear alkyl and branched chain alkyl; R 1 is selected from C1-C10 linear alkyl, C1-C10 branched alkyl, phenyl p-Methoxyphenyl o-Methoxyphenyl 2,4-dimethoxyphenyl p-trifluoromethylphenyl of one or more.
进一步优选地，R选自甲基、乙基中的一种或两种；R1选自对甲氧基苯基 Further preferably, R is selected from one or both of methyl and ethyl; R 1 is selected from p-methoxyphenyl
本发明所述合成方法，包括以下步骤：The synthesis method of the present invention includes the following steps:
步骤(a)、在第一溶剂中，式(1)化合物经侧链氧化反应，得到式(2)化合物；Step (a), in the first solvent, the compound of formula (1) undergoes a side chain oxidation reaction to obtain the compound of formula (2);
步骤(b)、在第二溶剂中，式(2)化合物经Wittig或Wittig-Horner反应，得到式(3)化合物；Step (b), in the second solvent, the compound of formula (2) is subjected to Wittig or Wittig-Horner reaction to obtain the compound of formula (3);
步骤(c)、在第三溶剂中，式(3)化合物经脱水反应，得到式(4)化合物；Step (c), in a third solvent, the compound of formula (3) undergoes a dehydration reaction to obtain the compound of formula (4);
步骤(d)、在第四溶剂中，式(4)化合物经A环及侧链双键氢化还原反应，得到式(5)化合物；Step (d), in the fourth solvent, the compound of formula (4) is subjected to a hydrogenation reduction reaction of the A ring and the side chain double bond to obtain the compound of formula (5);
步骤(g)、在第七溶剂中，式(5)化合物经酯化反应，得到式(7)化合物；Step (g): In the seventh solvent, the compound of formula (5) undergoes an esterification reaction to obtain the compound of formula (7);
步骤(h)、在第八溶剂中，式(7)化合物经C环氧化反应，得到式(8)化合物；Step (h): In the eighth solvent, the compound of formula (7) is subjected to C epoxidation reaction to obtain the compound of formula (8);
步骤(l)、在第十二溶剂中，式(8)化合物经C环双键氢化还原反应，得到式(11)化 合物；Step (1), in the twelfth solvent, the compound of formula (8) undergoes hydrogenation and reduction reaction of the C ring double bond to obtain the compound of formula (11) compound;
步骤(m)、在第十三溶剂中，式(11)化合物经C环羰基还原反应，得到式(12)化合物；Step (m), in the thirteenth solvent, the compound of formula (11) is subjected to the C ring carbonyl reduction reaction to obtain the compound of formula (12);
步骤(n)、在第十四溶剂中，式(12)化合物经水解反应，得到式(13)目标产物脱氧胆酸。Step (n): In the fourteenth solvent, the compound of formula (12) undergoes a hydrolysis reaction to obtain the target product deoxycholic acid of formula (13).
或，本发明所述合成方法，包括以下步骤：Or, the synthetic method of the present invention includes the following steps:
步骤(a)、在第一溶剂中，式(1)化合物经侧链氧化反应，得到式(2)化合物；Step (a), in the first solvent, the compound of formula (1) undergoes a side chain oxidation reaction to obtain the compound of formula (2);
步骤(b)、在第二溶剂中，式(2)化合物经Wittig或Wittig-Horner反应，得到式(3)化合物；Step (b), in the second solvent, the compound of formula (2) is subjected to Wittig or Wittig-Horner reaction to obtain the compound of formula (3);
步骤(c)、在第三溶剂中，式(3)化合物经脱水反应，得到式(4)化合物；Step (c), in a third solvent, the compound of formula (3) undergoes a dehydration reaction to obtain the compound of formula (4);
步骤(e)、在第五溶剂中，式(4)化合物经A环双键及侧链双键氢化还原反应，得到式(6)化合物；Step (e), in the fifth solvent, the compound of formula (4) is subjected to a hydrogenation reduction reaction of the A ring double bond and the side chain double bond to obtain the compound of formula (6);
步骤(f)、在第六溶剂中，式(6)化合物经A环羰基还原反应，得到式(5)化合物；Step (f): In the sixth solvent, the compound of formula (6) is subjected to the reduction reaction of the A ring carbonyl group to obtain the compound of formula (5);
步骤(g)、在第七溶剂中，式(5)化合物经酯化反应，得到式(7)化合物；Step (g): In the seventh solvent, the compound of formula (5) undergoes an esterification reaction to obtain the compound of formula (7);
步骤(h)、在第八溶剂中，式(7)化合物经C环氧化反应，得到式(8)化合物；Step (h): In the eighth solvent, the compound of formula (7) is subjected to C epoxidation reaction to obtain the compound of formula (8);
步骤(l)、在第十二溶剂中，式(8)化合物经C环双键氢化还原反应，得到式(11)化合物；Step (1), in the twelfth solvent, the compound of formula (8) undergoes hydrogenation and reduction reaction of the C ring double bond to obtain the compound of formula (11);
步骤(m)、在第十三溶剂中，式(11)化合物经C环羰基还原反应，得到式(12)化合物；Step (m), in the thirteenth solvent, the compound of formula (11) is subjected to the C ring carbonyl reduction reaction to obtain the compound of formula (12);
步骤(n)、在第十四溶剂中，式(12)化合物经水解反应，得到式(13)目标产物脱氧胆酸。Step (n): In the fourteenth solvent, the compound of formula (12) undergoes a hydrolysis reaction to obtain the target product deoxycholic acid of formula (13).
或，本发明所述合成方法，包括以下步骤：Or, the synthetic method of the present invention includes the following steps:
步骤(a)、在第一溶剂中，式(1)化合物经侧链氧化反应，得到式(2)化合物；Step (a), in the first solvent, the compound of formula (1) undergoes a side chain oxidation reaction to obtain the compound of formula (2);
步骤(b)、在第二溶剂中，式(2)化合物经Wittig或Wittig-Horner反应，得到式(3)化合物；Step (b), in the second solvent, the compound of formula (2) is subjected to Wittig or Wittig-Horner reaction to obtain the compound of formula (3);
步骤(c)、在第三溶剂中，式(3)化合物经脱水反应，得到式(4)化合物；Step (c), in a third solvent, the compound of formula (3) undergoes a dehydration reaction to obtain the compound of formula (4);
步骤(i)、在第九溶剂中，式(4)化合物经C环氧化反应，得到式(9)化合物；Step (i), in the ninth solvent, the compound of formula (4) is subjected to C epoxidation reaction to obtain the compound of formula (9);
步骤(j)、在第十溶剂中，式(9)化合物经A环及侧链双键氢化还原反应，得到式(10)化合物；Step (j): In the tenth solvent, the compound of formula (9) is subjected to a hydrogenation reduction reaction of the A ring and the side chain double bond to obtain the compound of formula (10);
步骤(k)、在第十一溶剂中，式(10)化合物经酯化反应，得到式(8)化合物；Step (k): In the eleventh solvent, the compound of formula (10) is subjected to an esterification reaction to obtain the compound of formula (8);
步骤(l)、在第十二溶剂中，式(8)化合物经C环双键氢化还原反应，得到式(11)化 合物；Step (1), in the twelfth solvent, the compound of formula (8) undergoes hydrogenation and reduction reaction of the C ring double bond to obtain the compound of formula (11) compound;
步骤(m)、在第十三溶剂中，式(11)化合物经C环羰基还原反应，得到式(12)化合物；Step (m), in the thirteenth solvent, the compound of formula (11) is subjected to the C ring carbonyl reduction reaction to obtain the compound of formula (12);
步骤(n)、在第十四溶剂中，式(12)化合物经水解反应，得到式(13)目标产物脱氧胆酸。Step (n): In the fourteenth solvent, the compound of formula (12) undergoes a hydrolysis reaction to obtain the target product deoxycholic acid of formula (13).
或，本发明所述合成方法，包括以下步骤：Or, the synthetic method of the present invention includes the following steps:
步骤(a)、在第一溶剂中，式(1)化合物经侧链氧化反应，得到式(2)化合物；Step (a), in the first solvent, the compound of formula (1) undergoes a side chain oxidation reaction to obtain the compound of formula (2);
步骤(b)、在第二溶剂中，式(2)化合物经Wittig或Wittig-Horner反应，得到式(3)化合物；Step (b), in the second solvent, the compound of formula (2) is subjected to Wittig or Wittig-Horner reaction to obtain the compound of formula (3);
步骤(o)、在第十五溶剂中，式(3)化合物经A环双键及侧链双键氢化还原反应，得到式(14)化合物；Step (o): In the fifteenth solvent, the compound of formula (3) is subjected to a hydrogenation reduction reaction of the A ring double bond and the side chain double bond to obtain the compound of formula (14);
步骤(p)、在第十六溶剂中，式(14)化合物经脱水反应，得到式(6)化合物；Step (p): In the sixteenth solvent, the compound of formula (14) undergoes a dehydration reaction to obtain the compound of formula (6);
步骤(f)、在第六溶剂中，式(6)化合物经A环羰基还原反应，得到式(5)化合物；Step (f): In the sixth solvent, the compound of formula (6) is subjected to the reduction reaction of the A ring carbonyl group to obtain the compound of formula (5);
步骤(g)、在第七溶剂中，式(5)化合物经酯化反应，得到式(7)化合物；Step (g): In the seventh solvent, the compound of formula (5) undergoes an esterification reaction to obtain the compound of formula (7);
步骤(h)、在第八溶剂中，式(7)化合物经C环氧化反应，得到式(8)化合物；Step (h): In the eighth solvent, the compound of formula (7) is subjected to C epoxidation reaction to obtain the compound of formula (8);
步骤(l)、在第十二溶剂中，式(8)化合物经C环双键氢化还原反应，得到式(11)化合物；Step (1), in the twelfth solvent, the compound of formula (8) undergoes hydrogenation and reduction reaction of the C ring double bond to obtain the compound of formula (11);
步骤(m)、在第十三溶剂中，式(11)化合物经C环羰基还原反应，得到式(12)化合物；Step (m), in the thirteenth solvent, the compound of formula (11) is subjected to the C ring carbonyl reduction reaction to obtain the compound of formula (12);
步骤(n)、在第十四溶剂中，式(12)化合物经水解反应，得到式(13)目标产物脱氧胆酸。Step (n): In the fourteenth solvent, the compound of formula (12) undergoes a hydrolysis reaction to obtain the target product deoxycholic acid of formula (13).
具体地，步骤(a)中，所述侧链氧化反应具体为：在第一溶剂中，式(1)化合物与2,2,6,6-四甲基哌啶氧化物TEMPO、碳酸氢钠、四丁基溴化铵、氧化剂发生侧链氧化反应，得到式(2)化合物。Specifically, in step (a), the side chain oxidation reaction is: in the first solvent, the compound of formula (1) and 2,2,6,6-tetramethylpiperidine oxide TEMPO, sodium bicarbonate , tetrabutylammonium bromide and oxidant undergo side chain oxidation reaction to obtain the compound of formula (2).
其中，式(1)化合物、TEMPO、碳酸氢钠、四丁基溴化铵、氧化剂的摩尔比为1：(0～1)：(0～20)：(0～1)：(1～5)；优选地，为1：0.01：1.35：0.1：1.15。Among them, the molar ratio of the compound of formula (1), TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and oxidant is 1: (0～1): (0～20): (0～1): (1～5 ); preferably, it is 1:0.01:1.35:0.1:1.15.
其中，所述侧链氧化反应在氧化剂的作用下进行，所述氧化剂选自N-氯代琥珀酰亚胺NCS、N-溴代琥珀酰亚胺NBS、2-碘酰基苯甲酸IBX、重铬酸吡啶盐PDC等中的一种或多种；优选地，为N-氯代琥珀酰亚胺NCS。Wherein, the side chain oxidation reaction is carried out under the action of an oxidant, and the oxidant is selected from N-chlorosuccinimide NCS, N-bromosuccinimide NBS, 2-iodoacylbenzoic acid IBX, dichromium One or more of the acid pyridinium salts PDC, etc.; preferably, it is N-chlorosuccinimide NCS.
其中，所述第一溶剂选自二氯甲烷、四氢呋喃、甲苯、二甲基亚砜、水等中的一种或多种；优选地，为二氯甲烷和水的混合溶剂(体积比V/V＝5/2)。 Wherein, the first solvent is selected from one or more of methylene chloride, tetrahydrofuran, toluene, dimethyl sulfoxide, water, etc.; preferably, it is a mixed solvent of methylene chloride and water (volume ratio V/ V=5/2).
其中，所述侧链氧化反应的温度为0～30℃；优选地，为0℃。Wherein, the temperature of the side chain oxidation reaction is 0-30°C; preferably, it is 0°C.
其中，所述侧链氧化反应的时间为3～8h；优选地，为6h。Wherein, the side chain oxidation reaction time is 3 to 8 hours; preferably, it is 6 hours.
在一具体实施方式中，式(2)化合物的合成步骤包括：式(1)化合物溶解在第一溶剂中，然后加入TEMPO、碳酸氢钠、四丁基溴化铵、氧化剂，发生侧链氧化反应，得到式(2)化合物。In a specific embodiment, the synthesis steps of the compound of formula (2) include: dissolving the compound of formula (1) in the first solvent, then adding TEMPO, sodium bicarbonate, tetrabutylammonium bromide, and oxidizing agent to cause side chain oxidation Reaction to obtain the compound of formula (2).
本发明步骤(b)中，所述Wittig反应具体为：在第二溶剂中，式(2)化合物与甲氧甲酰基亚甲基三苯基膦或乙氧甲酰基亚甲基三苯基膦或丙氧甲酰基亚甲基三苯基膦发生Wittig反应，得到式(3)化合物。In step (b) of the present invention, the Wittig reaction is specifically: in the second solvent, the compound of formula (2) and methoxyformylmethylenetriphenylphosphine or ethoxyformylmethylenetriphenylphosphine Or propoxyformyl methylene triphenylphosphine undergoes Wittig reaction to obtain the compound of formula (3).
其中，式(2)化合物、甲氧甲酰基亚甲基三苯基膦或乙氧甲酰基亚甲基三苯基膦或丙氧甲酰基亚甲基三苯基膦的摩尔比为1：(1～5)；优选地，为1：1.5。Wherein, the molar ratio of the compound of formula (2), methoxyformylmethylenetriphenylphosphine or ethoxyformylmethylenetriphenylphosphine or propoxyformylmethylenetriphenylphosphine is 1: ( 1～5); preferably, it is 1:1.5.
其中，所述第二溶剂为二甲苯、甲苯、苯、四氢呋喃、庚烷、己烷等中的一种或多种；优选地，为甲苯。Wherein, the second solvent is one or more of xylene, toluene, benzene, tetrahydrofuran, heptane, hexane, etc.; preferably, it is toluene.
其中，所述Wittig反应的温度为80～130℃；优选地，为110℃。Wherein, the temperature of the Wittig reaction is 80-130°C; preferably, it is 110°C.
其中，所述Wittig反应的时间为2～8h；优选地，为4h。Wherein, the Wittig reaction time is 2 to 8 hours; preferably, it is 4 hours.
在一具体实施方式中，式(3)化合物的合成步骤包括：式(2)化合物溶解在第二溶剂中，然后加入甲氧甲酰基亚甲基三苯基膦或乙氧甲酰基亚甲基三苯基膦或丙氧甲酰基亚甲基三苯基膦，发生Wittig反应，得到式(3)化合物。In a specific embodiment, the synthesis step of the compound of formula (3) includes: dissolving the compound of formula (2) in the second solvent, and then adding methoxyformylmethylenetriphenylphosphine or ethoxyformylmethylene Triphenylphosphine or propoxyformylmethylene triphenylphosphine undergoes Wittig reaction to obtain the compound of formula (3).
或，本发明步骤(b)中，所述Wittig-Horner反应具体为：在第二溶剂中，式(2)化合物与碱、膦酰基乙酸甲酯二乙酯或膦酰基乙酸三乙酯或膦酰基乙酸丙酯二乙酯发生Wittig-Horner反应，得到式(3)化合物。Or, in step (b) of the present invention, the Wittig-Horner reaction is specifically: in the second solvent, the compound of formula (2) and a base, diethyl methyl phosphonoacetate or triethyl phosphonoacetate or phosphine The Wittig-Horner reaction occurs with diethyl propyl acylacetate to obtain the compound of formula (3).
其中，式(2)化合物、碱、膦酰基乙酸甲酯二乙酯或膦酰基乙酸三乙酯或膦酰基乙酸丙酯二乙酯的摩尔比为1：(1～5)：(1～5)；优选地，为1：1.5：1.5。Among them, the molar ratio of the compound of formula (2), base, methyl phosphonoacetate diethyl ester or phosphonoacetate triethyl ester or phosphonoacetate propyl diethyl ester is 1: (1～5): (1～5 ); preferably, it is 1:1.5:1.5.
其中，所述第二溶剂选自二甲苯、甲苯、苯、四氢呋喃、庚烷、己烷等中的一种或多种；优选地，为四氢呋喃。Wherein, the second solvent is selected from one or more of xylene, toluene, benzene, tetrahydrofuran, heptane, hexane, etc.; preferably, it is tetrahydrofuran.
其中，所述碱选自钠氢、叔丁醇钾、叔丁醇钠、甲醇钠、乙醇钠、氢化锂等中的一种或多种；优选地，为钠氢。Wherein, the base is selected from one or more of sodium hydrogen, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, lithium hydride, etc.; preferably, it is sodium hydrogen.
其中，所述Wittig-Horner反应的温度为0～30℃；优选地，为0℃。Wherein, the temperature of the Wittig-Horner reaction is 0-30°C; preferably, it is 0°C.
其中，所述Wittig-Horner反应的时间为2～8h；优选地，为4h。Wherein, the Wittig-Horner reaction time is 2 to 8 hours; preferably, it is 4 hours.
在一具体实施方式中，式(3)化合物的合成步骤包括：将碱加入到第三溶剂中，搅拌，再加入膦酰基乙酸甲酯二乙酯或膦酰基乙酸三乙酯或膦酰基乙酸丙酯二乙酯、式(2)化合物，发生Wittig-Horner反应，得到式(3)化合物。 In a specific embodiment, the synthesis steps of the compound of formula (3) include: adding a base to the third solvent, stirring, and then adding methyl diethyl phosphonoacetate or triethyl phosphonoacetate or propyl phosphonoacetate. The ester diethyl ester and the compound of formula (2) undergo Wittig-Horner reaction to obtain the compound of formula (3).
本发明步骤(c)中，所述脱水反应具体为：在第三溶剂中，式(3)化合物与乙酸酐、酸发生脱水反应，得到式(4)化合物。In step (c) of the present invention, the dehydration reaction is specifically: in the third solvent, the compound of formula (3) undergoes a dehydration reaction with acetic anhydride and acid to obtain the compound of formula (4).
其中，式(3)化合物、乙酸酐、酸的摩尔比为1：(0～8)：(0.01～4)；优选地，为1：0：0.9。Among them, the molar ratio of the compound of formula (3), acetic anhydride, and acid is 1: (0-8): (0.01-4); preferably, it is 1:0:0.9.
其中，所述酸选自对甲基苯磺酸、硫酸、三氟化硼乙酸络合物等中的一种或多种；优选地，为硫酸。Wherein, the acid is selected from one or more of p-toluenesulfonic acid, sulfuric acid, boron trifluoride acetic acid complex, etc.; preferably, it is sulfuric acid.
其中，所述第三溶剂选自二氯甲烷、乙酸乙酯、氯仿、1,2-二氯乙烷、水、乙酸等中的一种或多种；优选地，为二氯甲烷。Wherein, the third solvent is selected from one or more of dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane, water, acetic acid, etc.; preferably, it is dichloromethane.
其中，所述脱水反应的温度为-40℃～80℃；优选地，为0℃。Wherein, the temperature of the dehydration reaction is -40°C to 80°C; preferably, it is 0°C.
其中，所述脱水反应的时间为0.5～10h；优选地，为1h。Wherein, the dehydration reaction time is 0.5 to 10 h; preferably, it is 1 h.
在一具体实施例中，式(4)化合物的合成步骤包括：式(3)化合物溶解在第三溶剂中，然后加入酸，发生脱水反应，得到式(4)化合物。In a specific embodiment, the synthesis step of the compound of formula (4) includes: dissolving the compound of formula (3) in a third solvent, and then adding acid to cause a dehydration reaction to obtain the compound of formula (4).
本发明步骤(d)中，所述A环及侧链双键氢化还原具体为：在第四溶剂中，式(4)化合物与雷尼镍、H2发生氢化还原反应，得到式(5)化合物。In step (d) of the present invention, the hydrogenation reduction of the A ring and side chain double bonds is specifically: in the fourth solvent, the compound of formula (4) undergoes a hydrogenation reduction reaction with Raney nickel and H 2 to obtain formula (5) compound.
其中，所述式(4)化合物、雷尼镍的质量比为1:(0.05～2)；优选地，为1：1。Wherein, the mass ratio of the compound of formula (4) to Raney nickel is 1: (0.05-2); preferably, it is 1:1.
其中，所述第四溶剂选自四氢呋喃、1,4-二氧六环、乙酸乙酯、2-甲基四氢呋喃、异丙醇、甲基叔丁基醚、甲苯等中的一种或多种；优选地，为四氢呋喃。Wherein, the fourth solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyltetrahydrofuran, isopropyl alcohol, methyl tert-butyl ether, toluene, etc. ; Preferably, it is tetrahydrofuran.
其中，所述A环及侧链双键氢化还原反应的H2压强为1-60atm；优选地，为40atm。Wherein, the H 2 pressure of the hydrogenation and reduction reaction of the A ring and side chain double bonds is 1-60 atm; preferably, it is 40 atm.
其中，所述A环及侧链双键氢化还原反应的温度为20～120℃；优选地，为80℃。Wherein, the temperature of the hydrogenation reduction reaction of the A ring and side chain double bonds is 20-120°C; preferably, it is 80°C.
其中，所述A环及侧链双键氢化还原反应的时间为1～12h，优选地，为3h。Wherein, the time for the hydrogenation and reduction reaction of the A ring and side chain double bonds is 1 to 12 hours, preferably 3 hours.
在一具体实施例中，式(5)化合物的合成步骤包括：将式(4)化合物溶解在第四溶剂中，加入雷尼镍，与H2发生氢化还原反应，得到式(5)化合物。In a specific embodiment, the synthesis steps of the compound of formula (5) include: dissolving the compound of formula (4) in a fourth solvent, adding Raney nickel, and performing a hydrogenation reduction reaction with H 2 to obtain the compound of formula (5).
本发明步骤(e)中，所述A环双键及侧链双键氢化还原反应具体为：在第五溶剂中，式(4)化合物与钯/碳(Pd/C)、碱、H2发生氢化还原反应，得到式(6)化合物。In step (e) of the present invention, the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is specifically: in the fifth solvent, the compound of formula (4) and palladium/carbon (Pd/C), alkali, H 2 A hydrogenation reduction reaction occurs to obtain the compound of formula (6).
其中，所述式(4)化合物、碱的摩尔比为1：(0.01～5)；优选地，为1：0.05。Wherein, the molar ratio of the compound of formula (4) and the base is 1: (0.01-5); preferably, it is 1:0.05.
其中，所述式(4)化合物、Pd/C的质量比为1：(0.02～0.3)；优选地，为1：0.05。Wherein, the mass ratio of the compound of formula (4) and Pd/C is 1: (0.02-0.3); preferably, it is 1:0.05.
其中，所述第五溶剂选自甲醇、乙醇、丙醇、乙酸乙酯、丙酮、二氯甲烷、四氢呋喃等中的一种或多种；优选地，为二氯甲烷和甲醇的混合溶液(体积比V/V＝20/1)。Wherein, the fifth solvent is selected from one or more of methanol, ethanol, propanol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, etc.; preferably, it is a mixed solution (volume) of dichloromethane and methanol. Ratio V/V=20/1).
其中，所述碱选自碳酸钠、碳酸氢钠、氨水、4-甲氧基吡啶、吡啶、4-二甲氨基吡啶等中的一种或多种；优选地，为吡啶。Wherein, the base is selected from one or more of sodium carbonate, sodium bicarbonate, ammonia, 4-methoxypyridine, pyridine, 4-dimethylaminopyridine, etc.; preferably, it is pyridine.
其中，所述A环双键及侧链双键氢化还原反应的H2压强为1～40atm；优选地，为1atm。 Wherein, the H 2 pressure of the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is 1 to 40 atm; preferably, it is 1 atm.
其中，所述A环双键及侧链双键氢化还原反应的温度为0～40℃；优选地，为25℃。Wherein, the temperature of the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is 0-40°C; preferably, it is 25°C.
其中，所述A环双键及侧链双键氢化还原反应的时间为1～48h；优选地，为12h。Wherein, the hydrogenation and reduction reaction time of the A ring double bond and the side chain double bond is 1 to 48 hours; preferably, it is 12 hours.
在一具体实施例中，式(6)化合物的合成步骤包括：将式(4)化合物溶解在第五溶剂，加入钯碳、碱、H2发生氢化还原反应，得到式(6)化合物。In a specific embodiment, the synthesis steps of the compound of formula (6) include: dissolving the compound of formula (4) in the fifth solvent, adding palladium carbon, alkali, and H 2 to perform a hydrogenation reduction reaction to obtain the compound of formula (6).
本发明步骤(f)中，所述A环羰基还原反应具体为：在第六溶剂中，式(6)化合物与七水合三氯化铈、还原剂发生A环羰基还原反应，得到式(5)化合物。In step (f) of the present invention, the A ring carbonyl reduction reaction is specifically: in the sixth solvent, the A ring carbonyl reduction reaction occurs between the compound of formula (6), cerium trichloride heptahydrate and a reducing agent to obtain formula (5 ) compound.
其中，所述式(6)化合物、七水合三氯化铈、还原剂的摩尔比为1：(0～2)：(1～5)；优选地，为1：1.1：2。Wherein, the molar ratio of the compound of formula (6), cerium trichloride heptahydrate, and the reducing agent is 1: (0-2): (1-5); preferably, it is 1:1.1:2.
其中，所述第六溶剂选自甲醇、乙酸乙酯、二氯甲烷、四氢呋喃、乙醇、水等中的一种或多种；优选地，为甲醇和四氢呋喃的混合溶液(体积比V/V＝1/7)。Wherein, the sixth solvent is selected from one or more of methanol, ethyl acetate, dichloromethane, tetrahydrofuran, ethanol, water, etc.; preferably, it is a mixed solution of methanol and tetrahydrofuran (volume ratio V/V = 1/7).
其中，所述还原剂选自硼氢化钠、硼氢化钾、三叔丁氧基氢化铝锂等中的一种或多种；优选地，为硼氢化钾。Wherein, the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium tri-tert-butoxyaluminum hydride, etc.; preferably, it is potassium borohydride.
其中，所述A环羰基还原反应的温度为-40～30℃；优选地，为-10℃。Wherein, the temperature of the A ring carbonyl reduction reaction is -40~30°C; preferably, it is -10°C.
其中，所述A环羰基还原反应的时间为0.1～8h；优选地，为5h。Wherein, the time for the reduction reaction of the carbonyl group of the A ring is 0.1 to 8 hours; preferably, it is 5 hours.
在一具体实施例中，式(5)化合物的合成步骤包括：将式(6)化合物溶解在第六溶剂中，加入依次七水合三氯化铈、还原剂，发生A环羰基还原反应，得到式(5)化合物。In a specific embodiment, the synthesis steps of the compound of formula (5) include: dissolving the compound of formula (6) in the sixth solvent, adding cerium trichloride heptahydrate and a reducing agent in sequence, and reducing the A ring carbonyl group to obtain Compounds of formula (5).
本发明步骤(g)中，当羟基保护试剂为酸酐时，所述酯化反应具体为：第七溶剂中，式(5)化合物与羟基保护试剂、碱发生酯化反应，得到式(7)化合物。In step (g) of the present invention, when the hydroxyl protecting reagent is an acid anhydride, the esterification reaction is specifically: in the seventh solvent, the compound of formula (5) undergoes an esterification reaction with the hydroxyl protecting reagent and a base to obtain formula (7) compound.
其中，所述第七溶剂选自乙酸乙酯、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、甲苯、四氢呋喃、2-甲基四氢呋喃等中的一种或多种；优选地，为二氯甲烷。Wherein, the seventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; preferably Ground, is methylene chloride.
其中，所述碱选自三乙胺、二异丙基乙基胺、咪唑、吡啶、4-二甲氨基吡啶DMAP等中的一种或多种；优选地，为DMAP。Wherein, the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine, DMAP, etc.; preferably, it is DMAP.
其中，所述式(5)化合物、羟基保护试剂、碱的摩尔比为1:(1～4):(0.05～5)；优选地，为1：2：0.2。Wherein, the molar ratio of the compound of formula (5), hydroxyl protecting reagent and base is 1:(1~4):(0.05~5); preferably, it is 1:2:0.2.
其中，所述酯化反应的温度为0～50℃；优选地，为25℃。Wherein, the temperature of the esterification reaction is 0-50°C; preferably, it is 25°C.
其中，所述酯化反应的时间为2～24h，优选地，为8h。Wherein, the time of the esterification reaction is 2 to 24 hours, preferably 8 hours.
本发明步骤(g)中，当羟基保护试剂为酰氯时，所述酯化反应具体为：第七溶剂中，式(5)化合物与羟基保护试剂、碱发生酯化反应，得到式(7)化合物。In step (g) of the present invention, when the hydroxyl protecting reagent is an acid chloride, the esterification reaction is specifically: in the seventh solvent, the compound of formula (5) undergoes an esterification reaction with the hydroxyl protecting reagent and a base to obtain formula (7) compound.
其中，所述第七溶剂选自乙酸乙酯、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、甲苯、四氢呋喃、2-甲基四氢呋喃等中的一种或多种；优选地，为二氯甲烷。Wherein, the seventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; preferably Ground, is methylene chloride.
其中，所述碱选自三乙胺、二异丙基乙基胺、咪唑、吡啶、4-二甲氨基吡啶DMAP等中 的一种或多种；优选地，为三乙胺和DMAP的混合碱；进一步优选地，为三乙胺和DMAP的摩尔比为10/1。Wherein, the base is selected from triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine DMAP, etc. One or more; preferably, it is a mixed base of triethylamine and DMAP; further preferably, the molar ratio of triethylamine and DMAP is 10/1.
其中，所述式(5)化合物、羟基保护试剂、碱的摩尔比为1:(1～4):(0.05～5)；优选地，为1：2：2.2。Wherein, the molar ratio of the compound of formula (5), hydroxyl protecting reagent, and base is 1:(1-4):(0.05-5); preferably, it is 1:2:2.2.
其中，所述酯化反应的温度为0～50℃；优选地，为25℃。Wherein, the temperature of the esterification reaction is 0-50°C; preferably, it is 25°C.
其中，所述酯化反应的时间为2～24h，优选地，为8h。Wherein, the time of the esterification reaction is 2 to 24 hours, preferably 8 hours.
在一具体实施例中，式(7)化合物的合成步骤包括：将式(5)化合物溶解在第七溶剂中，加入碱、羟基保护试剂，发生酯化反应，得到式(7)化合物。In a specific embodiment, the synthesis steps of the compound of formula (7) include: dissolving the compound of formula (5) in a seventh solvent, adding a base and a hydroxyl protecting reagent, and performing an esterification reaction to obtain the compound of formula (7).
本发明步骤(h)中，所述C环氧化反应具体为：在第八溶剂中，式(7)化合物与N-羟基邻苯二甲酰亚胺NHPI、氧化剂发生C环氧化反应，得到式(8)化合物。In step (h) of the present invention, the C epoxidation reaction is specifically: in the eighth solvent, the C epoxidation reaction occurs between the compound of formula (7), N-hydroxyphthalimide NHPI and an oxidant, Compounds of formula (8) are obtained.
其中，所述第八溶剂选自甲苯、丙酮、水、二氯甲烷、N,N-二甲基甲酰胺、乙酸乙酯、N-甲基吡咯烷酮、乙酸等中的一种或多种；优选地，为乙酸。Wherein, the eighth solvent is selected from one or more of toluene, acetone, water, methylene chloride, N,N-dimethylformamide, ethyl acetate, N-methylpyrrolidone, acetic acid, etc.; preferably The ground is acetic acid.
其中，所述式(7)化合物、氧化剂、N-羟基邻苯二甲酰亚胺的摩尔比为1：(1-5)：(0～5)；优选地，为1：4：0。Wherein, the molar ratio of the compound of formula (7), oxidizing agent and N-hydroxyphthalimide is 1: (1-5): (0~5); preferably, it is 1:4:0.
其中，所述氧化剂选自Na2Cr2O7、K2Cr2O7、重铬酸吡啶盐PDC、过氧化苯甲酰BPO、CrO3等中的一种或多种；优选地，为CrO3。Wherein, the oxidizing agent is selected from one or more of Na 2 Cr 2 O 7 , K 2 Cr 2 O 7 , pyridinium dichromate PDC, benzoyl peroxide BPO, CrO 3, etc.; preferably, it is CrO 3 .
其中，所述C环氧化反应的温度为0～50℃；优选地，为35℃。Wherein, the temperature of the C epoxidation reaction is 0-50°C; preferably, it is 35°C.
其中，所述C环氧化反应的时间为10～48h；优选地，为12h。Wherein, the time of the C epoxidation reaction is 10 to 48 hours; preferably, it is 12 hours.
在一具体实施例中，式(8)化合物的合成步骤包括：将式(7)化合物溶解在第八溶剂中，加入N-羟基邻苯二甲酰亚胺NHPI、氧化剂，发生C环氧化反应，得到式(8)化合物。In a specific embodiment, the synthesis steps of the compound of formula (8) include: dissolving the compound of formula (7) in the eighth solvent, adding N-hydroxyphthalimide NHPI and an oxidant, and causing C epoxidation Reaction to obtain the compound of formula (8).
本发明步骤(i)中，所述C环氧化反应具体为：在第九溶剂中，式(4)化合物与N-羟基邻苯二甲酰亚胺NHPI、氧化剂发生C环氧化反应，得到式(9)化合物。In step (i) of the present invention, the C epoxidation reaction is specifically: in the ninth solvent, the compound of formula (4) undergoes a C epoxidation reaction with N-hydroxyphthalimide NHPI and an oxidant, Compounds of formula (9) are obtained.
其中，所述第九溶剂选自甲苯、丙酮、水、二氯甲烷、N,N-二甲基甲酰胺、乙酸乙酯、N-甲基吡咯烷酮、乙酸等中的一种或多种；优选地，为丙酮/水。Wherein, the ninth solvent is selected from one or more of toluene, acetone, water, methylene chloride, N,N-dimethylformamide, ethyl acetate, N-methylpyrrolidone, acetic acid, etc.; preferably Ground is acetone/water.
其中，所述式(4)化合物、氧化剂、N-羟基邻苯二甲酰亚胺的摩尔比为1：(1-10)：(0～5)；优选地，为1：3：1。Wherein, the molar ratio of the compound of formula (4), oxidizing agent and N-hydroxyphthalimide is 1: (1-10): (0~5); preferably, it is 1:3:1.
其中，所述氧化剂选自Na2Cr2O7、K2Cr2O7、重铬酸吡啶盐PDC、过氧化苯甲酰BPO、CrO3等中的一种或多种；优选地，为PDC。Wherein, the oxidizing agent is selected from one or more of Na 2 Cr 2 O 7 , K 2 Cr 2 O 7 , pyridinium dichromate PDC, benzoyl peroxide BPO, CrO 3, etc.; preferably, it is PDC.
其中，所述C环氧化反应的温度为0～50℃；优选地，为45℃。Wherein, the temperature of the C epoxidation reaction is 0-50°C; preferably, it is 45°C.
其中，所述C环氧化反应的时间为10～48h；优选地，为12h。Wherein, the time of the C epoxidation reaction is 10 to 48 hours; preferably, it is 12 hours.
在一具体实施例中，式(9)化合物的合成步骤包括：将式(4)化合物溶解在第九溶剂 中，加入N-羟基邻苯二甲酰亚胺、氧化剂，发生C环氧化反应，得到式(9)化合物。In a specific embodiment, the synthesis step of the compound of formula (9) includes: dissolving the compound of formula (4) in the ninth solvent In, add N-hydroxyphthalimide and oxidant, C epoxidation reaction occurs, and the compound of formula (9) is obtained.
本发明步骤(j)中，所述A环及侧链双键氢化还原反应具体为：在第十溶剂中，式(9)化合物与雷尼镍、H2发生氢化还原反应，得到式(10)化合物。In step (j) of the present invention, the hydrogenation reduction reaction of the A ring and the side chain double bond is specifically: in the tenth solvent, the compound of formula (9) undergoes a hydrogenation reduction reaction with Raney nickel and H 2 to obtain formula (10 ) compound.
其中，所述式(9)化合物、雷尼镍的质量比为1:(0.05～2)；优选地，为1：1。Wherein, the mass ratio of the compound of formula (9) to Raney nickel is 1: (0.05-2); preferably, it is 1:1.
其中，所述第十溶剂选自四氢呋喃、1,4-二氧六环、乙酸乙酯、2-甲基四氢呋喃、异丙醇、甲基叔丁基醚、甲苯等中的一种或多种；优选地，为四氢呋喃。Wherein, the tenth solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyltetrahydrofuran, isopropyl alcohol, methyl tert-butyl ether, toluene, etc. ; Preferably, it is tetrahydrofuran.
其中，所述A环及侧链双键氢化还原反应的H2压强为1-60atm；优选地，为40atm。Wherein, the H 2 pressure of the hydrogenation and reduction reaction of the A ring and side chain double bonds is 1-60 atm; preferably, it is 40 atm.
其中，所述A环及侧链双键氢化还原反应的温度为20～120℃；优选地，为90℃。Wherein, the temperature of the hydrogenation reduction reaction of the A ring and side chain double bonds is 20-120°C; preferably, it is 90°C.
其中，所述A环及侧链双键氢化还原反应的时间为1～12h；优选地，为3h。Wherein, the time for the hydrogenation and reduction reaction of the A ring and side chain double bonds is 1 to 12 hours; preferably, it is 3 hours.
在一具体实施例中，式(10)化合物的合成步骤包括：式(9)化合物溶解在所述第十溶剂中，加入雷尼镍，在一定的H2压强下发生氢化还原反应，得到式(10)化合物。In a specific embodiment, the synthesis steps of the compound of formula (10) include: dissolving the compound of formula (9) in the tenth solvent, adding Raney nickel, and performing a hydrogenation reduction reaction under a certain H pressure to obtain the formula (10) Compounds.
本发明步骤(k)中，当羟基保护试剂为酸酐时，所述酯化反应具体为：在第十一溶剂中，式(10)化合物与羟基保护试剂、碱发生酯化反应，得到式(8)化合物。In step (k) of the present invention, when the hydroxyl protecting reagent is an acid anhydride, the esterification reaction is specifically: in the eleventh solvent, the compound of formula (10) undergoes an esterification reaction with the hydroxyl protecting reagent and a base to obtain the formula ( 8) Compounds.
其中，所述第十一溶剂选自乙酸乙酯、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、甲苯、四氢呋喃、2-甲基四氢呋喃等中的一种或多种；优选地，为二氯甲烷。Wherein, the eleventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; Preferably, it is methylene chloride.
其中，所述碱选自三乙胺、二异丙基乙基胺、咪唑、吡啶、4-二甲氨基吡啶DMAP等中的一种或多种；优选地，为DMAP。Wherein, the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine, DMAP, etc.; preferably, it is DMAP.
其中，所述式(10)化合物、羟基保护试剂、碱的摩尔比为1:(1～4):(0.05～5)；优选地，为1：2：0.2。Wherein, the molar ratio of the compound of formula (10), hydroxyl protecting reagent, and base is 1:(1-4):(0.05-5); preferably, it is 1:2:0.2.
其中，所述反应的温度为0～50℃；优选地，为25℃。Wherein, the temperature of the reaction is 0-50°C; preferably, it is 25°C.
其中，所述酯化反应的时间为2～24h，优选地，为8h。Wherein, the time of the esterification reaction is 2 to 24 hours, preferably 8 hours.
本发明步骤(k)中，当羟基保护试剂为酰氯时，所述酯化反应具体为：在第十一溶剂中，式(10)化合物与羟基保护试剂、碱发生酯化反应，得到式(8)化合物。In step (k) of the present invention, when the hydroxyl protecting reagent is an acid chloride, the esterification reaction is specifically: in the eleventh solvent, the compound of formula (10) undergoes an esterification reaction with the hydroxyl protecting reagent and a base to obtain the formula ( 8) Compounds.
其中，所述第十一溶剂选自乙酸乙酯、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、甲苯、四氢呋喃、2-甲基四氢呋喃等中的一种或多种；优选地，为二氯甲烷。Wherein, the eleventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; Preferably, it is methylene chloride.
其中，所述碱选自三乙胺、二异丙基乙基胺、咪唑、吡啶、4-二甲氨基吡啶DMAP等中的一种或多种；优选地，为三乙胺和DMAP的混合碱；进一步优选地，为三乙胺和DMAP的摩尔比为10/1。Wherein, the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, 4-dimethylaminopyridine DMAP, etc.; preferably, it is a mixture of triethylamine and DMAP Base; further preferably, the molar ratio of triethylamine and DMAP is 10/1.
其中，所述式(10)化合物、羟基保护试剂、碱的摩尔比为1:(1～4):(0.05～5)；优选地，为1：2：2.2。Wherein, the molar ratio of the compound of formula (10), hydroxyl protecting reagent and base is 1:(1~4):(0.05~5); preferably, it is 1:2:2.2.
其中，所述反应的温度为0～50℃；优选地，为25℃。 Wherein, the temperature of the reaction is 0-50°C; preferably, it is 25°C.
其中，所述酯化反应的时间为2～24h，优选地，为8h。Wherein, the time of the esterification reaction is 2 to 24 hours, preferably 8 hours.
在一具体实施例中，式(8)化合物的合成步骤包括：式(10)化合物溶解在所述第十一溶剂中，加入羟基保护试剂、碱，发生酯化反应，得到式(8)化合物。In a specific embodiment, the synthesis steps of the compound of formula (8) include: dissolving the compound of formula (10) in the eleventh solvent, adding a hydroxyl protecting reagent and a base, and causing an esterification reaction to obtain the compound of formula (8) .
本发明步骤(l)中，所述C环双键还原反应具体为：在第十二溶剂中，式(8)化合物与催化剂、H2发生C环双键还原反应，得到式(11)化合物。In step (l) of the present invention, the C-ring double bond reduction reaction is specifically: in the twelfth solvent, the C-ring double bond reduction reaction occurs between the compound of formula (8) and the catalyst and H 2 to obtain the compound of formula (11) .
其中，所述式(8)化合物、催化剂的质量比为1:(0.05～2)；优选地，为1：0.2。Wherein, the mass ratio of the compound of formula (8) to the catalyst is 1: (0.05-2); preferably, it is 1:0.2.
其中，所述催化剂选自雷尼镍、钯碳、氧化铂、氢氧化钯中的一种或多种；优选地，为钯碳。Wherein, the catalyst is selected from one or more of Raney nickel, palladium on carbon, platinum oxide, and palladium hydroxide; preferably, it is palladium on carbon.
其中，所述第十二溶剂选自四氢呋喃、1,4-二氧六环、乙酸乙酯、2-甲基四氢呋喃、异丙醇、甲基叔丁基醚、甲苯、二甲苯等中的一种或多种；优选地，为1,4-二氧六环。Wherein, the twelfth solvent is selected from tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyltetrahydrofuran, isopropyl alcohol, methyl tert-butyl ether, toluene, xylene, etc. One or more kinds; preferably, it is 1,4-dioxane.
其中，所述C环双键还原反应的H2压强为20-60atm；优选地，为40atm。Wherein, the H 2 pressure of the C ring double bond reduction reaction is 20-60 atm; preferably, it is 40 atm.
其中，所述C环双键还原反应的温度为70～120℃；优选地，为110℃。Wherein, the temperature of the C ring double bond reduction reaction is 70-120°C; preferably, it is 110°C.
其中，所述C环双键还原反应的时间为8～72h；优选地，为48h。Wherein, the time of the C ring double bond reduction reaction is 8 to 72 hours; preferably, it is 48 hours.
在一具体实施例中，式(11)化合物的合成步骤包括：将式(8)化合物溶解在第十二溶剂中，加入催化剂，在一定的H2压强下发生C环双键还原反应，得到式(11)化合物。In a specific embodiment, the synthesis steps of the compound of formula (11) include: dissolving the compound of formula (8) in a twelfth solvent, adding a catalyst, and performing a C ring double bond reduction reaction under a certain H 2 pressure to obtain Compound of formula (11).
本发明步骤(m)中，所述C环羰基还原反应具体为：在第十三溶剂中，式(11)化合物与还原剂发生C环羰基还原反应，得到式(12)化合物。In step (m) of the present invention, the C ring carbonyl reduction reaction is specifically: in the thirteenth solvent, the C ring carbonyl reduction reaction occurs between the compound of formula (11) and the reducing agent to obtain the compound of formula (12).
其中，所述式(11)化合物、还原剂的摩尔比为1：(1～5)；优选地，为1：1.5。Wherein, the molar ratio of the compound of formula (11) to the reducing agent is 1: (1-5); preferably, it is 1:1.5.
其中，所述第十三溶剂选自乙醇、甲醇、乙酸乙酯、二氯甲烷、四氢呋喃等中的一种或多种；优选地，为四氢呋喃。Wherein, the thirteenth solvent is selected from one or more of ethanol, methanol, ethyl acetate, methylene chloride, tetrahydrofuran, etc.; preferably, it is tetrahydrofuran.
其中，所述还原剂选自硼氢化钠、硼氢化钾、三叔丁氧基氢化铝锂等中的一种或多种；优选地，为三叔丁氧基氢化铝锂。Wherein, the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium tri-tert-butoxyaluminum hydride, etc.; preferably, it is lithium tri-tert-butoxyaluminum hydride.
其中，所述C环羰基还原反应的温度为-10～30℃；优选地，为0℃。Wherein, the temperature of the C ring carbonyl reduction reaction is -10~30°C; preferably, it is 0°C.
其中，所述C环羰基还原反应的时间为0.5～24h；优选地，为12h。Wherein, the time for the C ring carbonyl reduction reaction is 0.5 to 24 hours; preferably, it is 12 hours.
在一具体实施例中，式(12)化合物的合成步骤包括：将式(11)化合物溶解在第十三溶剂中，分批加入还原剂，发生C环羰基还原反应，得到式(12)化合物。In a specific embodiment, the synthesis steps of the compound of formula (12) include: dissolving the compound of formula (11) in the thirteenth solvent, adding a reducing agent in batches, and causing a C ring carbonyl reduction reaction to obtain the compound of formula (12) .
本发明步骤(n)中，所述水解反应具体为：在第十四溶剂中，式(12)化合物与碱发生水解反应，得到脱氧胆酸。In step (n) of the present invention, the hydrolysis reaction is specifically: in the fourteenth solvent, the compound of formula (12) undergoes a hydrolysis reaction with a base to obtain deoxycholic acid.
其中，式(12)化合物、碱的摩尔比为1：(1～5)；优选地，为1：2。Among them, the molar ratio of the compound of formula (12) and the base is 1: (1-5); preferably, it is 1:2.
其中，所述第十四溶剂选自1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、异丙醇、叔丁醇、甲醇、乙醇、二氯甲烷、水等中的一种或多种；优选地，为四氢呋喃和甲醇的混合溶液 (v/v＝1：1)。Wherein, the fourteenth solvent is selected from one of 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl alcohol, tert-butanol, methanol, ethanol, dichloromethane, water, etc. or A variety of; preferably, a mixed solution of tetrahydrofuran and methanol (v/v=1:1).
其中，所述碱选自叔丁醇钠、叔丁醇钾、乙醇钠、甲醇钠、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化锂一水合物等中的一种或多种；优选地，为氢氧化锂一水合物。Wherein, the base is selected from one or more of sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium hydroxide monohydrate, etc.; Preferably, it is lithium hydroxide monohydrate.
其中，所述水解反应的温度为20～80℃；优选地，为25℃。Wherein, the temperature of the hydrolysis reaction is 20-80°C; preferably, it is 25°C.
其中，所述水解反应的时间为3～24h；优选地，为12h。Wherein, the hydrolysis reaction time is 3 to 24 hours; preferably, it is 12 hours.
在一具体实施例中，脱氧胆酸的合成步骤包括：所述式(12)化合物溶解在第十四溶剂中，加入碱，发生水解反应，得到脱氧胆酸。In a specific embodiment, the synthesis step of deoxycholic acid includes: dissolving the compound of formula (12) in a fourteenth solvent, adding a base, and causing a hydrolysis reaction to obtain deoxycholic acid.
本发明步骤(o)中，所述A环双键及侧链双键氢化还原反应具体为：所述式(3)化合物溶解在所述第十五溶剂中，在Pd/C、碱和氢气的作用下，发生氢化还原反应，得到式(14)化合物。In step (o) of the present invention, the hydrogenation and 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, in Pd/C, alkali and hydrogen Under the action of , a hydrogenation reduction reaction occurs to obtain the compound of formula (14).
其中，所述式(3)化合物、碱的摩尔比为1：(0～5)；优选地，为1：0.01。Wherein, the molar ratio of the compound of formula (3) and the base is 1: (0-5); preferably, it is 1:0.01.
其中，所述式(3)化合物、Pd/C的质量比为1：(0.02～0.3)；优选地，为1：0.05。Wherein, the mass ratio of the compound of formula (3) and Pd/C is 1: (0.02-0.3); preferably, it is 1:0.05.
其中，所述第十五溶剂选自甲醇、乙醇、丙醇、乙酸乙酯、丙酮、二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺中的一种或多种；优选地，为N,N-二甲基甲酰胺。Wherein, the fifteenth solvent is selected from one or more of methanol, ethanol, propanol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, N,N-dimethylformamide; preferably, N,N-dimethylformamide.
其中，所述碱选自碳酸钠、碳酸氢钠、氨水、4-甲氧基吡啶、吡啶、4-二甲氨基吡啶中的一种或多种；优选地，为吡啶。Wherein, the base is selected from one or more of sodium carbonate, sodium bicarbonate, ammonia, 4-methoxypyridine, pyridine, and 4-dimethylaminopyridine; preferably, it is pyridine.
其中，所述A环双键及侧链双键氢化还原反应的H2压强为1～40atm；优选地，为4atm。Wherein, the H 2 pressure of the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is 1 to 40 atm; preferably, it is 4 atm.
其中，所述A环双键及侧链双键氢化还原反应的温度为0～40℃；优选地，为25℃。Wherein, the temperature of the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is 0-40°C; preferably, it is 25°C.
其中，所述A环双键及侧链双键氢化还原反应的时间为1～48h；优选地，为12h。Wherein, the hydrogenation and reduction reaction time of the A ring double bond and the side chain double bond is 1 to 48 hours; preferably, it is 12 hours.
在一具体实施例中，式(14)化合物的合成步骤包括：将式(3)化合物溶解在第十五溶剂中，在Pd/C、碱和氢气的作用下，发生氢化还原反应，得到式(14)化合物。In a specific embodiment, the synthesis steps of the compound of formula (14) include: dissolving the compound of formula (3) in the fifteenth solvent, and performing a hydrogenation reduction reaction under the action of Pd/C, alkali and hydrogen to obtain the formula (14) Compounds.
本发明步骤(p)中，所述脱水反应具体为：所述式(14)化合物、乙酸酐、酸在所述第十六溶剂中发生脱水反应，得到式(6)化合物。In step (p) of the present invention, the dehydration reaction is specifically: the compound of formula (14), acetic anhydride, and acid undergo a dehydration reaction in the sixteenth solvent to obtain the compound of formula (6).
其中，所述式(14)化合物、乙酸酐、酸的摩尔比为1：(0～8)：(0.01～4)；优选地，为1：0：0.9。Wherein, the molar ratio of the compound of formula (14), acetic anhydride, and acid is 1: (0-8): (0.01-4); preferably, it is 1:0:0.9.
其中，所述酸选自对甲基苯磺酸、硫酸、三氟化硼乙酸络合物中的一种或多种；优选地，为硫酸。Wherein, the acid is selected from one or more of p-toluenesulfonic acid, sulfuric acid, and boron trifluoride acetic acid complex; preferably, it is sulfuric acid.
其中，所述第十六溶剂选自二氯甲烷、乙酸乙酯、氯仿、1,2-二氯乙烷、水中的一种或多种；优选地，为二氯甲烷。Wherein, the sixteenth solvent is selected from one or more of dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane, and water; preferably, it is dichloromethane.
其中，所述脱水反应的温度为-40℃～80℃；优选地，为0℃。Wherein, the temperature of the dehydration reaction is -40°C to 80°C; preferably, it is 0°C.
其中，所述脱水反应的时间为0.5～10h；优选地，为1h。 Wherein, the dehydration reaction time is 0.5 to 10 h; preferably, it is 1 h.
在一具体实施例中，式(6)化合物的合成步骤包括：将式(14)化合物溶解在第十六溶剂中，在乙酸酐、酸的作用下，发生脱水反应，得到式(6)化合物。In a specific embodiment, the synthesis steps of the compound of formula (6) include: dissolving the compound of formula (14) in the sixteenth solvent, and dehydration reaction occurs under the action of acetic anhydride and acid to obtain the compound of formula (6) .
本发明还提供了新化合物，所述化合物的结构如下所示：

The present invention also provides new compounds, the structures of which are as follows:

本发明还提供了以上新化合物(2、3、4、6、7、8、9、11、12)的制备合成方法，以及所述新化合物(2、3、4、6、7、8、9、11、12)在制备以9,21-二羟基-20-甲基孕甾-4-烯-3-酮9-OH-BA为植物源原料合成脱氧胆酸中的应用。The invention also provides preparation and synthesis methods of the above new compounds (2, 3, 4, 6, 7, 8, 9, 11, 12), as well as the new compounds (2, 3, 4, 6, 7, 8, 9, 11, 12) Application in the preparation of deoxycholic acid using 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA as a plant source raw material.
本发明的有益效果包括：本发明植物源脱氧胆酸的制备方法中，所用原料9,21-二羟基-20-甲基孕甾-4-烯-3-酮9-OH-BA为植物源原料，避免了动物源原料可能存在的致病菌和病毒感染的风险；并且合成步骤相对较短、操作简便、收率高，副反应少，便于实现脱氧胆酸的工业化生产；解决了现有脱氧胆酸产品安全性差的问题。The beneficial effects of the present invention include: in the preparation method of plant-derived deoxycholic acid of the present invention, the raw material 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA is of plant origin. The raw materials avoid the risk of pathogenic bacteria and virus infection that may exist in animal-derived raw materials; and the synthesis steps are relatively short, easy to operate, high yield, and few side reactions, which facilitates the industrial production of deoxycholic acid; it solves the existing problems The problem of poor safety of deoxycholic acid products.
附图说明Description of the drawings
图1脱氧胆酸的核磁谱图(1H NMR和13C NMR)。Figure 1 NMR spectra ( 1H NMR and 13C NMR) of deoxycholic acid.
具体实施方式Detailed ways
结合以下具体实施例和附图，对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。The present invention will be further described in detail with reference to the following specific examples and drawings. The process, conditions, experimental methods, etc. for implementing the present invention, except those specifically mentioned below, are common knowledge and common sense in the field, and the present invention has no special limitations.
下述实施例中，化合物结构用核磁共振仪和高分辨质谱仪测定；试剂主要由上海国药化学试剂公司提供；产品纯化主要通过打浆、柱色谱；硅胶(200-300目)由青岛海洋化工厂生产。 In the following examples, the structure of the compound was determined with a nuclear magnetic resonance instrument and a high-resolution mass spectrometer; the reagents were mainly provided by Shanghai Sinopharm Chemical Reagent Company; the product was purified mainly through pulping and column chromatography; silica gel (200-300 mesh) was provided by Qingdao Ocean Chemical Plant Production.
实施例一式(2)化合物的制备
Example 1 Preparation of compound of formula (2)
于烧瓶中依次加入式(1)化合物(5.19g，15mmol)、TEMPO(23.5mg，0.15mmol)、二氯甲烷(40mL)、碳酸氢钠(1.76g，21mmol)、NCS(2.31g，17.3mmol)、四丁基溴化铵(0.484g，1.5mmol)和水(16mL)，0℃反应6h。TLC检测反应完毕后加入五水合硫代硫酸钠溶液(1.13g五水合硫代硫酸钠/23mL水)，5-10℃搅拌20min，分液，水相用二氯甲烷(60mL×2)萃取，合并有机层，用1％氢氧化钠溶液(30mL)洗涤，分液，有机相减压浓缩，得到式(2)化合物(4.96g，白色固体，摩尔收率95.9％)。1H NMR(600MHz,CDCl3)δ9.58(s,1H),5.89(s,1H),2.50–2.44(m,4H),2.40–2.28(m,2H),1.99–1.91(m,2H),1.85–1.77(m,2H),1.71–1.56(m,7H),1.48–1.40(m,2H),1.35(s,3H),1.30–1.26(m,1H),1.16(d,J＝6.9Hz,3H),0.79(s,3H).13C NMR(150MHz,CDCl3)δ204.76,199.03,168.45,126.98,76.38,50.69,49.40,48.68,44.37,42.84,37.36,34.73,34.03,31.73,28.47,26.95,26.69,25.37,24.38,19.89,13.44,11.48.Add formula (1) compound (5.19g, 15mmol), TEMPO (23.5mg, 0.15mmol), dichloromethane (40mL), sodium bicarbonate (1.76g, 21mmol), NCS (2.31g, 17.3mmol) to the flask in sequence. ), tetrabutylammonium bromide (0.484g, 1.5mmol) and water (16mL), react at 0°C for 6 hours. After the TLC detection reaction is completed, add sodium thiosulfate pentahydrate solution (1.13g sodium thiosulfate pentahydrate/23mL water), stir for 20 minutes at 5-10°C, separate the liquids, and extract the aqueous phase with dichloromethane (60mL×2). The organic layers were combined, 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 (600MHz, CDCl 3 ) δ9.58(s,1H),5.89(s,1H),2.50–2.44(m,4H),2.40–2.28(m,2H),1.99–1.91(m,2H ),1.85–1.77(m,2H),1.71–1.56(m,7H),1.48–1.40(m,2H),1.35(s,3H),1.30–1.26(m,1H),1.16(d,J =6.9Hz, 3H), 0.79 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) δ204.76,199.03,168.45,126.98,76.38,50.69,49.40,48.68,44.37,42.84,37.36,34.73,34.03, 31.73 ,28.47,26.95,26.69,25.37,24.38,19.89,13.44,11.48.
实施例二式(3)化合物的制备Example 2 Preparation of compound of formula (3)
(1)式(3-1)化合物的制备
(1) Preparation of compounds of formula (3-1)
于烧瓶中加入氢化钠(3.25g，81.25mmol)和四氢呋喃(200mL)，搅拌15min后依次加入膦酰基乙酸甲酯二乙酯(17.07g，81.25mmol)、式(2)化合物(20g，58.05mmol)，0℃下反应4h。TLC检测反应完全后减压浓缩，柱层析纯化，得到式(3-1)化合物(21.03g，白色固体，摩尔收率94.7％)。1H NMR(600MHz,CDCl3)δ6.84(dd,J＝15.5,9.0Hz,1H),5.88(s,1H),5.77(d,J＝15.6Hz,1H),3.74(s,3H),2.48–2.41(m,4H),2.31(d,J＝13.9Hz,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＝6.7Hz,3H),0.77(s,3H).13C NMR(150MHz,CDCl3)δ199.05,168.68,167.4,154.60,126.87,118.79,76.33,54.62,51.43,49.19,44.34,42.56,39.69,37.36,34.86,34.04,31.78,28.46,28.00,26.71,25.34,24.05,19.90,19.22,11.34. Add sodium hydride (3.25g, 81.25mmol) and tetrahydrofuran (200mL) to the flask, stir for 15 minutes, and then add methyl phosphonoacetate diethyl ester (17.07g, 81.25mmol) and the compound of formula (2) (20g, 58.05mmol) in sequence. ), react at 0°C for 4 hours. TLC detected that the reaction was complete, then concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (3-1) (21.03 g, white solid, molar yield 94.7%). 1 H NMR (600MHz, CDCl 3 ) δ6.84 (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＝13.9Hz,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＝6.7Hz,3H),0.77(s,3H). 13 C NMR(150MHz, CDCl 3 )δ199.05,168.68,167.4 ,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.
(2)式(3-2)化合物的制备
(2) Preparation of compounds of formula (3-2)
于烧瓶中加入氢化钠(805mg，20.13mmol)和四氢呋喃(50mL)，搅拌15min后依次加入膦酰基乙酸三乙酯(4.5g，20.13mmol)、式(2)化合物(5.17g，15mmol)，0℃下反应4h。TLC检测反应完全后减压浓缩，柱层析纯化，得到式(3-2)化合物(5.98g，白色固体，摩尔收率96％)。1H NMR(600MHz,CDCl3)δ6.83(dd,J＝15.5,9.0Hz,1H),5.88(s,1H),5.76(d,J＝15.6Hz,1H),4.21–4.18(m,2H),2.48–2.41(m,4H),2.31(d,J＝13.9Hz,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＝6.7Hz,3H),0.77(s,3H).13C NMR(150MHz,CDCl3)δ199.08,168.77,167.05,154.30,126.83,119.19,76.33,60.19,54.64,49.18,44.34,42.55,39.66,37.36,34.85,34.04,31.78,28.45,28.02,26.71,25.34,24.04,19.89,19.22,14.28,11.33.Add sodium hydride (805 mg, 20.13 mmol) and tetrahydrofuran (50 mL) to the flask, stir for 15 min, then add triethyl phosphonoacetate (4.5 g, 20.13 mmol), compound of formula (2) (5.17 g, 15 mmol), 0 React at ℃ for 4 hours. TLC detected that the reaction was complete, then concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (3-2) (5.98g, white solid, molar yield 96%). 1 H NMR (600MHz, CDCl 3 ) δ6.83 (dd, J＝15.5, 9.0Hz, 1H), 5.88 (s, 1H), 5.76 (d, J＝15.6Hz, 1H), 4.21–4.18 (m, 2H),2.48–2.41(m,4H),2.31(d,J＝13.9Hz,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＝6.7Hz,3H),0.77(s,3H). 13 C NMR (150MHz, CDCl 3 )δ199.08,168.77 ,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.
实施例三式(4)化合物的制备Example 3 Preparation of Compounds of Formula (4)
(1)式(4-1)化合物的制备
(1) Preparation of compounds of formula (4-1)
于烧瓶中加入二氯甲烷(150mL)和式(3-1)化合物(15.66g，39.09mmol)，搅拌溶清，缓慢滴加浓硫酸(1.9mL)，0℃搅拌1h，TLC检测反应完全后停止反应。将其缓慢倒入冰水中(200mL)，搅拌5min，滴加饱和碳酸钠溶液调PH值至7-8，分液，水相再用DCM(100mL)萃取一次，合并有机相，依次用水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(4-1)化合物(14.1g，白色固体，摩尔收率94.3％)。1H NMR(600MHz,CDCl3)δ6.86(dd,J＝15.6,9.0Hz,1H),5.79–5.76(m,2H),5.47(d,J＝5.7Hz,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＝6.5Hz,4H),0.71(s,3H).13C NMR(150MHz,CDCl3)δ199.39,170.07,167.03,154.33,144.67,123.92,119.21,118.84,54.96,54.94,52.56,41.67,41.09,40.92,39.71,37.32,34.28,33.77,32.92,32.16,28.50,26.14,25.26,18.84,11.72.Add dichloromethane (150 mL) and the compound of formula (3-1) (15.66 g, 39.09 mmol) to the flask, stir to dissolve, slowly add concentrated sulfuric acid (1.9 mL) dropwise, stir at 0°C for 1 hour, and TLC detects that the reaction is complete. Stop reacting. Slowly pour it into ice water (200 mL), stir for 5 minutes, add saturated sodium carbonate solution dropwise to adjust the pH value to 7-8, separate the liquids, extract the aqueous phase once more with DCM (100 mL), combine the organic phases, and use water and saturated sodium carbonate in turn. Wash with brine, concentrate under reduced pressure, and purify by column chromatography to obtain the compound of formula (4-1) (14.1 g, white solid, molar yield 94.3%). 1 H NMR (600MHz, CDCl 3 ) δ6.86 (dd, J＝15.6, 9.0Hz, 1H), 5.79–5.76 (m, 2H), 5.47 (d, J＝5.7Hz, 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＝6.5Hz,4H) ,0.71(s,3H). 13 C NMR (150MHz, CDCl 3 )δ199.39,170.07,167.03,154.33,144.67,123.92,119.21,118.84,54.96,54.94,52.56,41.67,41.09,40.92 ,39.71,37.32,34.28 ,33.77,32.92,32.16,28.50,26.14,25.26,18.84,11.72.
(2)式(4-2)化合物的制备
(2) Preparation of compounds of formula (4-2)
于烧瓶中加入二氯甲烷(40mL)和式(3-2)化合物(4.15g，10mmol)，搅拌溶清，向反应液中缓慢滴加浓硫酸(0.55mL)，10℃搅拌3h，TLC检测反应完全后停止反应。将其缓慢倒入冰水中(100mL)，搅拌5min，滴加饱和碳酸钠溶液调PH值至7-8，二氯甲烷(30mL*2)萃取，合并有机相，依次用水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(4-2)化合物(3.79g，白色固体，摩尔收率94.8％)。1H NMR(600MHz,CDCl3)δ6.85(dd,J＝15.6,8.9Hz,1H),5.77(d,J＝16.5Hz,2H),5.48(d,J＝5.7Hz,1H),4.19(q,J＝7.1Hz,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＝6.5Hz,4H),0.71(s,3H).13C NMR(150MHz,CDCl3)δ199.39,170.07,167.03,154.33,144.67,123.92,119.21,118.84,60.18,54.96,52.56,41.67,41.09,40.92,39.71,37.32,34.28,33.77,32.92,32.16,28.50,26.14,25.26,18.84,14.29,11.72.Add dichloromethane (40mL) and compound of formula (3-2) (4.15g, 10mmol) to the flask, stir to dissolve, slowly add concentrated sulfuric acid (0.55mL) dropwise to the reaction solution, stir at 10°C for 3h, and detect by TLC Stop the reaction after the reaction is complete. Slowly pour it into ice water (100mL), stir for 5 minutes, add saturated sodium carbonate solution dropwise to adjust the pH value to 7-8, extract with dichloromethane (30mL*2), combine the organic phases, and wash with water and saturated brine in sequence. Concentrate under reduced pressure and purify by column chromatography to obtain the compound of formula (4-2) (3.79g, white solid, molar yield 94.8%). 1 H NMR (600MHz, CDCl 3 ) δ6.85 (dd, J＝15.6, 8.9Hz, 1H), 5.77 (d, J＝16.5Hz, 2H), 5.48 (d, J＝5.7Hz, 1H), 4.19 (q,J＝7.1Hz,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=6.5Hz, 4H), 0.71 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) δ199.39,170.07,167.03,154.33,144.67,123.92,119.21,118.84,60.18,54.96,52.56,41.67, 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.
实施例四式(14)化合物的制备Example 4 Preparation of compound of formula (14)
(1)式(14-1)化合物的制备
(1) Preparation of compounds of formula (14-1)
于烧瓶中加入N,N-二甲基甲酰胺(10mL)、式(3-1)化合物(401mg,1mmol)，搅拌溶清，加入吡啶(1mg，0.01mmol)、10％Pd/C(20mg)，置换氢气三次，氢气压力4atm，25℃反应12h。TLC监测反应完全完毕后，滤除Pd/C，将滤液减压浓缩，干燥，柱层析纯化，得到式(14-1)化合物(350mg，白色固体，摩尔收率86.4％)。1H NMR(500MHz,CDCl3)δ3.68(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＝6.6Hz,3H),0.66(s,3H).13C NMR(150MHz,CDCl3)δ211.77,174.84,95.70,80.17,55.41,51.47,48.50,42.07,38.83,37.42,35.33,34.90,32.04,31.27,30.98,29.71,28.60,28.10,27.36,23.99,21.32,20.27,18.27,14.26,11.05.Add N,N-dimethylformamide (10 mL) and compound of formula (3-1) (401 mg, 1 mmol) to the flask, stir to dissolve, add pyridine (1 mg, 0.01 mmol), 10% Pd/C (20 mg ), replace hydrogen three times, hydrogen pressure is 4 atm, react at 25°C for 12 hours. After the TLC monitoring reaction was complete, 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%). 1 H NMR (500MHz, CDCl 3 ) δ3.68(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=6.6Hz, 3H), 0.66 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) δ211.77,174.84,95.70,80.17,55.41,51.47,48.50,42.07,38.83,37.42,35.33,34.90,32.04 ,31.27,30.98,29.71,28.60,28.10,27.36,23.99,21.32,20.27,18.27,14.26,11.05.
(2)式(14-2)化合物的制备
(2) Preparation of compounds of formula (14-2)
于烧瓶中加入N,N-二甲基甲酰胺(10mL)、式(3-2)化合物(414mg,1mmol)，搅拌溶清，加入吡啶(1mg，0.01mmol)、10％Pd/C(21mg)，置换氢气三次，氢气压力4atm，25℃反应12h。TLC监测反应完全完毕后，滤除Pd/C，将滤液减压浓缩，干燥，柱层析纯化，得到式(14-2)化合物(347mg，白色固体，摩尔收率82.8％)。1H NMR(500MHz,CDCl3)δ4.13(q,J＝7.1Hz,2H),2.36–2.30(m,1H),2.24–2.17(m,1H),2.06–2.01(m,1H),1.89–1.82(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,10H),0.95(s,3H),0.92(d,J＝6.6Hz,3H),0.65(s,3H).13C NMR(150MHz,CDCl3)δ211.77,174.40,95.70,80.16,60.18,55.46,48.50,42.08,39.03,38.84,37.43,35.33,34.90,32.05,31.27,31.00,29.70,28.60,28.10,27.36,23.99,21.32,20.28,18.27,14.26,11.05.Add N,N-dimethylformamide (10 mL) and compound of formula (3-2) (414 mg, 1 mmol) to the flask, stir to dissolve, add pyridine (1 mg, 0.01 mmol), 10% Pd/C (21 mg ), replace hydrogen three times, hydrogen pressure is 4 atm, react at 25°C for 12 hours. After the TLC monitoring reaction was complete, 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 (14-2) (347 mg, white solid, molar yield 82.8%). 1 H NMR (500MHz, CDCl 3 ) δ4.13 (q, J = 7.1Hz, 2H), 2.36–2.30 (m, 1H), 2.24–2.17 (m, 1H), 2.06–2.01 (m, 1H), 1.89–1.82(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,10H),0.95(s,3H ), 0.92 (d, J=6.6Hz, 3H), 0.65 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) δ211.77,174.40,95.70,80.16,60.18,55.46,48.50,42.08,39.03,38.84, 37.43,35.33,34.90,32.05,31.27,31.00,29.70,28.60,28.10,27.36,23.99,21.32,20.28,18.27,14.26,11.05.
实施例五式(6)化合物的制备Example 5 Preparation of compound of formula (6)
(1)式(6-1)化合物的制备
(1) Preparation of compounds of formula (6-1)
于烧瓶中加入二氯甲烷和甲醇(105mL，v/v＝20/1)的混合溶剂、式(4-1)化合物(3.83g,10mmol)，搅拌溶清，加入吡啶(40mg，0.5mmol)、10％Pd/C(192mg)，置换氢气三次，氢气压力1atm，25℃反应12h。TLC监测反应完全完毕后，滤除Pd/C，将滤液减压浓缩，干燥，柱层析纯化，得到式(6-1)化合物(3.37g，白色固体，摩尔收率87.9％)。1H NMR(500MHz,CDCl3)δ5.50(d,J＝5.4Hz,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＝6.5Hz,3H),0.62(s,3H).13C NMR(150MHz,CDCl3)δ213.70,174.72,139.37,119.65,56.07,53.27,51.52,44.68,43.80,41.93,41.04,38.82,38.30,37.49,36.32,35.24,31.06,30.95,28.92,28.27,26.50,26.44,25.25,17.94,11.70.
Add a mixed solvent of methylene chloride and methanol (105 mL, v/v=20/1) and the compound of formula (4-1) (3.83g, 10mmol) into the flask, stir to dissolve, and add pyridine (40mg, 0.5mmol) , 10% Pd/C (192 mg), replaced with hydrogen three times, hydrogen pressure 1 atm, reaction at 25°C for 12 hours. After the TLC monitoring reaction was complete, 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 (6-1) (3.37 g, white solid, molar yield 87.9%). 1 H NMR (500MHz, CDCl 3 ) δ5.50 (d, J = 5.4Hz, 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 = 6.5Hz, 3H), 0.62 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) 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.
于烧瓶中加入二氯甲烷(8mL)和式(14-1)化合物(404mg，1mmol)，搅拌溶清，缓慢滴加浓硫酸(0.05mL)，0℃搅拌1h，TLC检测反应完全后停止反应。将其缓慢倒入冰水中(20mL)，搅拌5min，滴加饱和碳酸钠溶液调PH值至7-8，分液，水相再用DCM(15mL)萃取一次，合并有机相，依次用水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(6-1)化合物(368mg，白色固体，摩尔收率95.1％)。1H NMR(500MHz,CDCl3)δ5.50(d,J＝5.4Hz,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＝6.5Hz,3H),0.62(s,3H).13C NMR(150MHz,CDCl3)δ213.70,174.72,139.37,119.65,56.07,53.27,51.52,44.68,43.80,41.93,41.04,38.82,38.30,37.49,36.32,35.24,31.06,30.95,28.92,28.27,26.50,26.44,25.25,17.94,11.70.Add dichloromethane (8 mL) and compound of formula (14-1) (404 mg, 1 mmol) to the flask, stir to dissolve, slowly add concentrated sulfuric acid (0.05 mL) dropwise, stir at 0°C for 1 hour, and stop the reaction after TLC detects that the reaction is complete. . Slowly pour it into ice water (20mL), stir for 5 minutes, add saturated sodium carbonate solution dropwise to adjust the pH value to 7-8, separate the liquids, extract the aqueous phase once more with DCM (15mL), combine the organic phases, and add water, saturated Wash with brine, concentrate under reduced pressure, and purify by column chromatography to obtain the compound of formula (6-1) (368 mg, white solid, molar yield 95.1%). 1 H NMR (500MHz, CDCl 3 ) δ5.50 (d, J = 5.4Hz, 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 = 6.5Hz, 3H), 0.62 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) 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.
(2)式(6-2)化合物的制备
(2) Preparation of compounds of formula (6-2)
于烧瓶中加入二氯甲烷(8mL)和式(14-2)化合物(419mg，1mmol)，搅拌溶清，缓慢滴加浓硫酸(0.05mL)，0℃搅拌1h，TLC检测反应完全后停止反应。将其缓慢倒入冰水中(20mL)，搅拌5min，滴加饱和碳酸钠溶液调PH值至7-8，分液，水相再用DCM(15mL)萃取一次，合并有机相，依次用水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(6-2)化合物(373mg，白色固体，摩尔收率93.2％)。1H NMR(500MHz,CDCl3)δ5.50(d,J＝5.4Hz,1H),4.13(q,J＝7.1Hz,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＝6.5Hz,3H),0.63(s,3H). Add dichloromethane (8 mL) and compound of formula (14-2) (419 mg, 1 mmol) to the flask, stir to dissolve, slowly add concentrated sulfuric acid (0.05 mL) dropwise, stir at 0°C for 1 hour, and stop the reaction after TLC detects that the reaction is complete. . Slowly pour it into ice water (20mL), stir for 5 minutes, add saturated sodium carbonate solution dropwise to adjust the pH value to 7-8, separate the liquids, extract the aqueous phase once more with DCM (15mL), combine the organic phases, and add water, saturated Wash with brine, concentrate under reduced pressure, and purify by column chromatography to obtain the compound of formula (6-2) (373 mg, white solid, molar yield 93.2%). 1 H NMR (500MHz, CDCl 3 ) δ5.50 (d, J = 5.4Hz, 1H), 4.13 (q, J = 7.1Hz, 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＝6.5Hz,3H),0.63(s,3H).
实施例六式(5)化合物的制备Example 6 Preparation of compound of formula (5)
(1)式(5-1)化合物的制备
(1) Preparation of compounds of formula (5-1)
于反应釜中加入四氢呋喃(8mL)、式(4-1)化合物(765mg,2mmol)，搅拌溶清，加入Raney Ni(770mg)，90℃、4MPa H2下反应3h，TLC检测反应完全后停止反应。将上述反应液滤除Raney Ni，减压浓缩，柱层析纯化，得式(5-1)化合物(535mg，白色固体，摩尔收率70％)。1H NMR(500MHz,CDCl3)δ5.38–5.30(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＝6.4Hz,3H),0.59(s,3H).13C NMR(150MHz,CDCl3)δ174.91,140.19,119.61,72.41,56.18,53.44,51.63,42.18,42.09,41.05,38.66,38.09,36.70,35.87,35.39,31.98,31.21,31.11,29.75,28.42,27.07,25.46,18.06,11.76.Add tetrahydrofuran (8mL) and the compound of formula (4-1) (765mg, 2mmol) to the reaction kettle, stir to dissolve, add Raney Ni (770mg), react at 90°C, 4MPa H 2 for 3 hours, and stop after TLC detects that the reaction is complete. reaction. The above reaction solution was filtered to remove 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 (500MHz, CDCl 3 ) δ5.38–5.30(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＝6.4Hz ,3H),0.59(s,3H). 13 C NMR (150MHz, CDCl 3 )δ174.91,140.19,119.61,72.41,56.18,53.44,51.63,42.18,42.09,41.05,38.66,38.09,36.70,35.87, 35.39, 31.98,31.21,31.11,29.75,28.42,27.07,25.46,18.06,11.76.
(2)式(5-1)化合物的制备
(2) Preparation of compounds of formula (5-1)
于烧瓶中加入四氢呋喃和甲醇(40mL，v/v＝7/1)的混合溶剂、式(6-1)化合物(3.86g,10mmol)和CeCl3.7H2O(3.18g，11mmol)，加入KBH4(1.08g，20mmol)，-10℃反应5h。TLC监测反应完全完毕后，加入丙酮(4mL)淬灭反应。将溶液减压浓缩，加入乙酸乙酯(60mL)/水(60mL)萃取，分液，有机相依次用水、饱和NaCl溶液洗涤，减压浓缩，柱层析纯化，得到式(5-1)化合物(3.4g，白色固体，摩尔收率88.1％)。1H NMR(500MHz,CDCl3)δ5.38–5.30(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＝6.4Hz,3H),0.59(s,3H).13C NMR(150MHz,CDCl3)δ174.91,140.19,119.61,72.41,56.18,53.44,51.63,42.18,42.09,41.05,38.66,38.09,36.70,35.87,35.39,31.98,31.21,31.11,29.75,28.42,27.07,25.46,18.06,11.76. Add a mixed solvent of tetrahydrofuran and methanol (40 mL, v/v=7/1), the compound of formula (6-1) (3.86g, 10mmol) and CeCl 3 .7H 2 O (3.18g, 11mmol) into the flask, and add KBH 4 (1.08g, 20mmol), reacted at -10°C for 5h. After the TLC monitoring reaction was complete, acetone (4 mL) was added to quench the reaction. The solution was concentrated under reduced pressure, and extracted with ethyl acetate (60 mL)/water (60 mL). The liquids were separated. The organic phase was washed with water and saturated NaCl solution in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (5-1). (3.4g, white solid, molar yield 88.1%). 1 H NMR (500MHz, CDCl 3 ) δ5.38–5.30(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＝6.4Hz ,3H),0.59(s,3H).13C NMR(150MHz,CDCl 3 )δ174.91,140.19,119.61,72.41,56.18,53.44,51.63,42.18,42.09,41.05,38.66,38.09,36.70,35.87,3 5.39,31.98 ,31.21,31.11,29.75,28.42,27.07,25.46,18.06,11.76.
(3)式(5-2)化合物的制备
(3) Preparation of compounds of formula (5-2)
于反应釜中加入四氢呋喃(8mL)、式(4-2)化合物(793mg,2mmol)，搅拌溶清，加入Raney Ni(795mg)，80℃、4MPa H2下反应3h，TLC检测反应完全后停止反应。将上述反应液滤除Raney Ni，减压浓缩，柱层析纯化，得式(5-2)化合物(572mg，白色固体，摩尔收率71.1％)。1H NMR(600MHz,CDCl3)δ5.35–5.29(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＝5.3Hz,3H),0.57(s,3H).13C NMR(150MHz,CDCl3)δ174.33,140.06,119.49,72.28,60.18,56.07,53.32,42.06,41.97,40.93,38.53,37.97,36.58,35.75,35.24,31.86,31.34,30.98,29.61,28.27,26.94,25.33,17.93,14.26,11.62.Add tetrahydrofuran (8mL) and the compound of formula (4-2) (793mg, 2mmol) to the reaction kettle, stir to dissolve, add Raney Ni (795mg), react at 80°C, 4MPa H 2 for 3 hours, and stop after TLC detects that the reaction is complete. reaction. The above reaction solution was filtered to remove Raney Ni, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (5-2) (572 mg, white solid, molar yield 71.1%). 1 H NMR (600MHz, CDCl 3 ) δ5.35–5.29(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 = 5.3Hz, 3H), 0.57 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) 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.
实施例七式(7)化合物的制备Example 7 Preparation of compound of formula (7)
(1)式(7-1)化合物的制备
(1) Preparation of compounds of formula (7-1)
于烧瓶中加入二氯甲烷(8mL)、式(5-1)化合物(500mg，1.28mmol)，搅拌溶清，加入DMAP(31.5mg，0.26mmol)和乙酸酐(263mg，2.56mmol)，25℃反应8h，TLC监测反应完全后，加入饱和氯化铵(1mL)淬灭反应，加入二氯甲烷(20mL)和水(20mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-1)化合物(白色固体536mg，摩尔收率97.4％)。1H NMR(600MHz,CDCl3)δ5.35–5.32(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＝6.5Hz,3H),0.60(s,3H).13C NMR(125MHz,CDCl3)δ174.90,170.81,140.07,119.70,74.99,56.23,53.43,51.64,42.16,41.92,41.06,38.70,36.64,35.53,35.39,33.97,31.22,31.12,29.73,28.41,27.98,26.99,26.89,25.44,22.33,18.07,11.77. Add dichloromethane (8mL) and compound of formula (5-1) (500mg, 1.28mmol) to the flask, stir to dissolve, add DMAP (31.5mg, 0.26mmol) and acetic anhydride (263mg, 2.56mmol), 25°C React for 8 hours. After TLC monitors that the reaction is complete, add saturated ammonium chloride (1mL) to quench the reaction, add methylene chloride (20mL) and water (20mL) for extraction, and then wash the organic phase with water, saturated brine, and concentrate under reduced pressure. Purification by column chromatography gave the compound of formula (7-1) (white solid 536 mg, molar yield 97.4%). 1 H NMR (600MHz, CDCl 3 ) δ5.35–5.32(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＝6.5Hz,3H),0.60(s,3H). 13 C NMR (125MHz, CDCl 3 ) δ174.90,170.81,140.07,119.70,74.99,56.23,53.43,51.64,42.16,41.92,41.06,38.70,36.64,35.53,35.39,33.97,31.2 2,31.12,29.73,28.41,27.98 ,26.99,26.89,25.44,22.33,18.07,11.77.
(2)式(7-2)化合物的制备
(2) Preparation of compounds of formula (7-2)
于烧瓶中加入二氯甲烷(40mL)、式(5-1)化合物(3.88g，10mmol)，搅拌溶清，加入三乙胺(2.02g，20mmol)、DMAP(0.25g，2mmol)和对甲氧基苯甲酰氯(3.4g，20mmol)，25℃反应8h，TLC监测反应完全后，加入饱和氯化铵(5mL)淬灭反应，加入二氯甲烷(50mL)和水(40mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-2)化合物(白色固体4.88g，摩尔收率93.5％)。1H NMR(600MHz,CDCl3)δ8.01(d,J＝8.9Hz,2H),6.92(d,J＝8.9Hz,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＝5.5Hz,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＝6.5Hz,3H),0.61(s,3H).13C NMR(150MHz,CDCl3)δ174.75,165.92,163.15,140.07,131.53,123.42,119.53,113.45,75.07,56.09,55.41,53.28,51.50,42.03,41.86,40.95,38.64,36.54,35.48,35.25,34.02,31.07,31.00,29.65,28.29,28.04,26.91,26.81,25.31,17.96,11.66.Add dichloromethane (40 mL) and compound of formula (5-1) (3.88 g, 10 mmol) to the flask, stir to dissolve, add triethylamine (2.02 g, 20 mmol), DMAP (0.25 g, 2 mmol) and p-methyl Oxybenzoyl chloride (3.4g, 20mmol) was reacted at 25°C for 8 hours. After TLC monitoring of the reaction was complete, saturated ammonium chloride (5mL) was added to quench the reaction, dichloromethane (50mL) and water (40mL) were added for extraction, and the organic The phase was washed with water and saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (7-2) (4.88 g of white solid, molar yield 93.5%). 1 H NMR (600MHz, CDCl 3 ) δ8.01(d,J＝8.9Hz,2H),6.92(d,J＝8.9Hz,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＝5.5Hz,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＝6.5Hz,3H),0.61(s,3H ). 13 C NMR (150MHz, CDCl 3 ) δ174.75,165.92,163.15,140.07,131.53,123.42,119.53,113.45,75.07,56.09,55.41,53.28,51.50,42.03,41.86,40.9 5,38.64,36.54,35.48,35.25 ,34.02,31.07,31.00,29.65,28.29,28.04,26.91,26.81,25.31,17.96,11.66.
(3)式(7-3)化合物的制备
(3) Preparation of compounds of formula (7-3)
于烧瓶中加入二氯甲烷(40mL)、式(5-2)化合物(4.02g，10mmol)，搅拌溶清，加入三乙胺(2.02g，20mmol)、DMAP(0.246g，2mmol)和对甲氧基苯甲酰氯(3.41g，20mmol)，25℃反应8h，TLC监测反应完全后，加入饱和氯化铵(5mL)淬灭反应，加入二氯甲烷(50mL)和水(40mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-3)化合物(白色固体4.98g，摩尔收率93％)。1H NMR(600MHz,CDCl3)δ8.01(d,J＝8.9Hz,2H),6.92(d,J＝8.9Hz,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＝5.6Hz,4H),1.48–1.45(m,1H),1.39–1.32(m,5H),1.28(t,J＝7.1Hz,3H),1.24–1.14(m,3H),1.11(s,3H),0.95 (d,J＝6.5Hz,3H),0.62(s,3H).13C NMR(150MHz,CDCl3)δ174.34,165.94,163.15,140.08,131.53,123.44,119.54,113.46,75.10,60.20,56.13,55.41,53.30,42.05,41.88,40.96,38.65,36.56,35.49,35.25,34.03,31.36,31.01,29.65,28.29,28.05,26.91,26.82,25.31,17.97,14.27,11.66.Add dichloromethane (40 mL) and compound of formula (5-2) (4.02 g, 10 mmol) to the flask, stir to dissolve, add triethylamine (2.02 g, 20 mmol), DMAP (0.246 g, 2 mmol) and p-methyl Oxybenzoyl chloride (3.41g, 20mmol), react for 8 hours at 25°C. After TLC monitoring of the reaction is complete, add saturated ammonium chloride (5mL) to quench the reaction, add dichloromethane (50mL) and water (40mL) for extraction, organic The phase was washed with water and saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (7-3) (4.98 g of white solid, molar yield 93%). 1 H NMR (600MHz, CDCl 3 ) δ8.01(d,J＝8.9Hz,2H),6.92(d,J＝8.9Hz,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＝5.6Hz,4H),1.48–1.45(m, 1H),1.39–1.32(m,5H),1.28(t,J＝7.1Hz,3H),1.24–1.14(m,3H),1.11(s,3H),0.95 (D, J = 6.5Hz, 3H), 0.62 (s, 3H). 13 C NMR (150MHz, CDCL 3 ) Δ174.34,165.94,163.15,1408,131.53,123.44,113.46,75.10,60,56.13,5 5.41 , 53.30,42.05,41.88,40.96,38.65,36.56,35.49,35.25,34.03,36,31.01,28.29,28.05,26.82,17.97,14.27,11.66.
(4)式(7-4)化合物的制备
(4) Preparation of compounds of formula (7-4)
于烧瓶中加入二氯甲烷(8mL)、式(5-1)化合物(500mg，1.28mmol)，搅拌溶清，加入DMAP(32mg，0.26mmol)和苯甲酸酐(583mg，2.56mmol)，25℃反应8h，TLC监测反应完全后，加入饱和氯化铵(1mL)淬灭反应，加入二氯甲烷(30mL)和水(20mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-4)化合物(白色固体601mg，摩尔收率95.3％)。1H NMR(500MHz,CDCl3)δ8.06(dd,J＝8.1,1.5Hz,2H),7.60–7.52(m,1H),7.44(t,J＝7.6Hz,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＝9.8,6.3Hz,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＝6.5Hz,3H),0.62(s,3H).13C NMR(125MHz,CDCl3)δ174.78,166.18,140.03,132.66,130.96,129.54,128.24,119.57,75.45,56.09,53.28,51.51,42.03,41.86,40.95,38.64,36.53,35.46,35.26,33.96,31.08,31.00,29.65,28.29,27.98,26.90,26.80,25.31,17.96,11.66.Add dichloromethane (8mL) and compound of formula (5-1) (500mg, 1.28mmol) to the flask, stir to dissolve, add DMAP (32mg, 0.26mmol) and benzoic anhydride (583mg, 2.56mmol), 25°C React for 8 hours. After TLC monitors that the reaction is complete, add saturated ammonium chloride (1mL) to quench the reaction, add dichloromethane (30mL) and water (20mL) for extraction, and then wash the organic phase with water, saturated brine, and concentrate under reduced pressure. Purification by column chromatography gave the compound of formula (7-4) (601 mg of white solid, molar yield 95.3%). 1 H NMR (500MHz, CDCl 3 ) δ8.06 (dd, J＝8.1, 1.5Hz, 2H), 7.60–7.52 (m, 1H), 7.44 (t, J＝7.6Hz, 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＝9.8,6.3Hz,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＝6.5Hz,3H),0.62(s,3H). 13 C NMR (125MHz, CDCl 3 )δ174.78,166.18,140.03,132.66,130.96,129.54,128.24,119.57,75.45,56.09,53.28,51.51,42.03,41.86,40.95,38.64,36.53,35.46,35.2 6,33.96,31.08,31.00,29.65,28.29,27.98 ,26.90,26.80,25.31,17.96,11.66.
(5)式(7-5)化合物的制备
(5) Preparation of compounds of formula (7-5)
于烧瓶中加入二氯甲烷(8mL)、式(5-1)化合物(500mg，1.28mmol)，搅拌溶清，加入DMAP(32mg，0.26mmol)、三乙胺(261mg，2.56mmol)和4-三氟甲基苯甲酰氯(534mg，2.56mmol)，25℃反应8h，TLC监测反应完全后，加入饱和氯化铵(1mL)淬灭反应，加入二氯甲烷(30mL)和水(30mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-5)化合物(白色固体677mg，摩尔收率94.4％)。1H NMR(500MHz,CDCl3)δ8.17(d,J＝8.1Hz,2H),7.70(d,J＝8.3Hz,2H),5.45–5.35(m,1H),5.03(q,J＝7.7,6.0Hz,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＝6.5Hz,3H),0.62(s,3H).13C NMR(125MHz,CDCl3)δ174.76,164.93,139.97,134.16,129.95,125.29,125.25,119.65,76.18,56.11,53.28,51.51,42.02,41.85,40.95,38.63,36.52,35.39,35.25,33.88,31.07,30.99,29.61,28.28,27.92,26.88,26.77,25.30,17.96,11.66.Add dichloromethane (8mL), compound of formula (5-1) (500mg, 1.28mmol) to the flask, stir to dissolve, add DMAP (32mg, 0.26mmol), triethylamine (261mg, 2.56mmol) and 4- Trifluoromethylbenzoyl chloride (534 mg, 2.56 mmol) was reacted at 25°C for 8 hours. After TLC monitoring of the reaction was complete, saturated ammonium chloride (1 mL) was added to quench the reaction, and dichloromethane (30 mL) and water (30 mL) were added for extraction. , the organic phase was washed with water, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (7-5) (white solid 677 mg, molar yield 94.4%). 1 H NMR (500MHz, CDCl 3 ) δ8.17 (d, J＝8.1Hz, 2H), 7.70 (d, J＝8.3Hz, 2H), 5.45–5.35 (m, 1H), 5.03 (q, J＝ 7.7,6.0Hz,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 = 6.5Hz, 3H), 0.62 (s, 3H). 13 C NMR (125MHz, CDCl 3 ) 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.
(6)式(7-6)化合物的制备
(6) Preparation of compounds of formula (7-6)
于烧瓶中加入二氯甲烷(8mL)、式(5-1)化合物(500mg，1.28mmol)，搅拌溶清，加入DMAP(32mg，0.26mmol)、三乙胺(261mg，2.56mmol)和2,4-二甲氧基苯甲酰氯(514mg，2.56mmol)，40℃反应6h，TLC监测反应完全后，加入饱和氯化铵(2mL)淬灭反应，加入二氯甲烷(30mL)和水(30mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-6)化合物(白色固体636mg，摩尔收率90％)。1H NMR(500MHz,CDCl3)δ7.82(d,J＝9.3Hz,1H),6.48(dd,J＝4.6,2.4Hz,2H),5.36(dd,J＝5.2,2.6Hz,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＝6.5Hz,3H),0.60(s,3H).Add dichloromethane (8mL), compound of formula (5-1) (500mg, 1.28mmol) to the flask, stir to dissolve, add DMAP (32mg, 0.26mmol), triethylamine (261mg, 2.56mmol) and 2, 4-Dimethoxybenzoyl chloride (514 mg, 2.56 mmol), react at 40°C for 6 hours. After TLC monitoring the reaction is complete, add saturated ammonium chloride (2 mL) to quench the reaction, add dichloromethane (30 mL) and water (30 mL) ) extraction, the organic phase was washed with water, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (7-6) (white solid 636 mg, molar yield 90%). 1 H NMR (500MHz, CDCl 3 ) δ7.82 (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＝6.5Hz,3H),0.60(s,3H).
13C NMR(125MHz,CDCl3)δ174.79,165.08,163.95,161.28,140.07,133.47,119.48,113.21,104.42,98.97,74.83,56.07,55.99,55.46,53.29,51.51,42.04,41.89,40.93,38.66,36.54,35.52,35.26,33.98,31.08,30.98,29.64,28.29,28.00,26.91,26.82,25.31,17.94,11.64. 13 C NMR (125MHz, CDCl 3 ) δ174.79,165.08,163.95,161.28,140.07,133.47,119.48,113.21,104.42,98.97,74.83,56.07,55.99,55.46,53.29,51.51 ,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.
(7)式(7-7)化合物的制备
(7) Preparation of compounds of formula (7-7)
于烧瓶中加入二氯甲烷(8mL)、式(5-1)化合物(500mg，1.28mmol)，搅拌溶清，加入DMAP(32mg，0.26mmol)、三乙胺(261mg，2.56mmol)和2-甲氧基苯甲酰氯(437mg，2.56mmol)，25℃反应8h，TLC监测反应完全后，加入饱和氯化铵(2mL)淬灭反应，加 入二氯甲烷(30mL)和水(30mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-7)化合物(白色固体614mg，摩尔收率92％)。1H NMR(500MHz,CDCl3)δ7.75(dd,J＝7.8,1.8Hz,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＝8.0Hz,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＝6.5Hz,3H),0.60(s,3H).13C NMR(150MHz,CDCl3)δ174.74,165.77,158.95,140.01,133.05,131.21,121.12,120.08,119.54,112.07,75.28,56.08,56.01,53.29,51.48,42.05,41.91,40.94,38.64,36.54,35.50,35.25,33.91,31.08,30.98,29.62,28.28,27.94,26.90,26.81,25.31,17.94,11.64.Add dichloromethane (8mL) and compound of formula (5-1) (500mg, 1.28mmol) to the flask, stir to dissolve, add DMAP (32mg, 0.26mmol), triethylamine (261mg, 2.56mmol) and 2- Methoxybenzoyl chloride (437 mg, 2.56 mmol) was reacted at 25°C for 8 hours. After the reaction was monitored by TLC, saturated ammonium chloride (2 mL) was added to quench the reaction. Dichloromethane (30 mL) and water (30 mL) were added for extraction, and the organic phase was washed with water, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (7-7) (white solid 614 mg, molar yield 92%). 1 H NMR (500MHz, CDCl 3 ) δ7.75 (dd, J＝7.8, 1.8Hz, 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＝8.0Hz,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＝6.5Hz,3H),0.60(s,3H). 13 C NMR(150MHz, CDCl 3 )δ174.74,165.77,158.95,140.01,133.05,131.21,121.12,120.08,119.54,112.07,75.28,56.08,56.01,53.29,51.48,42.05,41.91,40.9 4,38.64,36.54,35.50,35.25,33.91,31.08 ,30.98,29.62,28.28,27.94,26.90,26.81,25.31,17.94,11.64.
(8)式(7-8)化合物的制备
(8) Preparation of compounds of formula (7-8)
于烧瓶中加入二氯甲烷(8mL)、式(5-2)化合物(515mg，1.28mmol)，搅拌溶清，加入DMAP(32mg，0.26mmol)、三乙胺(392mg，3.87mmol)和4-三氟甲基苯甲酰氯(534mg，2.56mmol)，25℃反应8h，TLC监测反应完全后，加入饱和氯化铵(1mL)淬灭反应，加入二氯甲烷(30mL)和水(30mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-8)化合物。1H NMR(600MHz,CDCl3)δ8.14(d,J＝8.1Hz,2H),7.68(d,J＝8.1Hz,2H),5.43–5.33(m,1H),5.03–4.99(m,1H),4.12(q,J＝7.1Hz,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＝7.1Hz,3H),1.22–1.12(m,3H),1.10(s,3H),0.93(d,J＝6.5Hz,3H),0.59(s,3H).13C NMR(150MHz,CDCl3)δ174.31,164.92,139.97,134.30,134.18,134.08,129.94,125.30,125.27,125.25,119.66,76.19,60.20,56.14,53.30,42.04,41.86,40.96,38.63,36.54,35.40,35.23,33.89,31.35,30.99,29.61,28.27,27.93,26.89,26.78,25.30,17.97,14.26,11.65.Add dichloromethane (8mL), compound of formula (5-2) (515mg, 1.28mmol) to the flask, stir to dissolve, add DMAP (32mg, 0.26mmol), triethylamine (392mg, 3.87mmol) and 4- Trifluoromethylbenzoyl chloride (534 mg, 2.56 mmol) was reacted at 25°C for 8 hours. After TLC monitoring of the reaction was complete, saturated ammonium chloride (1 mL) was added to quench the reaction, and dichloromethane (30 mL) and water (30 mL) were added for extraction. , the organic phase was washed with water, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (7-8). 1 H NMR (600MHz, CDCl 3 ) δ8.14(d,J＝8.1Hz,2H),7.68(d,J＝8.1Hz,2H),5.43–5.33(m,1H),5.03–4.99(m, 1H),4.12(q,J＝7.1Hz,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＝7.1Hz,3H),1.22–1.12(m,3H),1.10(s,3H),0.93(d,J＝6.5Hz,3H),0.59(s,3H). 13 C NMR (150MHz, CDCl 3 ) δ174.31,164.92,139.97,134.30,134.18,134.08,129.94,125.30,125.27,125.25,119.66,76.19,60.20,56.14,53.30,42.04,41.86,40.96 ,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.
(9)式(7-9)化合物的制备
(9) Preparation of compounds of formula (7-9)
于烧瓶中加入二氯甲烷(8mL)、式(5-2)化合物(515mg，1.28mmol)，搅拌溶清，加入DMAP(33mg，0.27mmol)、三乙胺(390mg，3.85mmol)和2,4-二甲氧基苯甲酰氯(642mg，3.2mmol)，40℃反应8h，TLC监测反应完全后，加入饱和氯化铵(2mL)淬灭反应，加入二氯甲烷(30mL)和水(30mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-9)化合物。1H NMR(500MHz,CDCl3)δ7.82(d,J＝9.3Hz,1H),6.49–6.46(m,2H),5.38–5.32(m,1H),4.95(t,J＝7.4Hz,1H),4.13(q,J＝7.1Hz,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＝8.0Hz,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＝6.5Hz,3H),0.60(s,3H).13C NMR(125MHz,CDCl3)δ174.78,165.07,163.96,161.29,140.08,133.48,119.49,113.22,104.43,98.98,74.19,60.19,56.08,55.99,55.46,53.29,51.52,42.04,41.89,40.94,38.67,36.55,35.52,35.26,33.98,31.08,30.98,29.64,28.29,28.00,26.92,26.83,25.31,17.94,11.64.Add dichloromethane (8mL), compound of formula (5-2) (515mg, 1.28mmol) to the flask, stir to dissolve, add DMAP (33mg, 0.27mmol), triethylamine (390mg, 3.85mmol) and 2, 4-Dimethoxybenzoyl chloride (642 mg, 3.2 mmol), react at 40°C for 8 hours. After TLC monitoring of the reaction is complete, add saturated ammonium chloride (2 mL) to quench the reaction, add dichloromethane (30 mL) and water (30 mL) ) extraction, the organic phase is washed with water, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (7-9). 1 H NMR (500MHz, CDCl 3 ) δ7.82 (d, J = 9.3Hz, 1H), 6.49–6.46 (m, 2H), 5.38–5.32 (m, 1H), 4.95 (t, J = 7.4Hz, 1H),4.13(q,J＝7.1Hz,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＝8.0Hz,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=6.5Hz,3H),0.60(s,3H). 13 C NMR (125MHz, CDCl 3 )δ174.78,165.07,163.96,161.29,140.08,133.48 ,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.
(10)式(7-10)化合物的制备
(10) Preparation of compounds of formula (7-10)
于烧瓶中加入二氯甲烷(8mL)、式(5-2)化合物(515mg，1.28mmol)，搅拌溶清，加入DMAP(33mg，0.27mmol)、三乙胺(385mg，3.81mmol)和2-甲氧基苯甲酰氯(655mg，3.84mmol)，45℃反应8h，TLC监测反应完全后，加入饱和氯化铵(2mL)淬灭反应，加入二氯甲烷(30mL)和水(30mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-10)化合物。1H NMR(600MHz,CDCl3)δ7.75(dd,J＝7.9,1.9Hz,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＝7.2Hz,3H),1.22–1.12(m,3H),1.11(s,3H),0.94(d,J＝6.5Hz,3H),0.61(s,3H).13C NMR(150MHz,CDCl3)δ174.76,165.78,158.94,140.02,133.07,131.20,121.13,120.09,119.55,112.09,74.17,60.18,56.08,56.02,53.29,51.48,42.05,41.91,40.94,38.64,36.54,35.50,35.25,33.91,31.08,30.98,29.62,28.28,27.94,26.90,26.81,25.31,17.94,11.64.Add dichloromethane (8mL) and compound of formula (5-2) (515mg, 1.28mmol) to the flask, stir to dissolve, add DMAP (33mg, 0.27mmol), triethylamine (385mg, 3.81mmol) and 2- Methoxybenzoyl chloride (655 mg, 3.84 mmol) was reacted at 45°C for 8 hours. After TLC monitoring of the reaction was complete, saturated ammonium chloride (2 mL) was added to quench the reaction, dichloromethane (30 mL) and water (30 mL) were added for extraction. The organic phase was washed with water, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (7-10). 1 H NMR (600MHz, CDCl 3 ) δ7.75 (dd, J＝7.9, 1.9Hz, 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＝7.2Hz,3H),1.22–1.12(m,3H),1.11(s,3H),0.94(d,J =6.5Hz, 3H), 0.61 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) δ174.76,165.78,158.94,140.02,133.07,131.20,121.13,120.09,119.55,112.09,74.17,60.18, 56.08,56.02 , 53.29,51.48,42.05,41.91,40.94,38.64,36.54,35.50, 33.91,31.08, 30.9.628.28,26.90,26.8.31,17.94,11.64.
(11)式(7-11)化合物的制备
(11) Preparation of compounds of formula (7-11)
于烧瓶中加入二氯甲烷(8mL)、式(5-2)化合物(515mg，1.28mmol)，搅拌溶清，加入DMAP(32mg，0.26mmol)和苯甲酸酐(583mg，2.56mmol)，25℃反应8h，TLC监测反应完全后，加入饱和氯化铵(1mL)淬灭反应，加入二氯甲烷(30mL)和水(20mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(7-11)化合物(白色固体605mg，摩尔收率93.4％)。1H NMR(600MHz,CDCl3)δ8.10–8.03(m,2H),7.58–7.53(m,1H),7.44(t,J＝7.8Hz,2H),5.42–5.35(m,1H),5.06–4.97(m,1H),4.15(q,J＝7.1Hz,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＝7.1Hz,3H),1.24–1.13(m,3H),1.12(s,3H),0.95(d,J＝6.6Hz,3H),0.62(s,3H).13C NMR(150MHz,CDCl3)δ174.33,166.17,140.03,132.66,130.97,129.54,128.24,119.58,75.44,60.20,56.12,53.29,42.04,41.87,40.95,38.65,36.54,35.46,35.24,33.96,31.35,31.00,29.65,28.29,27.99,26.90,26.81,25.31,17.97,14.28,11.66.Add dichloromethane (8mL) and compound of formula (5-2) (515mg, 1.28mmol) to the flask, stir to dissolve, add DMAP (32mg, 0.26mmol) and benzoic anhydride (583mg, 2.56mmol), 25°C React for 8 hours. After TLC monitors that the reaction is complete, add saturated ammonium chloride (1mL) to quench the reaction, add dichloromethane (30mL) and water (20mL) for extraction, and then wash the organic phase with water, saturated brine, and concentrate under reduced pressure. Purification by column chromatography gave the compound of formula (7-11) (605 mg of white solid, molar yield 93.4%). 1 H NMR (600MHz, CDCl 3 ) δ8.10–8.03(m,2H),7.58–7.53(m,1H),7.44(t,J＝7.8Hz,2H),5.42–5.35(m,1H), 5.06–4.97(m,1H),4.15(q,J＝7.1Hz,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＝7.1Hz,3H),1.24–1.13(m,3H),1.12(s,3H),0.95(d,J＝6.6Hz,3H),0.62(s,3H). 13 C NMR (150MHz, CDCl 3 ) δ174.33,166.17,140.03,132.66,130.97,129.54,128.24,119.58,75.44,60.20,56.12,53.29,42.04,41.87,40.95,38.65,36. 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.
实施例八式(9)化合物的制备Example 8 Preparation of compound of formula (9)
(1)式(9-1)化合物的制备
(1) Preparation of compounds of formula (9-1)
于烧瓶中加入丙酮/水(100mL，v/v＝9：1)、式(4-1)化合物(3.82g，10mmol)，搅拌溶清，加入PDC(11.3g，30mmol)和NHPI(1.63g，10mmol)，45℃搅拌12h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(120mL)和水(100mL)萃取，有机相依次水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(9-1)化合物(1.97g，白色固体，摩尔收率49.7％)。1H NMR(600MHz,CDCl3)δ6.94(dd,J＝15.6,9.2Hz,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＝6.9,1.4Hz,3H),0.96(s,3H).13C NMR(150MHz,CDCl3)δ204.46,198.16,167.35,166.55,154.18,125.20,122.14,119.62,52.66,52.17,51.43,46.87,41.59,39.29,38.56,33.95,33.32,32.19,30.98,26.52,26.25,23.98,20.90,11.46. Add acetone/water (100mL, v/v=9:1) and compound of formula (4-1) (3.82g, 10mmol) to the flask, stir to dissolve, add PDC (11.3g, 30mmol) and NHPI (1.63g , 10 mmol), stir at 45°C for 12 h, and stop the reaction after TLC detects that the reaction is complete. Ethyl acetate (120 mL) and water (100 mL) were added to the reaction solution for extraction. The organic phase was washed with water and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (9-1) (1.97 g, white solid) , molar yield 49.7%). 1 H NMR (600MHz, CDCl 3 ) δ6.94 (dd, J＝15.6, 9.2Hz, 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 ＝6.9,1.4Hz,3H),0.96(s,3H). 13 C NMR (150MHz, CDCl 3 )δ204.46,198.16,167.35,166.55,154.18,125.20,122.14,119.62,52.66,52.17,51.43,46.8 7,41.59 ,39.29,38.56,33.95,33.32,32.19,30.98,26.52,26.25,23.98,20.90,11.46.
于烧瓶中加入乙酸(20mL)、三氧化铬(4g，40mmol)，搅拌溶清，加入式(4-1)化合物(3.82g，10mmol)，45℃搅拌12h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(60mL)和水(60mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(9-1)化合物(1.9g，白色固体，摩尔收率47.9％)。1H NMR(600MHz,CDCl3)δ6.94(dd,J＝15.6,9.2Hz,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＝6.9,1.4Hz,3H),0.96(s,3H).13C NMR(150MHz,CDCl3)δ204.46,198.16,167.35,166.55,154.18,125.20,122.14,119.62,52.66,52.17,51.43,46.87,41.59,39.29,38.56,33.95,33.32,32.19,30.98,26.52,26.25,23.98,20.90,11.46.Add acetic acid (20 mL) and chromium trioxide (4 g, 40 mmol) to the flask, stir to dissolve, add the compound of formula (4-1) (3.82 g, 10 mmol), stir at 45°C for 12 hours, and stop the reaction after TLC detects that the reaction is complete. Ethyl acetate (60 mL) and water (60 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (9-1). (1.9g, white solid, molar yield 47.9%). 1 H NMR (600MHz, CDCl 3 ) δ6.94 (dd, J＝15.6, 9.2Hz, 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 ＝6.9,1.4Hz,3H),0.96(s,3H). 13 C NMR (150MHz, CDCl 3 )δ204.46,198.16,167.35,166.55,154.18,125.20,122.14,119.62,52.66,52.17,51.43,46.8 7,41.59 ,39.29,38.56,33.95,33.32,32.19,30.98,26.52,26.25,23.98,20.90,11.46.
(2)式(9-2)化合物的制备
(2) Preparation of compounds of formula (9-2)
于烧瓶中加入乙酸(20mL)、三氧化铬(4g，40mmol)，搅拌溶清，加入式(4-2)化合物(3.96g，10mmol)，40℃搅拌20h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(60mL)和水(60mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(9-2)化合物(2.25g，白色固体，摩尔收率54.8％)。1H NMR(600MHz,CDCl3)δ6.94(dd,J＝15.6,9.2Hz,1H),5.86–5.75(m,3H),4.19(q,J＝7.2Hz,2H),2.70–2.43(m,6H),2.21–2.01(m,4H),1.91–1.83(m,2H),1.75–1.68(m,2H),1.52–1.45(m,5H),1.35–1.29(m,3H),1.27–1.21(m,2H),1.18(dd,J＝6.9,1.4Hz,3H),0.98(s,3H).13C NMR(150MHz,CDCl3)δ204.46,198.16,166.97,166.53,153.86,125.20,122.14,120.03,60.19,52.66,52.17,46.87,41.59,39.29,38.56,33.95,33.32,32.19,30.98,26.52,26.25,23.98,20.90,14.28,11.46.Add acetic acid (20 mL) and chromium trioxide (4 g, 40 mmol) to the flask, stir to dissolve, add the compound of formula (4-2) (3.96 g, 10 mmol), stir at 40°C for 20 h, and stop the reaction after TLC detects that the reaction is complete. Ethyl acetate (60 mL) and water (60 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (9-2). (2.25g, white solid, molar yield 54.8%). 1 H NMR (600MHz, CDCl 3 ) δ6.94 (dd, J＝15.6, 9.2Hz, 1H), 5.86–5.75 (m, 3H), 4.19 (q, J＝7.2Hz, 2H), 2.70–2.43 ( m,6H),2.21–2.01(m,4H),1.91–1.83(m,2H),1.75–1.68(m,2H),1.52–1.45(m,5H),1.35–1.29(m,3H), 1.27–1.21(m,2H),1.18(dd,J=6.9,1.4Hz,3H),0.98(s,3H). 13 C NMR(150MHz, CDCl 3 )δ204.46,198.16,166.97,166.53,153.86,125.20 ,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.
实施例九式(10)化合物的制备Example 9 Preparation of compound of formula (10)
(1)式(10-1)化合物的制备
(1) Preparation of compounds of formula (10-1)
于反应釜中加入四氢呋喃(8mL)、式(9-1)化合物(793mg,2mmol)，搅拌溶清，加入Raney Ni(794mg)，90℃、4MPa H2下反应3h，TLC检测反应完全后停止反应。将 上述反应液滤除Raney Ni，减压浓缩，柱层析纯化，得式(10-1)化合物(540mg，白色固体，摩尔收率67％)。1H NMR(600MHz,CDCl3)δ5.67(d,J＝2.3Hz,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＝6.6Hz),0.87(s,3H).13C NMR(150MHz,CDCl3)δ205.04,174.61,164.29,123.49,71.37,53.34,52.89,51.33,47.12,41.87,39.82,37.94,37.75,35.16,35.26,31.64,31.36,30.50,29.67,27.25,26.46,26.22,24.08,19.34,10.62。Add tetrahydrofuran (8mL) and the compound of formula (9-1) (793mg, 2mmol) to the reaction kettle, stir to dissolve, add Raney Ni (794mg), and react at 90°C and 4MPa H for 3 hours. TLC will detect that the reaction is complete and then stop. reaction. Will The above reaction solution was filtered to remove Raney Ni, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (10-1) (540 mg, white solid, molar yield 67%). 1 H NMR (600MHz, CDCl 3 ) δ5.67 (d, J = 2.3Hz, 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 (150MHz, CDCl 3 ) δ205.04,174.61,164.29,123.49,71.37,53.34,52.89,51.33,47.12,41.87,39.82,37.94,37.75,35.16,3 5.26,31.64 ,31.36,30.50,29.67,27.25,26.46,26.22,24.08,19.34,10.62.
(2)式(10-2)化合物的制备
(2) Preparation of compounds of formula (10-2)
于反应釜中加入四氢呋喃(8mL)、式(9-2)化合物(821mg,2mmol)，搅拌溶清，加入Raney Ni(821mg)，85℃、4MPa H2下反应4h，TLC检测反应完全后停止反应。将上述反应液滤除Raney Ni，减压浓缩，柱层析纯化，得式(10-2)化合物(530mg，白色固体，摩尔收率64.6％)。1H NMR(600MHz,CDCl3)δ5.74(d,J＝2.4Hz,1H),4.19(q,J＝7.2Hz,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＝6.6Hz,3H),0.93(s,3H).Add tetrahydrofuran (8mL) and the compound of formula (9-2) (821mg, 2mmol) to the reaction kettle, stir to dissolve, add Raney Ni (821mg), react at 85°C, 4MPa H 2 for 4 hours, and stop after TLC detects that the reaction is complete. reaction. The above reaction solution was filtered to remove Raney Ni, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (10-2) (530 mg, white solid, molar yield 64.6%). 1 H NMR (600MHz, CDCl 3 ) δ5.74 (d, J = 2.4Hz, 1H), 4.19 (q, J = 7.2Hz, 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＝6.6Hz,3H),0.93(s,3H) .
实施例十式(8)化合物的制备Example 10 Preparation of compound of formula (8)
(1)式(8-1)化合物的制备
(1) Preparation of compounds of formula (8-1)
于烧瓶中加入乙酸乙酯(40mL)、式(10-1)化合物(4.02g，10mmol)，搅拌溶清，加入DMAP(246mg，2mmol)和乙酸酐(2.04g，20mmol)，25℃反应8h，TLC监测反应完全后，加入水(40mL)淬灭反应，乙酸乙酯(50mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，得到式(8-1)化合物(白色固体4.35g，摩尔收率97.8％)。1H NMR(600MHz,CDCl3)δ5.73(d,J＝2.3Hz,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＝11.0Hz,1H),1.49–1.27(m,9H),1.22(s,3H),1.04(d,J＝6.5Hz,3H), 0.93(s,3H).13C NMR(150MHz,CDCl3)δ205.16,174.74,170.67,164.03,123.72,73.82,53.53,53.09,51.49,47.29,41.85,39.98,37.85,35.32,35.07,34.04,31.51,30.66,29.78,27.68,27.41,26.54,26.21,24.23,21.38,19.49,10.75.Add ethyl acetate (40mL) and the compound of formula (10-1) (4.02g, 10mmol) into the flask, stir to dissolve, add DMAP (246mg, 2mmol) and acetic anhydride (2.04g, 20mmol), and react at 25°C for 8 hours. , TLC monitors that after the reaction is complete, add water (40 mL) to quench the reaction, extract with ethyl acetate (50 mL), wash the organic phase with water, saturated brine, and concentrate under reduced pressure to obtain the compound of formula (8-1) (white solid 4.35g, molar yield 97.8%). 1 H NMR (600MHz, CDCl 3 ) δ5.73 (d, J = 2.3Hz, 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＝11.0Hz,1H),1.49–1.27(m,9H),1.22(s,3H),1.04(d,J＝6.5Hz,3H), 0.93 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) δ205.16,174.74,170.67,164.03,123.72,73.82,53.53,53.09,51.49,47.29,41.85,39.98,37.85,35.32,35. 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.
(2)式(8-2)化合物的制备
(2) Preparation of compounds of formula (8-2)
于烧瓶中加入二氯甲烷(40mL)、式(10-1)化合物(4.02g，10mmol)，搅拌溶清，加入三乙胺(2.02g，20mmol)、DMAP(246mg，2mmol)和对甲氧基苯甲酰氯(2.56g，15mmol)，25℃反应8h，TLC监测反应完全后，加入饱和氯化铵(5mL)淬灭反应，加入二氯甲烷(100mL)和水(80mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(8-2)化合物(白色固体5.1g，摩尔收率94.9％)。1H NMR(500MHz,CDCl3)δ7.99(d,J＝8.9Hz,2H),6.92(d,J＝8.9Hz,2H),5.78(d,J＝2.3Hz,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＝6.6Hz,3H),0.95(s,3H).13C NMR(150MHz,CDCl3)δ205.36,174.76,165.86,164.27,163.27,131.58,123.73,123.06,113.52,73.98,55.43,53.53,53.11,51.50,47.31,41.91,40.06,37.88,35.31,35.16,34.23,31.51,30.67,29.80,27.87,27.39,26.58,26.23,24.23,19.52,10.76.Add dichloromethane (40 mL) and compound of formula (10-1) (4.02 g, 10 mmol) to the flask, stir to dissolve, add triethylamine (2.02 g, 20 mmol), DMAP (246 mg, 2 mmol) and p-methoxy benzoyl chloride (2.56g, 15mmol), react at 25°C for 8 hours, after TLC monitoring the reaction is complete, add saturated ammonium chloride (5mL) to quench the reaction, add dichloromethane (100mL) and water (80mL) for extraction, and extract the organic phase After washing with water, washing with saturated brine, concentration under reduced pressure, and purification by column chromatography, the compound of formula (8-2) (5.1 g of white solid, molar yield 94.9%) was obtained. 1 H NMR (500MHz, CDCl 3 ) δ7.99 (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＝6.6Hz,3H),0.95(s,3H). 13 C NMR (150MHz, CDCl 3 ) δ205.36,174.76,165.86,164.27,163.27,131.58,123.73,123.06,113.52,73.98,55.43,53.53,53.11,51.50,47.31,41.91,40.06,37.88,35. 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.
(3)式(8-2)化合物的制备
(3) Preparation of compounds of formula (8-2)
于烧瓶中加入乙酸(20mL)、三氧化铬(4g，40mmol)，搅拌溶清，加入式(7-2)化合物(5.22g，10mmol)，35℃搅拌12h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(90mL)和水(100mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(8-2)化合物(4.95g，白色固体，摩尔收率92.3％)。1H NMR(500MHz,CDCl3)δ7.99(d,J＝8.9Hz,2H),6.92(d,J＝8.9Hz,2H),5.78(d,J＝2.3Hz,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＝6.6Hz,3H),0.95(s,3H).13C NMR(150MHz,CDCl3)δ205.36,174.76,165.86,164.27,163.27,131.58,123.73, 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.Add acetic acid (20 mL) and chromium trioxide (4 g, 40 mmol) to the flask, stir to dissolve, add the compound of formula (7-2) (5.22 g, 10 mmol), stir at 35°C for 12 hours, and stop the reaction after TLC detects that the reaction is complete. Ethyl acetate (90 mL) and water (100 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-2). (4.95g, white solid, molar yield 92.3%). 1 H NMR (500MHz, CDCl 3 ) δ7.99 (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＝6.6Hz,3H),0.95(s,3H). 13 C NMR (150MHz, CDCl 3 ) δ205.36,174.76,165.86,164.27,163.27,131.58,123.73, 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.
(4)式(8-3)化合物的制备
(4) Preparation of compounds of formula (8-3)
于烧瓶中加入二氯甲烷(40mL)、式(10-2)化合物(4.17g，10mmol)，搅拌溶清，加入三乙胺(2.02g，20mmol)、DMAP(0.123g，1mmol)和对甲氧基苯甲酰氯(2.56g，15mmol)，25℃反应8h，TLC监测反应完全后，加入饱和氯化铵(5mL)淬灭反应，加入二氯甲烷(80mL)和水(100mL)萃取，有机相再经过水洗，饱和食盐水洗涤，减压浓缩，柱层析纯化，得到式(8-3)化合物(白色固体5.28g，摩尔收率95.8％)。1H NMR(500MHz,CDCl3)δ7.99(d,J＝8.9Hz,2H),6.92(d,J＝8.9Hz,2H),5.78(d,J＝2.3Hz,1H),5.01–4.96(m,1H),4.14(q,J＝7.2Hz,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＝7.1Hz,3H),1.25(s,3H),1.05(d,J＝6.6Hz,3H),0.95(s,3H).13C NMR(150MHz,CDCl3)δ205.29,174.31,165.85,164.19,163.28,131.57,123.75,123.09,113.52,73.98,60.18,55.42,53.55,53.12,47.35,41.93,40.05,37.89,35.31,35.17,34.24,31.79,30.68,29.79,27.87,27.39,26.58,26.24,24.23,19.52,14.26,10.75.Add dichloromethane (40 mL) and compound of formula (10-2) (4.17 g, 10 mmol) to the flask, stir to dissolve, add triethylamine (2.02 g, 20 mmol), DMAP (0.123 g, 1 mmol) and p-methyl Oxybenzoyl chloride (2.56g, 15mmol) was reacted at 25°C for 8 hours. After TLC monitoring of the reaction was complete, saturated ammonium chloride (5mL) was added to quench the reaction, dichloromethane (80mL) and water (100mL) were added for extraction, and the organic The phase was washed with water, washed with saturated brine, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-3) (5.28 g of white solid, molar yield 95.8%). 1 H NMR (500MHz, CDCl 3 ) δ7.99 (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＝7.2Hz,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＝7.1Hz,3H),1.25(s,3H),1.05(d,J＝6.6Hz,3H) ,0.95(s,3H). 13 C NMR (150MHz, CDCl 3 )δ205.29,174.31,165.85,164.19,163.28,131.57,123.75,123.09,113.52,73.98,60.18,55.42,53.55,53.1 2,47.35,41.93,40.05 ,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.
(5)式(8-3)化合物的制备
(5) Preparation of compounds of formula (8-3)
于烧瓶中加入乙酸(10mL)、三氧化铬(2g，20mmol)，搅拌溶清，加入式(7-3)化合物(2.68g，5mmol)，35℃搅拌12h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(70mL)和水(80mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(8-3)化合物(2.48g，白色固体，摩尔收率90.1％)。1H NMR(500MHz,CDCl3)δ7.99(d,J＝8.9Hz,2H),6.92(d,J＝8.9Hz,2H),5.78(d,J＝2.3Hz,1H),5.01–4.96(m,1H),4.14(q,J＝7.2Hz,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＝7.1Hz,3H),1.25(s,3H),1.05(d,J＝6.6Hz,3H),0.95(s,3H).13C NMR(150MHz,CDCl3)δ205.29,174.31,165.85,164.19,163.28,131.57,123.75,123.09,113.52,73.98,60.18,55.42,53.55,53.12,47.35, 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.Add acetic acid (10 mL) and chromium trioxide (2 g, 20 mmol) to the flask, stir to dissolve, add the compound of formula (7-3) (2.68 g, 5 mmol), stir at 35°C for 12 hours, and stop the reaction after TLC detects that the reaction is complete. Ethyl acetate (70 mL) and water (80 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-3). (2.48g, white solid, molar yield 90.1%). 1 H NMR (500MHz, CDCl 3 ) δ7.99 (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＝7.2Hz,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＝7.1Hz,3H),1.25(s,3H),1.05(d,J＝6.6Hz,3H) ,0.95(s,3H). 13 C NMR (150MHz, CDCl 3 )δ205.29,174.31,165.85,164.19,163.28,131.57,123.75,123.09,113.52,73.98,60.18,55.42,53.55,53.1 2,47.35, 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.
(6)式(8-4)化合物的制备
(6) Preparation of compounds of formula (8-4)
于烧瓶中加入乙酸(10mL)、三氧化铬(1.5g，15mmol)，搅拌溶清，加入式(7-4)化合物(2.46g，5mmol)，35℃搅拌12h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(40mL)和水(50mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(8-4)化合物(2.2g，白色固体，摩尔收率87％)。1H NMR(500MHz,CDCl3)δ8.09–8.01(m,2H),7.55(d,J＝7.5Hz,1H),7.44(t,J＝7.6Hz,2H),5.78(d,J＝2.3Hz,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＝13.6Hz,5H),1.05(d,J＝6.6Hz,3H),0.95(s,3H).13C NMR(125MHz,CDCl3)δ205.32,174.77,166.10,164.17,132.82,130.61,129.56,128.29,123.76,74.34,53.52,53.12,51.51,47.30,41.90,40.05,37.87,35.31,35.13,34.16,31.51,30.66,29.80,27.81,27.39,26.57,26.23,24.23,19.52,10.77.Add acetic acid (10 mL) and chromium trioxide (1.5 g, 15 mmol) to the flask, stir to dissolve, add the compound of formula (7-4) (2.46 g, 5 mmol), stir at 35°C for 12 hours, and stop the reaction after TLC detects that the reaction is complete. . Ethyl acetate (40 mL) and water (50 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-4). (2.2g, white solid, molar yield 87%). 1 H NMR (500MHz, CDCl 3 ) δ8.09–8.01(m,2H),7.55(d,J＝7.5Hz,1H),7.44(t,J＝7.6Hz,2H),5.78(d,J＝ 2.3Hz,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＝13.6Hz,5H),1.05(d,J＝6.6Hz,3H), 0.95(s,3H). 13 C NMR (125MHz, CDCl 3 ) δ205.32,174.77,166.10,164.17,132.82,130.61,129.56,128.29,123.76,74.34,53.52,53.12,51.51,47.30 ,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.
(7)式(8-5)化合物的制备
(7) Preparation of compounds of formula (8-5)
于烧瓶中加入乙酸(15mL)、三氧化铬(2.5g，25mmol)，搅拌溶清，加入式(7-5)化合物(2.8g，5mmol)，40℃搅拌8h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(50mL)和水(70mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(8-5)化合物(2.49g，白色固体，摩尔收率86.7％)。1H NMR(600MHz,CDCl3)δ8.14(d,J＝8.1Hz,2H),7.70(d,J＝8.1Hz,2H),5.78(s,1H),5.04(t,J＝5.0Hz,1H),3.69(s,3H),2.45–2.40(m,2H),2.31(d,J＝7.9Hz,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＝8.8Hz,5H),1.05(d,J＝6.6Hz,3H),0.95(d,J＝2.8Hz,3H).13C NMR(150MHz,CDCl3)δ205.30,174.74,164.85,163.96, 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.Add acetic acid (15 mL) and chromium trioxide (2.5 g, 25 mmol) to the flask, stir to dissolve, add the compound of formula (7-5) (2.8 g, 5 mmol), stir at 40°C for 8 hours, and stop the reaction after TLC detects that the reaction is complete. . Ethyl acetate (50 mL) and water (70 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-5). (2.49g, white solid, molar yield 86.7%). 1 H NMR (600MHz, CDCl 3 ) δ8.14 (d, J = 8.1Hz, 2H), 7.70 (d, J = 8.1Hz, 2H), 5.78 (s, 1H), 5.04 (t, J = 5.0Hz ,1H),3.69(s,3H),2.45–2.40(m,2H),2.31(d,J＝7.9Hz,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＝8.8Hz,5H),1.05(d,J＝6.6Hz,3H),0.95(d,J＝2.8Hz ,3H). 13 C NMR (150MHz, CDCl 3 ) δ205.30,174.74,164.85,163.96, 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.
(8)式(8-6)化合物的制备
(8) Preparation of compounds of formula (8-6)
于烧瓶中加入乙酸(10mL)、三氧化铬(2g，20mmol)，搅拌溶清，加入式(7-6)化合物(2.76g，5mmol)，30℃搅拌16h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(60mL)和水(70mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(8-6)化合物(2.04g，白色固体，摩尔收率72.1％)。1H NMR(500MHz,CDCl3)δ7.85–7.75(m,1H),6.49–6.47(m,2H),5.76(d,J＝2.3Hz,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＝6.5Hz,3H),0.96–0.90(m,3H).13C NMR(125MHz,CDCl3)δ205.33,174.75,164.94,164.35,164.12,161.40,133.67,123.68,112.71,104.41,98.96,73.68,55.96,55.48,53.50,53.08,51.49,47.28,41.94,40.08,37.89,35.31,35.19,34.22,31.50,30.66,29.80,29.70,27.85,27.41,26.59,26.25,24.22,19.50,10.76.Add acetic acid (10 mL) and chromium trioxide (2 g, 20 mmol) to the flask, stir to dissolve, add the compound of formula (7-6) (2.76 g, 5 mmol), stir at 30°C for 16 hours, and stop the reaction after TLC detects that the reaction is complete. Ethyl acetate (60 mL) and water (70 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-6). (2.04g, white solid, molar yield 72.1%). 1 H NMR (500MHz, CDCl 3 ) δ7.85–7.75 (m, 1H), 6.49–6.47 (m, 2H), 5.76 (d, J = 2.3Hz, 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＝6.5Hz, 3H),0.96–0.90(m,3H). 13 C NMR (125MHz, CDCl 3 ) δ205.33,174.75,164.94,164.35,164.12,161.40,133.67,123.68,112.71,104.41,98.96,73.68,5 5.96,55.48,53.50 , 53.08,51.49,47.28,41.94,40.08,37.89,35.31,35.19,34.22,31.50, 30.66,29.70, 27.85,26.59,26.22,19.50.76.
(9)式(8-7)化合物的制备
(9) Preparation of compounds of formula (8-7)
于烧瓶中加入乙酸(10mL)、三氧化铬(2g，20mmol)，搅拌溶清，加入式(7-7)化合物(2.62g，5mmol)，35℃搅拌12h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(60mL)和水(80mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(8-7)化合物(2.01g，白色固体，摩尔收率75％)。1H NMR(500MHz,CDCl3)δ7.75(dd,J＝7.9,1.9Hz,1H),7.48–7.44(m,1H),6.99–6.96(m,2H),5.77(d,J＝2.3Hz,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＝6.5Hz,3H),0.94(s,3H). 13C NMR(150MHz,CDCl3)δ205.20,174.73,165.65,164.18,159.10,133.28,131.41,123.72,120.63,120.10,112.04,74.17,56.00,53.50,53.09,51.46,47.31,41.97,40.07,37.90,35.32,35.18,34.15,31.51,30.67,29.80,27.81,27.39,26.58,26.26,24.23,19.50,10.76.Add acetic acid (10 mL) and chromium trioxide (2 g, 20 mmol) to the flask, stir to dissolve, add the compound of formula (7-7) (2.62 g, 5 mmol), stir at 35°C for 12 hours, and stop the reaction after TLC detects that the reaction is complete. Ethyl acetate (60 mL) and water (80 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-7). (2.01g, white solid, molar yield 75%). 1 H NMR (500MHz, CDCl 3 ) δ7.75 (dd, J＝7.9, 1.9Hz, 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＝6.5Hz,3H),0.94(s,3H). 13 C NMR (150MHz, CDCl 3 ) δ205.20,174.73,165.65,164.18,159.10,133.28,131.41,123.72,120.63,120.10,112.04,74.17,56.00,53.50,53.09,51. 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.
(10)式(8-8)化合物的制备
(10) Preparation of compounds of formula (8-8)
于烧瓶中加入乙酸(10mL)、三氧化铬(2g，20mmol)，搅拌溶清，加入式(7-8)化合物(2.87g，5mmol)，40℃搅拌18h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(50mL)和水(70mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(8-8)化合物(2.5g，白色固体，摩尔收率85％)。1H NMR(600MHz,CDCl3)δ8.14(d,J＝8.1Hz,2H),7.70(d,J＝8.1Hz,2H),5.78(d,J＝2.4Hz,1H),5.07–5.02(m,1H),4.14(q,J＝7.1Hz,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＝6.6Hz,3H),0.95(s,3H).13C NMR(150MHz,CDCl3)δ205.26,174.28,164.84,163.91,134.44,134.22,133.85,129.97,125.36,125.33,125.31,125.28,123.80,75.06,60.19,53.57,53.15,47.35,41.90,40.00,37.87,35.30,35.07,34.08,31.77,30.66,29.74,27.76,27.39,26.56,26.21,24.23,19.51,14.26,10.73.Add acetic acid (10 mL) and chromium trioxide (2 g, 20 mmol) to the flask, stir to dissolve, add the compound of formula (7-8) (2.87 g, 5 mmol), stir at 40°C for 18 hours, and stop the reaction after TLC detects that the reaction is complete. Ethyl acetate (50 mL) and water (70 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-8). (2.5g, white solid, molar yield 85%). 1 H NMR (600MHz, CDCl 3 ) δ8.14(d,J＝8.1Hz,2H),7.70(d,J＝8.1Hz,2H),5.78(d,J＝2.4Hz,1H),5.07–5.02 (m,1H),4.14(q,J＝7.1Hz,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＝6.6Hz,3H),0.95(s,3H). 13 C NMR (150MHz, CDCl 3 ) δ205.26,174.28,164.84,163.91,134.44,134.22,133.85,129.97,125.36,125.33,125.31,125.28,123.80,75.06,60.19,5 3.57,53.15,47.35,41.90,40.00,37.87 ,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.
(11)式(8-9)化合物的制备
(11) Preparation of compounds of formula (8-9)
于烧瓶中加入乙酸(3mL)、三氧化铬(500mg，5mmol)，搅拌溶清，加入式(7-9)化合物(567mg，1mmol)，30℃搅拌16h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(15mL)和水(30mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(8-9)化合物(424mg，白色固体，摩尔收率73％)。1H NMR(500MHz,CDCl3)δ7.85–7.78(m,1H),6.49–6.46(m,2H),5.76(s,1H),4.96(m,1H),4.13(d,J＝7.1Hz,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＝6.5Hz,3H),0.95–0.91(m,3H). Add acetic acid (3mL) and chromium trioxide (500mg, 5mmol) to the flask, stir to dissolve, add the compound of formula (7-9) (567mg, 1mmol), stir at 30°C for 16h, and stop the reaction after TLC detects that the reaction is complete. Ethyl acetate (15 mL) and water (30 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-9). (424 mg, white solid, molar yield 73%). 1 H NMR (500MHz, CDCl 3 ) δ7.85–7.78(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＝6.5Hz,3H),0.95–0.91(m,3H).
(12)式(8-10)化合物的制备
(12) Preparation of compounds of formula (8-10)
于烧瓶中加入乙酸(12mL)、三氧化铬(2.3g，23mmol)，搅拌溶清，加入式(7-10)化合物(2.69g，5mmol)，25℃搅拌16h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(60mL)和水(80mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(8-10)化合物(2.03g，白色固体，摩尔收率73.8％)。1H NMR(500MHz,CDCl3)δ7.83–7.69(m,1H),7.53–7.42(m,1H),7.06–6.93(m,2H),5.76(d,J＝2.3Hz,1H),5.03–4.98(m,1H),4.13(d,J＝7.1Hz,2H),3.90(s,3H),2.43–2.37(m,2H),2.31–2.23(m,1H),2.18–2.06(m,2H),1.97–1.71(m,7H),1.54–1.31(m,9H),1.28–1.24(m,8H),1.04(d,J＝6.6Hz,3H),0.93(s,3H).13C NMR(150MHz,CDCl3)δ205.22,174.31,165.65,164.16,159.09,133.29,131.41,123.72,120.60,120.10,112.03,60.18,55.99,53.51,53.09,47.31,41.96,40.06,37.90,35.31,35.17,34.15,31.79,30.67,29.80,27.80,27.41,26.58,26.26,24.23,19.51,14.26,10.75.Add acetic acid (12mL) and chromium trioxide (2.3g, 23mmol) to the flask, stir to dissolve, add the compound of formula (7-10) (2.69g, 5mmol), stir at 25°C for 16h, and stop the reaction after TLC detects that the reaction is complete. . Ethyl acetate (60 mL) and water (80 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-10). (2.03g, white solid, molar yield 73.8%). 1 H NMR (500MHz, CDCl 3 ) δ7.83–7.69 (m, 1H), 7.53–7.42 (m, 1H), 7.06–6.93 (m, 2H), 5.76 (d, J = 2.3Hz, 1H), 5.03–4.98(m,1H),4.13(d,J＝7.1Hz,2H),3.90(s,3H),2.43–2.37(m,2H),2.31–2.23(m,1H),2.18–2.06( m,2H),1.97–1.71(m,7H),1.54–1.31(m,9H),1.28–1.24(m,8H),1.04(d,J＝6.6Hz,3H),0.93(s,3H) . 13 C NMR (150MHz, CDCl 3 ) δ205.22,174.31,165.65,164.16,159.09,133.29,131.41,123.72,120.60,120.10,112.03,60.18,55.99,53.51,53.09,4 7.31,41.96,40.06,37.90,35.31, 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.
(13)式(8-11)化合物的制备
(13) Preparation of compounds of formula (8-11)
于烧瓶中加入乙酸(3mL)、三氧化铬(400mg，4mmol)，搅拌溶清，加入式(7-11)化合物(506mg，1mmol)，35℃搅拌12h，TLC检测反应完全后停止反应。反应液中加入乙酸乙酯(20mL)和水(20mL)萃取，有机相依次用饱和NaHCO3水溶液、水、饱和食盐水洗涤，减压浓缩，柱层析纯化，得式(8-11)化合物(457mg，白色固体，摩尔收率87.8％)。1H NMR(500MHz,CDCl3)δ8.07–8.01(m,2H),7.59–7.52(m,1H),7.44(t,J＝7.8Hz,2H),5.78(d,J＝2.3Hz,1H),5.04–5.00(m,1H),4.15(q,J＝7.1Hz,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＝6.6Hz,3H),0.95(s,3H).13C NMR(125MHz,CDCl3)δ205.25,174.29,166.08,164.09,132.79,130.64,129.56,128.27,123.77,74.34,60.18,53.54,53.12,47.35,41.92,40.04,37.89,35.31,35.14,34.17,31.79,30.67,29.79,27.83,27.39,26.58,26.24,24.24,19.52,14.26,10.75. Add acetic acid (3mL) and chromium trioxide (400mg, 4mmol) to the flask, stir to dissolve, add the compound of formula (7-11) (506mg, 1mmol), stir at 35°C for 12h, and stop the reaction after TLC detects that the reaction is complete. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution for extraction. The organic phase was washed with saturated NaHCO 3 aqueous solution, water, and saturated brine in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (8-11). (457 mg, white solid, molar yield 87.8%). 1 H NMR (500MHz, CDCl 3 ) δ8.07–8.01 (m, 2H), 7.59–7.52 (m, 1H), 7.44 (t, J = 7.8Hz, 2H), 5.78 (d, J = 2.3Hz, 1H),5.04–5.00(m,1H),4.15(q,J＝7.1Hz,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＝6.6Hz,3H),0.95 (s,3H). 13 C NMR (125MHz, CDCl 3 ) δ205.25,174.29,166.08,164.09,132.79,130.64,129.56,128.27,123.77,74.34,60.18,53.54,53.12,47.35,41.9 2,40.04,37.89,35.31 ,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.
实施例十一式(11)化合物的制备Example 11 Preparation of compound of formula (11)
(1)式(11-1)化合物的制备
(1) Preparation of compounds of formula (11-1)
于反应釜中加入式(8-1)化合物(889mg，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(178mg，20％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4MPa，将反应体系加热至110℃，搅拌48h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-1)化合物(535mg，白色固体，摩尔收率60.5％)。1H NMR(600MHz,CDCl3)δ4.77–4.67(m,1H),3.69(s,3H),2.50(t,J＝12.4Hz,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＝2.6Hz,6H),0.87(d,J＝6.7Hz,3H).13C NMR(150MHz,CDCl3)δ214.72,174.69,170.67,73.73,58.66,57.52,51.49,46.48,44.06,41.36,38.11,35.67,35.64,35.37,34.95,32.15,31.32,30.52,27.53,26.95,26.36,26.01,24.35,22.76,21.42,18.59,11.70.Add the compound of formula (8-1) (889 mg, 2 mmol), 1,4-dioxane (10 mL) and 10% Pd/C (178 mg, 20% wt) to the reaction kettle, and perform nitrogen replacement and hydrogen replacement successively. , keep the system pressure at 4MPa, heat the reaction system to 110°C, stir for 48 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (862 mg, 4 mmol), continue stirring for 4 hours, filter, wash the filtrate with water, and combine. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (11-1) (535 mg, white solid, molar yield 60.5%). 1 H NMR (600MHz, CDCl 3 ) δ4.77–4.67(m,1H),3.69(s,3H),2.50(t,J＝12.4Hz,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＝2.6Hz,6H),0.87(d,J＝6.7Hz,3H). 13 C NMR (150MHz, CDCl 3 )δ214.72,174.69,170.67, 73.73,58.66,57.52,51.49,46.48,44.06,41.36,38.11,35.67,35.64,35.37,34.95,32.15,31.32,30.52,27.53,26.95,26.36,26.01,24.35,2 2.76,21.42,18.59,11.70.
(2)式(11-2)化合物的制备
(2) Preparation of compounds of formula (11-2)
于反应釜中加入式(8-2)化合物(1.07g，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(214mg，20％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4MPa，将反应体系加热至110℃，搅拌48h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862.7mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-2)化合物(964mg，白色固体，摩尔收率90.1％)。1H NMR(500MHz,CDCl3)δ8.00(d,J＝8.8Hz,2H),6.93(d,J＝8.9Hz,2H),4.97–4.92(m,1H),3.88(s,3H),3.69(s,3H),2.53(t,J＝12.6Hz,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),1.23–1.13m,2H), 1.06(d,J＝10.5Hz,6H),0.88(d,J＝6.5Hz,3H).13C NMR(150MHz,CDCl3)δ214.98,174.36,165.96,163.34,131.65,123.27,113.62,74.26,58.82,57.67,55.53,46.61,44.25,41.52,38.27,35.80,35.74,35.54,35.14,32.43,31.70,30.64,27.64,27.08,26.65,26.15,24.46,22.88,18.72,14.37,11.80.Add the compound of formula (8-2) (1.07g, 2mmol), 1,4-dioxane (10mL) and 10% Pd/C (214mg, 20%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen gas successively. Replace, keep the system pressure at 4MPa, heat the reaction system to 110°C, stir for 48 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (862.7 mg, 4 mmol), continue stirring for 4 hours, filter, and wash the filtrate with water. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (11-2) (964 mg, white solid, molar yield 90.1%). 1 H NMR (500MHz, CDCl 3 ) δ8.00(d,J＝8.8Hz,2H),6.93(d,J＝8.9Hz,2H),4.97–4.92(m,1H),3.88(s,3H) ,3.69(s,3H),2.53(t,J＝12.6Hz,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),1.23–1.13m,2H), 1.06 (d, J=10.5Hz, 6H), 0.88 (d, J=6.5Hz, 3H). 13 C NMR (150MHz, CDCl 3 ) δ214.98,174.36,165.96,163.34,131.65,123.27,113.62,74.26,58.82 ,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.
(3)式(11-3)化合物的制备
(3) Preparation of compounds of formula (11-3)
于反应釜中加入式(8-3)化合物(1.11g，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(223mg，20％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4MPa，将反应体系加热至110℃，搅拌55h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862.8mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-3)化合物(983mg，白色固体，摩尔收率88.9％)。1H NMR(500MHz,CDCl3)δ8.00(d,J＝8.8Hz,2H),6.93(d,J＝8.9Hz,2H),4.97–4.92(m,1H),3.88(s,3H),4.14(q,J＝7.2Hz,2H),2.53(t,J＝12.6Hz,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＝10.5Hz,6H),0.88(d,J＝6.5Hz,3H).13C NMR(150MHz,CDCl3)δ214.88,174.26,165.86,163.24,131.55,123.17,113.52,73.92,60.19,58.71,57.57,55.43,46.51,44.15,41.42,38.17,35.70,35.64,35.44,35.04,32.33,31.60,30.54,27.54,26.98,26.54,26.04,24.36,22.78,18.62,14.27,11.70.Add the compound of formula (8-3) (1.11g, 2mmol), 1,4-dioxane (10mL) and 10% Pd/C (223mg, 20%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen gas successively. Replace, keep the system pressure at 4MPa, heat the reaction system to 110°C, stir for 55 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (862.8 mg, 4 mmol), continue stirring for 4 hours, filter, and wash the filtrate with water. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (11-3) (983 mg, white solid, molar yield 88.9%). 1 H NMR (500MHz, CDCl 3 ) δ8.00(d,J＝8.8Hz,2H),6.93(d,J＝8.9Hz,2H),4.97–4.92(m,1H),3.88(s,3H) ,4.14(q,J＝7.2Hz,2H),2.53(t,J＝12.6Hz,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 = 10.5Hz, 6H), 0.88 (d, J = 6.5Hz, 3H). 13 C NMR (150MHz, CDCl 3 ) 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.
于反应釜中加入式(8-3)化合物(1.11g，2mmol)、甲苯(10mL)和10％Pd/C(333mg，30％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4.5MPa，将反应体系加热至110℃，搅拌40h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862.5mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-3)化合物(969mg，白色固体，摩尔收率88.1％)。Add the compound of formula (8-3) (1.11g, 2mmol), toluene (10mL) and 10% Pd/C (333mg, 30%w.t.) to the reaction kettle, and perform nitrogen replacement and hydrogen replacement successively to keep the system pressure at 4.5 MPa, heat the reaction system to 110°C, stir for 40 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (862.5 mg, 4 mmol), continue stirring for 4 hours, filter, and wash the filtrate with water. The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (11-3) (969 mg, white solid, molar yield 88.1%).
于反应釜中加入式(8-3)化合物(1.11g，2mmol)、二甲苯(10mL)和10％Pd/C(278mg，25％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4MPa，将反应体系加热至120℃，搅拌48h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用 乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862.4mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-3)化合物(962mg，白色固体，摩尔收率87.4％)。Add the compound of formula (8-3) (1.11g, 2mmol), xylene (10mL) and 10% Pd/C (278mg, 25%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen replacement successively to keep the system pressure at 4MPa, heat the reaction system to 120°C, stir for 48 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Pd/C is recovered by filtration, and the solvent is removed from the filtrate under reduced pressure before use. Dissolve ethyl acetate (10 mL), control the system temperature at 25°C, add pyridinium chlorochromate (862.4 mg, 4 mmol), continue stirring for 4 hours, filter, wash the filtrate with water, combine the organic phases, concentrate under reduced pressure, and perform column chromatography After purification, the compound of formula (11-3) (962 mg, white solid, molar yield 87.4%) was obtained.
(4)式(11-4)化合物的制备
(4) Preparation of compounds of formula (11-4)
于反应釜中加入式(8-4)化合物(1.01g，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(200mg，20％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4MPa，将反应体系加热至105℃，搅拌50h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-4)化合物(857mg，白色固体，摩尔收率84％)。1H NMR(600MHz,CDCl3)δ8.04(d,J＝7.5Hz,2H),7.55(t,J＝7.4Hz,1H),7.44(t,J＝7.5Hz,2H),4.98(d,J＝11.8Hz,1H),3.68(s,3H),2.52(t,J＝12.4Hz,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＝10.8Hz,4H),1.75(d,J＝16.4Hz,3H),1.66–1.51(m,3H),1.48–1.25(m,6H),1.22–1.11(m,2H),1.05(d,J＝14.7Hz,6H),0.87(d,J＝6.5Hz,3H).13C NMR(150MHz,CDCl3)δ214.79,174.66,166.08,132.78,130.73,129.54,128.29,74.28,58.69,57.55,51.50,46.48,44.13,41.41,38.16,35.69,35.63,35.43,35.01,32.26,31.31,30.53,27.54,26.97,26.50,26.03,24.35,22.78,18.61,11.70.Add the compound of formula (8-4) (1.01g, 2mmol), 1,4-dioxane (10mL) and 10% Pd/C (200mg, 20%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen gas successively. Replace, keep the system pressure at 4MPa, heat the reaction system to 105°C, stir for 50 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (862 mg, 4 mmol), continue stirring for 4 hours, filter, wash the filtrate with water, and combine. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (11-4) (857 mg, white solid, molar yield 84%). 1 H NMR (600MHz, CDCl 3 ) δ8.04(d,J＝7.5Hz,2H),7.55(t,J＝7.4Hz,1H),7.44(t,J＝7.5Hz,2H),4.98(d ,J＝11.8Hz,1H),3.68(s,3H),2.52(t,J＝12.4Hz,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＝10.8Hz,4H),1.75(d,J＝16.4Hz,3H),1.66–1.51(m,3H),1.48–1.25 (m,6H),1.22–1.11(m,2H),1.05(d,J＝14.7Hz,6H),0.87(d,J＝6.5Hz,3H). 13 C NMR (150MHz, CDCl 3 )δ214. 79,174.66,166.08,132.78,130.73,129.54,128.29,74.28,58.69,57.55,51.50,46.48,44.13,41.41,38.16,35.69,35.63,35.43,35.01,32.2 6,31.31,30.53,27.54,26.97,26.50,26.03, 24.35,22.78,18.61,11.70.
(5)式(11-5)化合物的制备
(5) Preparation of compounds of formula (11-5)
于反应釜中加入式(8-5)化合物(1.15g，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(345mg，30％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4MPa，将反应体系加热至110℃，搅拌24h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-5) 化合物(990mg，白色固体，摩尔收率86.1％)。1H NMR(600MHz,CDCl3)δ8.14(d,J＝8.0Hz,2H),7.70(d,J＝8.0Hz,2H),5.02–4.97(m,1H),3.67(s,3H),2.53(t,J＝12.6Hz,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＝6.6Hz,3H).13C NMR(150MHz,CDCl3)δ214.78,174.65,164.83,134.38,134.16,133.94,129.94,125.36,125.34,125.31,125.29,124.58,122.77,75.01,58.72,57.57,51.48,46.49,44.15,41.40,38.15,35.67,35.62,35.40,34.94,32.17,31.29,30.52,27.52,26.93,26.42,26.02,24.34,22.74,18.59,11.69.Add the compound of formula (8-5) (1.15g, 2mmol), 1,4-dioxane (10mL) and 10% Pd/C (345mg, 30%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen gas successively. Replace, keep the system pressure at 4MPa, heat the reaction system to 110°C, stir for 24 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (862 mg, 4 mmol), continue stirring for 4 hours, filter, wash the filtrate with water, and combine. The organic phase is concentrated under reduced pressure and purified by column chromatography to obtain formula (11-5) Compound (990 mg, white solid, molar yield 86.1%). 1 H NMR (600MHz, CDCl 3 ) δ8.14(d,J＝8.0Hz,2H),7.70(d,J＝8.0Hz,2H),5.02–4.97(m,1H),3.67(s,3H) ,2.53(t,J＝12.6Hz,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=6.6Hz,3H). 13 C NMR (150MHz, CDCl 3 ) δ214.78,174.65,164.83,134.38,134.16,133.94,129.94,125.36,125.34,125.31,125 .29 ,124.58,122.77,75.01,58.72,57.57,51.48,46.49,44.15,41.40,38.15,35.67,35.62,35.40,34.94,32.17,31.29,30.52,27.52,26.93,26.4 2,26.02,24.34,22.74,18.59,11.69 .
(6)式(11-6)化合物的制备
(6) Preparation of compounds of formula (11-6)
于反应釜中加入式(8-6)化合物(1.13g，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(283mg，25％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4MPa，将反应体系加热至110℃，搅拌48h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(863mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-6)化合物(820mg，白色固体，摩尔收率72.5％)。1H NMR(600MHz,CDCl3)δ7.83(d,J＝8.4Hz,1H),6.50(d,J＝9.1Hz,2H),4.96–4.90(m,1H),3.89(s,3H),3.86(s,3H),3.68(s,3H),2.51(t,J＝12.6Hz,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＝13.7Hz,1H),1.58–1.50(m,2H),1.43–1.27(m,6H),1.21–1.12(m,2H),1.05(d,J＝11.0Hz,6H),0.87(d,J＝6.6Hz,3H).13C NMR(150MHz,CDCl3)δ214.94,174.71,165.04,164.09,161.37,133.62,112.91,104.43,99.02,73.63,58.70,57.55,55.98,55.48,51.49,46.47,44.13,41.45,38.16,35.70,35.64,35.46,35.08,32.32,31.32,30.53,27.54,27.00,26.53,26.05,24.35,22.77,18.60,11.70.Add the compound of formula (8-6) (1.13g, 2mmol), 1,4-dioxane (10mL) and 10% Pd/C (283mg, 25%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen gas successively. Replace, keep the system pressure at 4MPa, heat the reaction system to 110°C, stir for 48 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (863 mg, 4 mmol), continue stirring for 4 hours, filter, wash the filtrate with water, and combine The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (11-6) (820 mg, white solid, molar yield 72.5%). 1 H NMR (600MHz, CDCl 3 ) δ7.83 (d, J = 8.4Hz, 1H), 6.50 (d, J = 9.1Hz, 2H), 4.96–4.90 (m, 1H), 3.89 (s, 3H) ,3.86(s,3H),3.68(s,3H),2.51(t,J＝12.6Hz,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＝13.7Hz,1H),1.58–1.50(m,2H ),1.43–1.27(m,6H),1.21–1.12(m,2H),1.05(d,J＝11.0Hz,6H),0.87(d,J＝6.6Hz,3H). 13 C NMR(150MHz, CDCl 3 )δ214.94,174.71,165.04,164.09,161.37,133.62,112.91,104.43,99.02,73.63,58.70,57.55,55.98,55.48,51.49,46.47,44.13,41.45, 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.
(7)式(11-7)化合物的制备
(7) Preparation of compounds of formula (11-7)
于反应釜中加入式(8-7)化合物(1.07g，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(268mg，25％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4.5MPa，将反应体系加热至110℃，搅拌24h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-7)化合物(803mg，白色固体，摩尔收率75.1％)。1H NMR(500MHz,CDCl3)δ7.76(dd,J＝8.0,1.8Hz,1H),7.49–7.43(m,1H),6.99(t,J＝7.3Hz,2H),5.00–4.95(m,1H),3.91(s,3H),3.68(s,3H),2.51(t,J＝12.6Hz,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＝3.5Hz,2H),1.05(d,J＝11.9Hz,6H),0.87(d,J＝6.6Hz,3H).13C NMR(125MHz,CDCl3)δ214.80,174.68,165.72,159.06,133.23,131.37,120.76,120.11,112.05,74.1,58.67,57.54,56.01,51.48,46.47,44.10,41.46,38.14,35.70,35.64,35.45,35.05,32.24,31.32,30.52,27.53,26.99,26.47,26.04,24.35,22.77,18.59,11.70.Add the compound of formula (8-7) (1.07g, 2mmol), 1,4-dioxane (10mL) and 10% Pd/C (268mg, 25%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen gas successively. Replace, keep the system pressure at 4.5MPa, heat the reaction system to 110°C, stir for 24 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (862 mg, 4 mmol), continue stirring for 4 hours, filter, wash the filtrate with water, and combine. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (11-7) (803 mg, white solid, molar yield 75.1%). 1 H NMR (500MHz, CDCl 3 ) δ7.76 (dd, J＝8.0, 1.8Hz, 1H), 7.49–7.43 (m, 1H), 6.99 (t, J＝7.3Hz, 2H), 5.00–4.95 ( m,1H),3.91(s,3H),3.68(s,3H),2.51(t,J＝12.6Hz,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＝ 3.5Hz, 2H), 1.05 (d, J = 11.9Hz, 6H), 0.87 (d, J = 6.6Hz, 3H). 13 C NMR (125MHz, CDCl 3 ) δ 214.80, 174.68, 165.72, 159.06, 133.23, 131.37 ,120.76,120.11,112.05,74.1,58.67,57.54,56.01,51.48,46.47,44.10,41.46,38.14,35.70,35.64,35.45,35.05,32.24,31.32,30.52,27.5 3,26.99,26.47,26.04,24.35,22.77 ,18.59,11.70.
(8)式(11-8)化合物的制备
(8) Preparation of compounds of formula (11-8)
于反应釜中加入式(8-8)化合物(1.18g，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(354mg，30％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4MPa，将反应体系加热至110℃，搅拌48h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-8)化合物(1g，白色固体，摩尔收率85.3％)。1H NMR(600MHz,CDCl3)δ8.15(d,J＝8.1Hz,2H),7.71(d,J＝8.2Hz,2H),5.03–4.97(m,1H),4.16–4.12(m,2H),2.53(t,J＝12.6Hz,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＝7.1Hz,3H),1.23–1.13(m,2H),1.08(s,3H),1.05(s,3H),0.88(d,J＝6.6Hz,3H).13C NMR(150MHz,CDCl3)δ214.79,174.23,164.84,134.39,134.17,133.94,129.94,125.36,125.34,125.31,125.29,124.58,122.77,75.02,60.19,58.73,57.58,46.52,44.15,41.40,38.15,35.69,35.62,35.41,34.95,32.17,31.58,30.53,27.52,26.94,26.43,26.02,24.35,22.74,18.61,14.26,11.69. Add the compound of formula (8-8) (1.18g, 2mmol), 1,4-dioxane (10mL) and 10% Pd/C (354mg, 30%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen gas successively. Replace, keep the system pressure at 4MPa, heat the reaction system to 110°C, stir for 48 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (862 mg, 4 mmol), continue stirring for 4 hours, filter, wash the filtrate with water, and combine. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (11-8) (1 g, white solid, molar yield 85.3%). 1 H NMR (600MHz, CDCl 3 ) δ8.15(d,J＝8.1Hz,2H),7.71(d,J＝8.2Hz,2H),5.03–4.97(m,1H),4.16–4.12(m, 2H),2.53(t,J＝12.6Hz,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＝7.1Hz,3H),1.23 –1.13(m,2H),1.08(s,3H),1.05(s,3H),0.88(d,J＝6.6Hz,3H). 13 C NMR(150MHz, CDCl 3 )δ214.79,174.23,164.84,134.39 ,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.
(9)式(11-9)化合物的制备
(9) Preparation of compounds of formula (11-9)
于反应釜中加入式(8-9)化合物(1.16g，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(290mg，25％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4.5MPa，将反应体系加热至110℃，搅拌50h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(863mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-9)化合物(812mg，白色固体，摩尔收率70％)。1H NMR(600MHz,CDCl3)δ7.83(d,J＝8.4Hz,1H),6.50(d,J＝9.0Hz,2H),4.96–4.91(m,1H),4.14(q,J＝7.1Hz,2H),3.90(s,3H),3.87(s,3H),2.52(t,J＝12.6Hz,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＝8.9Hz,3H).13C NMR(150MHz,CDCl3)δ214.85,174.29,165.47,164.09,161.38,133.63,112.92,104.43,99.02,73.64,60.20,58.71,57.56,55.99,55.48,46.50,44.13,41.45,38.16,35.71,35.64,35.46,35.08,32.32,31.61,30.54,29.71,27.54,27.00,26.53,26.06,24.36,22.78,18.61,11.70.Add the compound of formula (8-9) (1.16g, 2mmol), 1,4-dioxane (10mL) and 10% Pd/C (290mg, 25%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen gas successively. Replace, keep the system pressure at 4.5MPa, heat the reaction system to 110°C, stir for 50 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (863 mg, 4 mmol), continue stirring for 4 hours, filter, wash the filtrate with water, and combine The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (11-9) (812 mg, white solid, molar yield 70%). 1 H NMR (600MHz, CDCl 3 ) δ7.83 (d, J＝8.4Hz, 1H), 6.50 (d, J＝9.0Hz, 2H), 4.96–4.91 (m, 1H), 4.14 (q, J＝ 7.1Hz,2H),3.90(s,3H),3.87(s,3H),2.52(t,J＝12.6Hz,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=8.9Hz,3H). 13 C NMR (150MHz, CDCl 3 )δ214.85,174.29,165.47,164.09,161.38,133.63 ,112.92,104.43,99.02,73.64,60.20,58.71,57.56,55.99,55.48,46.50,44.13,41.45,38.16,35.71,35.64,35.46,35.08,32.32,31.61,30.5 4,29.71,27.54,27.00,26.53,26.06 ,24.36,22.78,18.61,11.70.
(10)式(11-10)化合物的制备
(10) Preparation of compounds of formula (11-10)
于反应釜中加入式(8-10)化合物(1.10g，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(220mg，20％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4.5MPa，将反应体系加热至100℃，搅拌40h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-10)化合物(838mg，白色固体，摩尔收率76.2％)。1H NMR(500MHz,CDCl3)δ7.75(dd,J＝7.9,1.9Hz,1H),7.47–7.44(m,1H),6.98(t,J＝7.3Hz,2H),5.01–4.91(m,1H),4.12(t,J＝7.1Hz,2H),3.90(s,3H),2.51(t,J＝12.5Hz,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＝13.3,4.7Hz,1H),1.58–1.51(m,2H),1.44–1.24(m,10H),1.23–1.11(m,2H),1.05(d,J＝11.8Hz,6H),0.87(d,J＝6.6Hz,3H).13C NMR(125MHz,CDCl3)δ214.78,174.24,165.72,159.05,133.23,131.36,120.76,120.10,112.05,74.10,60.17,58.67,57.53,56.00,46.49,44.09,41.45,38.14,35.69,35.62,35.44,35.04,32.23,31.59,30.52,27.53,26.99,26.47,26.04,24.35,22.76,18.60,14.26,11.69.Add the compound of formula (8-10) (1.10g, 2mmol), 1,4-dioxane (10mL) and 10% Pd/C (220mg, 20%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen gas successively. Replace, keep the system pressure at 4.5MPa, heat the reaction system to 100°C, stir for 40 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (862 mg, 4 mmol), continue stirring for 4 hours, filter, wash the filtrate with water, and combine. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (11-10) (838 mg, white solid, molar yield 76.2%). 1 H NMR (500MHz, CDCl 3 ) δ7.75 (dd, J＝7.9, 1.9Hz, 1H), 7.47–7.44 (m, 1H), 6.98 (t, J＝7.3Hz, 2H), 5.01–4.91 ( m,1H),4.12(t,J＝7.1Hz,2H),3.90(s,3H),2.51(t,J＝12.5Hz,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＝13.3,4.7Hz,1H),1.58–1.51 (m,2H),1.44–1.24(m,10H),1.23–1.11(m,2H),1.05(d,J＝11.8Hz,6H),0.87(d,J＝6.6Hz,3H). 13 C NMR (125MHz, CDCl 3 ) δ214.78,174.24,165.72,159.05,133.23,131.36,120.76,120.10,112.05,74.10,60.17,58.67,57.53,56.00,46.49,44.09,41. 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.
(11)式(11-11)化合物的制备
(11) Preparation of compounds of formula (11-11)
于反应釜中加入式(8-11)化合物(1.04g，2mmol)、1,4-二氧六环(10mL)和10％Pd/C(208mg，20％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4.0MPa，将反应体系加热至110℃，搅拌48h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压除去溶剂后用乙酸乙酯(10mL)溶解，控制体系温度在25℃，加入氯铬酸吡啶盐(862mg，4mmol)，继续搅拌4h，过滤，滤液水洗，合并有机相，有机相减压浓缩，柱层析纯化，得到式(11-11)化合物(864mg，白色固体，摩尔收率83.1％)。1H NMR(600MHz,CDCl3)δ8.03(d,J＝7.6Hz,2H),7.55(t,J＝7.4Hz,1H),7.44(t,J＝7.6Hz,2H),5.07–4.90(m,1H),4.14(q,J＝7.3Hz,2H),2.52(t,J＝12.5Hz,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＝14.5Hz,6H),0.87(d,J＝6.5Hz,3H).13C NMR(150MHz,CDCl3)δ214.80,174.23,166.08,132.77,130.72,129.54,128.29,74.28,60.18,58.69,57.56,46.50,44.13,41.41,38.16,35.69,35.62,35.43,35.01,32.26,31.59,30.53,27.53,26.97,26.49,26.03,24.35,22.78,18.62,14.27,11.70.Add the compound of formula (8-11) (1.04g, 2mmol), 1,4-dioxane (10mL) and 10% Pd/C (208mg, 20%wt) to the reaction kettle, and perform nitrogen replacement and hydrogen gas successively. Replace, keep the system pressure at 4.0MPa, heat the reaction system to 110°C, stir for 48 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Filtrate and recover Pd/C. Remove the solvent from the filtrate under reduced pressure and dissolve it in ethyl acetate (10 mL). Control the system temperature at 25°C, add pyridinium chlorochromate (862 mg, 4 mmol), continue stirring for 4 hours, filter, wash the filtrate with water, and combine. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain the compound of formula (11-11) (864 mg, white solid, molar yield 83.1%). 1 H NMR (600MHz, CDCl 3 ) δ8.03(d,J＝7.6Hz,2H),7.55(t,J＝7.4Hz,1H),7.44(t,J＝7.6Hz,2H),5.07–4.90 (m,1H),4.14(q,J＝7.3Hz,2H),2.52(t,J＝12.5Hz,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＝14.5Hz,6H),0.87(d,J＝6.5Hz,3H). 13 C NMR(150MHz, CDCl 3 )δ214.80,174.23,166.08, 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.
实施例十二式(12)化合物的制备Example 12 Preparation of compound of formula (12)
(1)式(12-1)化合物的制备
(1) Preparation of compounds of formula (12-1)
烧瓶中加入式(11-1)化合物(4.46g，10mmol)，四氢呋喃(45mL)，搅拌溶清。在0℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(15mL，15mmol)，继续搅拌12h。TLC 监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-1)化合物(4.0g，白色固体，摩尔收率89.7％)。1H NMR(600MHz,CDCl3)δ4.76–4.65(m,1H),3.98(t,J＝2.5Hz,1H),3.66(s,3H),2.39–2.34(m,1H),2.26–2.21(m,1H),2.01(d,J＝1.7Hz,3H),1.87–1.80(m,5H),1.69(t,J＝9.6Hz,2H),1.62–1.38(m,10H),1.28–1.24(m,2H),1.14–1.02(m,3H),0.97(d,J＝6.1Hz,3H),0.91(d,J＝1.5Hz,3H),0.68(s,3H).13C NMR(150MHz,CDCl3)δ174.67,170.68,74.27,73.07,51.49,48.26,47.31,46.49,41.84,35.97,35.08,34.87,34.11,33.62,32.14,31.04,30.89,28.71,27.43,26.95,26.48,26.01,23.60,23.11,21.45,17.31,12.73.Add the compound of formula (11-1) (4.46g, 10mmol) and tetrahydrofuran (45mL) to the flask, and stir to dissolve. At 0°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (15 mL, 15 mmol) was added dropwise, and stirring was continued for 12 h. TLC After monitoring the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-1) Compound (4.0g, white solid, molar yield 89.7%). 1 H NMR (600MHz, CDCl 3 ) δ4.76–4.65(m,1H),3.98(t,J＝2.5Hz,1H),3.66(s,3H),2.39–2.34(m,1H),2.26– 2.21(m,1H),2.01(d,J＝1.7Hz,3H),1.87–1.80(m,5H),1.69(t,J＝9.6Hz,2H),1.62–1.38(m,10H),1.28 13 C NMR (150MHz, CDCl 3 ) δ174.67,170.68,74.27,73.07,51.49,48.26,47.31,46.49,41.84,35.97,35.08,34.87,34.11,33.62,32.14,31.04,30.89,28.7 1,27.43,26.95,26.48,26.01 ,23.60,23.11,21.45,17.31,12.73.
(2)式(12-2)化合物的制备
(2) Preparation of compounds of formula (12-2)
烧瓶中加入式(11-2)化合物(2.69g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在0℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(7.5mL，7.5mmol)，继续搅拌12h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-2)化合物(2.42g，白色固体，摩尔收率90％)。1H NMR(600MHz,CDCl3)δ8.01(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),4.98–4.93(m,1H),4.03(t,J＝3.0Hz,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＝12.5Hz,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＝6.3Hz,3H),0.97(s,3H),0.72(s,3H).13C NMR(150MHz,CDCl3)δ174.73,165.96,163.18,131.56,123.33,113.48,74.50,73.23,55.42,51.53,48.36,47.39,46.52,41.95,36.02,35.08,34.96,34.20,33.75,32.37,31.05,30.92,28.77,27.44,27.00,26.72,26.05,23.61,23.17,17.37,12.76.Add the compound of formula (11-2) (2.69g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 0°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (7.5 mL, 7.5 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-2) Compound (2.42g, white solid, molar yield 90%). 1 H NMR (600MHz, CDCl 3 ) δ8.01 (d, J＝8.8Hz, 2H), 6.93 (d, J＝8.8Hz, 2H), 4.98–4.93 (m, 1H), 4.03 (t, J＝ 3.0Hz,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＝12.5Hz,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 =6.3Hz,3H),0.97(s,3H),0.72(s,3H). 13 C NMR (150MHz, CDCl 3 )δ174.73,165.96,163.18,131.56,123.33,113.48,74.50,73.23,55.42,51.53, 48.36,47.39,46.52,41.95,36.02,35.08,34.96,34.20,33.75,32.37,31.05,30.92,28.77,27.44,27.00,26.72,26.05,23.61,23.17,17.37,1 2.76.
烧瓶中加入式(11-2)化合物(2.69g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在0℃条件下，加入硼氢化钾(0.54g，10mmol)，继续搅拌12h。TLC监测原料反应完全后，停止反应。滴加丙酮淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-2)化合物(2.3g，白色固体，摩尔收率85.5％)。1H NMR(600MHz,CDCl3)δ8.01(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),4.98–4.93(m,1H),4.03(t,J＝3.0Hz,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＝12.5Hz,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＝6.3Hz,3H),0.97(s,3H),0.72(s,3H).13C NMR(150MHz,CDCl3)δ174.73,165.96,163.18,131.56,123.33,113.48,74.50,73.23,55.42,51.53,48.36,47.39,46.52,41.95,36.02,35.08,34.96,34.20,33.75,32.37,31.05,30.92,28.77,27.44,27.00,26.72,26.05,23.61,23.17,17.37,12.76.Add the compound of formula (11-2) (2.69g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 0°C, potassium borohydride (0.54g, 10mmol) was added, and stirring was continued for 12h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add acetone dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain formula (12-2 ) compound (2.3g, white solid, molar yield 85.5%). 1 H NMR (600MHz, CDCl 3 ) δ8.01 (d, J＝8.8Hz, 2H), 6.93 (d, J＝8.8Hz, 2H), 4.98–4.93 (m, 1H), 4.03 (t, J＝ 3.0Hz,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＝12.5Hz,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＝6.3Hz,3H),0.97(s,3H),0.72(s,3H). 13 C NMR (150MHz, CDCl 3 )δ174 .73,165.96,163.18,131.56,123.33,113.48,74.50,73.23,55.42,51.53,48.36,47.39,46.52,41.95,36.02,35.08,34.96,34.20,33.75,32.3 7,31.05,30.92,28.77,27.44,27.00,26.72 ,26.05,23.61,23.17,17.37,12.76.
烧瓶中加入式(11-2)化合物(2.69g，5mmol)，四氢呋喃(15mL)和甲醇(10mL)的混合溶液，搅拌溶清。在5℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(10mL，10mmol)，继续搅拌12h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-2)化合物(2.34g，白色固体，摩尔收率86.9％)。1H NMR(600MHz,CDCl3)δ8.01(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),4.98–4.93(m,1H),4.03(t,J＝3.0Hz,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＝12.5Hz,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＝6.3Hz,3H),0.97(s,3H),0.72(s,3H).13C NMR(150MHz,CDCl3)δ174.73,165.96,163.18,131.56,123.33,113.48,74.50,73.23,55.42,51.53,48.36,47.39,46.52,41.95,36.02,35.08,34.96,34.20,33.75,32.37,31.05,30.92,28.77,27.44,27.00,26.72,26.05,23.61,23.17,17.37,12.76.Add a mixed solution of the compound of formula (11-2) (2.69g, 5mmol), tetrahydrofuran (15mL) and methanol (10mL) into the flask, and stir to dissolve. At 5°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (10 mL, 10 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-2) Compound (2.34g, white solid, molar yield 86.9%). 1 H NMR (600MHz, CDCl 3 ) δ8.01 (d, J＝8.8Hz, 2H), 6.93 (d, J＝8.8Hz, 2H), 4.98–4.93 (m, 1H), 4.03 (t, J＝ 3.0Hz,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＝12.5Hz,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 =6.3Hz,3H),0.97(s,3H),0.72(s,3H). 13 C NMR (150MHz, CDCl 3 )δ174.73,165.96,163.18,131.56,123.33,113.48,74.50,73.23,55.42,51.53, 48.36,47.39,46.52,41.95,36.02,35.08,34.96,34.20,33.75,32.37,31.05,30.92,28.77,27.44,27.00,26.72,26.05,23.61,23.17,17.37,1 2.76.
(3)式(12-3)化合物的制备
(3) Preparation of compounds of formula (12-3)
烧瓶中加入式(11-3)化合物(2.76g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在0℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(7.5mL，7.5mmol)，继续搅拌12h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-3)化合物(2.5g，白色固体，摩尔收率90.6％)。1H NMR(600MHz,CDCl3)δ8.02(d,J＝8.8Hz,2H),6.93(d,J＝8.8Hz,2H),4.98–4.94(m,1H),4.15(q,J＝7.1Hz,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＝12.5Hz,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＝6.4Hz,3H),0.97(s,3H),0.72(s,3H).13C NMR(150MHz,CDCl3)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.Add the compound of formula (11-3) (2.76g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 0°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (7.5 mL, 7.5 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-3) Compound (2.5g, white solid, molar yield 90.6%). 1 H NMR (600MHz, CDCl 3 ) δ8.02 (d, J＝8.8Hz, 2H), 6.93 (d, J＝8.8Hz, 2H), 4.98–4.94 (m, 1H), 4.15 (q, J＝ 7.1Hz,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＝12.5Hz,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＝6.4Hz,3H),0.97(s,3H),0.72(s,3H). 13 C NMR (150MHz, CDCl 3 )δ 174.27,165.94,163.18,131.56,123.35,113.49,74.49,73.23,60.23,55.43,48.37,47.45,46.53,41.96,36.03,35.06,34.97,34.20,33.76,3 2.38,31.34,30.92,28.77,27.45,27.01, 26.73,26.05,23.61,23.18,17.39,14.28,12.77.
(4)式(12-4)化合物的制备
(4) Preparation of compounds of formula (12-4)
烧瓶中加入式(11-4)化合物(2.55g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在0℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(7.5mL，7.5mmol)，继续搅拌12h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-4)化合物(2.3g，白色固体，摩尔收率90.2％)。1H NMR(600MHz,CDCl3)δ8.06(dd,J＝8.1,1.5Hz,2H),7.59–7.54(m,1H),7.45(t,J＝7.7Hz,2H),5.01–4.97(m,1H),4.04(d,J＝3.0Hz,1H),3.69(s,3H),2.42–2.37(m,1H),2.29–2.23(m,1H),2.03(q,J＝12.5Hz,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).13C NMR(150MHz,CDCl3)δ174.70,166.18,132.70,130.89,129.56,128.26,74.86,73.21,51.52,48.36,47.40,46.52,41.95,36.02,35.07,34.94,34.20,33.76,32.31,31.05,30.92,28.79,27.44,27.00,26.67,26.04,23.61,23.17,17.37,12.77.Add the compound of formula (11-4) (2.55g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 0°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (7.5 mL, 7.5 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-4) Compound (2.3g, white solid, molar yield 90.2%). 1 H NMR (600MHz, CDCl 3 ) δ8.06 (dd, J＝8.1, 1.5Hz, 2H), 7.59–7.54 (m, 1H), 7.45 (t, J＝7.7Hz, 2H), 5.01–4.97 ( m,1H),4.04(d,J＝3.0Hz,1H),3.69(s,3H),2.42–2.37(m,1H),2.29–2.23(m,1H),2.03(q,J＝12.5Hz ,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 (150MHz, CDCl 3 )δ174.70,166.18,132.70,130.89, 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.
(5)式(12-5)化合物的制备
(5) Preparation of compounds of formula (12-5)
烧瓶中加入式(11-5)化合物(2.89g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在0℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(10mL，10mmol)，继续搅拌15h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-5)化合物(2.57g，白色固体，摩尔收率88.9％)。1H NMR(600MHz,CDCl3)δ8.17(d,J＝8.1Hz,2H),7.71(d,J＝8.1Hz,2H),5.04–4.99(m,1H),4.04(d,J＝3.0Hz,1H),3.68(s,3H),2.42– 2.36(m,1H),2.28–2.23(m,1H),2.04(q,J＝12.5Hz,1H),1.96–1.80(m,6H),1.72(q,J＝9.5Hz,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).13C NMR(150MHz,CDCl3)δ174.68,164.92,134.32,134.09,129.96,125.31,125.28,124.60,122.80,75.60,73.20,51.53,48.37,47.42,46.53,41.94,36.01,35.05,34.88,34.18,33.77,32.22,31.04,30.90,28.76,27.43,26.96,26.61,26.02,23.59,23.14,17.38,12.76.Add the compound of formula (11-5) (2.89g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 0°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (10 mL, 10 mmol) was added dropwise, and stirring was continued for 15 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-5) Compound (2.57g, white solid, molar yield 88.9%). 1 H NMR (600MHz, CDCl 3 ) δ8.17(d,J＝8.1Hz,2H),7.71(d,J＝8.1Hz,2H),5.04–4.99(m,1H),4.04(d,J＝ 3.0Hz,1H),3.68(s,3H),2.42– 2.36(m,1H),2.28–2.23(m,1H),2.04(q,J＝12.5Hz,1H),1.96–1.80(m,6H),1.72(q,J＝9.5Hz,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 (150MHz, CDCl 3 )δ174.68,164.92,134.32,134.09,129.96,125.31,125.28,124.60,122.80,75.60,73. 20, 51.53,48.37,47.42,46.53,41.94,36.01,35.05,34.88,34.18,33.77,32.22,31.04,30.90,28.76,27.43,26.96,26.61,26.02,23.59,23.14,1 7.38,12.76.
(6)式(12-6)化合物的制备
(6) Preparation of compounds of formula (12-6)
烧瓶中加入式(11-6)化合物(2.85g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在0℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(10mL，10mmol)，继续搅拌15h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-6)化合物(2.59g，白色固体，摩尔收率90.8％)。1H NMR(600MHz,CDCl3)δ7.84(d,J＝8.4Hz,1H),6.49(d,J＝8.3Hz,2H),4.96–4.92(m,1H),4.02(d,J＝3.0Hz,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＝12.5Hz,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＝6.3Hz,3H),0.96(s,3H),0.71(s,3H).13C NMR(150MHz,CDCl3)δ174.72,165.06,164.01,161.33,133.59,113.09,104.39,99.01,73.20,55.98,55.48,51.52,48.32,47.36,46.50,41.98,36.03,35.08,35.00,34.22,33.72,32.35,31.06,30.91,28.77,27.44,27.03,26.71,26.06,23.62,23.16,17.34,12.75.Add the compound of formula (11-6) (2.85g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 0°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (10 mL, 10 mmol) was added dropwise, and stirring was continued for 15 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-6) Compound (2.59g, white solid, molar yield 90.8%). 1 H NMR (600MHz, CDCl 3 ) δ7.84 (d, J＝8.4Hz, 1H), 6.49 (d, J＝8.3Hz, 2H), 4.96–4.92 (m, 1H), 4.02 (d, J＝ 3.0Hz,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 ＝12.5Hz,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 = 6.3Hz, 3H), 0.96 (s, 3H), 0.71 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) 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.
(7)式(12-7)化合物的制备
(7) Preparation of compounds of formula (12-7)
烧瓶中加入式(11-7)化合物(2.69g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在0℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(7.5mL，7.5mmol)，继续搅拌12h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取， 分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-7)化合物(2.3g，白色固体，摩尔收率85.6％)。1H NMR(600MHz,CDCl3)δ7.79–7.76(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＝12.5Hz,1H),1.91–1.81(m,6H),1.71(d,J＝9.7Hz,2H),1.64–1.58(m,3H),1.55(q,J＝5.1,4.0Hz,2H),1.47–1.39(m,4H),1.33–1.25(m,3H),1.17–1.08(m,4H),0.99(d,J＝6.3Hz,3H),0.96(s,3H),0.71(s,3H).13C NMR(150MHz,CDCl3)δ174.71,165.75,159.02,133.15,131.34,120.95,120.09,112.03,74.68,73.17,56.01,51.52,48.30,47.37,46.51,41.98,36.03,35.08,34.98,34.22,33.71,32.28,31.06,30.91,28.76,27.44,27.02,26.64,26.06,23.62,23.16,17.34,12.76.Add the compound of formula (11-7) (2.69g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 0°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (7.5 mL, 7.5 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, and add ethyl acetate for extraction. The liquids were separated, and the organic phases were combined. The organic phase was washed with water and saturated sodium chloride in sequence, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of formula (12-7) (2.3 g, white solid, molar yield 85.6%). 1 H NMR (600MHz, CDCl 3 ) δ7.79–7.76(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＝12.5Hz,1H),1.91– 1.81(m,6H),1.71(d,J＝9.7Hz,2H),1.64–1.58(m,3H),1.55(q,J＝5.1,4.0Hz,2H),1.47–1.39(m,4H) ,1.33–1.25(m,3H),1.17–1.08(m,4H),0.99(d,J＝6.3Hz,3H),0.96(s,3H),0.71(s,3H). 13 C NMR(150MHz , CDCl 3 )δ174.71,165.75,159.02,133.15,131.34,120.95,120.09,112.03,74.68,73.17,56.01,51.52,48.30,47.37,46.51,41.98,36.03,35.0 8,34.98,34.22,33.71,32.28,31.06, 30.91,28.76,27.44,27.02,26.64,26.06,23.62,23.16,17.34,12.76.
(8)式(12-8)化合物的制备
(8) Preparation of compounds of formula (12-8)
烧瓶中加入式(11-8)化合物(2.95g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在5℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(10mL，10mmol)，继续搅拌10h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-8)化合物(2.69g，白色固体，摩尔收率91.2％)。1H NMR(600MHz,CDCl3)δ8.17(d,J＝8.1Hz,2H),7.71(d,J＝8.2Hz,2H),5.04–4.99(m,1H),4.17–4.12(m,2H),4.04(t,J＝3.0Hz,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＝6.5Hz,3H),0.98(s,3H),0.72(s,3H).13C NMR(150MHz,CDCl3)δ174.25,164.93,134.32,134.10,129.97,125.33,125.31,125.28,75.61,73.20,60.23,48.36,47.47,46.54,41.94,36.01,35.04,34.88,34.19,33.77,32.23,31.32,30.90,28.74,27.43,26.97,26.61,26.03,23.59,23.14,17.39,14.26,12.76.Add the compound of formula (11-8) (2.95g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 5°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (10 mL, 10 mmol) was added dropwise, and stirring was continued for 10 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-8) Compound (2.69g, white solid, molar yield 91.2%). 1 H NMR (600MHz, CDCl 3 ) δ8.17(d,J＝8.1Hz,2H),7.71(d,J＝8.2Hz,2H),5.04–4.99(m,1H),4.17–4.12(m, 2H),4.04(t,J＝3.0Hz,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 = 6.5Hz, 3H), 0.98 (s, 3H), 0.72 (s, 3H). 13 C NMR (150MHz, CDCl 3 ) δ 174.25, 164.93, 134.32, 134.10, 129.97, 125.33,125.31,125.28,75.61,73.20,60.23,48.36,47.47,46.54,41.94,36.01,35.04,34.88,34.19,33.77,32.23,31.32,30.90,28.74,27.4 3,26.97,26.61,26.03,23.59,23.14, 17.39,14.26,12.76.
(9)式(12-9)化合物的制备
(9) Preparation of compounds of formula (12-9)
烧瓶中加入式(11-9)化合物(2.91g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在0℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(10mL，10mmol)，继续搅拌15h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-9)化合物(2.56g，白色固体，摩尔收率88％)。1H NMR(600MHz,CDCl3)δ7.85(d,J＝8.4Hz,1H),6.50(d,J＝8.5Hz,2H),4.97–4.92(m,1H),4.20–4.10(m,2H),4.02(t,J＝3.0Hz,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＝12.5Hz,1H),1.92–1.81(m,5H),1.71(t,J＝10.2Hz,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＝6.4Hz,3H),0.96(s,3H),0.71(s,3H).13C NMR(150MHz,CDCl3)δ174.30,165.07,164.01,161.34,133.60,113.11,104.39,99.02,74.20,73.23,60.23,55.98,55.48,48.33,47.42,46.52,41.98,36.04,35.07,35.01,34.23,33.73,32.36,31.35,30.91,29.71,28.75,27.44,27.03,26.71,26.07,23.62,23.17,17.36,14.27,12.75.Add the compound of formula (11-9) (2.91g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 0°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (10 mL, 10 mmol) was added dropwise, and stirring was continued for 15 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-9) Compound (2.56g, white solid, molar yield 88%). 1 H NMR (600MHz, CDCl 3 ) δ7.85 (d, J = 8.4Hz, 1H), 6.50 (d, J = 8.5Hz, 2H), 4.97–4.92 (m, 1H), 4.20–4.10 (m, 2H),4.02(t,J＝3.0Hz,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＝12.5Hz,1H),1.92–1.81(m,5H),1.71(t,J＝10.2Hz,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=6.4Hz,3H),0.96(s,3H),0.71(s,3H). 13 C NMR (150MHz, CDCl 3 )δ174.30,165.07,164.01,161.34,133.60,113.11,104.39,99.02,74.20,73.23,60.23,55.98,55.48,48.33,47.42,46.52,41.98,36.04,35.07 ,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.
(10)式(12-10)化合物的制备
(10) Preparation of compounds of formula (12-10)
烧瓶中加入式(11-10)化合物(2.76g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在0℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(7.5mL，7.5mmol)，继续搅拌12h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-10)化合物(2.41g，白色固体，摩尔收率87.3％)。1H NMR(600MHz,CDCl3)δ7.79–7.75(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＝3.0Hz,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＝11.6,7.6Hz,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＝6.4Hz,3H),0.96(s,3H),0.70(s,3H).13C NMR(150MHz,CDCl3)δ174.28,165.75,159.01,133.14,131.33,120.93,120.08,112.02,74.69,73.15,60.21,55.99,48.28,47.37,46.50,41.98,36.03,35.07,34.98,34.21,33.70,32.27,31.33,30.90,28.74,27.44,27.02,26.63,26.06,23.62,23.15,17.34,14.27,12.75.Add the compound of formula (11-10) (2.76g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 0°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (7.5 mL, 7.5 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-10) Compound (2.41g, white solid, molar yield 87.3%). 1 H NMR (600MHz, CDCl 3 ) δ7.79–7.75(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＝3.0Hz,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＝11.6,7.6Hz,2H),1.62–1.53(m,6H),1.47–1.41(m,3H),1.39–1.34(m,1H 13 C NMR ( 150MHz, CDCl 3 )δ174.28,165.75,159.01,133.14,131.33,120.93,120.08,112.02,74.69,73.15,60.21,55.99,48.28,47.37,46.50,41.98,36.03, 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.
(11)式(12-11)化合物的制备
(11) Preparation of compounds of formula (12-11)
烧瓶中加入式(11-11)化合物(2.61g，5mmol)，四氢呋喃(25mL)，搅拌溶清。在0℃条件下，滴加1mol/L三叔丁氧基氢化铝锂四氢呋喃溶液(10mL，10mmol)，继续搅拌12h。TLC监测原料反应完全后，停止反应。滴加1mol/L盐酸淬灭反应，减压浓缩，加入乙酸乙酯萃取，分液，合并有机相，有机相依次用水、饱和氯化钠洗涤，减压浓缩，柱层析纯化，得式(12-11)化合物(2.37g，白色固体，摩尔收率90.4％)。1H NMR(600MHz,CDCl3)δ8.07(d,J＝7.7Hz,2H),7.56(t,J＝7.4Hz,1H),7.45(t,J＝7.6Hz,2H),5.02–4.98(m,1H),4.15(q,J＝7.1Hz,2H),4.04(d,J＝2.9Hz,1H),2.41–2.36(m,1H),2.27–2.22(m,1H),2.03(q,J＝12.5Hz,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).13C NMR(150MHz,CDCl3)δ174.28,166.06,132.70,130.89,129.57,128.26,74.86,73.23,60.23,48.36,47.46,46.54,41.95,36.03,35.06,34.94,34.21,33.76,32.31,31.34,30.91,28.76,27.44,27.00,26.68,26.05,23.61,23.17,17.39,14.27,12.77.Add the compound of formula (11-11) (2.61g, 5mmol) and tetrahydrofuran (25mL) into the flask, and stir to dissolve. At 0°C, 1 mol/L lithium tri-tert-butoxyaluminum hydride in tetrahydrofuran solution (10 mL, 10 mmol) was added dropwise, and stirring was continued for 12 h. After TLC monitors the complete reaction of the raw materials, stop the reaction. Add 1 mol/L hydrochloric acid dropwise to quench the reaction, concentrate under reduced pressure, add ethyl acetate for extraction, separate the liquids, combine the organic phases, wash the organic phases with water and saturated sodium chloride in sequence, concentrate under reduced pressure, and purify by column chromatography to obtain the formula ( 12-11) Compound (2.37g, white solid, molar yield 90.4%). 1 H NMR (600MHz, CDCl 3 ) δ8.07(d,J＝7.7Hz,2H),7.56(t,J＝7.4Hz,1H),7.45(t,J＝7.6Hz,2H),5.02–4.98 (m,1H),4.15(q,J＝7.1Hz,2H),4.04(d,J＝2.9Hz,1H),2.41–2.36(m,1H),2.27–2.22(m,1H),2.03( q,J＝12.5Hz,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 (150MHz, CDCl 3 )δ174. 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.
实施例十三脱氧胆酸的制备Example 13 Preparation of deoxycholic acid
(1)式(12-1)化合物制备脱氧胆酸
(1) Preparation of deoxycholic acid from the compound of formula (12-1)
烧瓶中加入式(12-1)化合物(2.24g，5mmol)，四氢呋喃(10mL)和甲醇(10mL)，搅拌溶解，加入LiOH.H2O(0.42g，10mmol)，25℃搅拌12h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥得到脱氧胆酸(1.85g，白色固体，摩尔收率94.4％)。1H NMR(500MHz,DMSO-d6)δ11.94(s,1H),4.47(d,J＝4.3Hz,1H),4.22(d,J＝4.1Hz,1H),3.81(d,J＝3.5Hz,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＝6.5Hz,3H),0.93–0.89(m,1H),0.87(s,3H),0.62(s,3H).13C NMR(125MHz,DMSO-d6)δ175.38,71.46,70.41,47.91,46.62,46.46,42.08,36.76,36.12,35.62,35.44,34.27,33.38,31.29,31.21,30.70,29.06,27.65,27.45,26.57, 23.97,23.54,17.37,12.89.Add the compound of formula (12-1) (2.24g, 5mmol), tetrahydrofuran (10mL) and methanol (10mL) to the flask, stir to dissolve, add LiOH.H 2 O (0.42g, 10mmol), and stir at 25°C for 12h. After the reaction was monitored by TLC, concentrate under reduced pressure, add water-soluble clear solution, and dropwise add 1 mol/L hydrochloric acid to adjust the pH to 3-4. A large amount of white solid precipitated, filtered, and dried to obtain deoxycholic acid (1.85 g, white solid, molar recovery rate 94.4%). 1 H NMR (500MHz, DMSO-d 6 ) δ11.94 (s, 1H), 4.47 (d, J = 4.3Hz, 1H), 4.22 (d, J = 4.1Hz, 1H), 3.81 (d, J = 3.5Hz,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＝6.5Hz,3H),0.93–0.89 (m,1H),0.87(s,3H),0.62(s,3H). 13 C NMR (125MHz, DMSO-d 6 )δ175.38,71.46,70.41,47.91,46.62,46.46,42.08,36.76,36.12 ,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.
(2)式(12-2)化合物制备脱氧胆酸
(2) Preparation of deoxycholic acid from the compound of formula (12-2)
烧瓶中加入式(12-2)化合物(2.7g，5mmol)，甲醇(20mL)，搅拌溶解，加入氢氧化钠(0.60g，15mmol)，25℃搅拌16h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥，柱层析纯化，得到脱氧胆酸(1.86g，白色固体，摩尔收率94.9％)。Add the compound of formula (12-2) (2.7g, 5mmol) and methanol (20mL) to the flask, stir to dissolve, add sodium hydroxide (0.60g, 15mmol), and stir at 25°C for 16h. After the TLC monitoring reaction is completed, concentrate under reduced pressure, add water-soluble clear solution, add 1 mol/L hydrochloric acid dropwise to adjust the pH to 3-4, a large amount of white solid will precipitate, filter, dry, and purify by column chromatography to obtain deoxycholic acid (1.86g , white solid, molar yield 94.9%).
(3)式(12-3)化合物制备脱氧胆酸
(3) Preparation of deoxycholic acid from the compound of formula (12-3)
烧瓶中加入式(12-3)化合物(2.77g，5mmol)，四氢呋喃(10mL)和甲醇(10mL)，搅拌溶解，加入LiOH.H2O(0.42g，10mmol)，25℃搅拌12h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥，柱层析纯化，得到脱氧胆酸(1.88g，白色固体，摩尔收率95.9％)。Add the compound of formula (12-3) (2.77g, 5mmol), tetrahydrofuran (10mL) and methanol (10mL) to the flask, stir to dissolve, add LiOH.H 2 O (0.42g, 10mmol), and stir at 25°C for 12h. After the TLC monitoring reaction is completed, concentrate under reduced pressure, add water-soluble clear solution, and dropwise add 1mol/L hydrochloric acid to adjust the pH to 3-4. A large amount of white solid will precipitate, filter, dry, and purify by column chromatography to obtain deoxycholic acid (1.88g , white solid, molar yield 95.9%).
(4)式(12-4)化合物制备脱氧胆酸
(4) Preparation of deoxycholic acid from the compound of formula (12-4)
烧瓶中加入式(12-4)化合物(2.55g，5mmol)，二氯甲烷(10mL)和甲醇(10mL)，搅拌溶解，加入LiOH.H2O(0.42g，10mmol)，45℃搅拌8h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥，柱层析纯化，得到脱氧胆酸(1.86g，白色固体，摩尔收率94.9％)。Add the compound of formula (12-4) (2.55g, 5mmol), dichloromethane (10mL) and methanol (10mL) to the flask, stir to dissolve, add LiOH.H 2 O (0.42g, 10mmol), and stir at 45°C for 8 hours. After the TLC monitoring reaction is completed, concentrate under reduced pressure, add water-soluble clear solution, add 1 mol/L hydrochloric acid dropwise to adjust the pH to 3-4, a large amount of white solid will precipitate, filter, dry, and purify by column chromatography to obtain deoxycholic acid (1.86g , white solid, molar yield 94.9%).
(5)式(12-5)化合物制备脱氧胆酸
(5) Preparation of deoxycholic acid from the compound of formula (12-5)
烧瓶中加入式(12-5)化合物(2.89g，5mmol)，四氢呋喃(10mL)和甲醇(15mL)，搅拌溶解，加入LiOH.H2O(0.42g，10mmol)，25℃搅拌12h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥，柱层析纯化，得到脱氧胆酸(1.87g，白色固体，摩尔收率95.4％)。Add the compound of formula (12-5) (2.89g, 5mmol), tetrahydrofuran (10mL) and methanol (15mL) to the flask, stir to dissolve, add LiOH.H 2 O (0.42g, 10mmol), and stir at 25°C for 12h. After the TLC monitoring reaction is completed, concentrate under reduced pressure, add water-soluble clear solution, add 1 mol/L hydrochloric acid dropwise to adjust the pH to 3-4, a large amount of white solid will precipitate, filter, dry, and purify by column chromatography to obtain deoxycholic acid (1.87g , white solid, molar yield 95.4%).
(6)式(12-6)化合物制备脱氧胆酸
(6) Preparation of deoxycholic acid from the compound of formula (12-6)
烧瓶中加入式(12-6)化合物(2.86g，5mmol)，四氢呋喃(15mL)和乙醇(15mL)，搅拌溶解，加入LiOH.H2O(0.63g，15mmol)，25℃搅拌12h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥，柱层析纯化，得到脱氧胆酸(1.84g，白色固体，摩尔收率93.8％)。Add the compound of formula (12-6) (2.86g, 5mmol), tetrahydrofuran (15mL) and ethanol (15mL) to the flask, stir to dissolve, add LiOH.H 2 O (0.63g, 15mmol), and stir at 25°C for 12h. After the TLC monitoring reaction is completed, concentrate under reduced pressure, add water-soluble clear solution, add 1 mol/L hydrochloric acid dropwise to adjust the pH to 3-4, a large amount of white solid will precipitate, filter, dry, and purify by column chromatography to obtain deoxycholic acid (1.84g , white solid, molar yield 93.8%).
(7)式(12-7)化合物制备脱氧胆酸
(7) Preparation of deoxycholic acid from the compound of formula (12-7)
烧瓶中加入式(12-7)化合物(2.71g，5mmol)，2-甲基四氢呋喃(10mL)和甲醇(15mL)，搅拌溶解，加入KOH(0.56g，10mmol)，25℃搅拌12h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥，柱层析纯化，得到脱氧胆酸(1.86g，白色固体，摩尔收率94.9％)。Add the compound of formula (12-7) (2.71g, 5mmol), 2-methyltetrahydrofuran (10mL) and methanol (15mL) to the flask, stir to dissolve, add KOH (0.56g, 10mmol), and stir at 25°C for 12h. After the TLC monitoring reaction is completed, concentrate under reduced pressure, add water-soluble clear solution, add 1 mol/L hydrochloric acid dropwise to adjust the pH to 3-4, a large amount of white solid will precipitate, filter, dry, and purify by column chromatography to obtain deoxycholic acid (1.86g , white solid, molar yield 94.9%).
(8)式(12-8)化合物制备脱氧胆酸
(8) Preparation of deoxycholic acid from the compound of formula (12-8)
烧瓶中加入式(12-8)化合物(2.96g，5mmol)，四氢呋喃(10mL)和甲醇(15mL)，搅拌溶解，加入LiOH.H2O(0.42g，10mmol)，25℃搅拌12h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥，柱层析纯化，得到脱氧胆酸(1.86g，白色固体，摩尔收率94.9％)。Add the compound of formula (12-8) (2.96g, 5mmol), tetrahydrofuran (10mL) and methanol (15mL) to the flask, stir to dissolve, add LiOH.H 2 O (0.42g, 10mmol), and stir at 25°C for 12h. After the TLC monitoring reaction is completed, concentrate under reduced pressure, add water-soluble clear solution, add 1 mol/L hydrochloric acid dropwise to adjust the pH to 3-4, a large amount of white solid will precipitate, filter, dry, and purify by column chromatography to obtain deoxycholic acid (1.86g , white solid, molar yield 94.9%).
(9)式(12-9)化合物制备脱氧胆酸
(9) Preparation of deoxycholic acid from the compound of formula (12-9)
烧瓶中加入式(12-9)化合物(2.92g，5mmol)，四氢呋喃(15mL)和甲醇(15mL)，搅拌溶解，加入LiOH.H2O(0.63g，15mmol)，25℃搅拌12h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥，柱层析纯化，得到脱氧胆酸(1.80g，白色固体，摩尔收率91.8％)。Add the compound of formula (12-9) (2.92g, 5mmol), tetrahydrofuran (15mL) and methanol (15mL) to the flask, stir to dissolve, add LiOH.H 2 O (0.63g, 15mmol), and stir at 25°C for 12h. After the TLC monitoring reaction is completed, concentrate under reduced pressure, add water-soluble clear solution, add 1 mol/L hydrochloric acid dropwise to adjust the pH to 3-4, a large amount of white solid will precipitate, filter, dry, and purify by column chromatography to obtain deoxycholic acid (1.80g , white solid, molar yield 91.8%).
(10)式(12-10)化合物制备脱氧胆酸
(10) Preparation of deoxycholic acid from the compound of formula (12-10)
烧瓶中加入式(12-10)化合物(2.77g，5mmol)，二氯甲烷(10mL)和甲醇(15mL)，搅拌溶解，加入LiOH.H2O(0.42g，10mmol)，25℃搅拌12h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥，柱层析纯化，得到脱氧胆酸(1.82g，白色固体，摩尔收率92.8％)。Add the compound of formula (12-10) (2.77g, 5mmol), dichloromethane (10mL) and methanol (15mL) to the flask, stir to dissolve, add LiOH.H 2 O (0.42g, 10mmol), and stir at 25°C for 12h. After the TLC monitoring reaction is completed, concentrate under reduced pressure, add water-soluble clear solution, add 1 mol/L hydrochloric acid dropwise to adjust the pH to 3-4, a large amount of white solid will precipitate, filter, dry, and purify by column chromatography to obtain deoxycholic acid (1.82g , white solid, molar yield 92.8%).
(11)式(12-11)化合物制备脱氧胆酸
(11) Preparation of deoxycholic acid from the compound of formula (12-11)
烧瓶中加入式(12-11)化合物(2.62g，5mmol)，二氯甲烷(10mL)和甲醇(15mL)，搅拌溶解，加入氢氧化钾(0.56g，10mmol)，25℃搅拌12h。TLC监测反应完成后，减压浓缩，加入水溶清，滴加1mol/L盐酸调节pH至3-4，有大量白色固体析出，抽滤，干燥，柱层析纯化，得到脱氧胆酸(1.85g，白色固体，摩尔收率94.4％)。 Add the compound of formula (12-11) (2.62g, 5mmol), dichloromethane (10mL) and methanol (15mL) to the flask, stir to dissolve, add potassium hydroxide (0.56g, 10mmol), and stir at 25°C for 12h. After the TLC monitoring reaction is completed, concentrate under reduced pressure, add water-soluble clear solution, and dropwise add 1mol/L hydrochloric acid to adjust the pH to 3-4. A large amount of white solid will precipitate, filter, dry, and purify by column chromatography to obtain deoxycholic acid (1.85g) , white solid, molar yield 94.4%).
对比例一Comparative Example 1
专利路线及方法：(WO 2012/021133)
Patented route and method: (WO 2012/021133)
该专利以式(7-1)化合物为原料(3位羟基用乙酰基保护)，以乙酸为溶剂，在CrO3的作用下发生氧化反应，60℃反应36h，原料完全转化，文献反应收率为60.5％。This patent uses the compound of formula (7-1) as the raw material (the 3-position hydroxyl group is protected by an acetyl group), uses acetic acid as the solvent, and undergoes an oxidation reaction under the action of CrO 3. The reaction is carried out at 60°C for 36 hours. The raw material is completely converted. The literature reaction yield is 60.5%.
按照上述专利(WO 2012/021133)所提供的实验方法尝试式(7-1)化合物的氧化反应：以式(7-1)化合物为原料，乙酸为溶剂，在CrO3的作用下，60℃反应24h，仍有少量原料剩余，延长反应时间至36h，原料基本完全转化，柱层析分离，所得氧化产物式(8-1)化合物的摩尔收率较低，为58％，反应结果与文献基本相符。According to the experimental method provided by the above patent (WO 2012/021133), try the oxidation reaction of the compound of formula (7-1): use the compound of formula (7-1) as the raw material, acetic acid as the solvent, under the action of CrO 3 , 60°C After 24 hours of reaction, there is still a small amount of raw materials remaining. The reaction time is extended to 36 hours. The raw materials are basically completely converted and separated by column chromatography. The molar yield of the obtained oxidation product formula (8-1) compound is low, 58%. The reaction results are consistent with the literature. Basically consistent.
本发明经多次试验发现，将式(7-1)化合物的3位乙酰基替换为对甲氧基苯甲酰基，即用对甲氧基苯甲酰氯与式(5-1)化合物的3位羟基反应得到式(7-2)化合物，该式(7-2)化合物在乙酸溶剂中，CrO3的作用下发生氧化反应，35℃反应12h，原料完全转化，产物收率可达到92.3％(见实施例十–(3))，并且反应温度低，反应时间短，更有利于工业化生产。本发明经多次试验表明3位羟基保护基的选择对于C环的氧化反应有重要的影响；当3位羟基保护基选用芳香酰基时，与专利路线(WO 2012/021133)中3位羟基保护基选用烷酰基如乙酰基相比，3位芳香酰基保护基更利于C环双键α位的氧化反应，其收率更高，时间更短。The present invention has discovered through many experiments that the acetyl group at position 3 of the compound of formula (7-1) is replaced with p-methoxybenzoyl group, that is, p-methoxybenzoyl chloride and the 3-position group of the compound of formula (5-1) are used. The compound of formula (7-2) is obtained by reacting the hydroxyl group at the position. The compound of formula (7-2) undergoes oxidation reaction under the action of CrO 3 in acetic acid solvent. After reaction at 35°C for 12 hours, the raw material is completely converted and the product yield can reach 92.3%. (See Example 10-(3)), and the reaction temperature is low and the reaction time is short, which is more conducive to industrial production. The present invention has shown through many tests that the selection of the 3-position hydroxyl protecting group has an important influence on the oxidation reaction of the C ring; when the 3-position hydroxyl protecting group is an aromatic acyl group, it is consistent with the 3-position hydroxyl protection in the patented route (WO 2012/021133). Compared with using an alkanoyl group such as an acetyl group as the base, the aromatic acyl protecting group at the 3-position is more conducive to the oxidation reaction at the α position of the C-ring double bond, with a higher yield and shorter time.
对比例二Comparative Example 2
专利路线及方法：(CN 106146593 B)
Patented route and method: (CN 106146593 B)
该专利以式(7-4)化合物为原料(3位羟基用苯甲酰基保护)，以乙腈为溶剂，在碘化亚铜和过氧化氢叔丁醇TBHP的作用下发生氧化反应，50℃反应24h，原料完全转化，得到式(8-4)化合物及式(15-4)的混合物；然后此混合物用PCC氧化，式(15-4)化合物转化为式(8-4)化合物，最终，式(8-4)化合物的摩尔收率为71％。This patent uses the compound of formula (7-4) as raw material (the 3-position hydroxyl group is protected with benzoyl group), uses acetonitrile as the solvent, and undergoes an oxidation reaction under the action of copper iodide and tert-butyl hydrogen peroxide TBHP at 50°C After reacting for 24 hours, the raw materials were completely converted to obtain a mixture of the compound of formula (8-4) and the formula (15-4); then the mixture was oxidized with PCC, and the compound of formula (15-4) was converted into the compound of formula (8-4). Finally, , the molar yield of the compound of formula (8-4) was 71%.
按照上述参考文献所提供的实验方法尝试式(7-4)化合物的氧化反应：以式(7-4)化 合物为原料，乙腈为溶剂，按照该专利的用量加入碘化亚铜和TBHP，50℃反应24h，原料基本完全转化；经过后处理，混合物中再加入PCC氧化，25℃搅拌4h，式(15-4)化合物基本完全转化为式(8-4)化合物，再经过后处理，柱层析纯化，所得式(8-4)化合物的摩尔收率为65％，反应结果与文献基本相符。说明该专利(CN 106146593 B)虽然3位羟基选用与本发明类似的苯甲酰基保护，但其氧化方法不同于本发明，该专利描述的氧化反应收率较低，反应时间较长，并且该反应实际为两步操作，比较繁琐，不利于工业化生产。According to the experimental methods provided by the above references, try the oxidation reaction of the compound of formula (7-4): The compound was used as the raw material, acetonitrile was used as the solvent, copper iodide and TBHP were added according to the dosage of the patent, and the reaction was carried out at 50°C for 24 hours. The raw materials were basically completely converted; after post-treatment, PCC was added to the mixture for oxidation, and stirred at 25°C for 4 hours. The formula ( The compound 15-4) is basically completely converted into the compound of formula (8-4), and then undergoes post-treatment and column chromatography purification. The molar yield of the compound of formula (8-4) obtained is 65%. The reaction results are basically consistent with the literature. It shows that although the 3-position hydroxyl group in this patent (CN 106146593 B) is protected by a benzoyl group similar to that of the present invention, its oxidation method is different from that of the present invention. The oxidation reaction yield described in this patent is low and the reaction time is long, and the The reaction is actually a two-step operation, which is relatively cumbersome and not conducive to industrial production.
本发明以式(7-4)化合物为原料，乙酸为溶剂，在CrO3的作用下发生氧化反应，35℃反应12h，原料完全转化，产物摩尔收率可达到87％(见实施例十–(6))；此外，当A环中3位羟基的取代基为对甲氧基苯甲酰基时，该氧化反应的摩尔收率可达到92％以上(见实施例九–(3))。本发明中经多次试验发现的氧化方法，其氧化剂效率更高，收率高、操作简单、反应时间短，更利于工业化生产。The present invention uses the compound of formula (7-4) as the raw material, acetic acid as the solvent, and an oxidation reaction occurs under the action of CrO 3. After the reaction at 35°C for 12 hours, the raw material is completely converted, and the product molar yield can reach 87% (see Example 10- (6)); In addition, when the substituent of the 3-position hydroxyl group in the A ring is p-methoxybenzoyl, the molar yield of the oxidation reaction can reach more than 92% (see Example 9-(3)). The oxidation method discovered through many experiments in the present invention has higher oxidant efficiency, high yield, simple operation, short reaction time, and is more conducive to industrial production.
对比例三Comparative Example 3
文献路线及方法：(Journal of the American Chemical Society,1977,99(23),7686–7695)
Literature routes and methods: (Journal of the American Chemical Society, 1977, 99(23), 7686–7695)
该文献以式(1)化合物为原料，乙酸乙酯为溶剂，在10％Pd/C-H2(1atm)的作用下，30℃反应，经柱层析纯化，以75.8％的摩尔收率得到式(2)化合物。我们尝试该文献方法，以式(10-1)化合物为原料，10％Pd/C为催化剂，30℃氢化还原反应24h，反应液中未监测到目标化合物式(14-1)。后续实验中，我们提高反应温度和氢气压强，尝试用Raney Ni-H2或10％Pd/C-H2氢化还原C环羰基和双键，所得反应液中主要产物为式(13)化合物(包括式(13-1)和式(13-2)化合物)，有少量式(14)化合物(包括式(14-1)和式(14-2)化合物)；并且这四个化合物极性相近，较难分离纯化。实验表明如不保护3位羟基，直接以式(10-1)化合物为原料氢化还原C环羰基和双键的策略不可行。This document uses the compound of formula (1) as the raw material, ethyl acetate as the solvent, reacts at 30°C under the action of 10% Pd/CH 2 (1 atm), and purifies by column chromatography to obtain the formula with a molar yield of 75.8%. (2) Compounds. We tried this literature method, using the compound of formula (10-1) as raw material, 10% Pd/C as the catalyst, and hydrogenation reduction reaction at 30°C for 24 hours. The target compound of formula (14-1) was not detected in the reaction solution. In subsequent experiments, we increased the reaction temperature and hydrogen pressure, and tried to use Raney Ni-H 2 or 10% Pd/CH 2 to hydrogenate the C ring carbonyl group and double bond. The main product in the reaction solution was the compound of formula (13) (including the formula (13-1) and formula (13-2) compounds), there are a small amount of formula (14) compounds (including formula (14-1) and formula (14-2) compounds); and these four compounds have similar polarities and are relatively Difficult to isolate and purify. Experiments show that without protecting the 3-position hydroxyl group, the strategy of directly using the compound of formula (10-1) as raw material to hydrogenate and reduce the C-ring carbonyl group and double bond is not feasible.
本发明经多次试验，将3位羟基保护后氢化还原C环羰基和双键，再经氧化，所得目标化合物收率高，易分离纯化。例如，以式(8-2)化合物(即用对甲氧基苯甲酰氯与式(10-1)化合物的3位羟基反应得到式(8-2)化合物)为原料，1,4-二氧六环为溶剂，在10％Pd/C-H2的作用下110℃反应24h，反应液经PCC氧化，得到C环双键氢化还原的产物式(11-2)化合物，摩尔收率可达到90.1％(见实施例十一–(2))。
After many tests, the present invention protects the 3-position hydroxyl group, hydrogenates and reduces the C ring carbonyl group and double bond, and then oxidizes the target compound to obtain a high yield and easy separation and purification. For example, the compound of formula (8-2) is used as a raw material (that is, 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 a raw material, and 1,4-bis Oxyhexanes were used as solvents, and the reaction was carried out at 110°C for 24 hours under the action of 10% Pd/CH 2. The reaction solution was oxidized by PCC to obtain the compound of formula (11-2), the product of the hydrogenation reduction of the C-ring double bond, with a molar yield of 90.1 % (see Example 11-(2)).
具体的实验步骤：Specific experimental steps:
于反应釜中加入式(10-1)化合物(402mg，1mmol)、1,4-二氧六环(8mL)和10％Pd/C(126mg，30％w.t.)，先后进行氮气置换和氢气置换，保持体系压力在4MPa，将反应体系加热至110℃，搅拌24h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压浓缩，经1H NMR判断，产物中式(13)化合物(包括式(13-1)和式(13-2)化合物)及式(14)化合物(包括式(14-1)和式(14-2)化合物)的比例约为4：1。Add the compound of formula (10-1) (402 mg, 1 mmol), 1,4-dioxane (8 mL) and 10% Pd/C (126 mg, 30% wt) to the reaction kettle, and perform nitrogen replacement and hydrogen replacement successively. , keep the system pressure at 4MPa, heat the reaction system to 110°C, stir for 24 hours, and stop the reaction after HPLC monitors the complete reaction of the raw materials. Pd/C was recovered by filtration, and the filtrate was concentrated under reduced pressure. According to 1 H NMR, the product was a compound of formula (13) (including compounds of formula (13-1) and formula (13-2)) and a compound of formula (14) (including compounds of formula (13-1) and (13-2)). 14-1) and the compound of formula (14-2)) is about 4:1.
于反应釜中加入式(10-1)化合物(402mg，1mmol)、1,4-二氧六环(8mL)和Raney Ni(1g)，先后进行氮气置换和氢气置换，保持体系压力在4MPa，将反应体系加热至110℃，搅拌24h，HPLC监测原料反应完全后，停止反应。过滤回收Pd/C，滤液减压浓缩，经1H NMR判断，产物中式(13)化合物(包括式(13-1)和式(13-2)化合物)及式(14)化合物(包括式(14-1)和式(14-2)化合物)的比例约为9：1。Add the compound of formula (10-1) (402mg, 1mmol), 1,4-dioxane (8mL) and Raney Ni (1g) to the reaction kettle, perform nitrogen replacement and hydrogen replacement successively, and keep the system pressure at 4MPa. The reaction system was heated to 110°C and stirred for 24 hours. After HPLC monitored the complete reaction of the raw materials, the reaction was stopped. Pd/C was recovered by filtration, and the filtrate was concentrated under reduced pressure. According to 1 H NMR, the product was a compound of formula (13) (including compounds of formula (13-1) and formula (13-2)) and a compound of formula (14) (including compounds of formula (13-1) and (13-2)). 14-1) and the compound of formula (14-2)) is about 9:1.
该实验说明以式(10-1)化合物为原料直接氢化还原C环羰基和双键的策略不可行，较难得到脱氧胆酸甲酯。因此，本发明先用乙酰基、对甲氧基苯甲酰基等保护基团保护A环羟基，再尝试氢化还原C环的羰基和双键。经过筛选不同的3位羟基取代基、催化剂、溶剂、温度及氢气压力等条件，最终以较高收率得到目标化合物。This experiment shows that the strategy of direct hydrogenation reduction of the C ring carbonyl group and double bond using the compound of formula (10-1) as raw material is not feasible, and it is difficult to obtain methyl deoxycholate. Therefore, the present invention first protects the hydroxyl group of the A ring with acetyl, p-methoxybenzoyl and other protecting groups, and then attempts to hydrogenate and reduce the carbonyl group and double bond of the C ring. After screening different 3-position hydroxyl substituents, catalysts, solvents, temperatures, hydrogen pressure and other conditions, the target compound was finally obtained with a higher yield.
本发明的保护内容不局限于以上实施例。在不背离本发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。 The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the concept of the present invention, changes and advantages that can be thought of by those skilled in the art are included in the present invention, and are protected by the appended claims.

Claims (20)

  1. 一种以植物源9,21-二羟基-20-甲基孕甾-4-烯-3-酮9-OH-BA为原料合成脱氧胆酸的方法，其特征在于，所述方法以9-OH-BA为原料，经侧链氧化反应、Wittig或Wittig-Horner反应、脱水反应、A环及侧链双键氢化还原反应、酯化反应、C环氧化反应、C环双键氢化还原反应、C环羰基还原反应、水解反应步骤合成所述脱氧胆酸；或经侧链氧化反应、Wittig或Wittig-Horner反应、脱水反应、A环双键及侧链双键氢化还原反应、A环羰基还原反应、酯化反应、C环氧化反应、C环双键氢化还原反应、C环羰基还原反应、水解步骤合成所述脱氧胆酸；或经侧链氧化反应、Wittig或Wittig-Horner反应、脱水反应、C环氧化反应、A环及侧链双键氢化还原反应、酯化反应、C环双键氢化还原反应、C环羰基还原反应、水解反应步骤合成所述脱氧胆酸；或经侧链氧化反应、Wittig或Wittig-Horner反应、A环双键和侧链双键氢化还原反应、脱水反应、A环羰基还原反应、酯化反应、C环氧化反应、C环双键氢化还原反应、C环羰基还原反应、水解反应步骤合成所述脱氧胆酸；A method for synthesizing deoxycholic acid using plant source 9,21-dihydroxy-20-methylpregnant-4-en-3-one 9-OH-BA as raw material, characterized in that the method uses 9- OH-BA is used as raw material, and undergoes side chain oxidation reaction, Wittig or Wittig-Horner reaction, dehydration reaction, A ring and side chain double bond hydrogenation reduction reaction, esterification reaction, C epoxidation reaction, C ring double bond hydrogenation reduction reaction , C ring carbonyl reduction reaction, hydrolysis reaction steps to synthesize the deoxycholic acid; 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 epoxidation reaction, C ring double bond hydrogenation reduction reaction, C ring carbonyl reduction reaction, hydrolysis step to synthesize the deoxycholic acid; or through side chain oxidation reaction, Wittig or Wittig-Horner reaction, The deoxycholic acid is synthesized through dehydration reaction, C epoxidation 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, and hydrolysis reaction steps; 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 epoxidation reaction, C ring double bond hydrogenation reduction reaction reaction, C ring carbonyl reduction reaction, and hydrolysis reaction steps to synthesize the deoxycholic acid;
    所述方法的反应过程如路线(A)所示：
    The reaction process of the method is as shown in route (A):
    路线(A) Route(A)
    合成路线分别为：
    The synthetic routes are:
    路线一
    Route one
    路线二
    Route 2
    路线三
    Route three
    路线四Route four
    其中，R选自烷基，R1选自烷基、芳基、取代的芳基；Wherein, R is selected from alkyl, R 1 is selected from alkyl, aryl, substituted aryl;
    所述方法中各反应步骤分别如下：Each reaction step in the method is as follows:
    步骤(a)、在第一溶剂中，式(1)化合物经侧链氧化反应，得到式(2)化合物；Step (a), in the first solvent, the compound of formula (1) undergoes a side chain oxidation reaction to obtain the compound of formula (2);
    步骤(b)、在第二溶剂中，式(2)化合物经Wittig或Wittig-Horner反应，得到式(3)化合物；Step (b), in the second solvent, the compound of formula (2) is subjected to Wittig or Wittig-Horner reaction to obtain the compound of formula (3);
    步骤(c)、在第三溶剂中，式(3)化合物经脱水反应，得到式(4)化合物； Step (c), in a third solvent, the compound of formula (3) undergoes a dehydration reaction to obtain the compound of formula (4);
    步骤(d)、在第四溶剂中，式(4)化合物经A环及侧链双键氢化还原反应，得到式(5)化合物；Step (d), in the fourth solvent, the compound of formula (4) is subjected to a hydrogenation reduction reaction of the A ring and the side chain double bond to obtain the compound of formula (5);
    步骤(e)、在第五溶剂中，式(4)化合物经A环双键及侧链双键氢化还原反应，得到式(6)化合物；Step (e), in the fifth solvent, the compound of formula (4) is subjected to a hydrogenation reduction reaction of the A ring double bond and the side chain double bond to obtain the compound of formula (6);
    步骤(f)、在第六溶剂中，式(6)化合物经A环羰基还原反应，得到式(5)化合物；Step (f): In the sixth solvent, the compound of formula (6) is subjected to the reduction reaction of the A ring carbonyl group to obtain the compound of formula (5);
    步骤(g)、在第七溶剂中，式(5)化合物经酯化反应，得到式(7)化合物；Step (g): In the seventh solvent, the compound of formula (5) undergoes an esterification reaction to obtain the compound of formula (7);
    步骤(h)、在第八溶剂中，式(7)化合物经C环氧化反应，得到式(8)化合物；Step (h): In the eighth solvent, the compound of formula (7) is subjected to C epoxidation reaction to obtain the compound of formula (8);
    步骤(i)、在第九溶剂中，式(4)化合物经C环氧化反应，得到式(9)化合物；Step (i), in the ninth solvent, the compound of formula (4) is subjected to C epoxidation reaction to obtain the compound of formula (9);
    步骤(j)、在第十溶剂中，式(9)化合物经A环及侧链双键氢化还原反应，得到式(10)化合物；Step (j): In the tenth solvent, the compound of formula (9) is subjected to a hydrogenation reduction reaction of the A ring and the side chain double bond to obtain the compound of formula (10);
    步骤(k)、在第十一溶剂中，式(10)化合物经酯化反应，得到式(8)化合物；Step (k): In the eleventh solvent, the compound of formula (10) is subjected to an esterification reaction to obtain the compound of formula (8);
    步骤(l)、在第十二溶剂中，式(8)化合物经C环双键氢化还原反应，得到式(11)化合物；Step (1), in the twelfth solvent, the compound of formula (8) undergoes hydrogenation and reduction reaction of the C ring double bond to obtain the compound of formula (11);
    步骤(m)、在第十三溶剂中，式(11)化合物经C环羰基还原反应，得到式(12)化合物；Step (m), in the thirteenth solvent, the compound of formula (11) is subjected to the C ring carbonyl reduction reaction to obtain the compound of formula (12);
    步骤(n)、在第十四溶剂中，式(12)化合物经水解反应，得到式(13)化合物即脱氧胆酸；Step (n), in the fourteenth solvent, the compound of formula (12) undergoes a hydrolysis reaction to obtain the compound of formula (13), that is, deoxycholic acid;
    步骤(o)、在第十五溶剂中，式(3)化合物经A环双键及侧链双键氢化还原反应，得到式(14)化合物；Step (o): In the fifteenth solvent, the compound of formula (3) is subjected to a hydrogenation reduction reaction of the A ring double bond and the side chain double bond to obtain the compound of formula (14);
    步骤(p)、在第十六溶剂中，式(14)化合物经脱水反应，得到式(6)化合物。Step (p): In the sixteenth solvent, the compound of formula (14) undergoes dehydration reaction to obtain the compound of formula (6).
  2. 如权利要求1所述的方法，其特征在于，所述R选自C1-C10直链及支链烷基中的一种或多种；R1选自C1-C10直链烷基、C1-C10支链烷基、苯基对甲氧基苯基邻甲氧基苯基2,4-二甲氧基苯基对三氟甲基苯基的一种或多种。The method of claim 1, wherein R is selected from one or more C1-C10 linear and branched alkyl groups; R1 is selected from C1-C10 linear alkyl, C1- C10 branched alkyl, phenyl p-Methoxyphenyl o-Methoxyphenyl 2,4-dimethoxyphenyl p-trifluoromethylphenyl of one or more.
  3. 如权利要求1所述的方法，其特征在于，所述步骤(a)中，所述侧链氧化反应为：在所述第一溶剂中，式(1)所示的化合物与2,2,6,6-四甲基哌啶氧化物TEMPO、碳酸氢钠、四丁基溴化铵、氧化剂发生氧化反应，得到式(2)化合物；The method of claim 1, wherein in step (a), the side chain oxidation reaction is: in the first solvent, the compound represented by formula (1) and 2,2, An oxidation reaction occurs between 6,6-tetramethylpiperidine oxide TEMPO, sodium bicarbonate, tetrabutylammonium bromide and an oxidizing agent to obtain the compound of formula (2);
    其中，所述式(1)所示的BA、TEMPO、碳酸氢钠、四丁基溴化铵、氧化剂的摩尔比为 1：(0～1)：(0～20)：(0～1)：(1～5)；和/或，所述氧化剂选自N-氯代琥珀酰亚胺NCS、N-溴代琥珀酰亚胺NBS、2-碘酰基苯甲酸IBX、重铬酸吡啶盐PDC中的一种或多种；和/或，所述第一溶剂选自二氯甲烷、四氢呋喃、甲苯、二甲基亚砜、水中的一种或多种；和/或，所述侧链氧化反应的温度为0～30℃；和/或，所述侧链氧化反应的时间为3～8h。Wherein, the molar ratio of BA, TEMPO, sodium bicarbonate, tetrabutylammonium bromide and oxidant represented by the formula (1) is 1: (0～1): (0～20): (0～1): (1～5); and/or, the oxidizing agent is selected from N-chlorosuccinimide NCS, N-bromosuccinimide One or more of imide NBS, 2-iodoacylbenzoic acid IBX, and pyridinium dichromate PDC; and/or, the first solvent is selected from dichloromethane, tetrahydrofuran, toluene, dimethylsulfide One or more of sulfone and water; and/or the temperature of the side chain oxidation reaction is 0-30°C; and/or the time of the side chain oxidation reaction is 3-8 hours.
  4. 如权利要求1所述的方法，其特征在于，所述步骤(b)中，所述Wittig反应为：式(2)化合物、甲氧甲酰基亚甲基三苯基膦或乙氧甲酰基亚甲基三苯基膦或丙氧甲酰基亚甲基三苯基膦加入到所述第二溶剂中，发生Wittig反应，得到式(3)化合物；The method of claim 1, wherein in step (b), the Wittig reaction is: a compound of formula (2), methoxyformylmethylenetriphenylphosphine or ethoxyformylmethylenetriphenylphosphine. Methyltriphenylphosphine or propoxyformylmethylenetriphenylphosphine is added to the second solvent, and Wittig reaction occurs to obtain the compound of formula (3);
    其中，所述式(2)化合物、甲氧甲酰基亚甲基三苯基膦或乙氧甲酰基亚甲基三苯基膦或丙氧甲酰基亚甲基三苯基膦的摩尔比为1：(1～5)；和/或，所述第二溶剂选自二甲苯、甲苯、苯、四氢呋喃、庚烷、己烷中的一种或多种；和/或，所述Wittig反应的温度为80～130℃；和/或，所述Wittig反应的时间为2～8h。Wherein, the molar ratio of the compound of formula (2), methoxyformylmethylenetriphenylphosphine or ethoxyformylmethylenetriphenylphosphine or propoxyformylmethylenetriphenylphosphine is 1 (1-5); and/or, the second solvent is selected from one or more of xylene, toluene, benzene, tetrahydrofuran, heptane, and hexane; and/or, the temperature of the Wittig reaction The temperature is 80-130°C; and/or the Wittig reaction time is 2-8 hours.
  5. 如权利要求1所述的方法，其特征在于，所述步骤(b)中，所述Wittig-Horner反应是指：将碱、膦酰基乙酸甲酯二乙酯或膦酰基乙酸三乙酯或膦酰基乙酸丙酯二乙酯、式(2)化合物加入到第二溶剂中，发生Wittig-Horner反应，得到式(3)化合物；The method of claim 1, wherein in step (b), the Wittig-Horner reaction refers to: adding a base, diethyl methyl phosphonoacetate or triethyl phosphonoacetate or phosphine Diethyl acyl propyl acetate and the compound of formula (2) are added to the second solvent, and a Wittig-Horner reaction occurs to obtain the compound of formula (3);
    其中，所述第二溶剂选自苯、甲苯、乙酸乙酯、四氢呋喃、己烷、庚烷、二甲苯中的一种或多种；和/或，所述碱选自钠氢、叔丁醇钾、叔丁醇钠、甲醇钠、乙醇钠、氢化锂中的一种或多种；和/或，所述式(2)化合物、碱、膦酰基乙酸甲酯二乙酯或膦酰基乙酸三乙酯或膦酰基乙酸丙酯二乙酯的摩尔比为1：(1～5)：(1～5)；和/或，所述Wittig-Horner反应的温度为0～30℃；和/或，所述Wittig-Horner反应的时间为2～8h。Wherein, the second solvent is selected from one or more of benzene, toluene, ethyl acetate, tetrahydrofuran, hexane, heptane, and xylene; and/or the base is selected from sodium hydrogen, tert-butanol One or more of potassium, sodium tert-butoxide, sodium methoxide, sodium ethoxide, and lithium hydride; and/or, the compound of formula (2), a base, methyl phosphonoacetate diethyl ester or triphosphonoacetate The molar ratio of ethyl ester or diethyl phosphonoacetate propyl ester is 1: (1～5): (1～5); and/or, the temperature of the Wittig-Horner reaction is 0～30°C; and/or , the Wittig-Horner reaction time is 2 to 8 hours.
  6. 如权利要求1所述的方法，其特征在于，所述步骤(c)中，所述脱水反应为：所述式(3)化合物、乙酸酐、酸在所述第三溶剂中发生脱水反应，得到式(4)化合物；The method of claim 1, wherein in step (c), the dehydration reaction is: the compound of formula (3), acetic anhydride, and acid undergo a dehydration reaction in the third solvent, Obtain the compound of formula (4);
    其中，所述式(3)化合物、乙酸酐、酸的摩尔比为1：(0～8)：(0.01～4)；和/或，所述酸选自对甲基苯磺酸、硫酸、三氟化硼乙酸络合物中的一种或多种；和/或，所述第三溶剂选自二氯甲烷、乙酸乙酯、氯仿、1,2-二氯乙烷、水、乙酸中的一种或多种；和/或，所述脱水反应的温度为-40℃～80℃；和/或，所述脱水反应的时间为0.5～10h。Wherein, the molar ratio of the compound of formula (3), acetic anhydride and acid is 1: (0~8): (0.01~4); and/or the acid is selected from p-toluenesulfonic acid, sulfuric acid, One or more boron trifluoride acetic acid complexes; and/or the third solvent is selected from dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane, water, and acetic acid. One or more of; and/or, the temperature of the dehydration reaction is -40°C to 80°C; and/or, the time of the dehydration reaction is 0.5 to 10h.
  7. 如权利要求1所述的方法，其特征在于，所述步骤(d)中，所述A环及侧链双键氢化还原反应具体为：所述式(4)化合物、雷尼镍、H2在所述第四溶剂中发生氢化还原反应，得到式(5)化合物；The method of claim 1, wherein in step (d), the hydrogenation and reduction reaction of the A ring and side chain double bonds is specifically: the compound of formula (4), Raney nickel, H 2 A hydrogenation reduction reaction occurs in the fourth solvent to obtain a compound of formula (5);
    其中，所述式(4)化合物、雷尼镍的质量比为1:(0.05～2)；和/或，所述第四溶剂选自四氢呋喃、1,4-二氧六环、乙酸乙酯、2-甲基四氢呋喃、异丙醇、甲基叔丁基醚、甲苯中的一种或多种；和/或，所述A环及侧链双键氢化还原反应的H2压强为1-60atm；和/或，所述 A环及侧链双键氢化还原反应的温度为20～120℃；和/或，所述A环及侧链双键氢化还原反应的时间为1～12h。Wherein, the mass ratio of the compound of formula (4) to Raney Nickel is 1:(0.05~2); and/or the fourth solvent is selected from tetrahydrofuran, 1,4-dioxane, ethyl acetate , one or more of 2-methyltetrahydrofuran, isopropyl alcohol, methyl tert-butyl ether, and toluene; and/or the H 2 pressure of the hydrogenation reduction reaction of the A ring and side chain double bonds is 1- 60atm; and/or, as stated The temperature of the hydrogenation reduction reaction of the A ring and the side chain double bonds is 20 to 120°C; and/or the time of the hydrogenation reduction reaction of the A ring and the side chain double bonds is 1 to 12 hours.
  8. 如权利要求1所述的方法，其特征在于，所述步骤(e)中，所述A环双键及侧链双键氢化还原反应具体为：所述式(4)化合物，在Pd/C和碱的作用下，与H2在所述第五溶剂中，发生氢化还原反应，得到式(6)化合物；The method of claim 1, wherein in step (e), the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is specifically: the compound of formula (4), in Pd/C Under the action of alkali and alkali, a hydrogenation reduction reaction occurs with H 2 in the fifth solvent to obtain the compound of formula (6);
    其中，所述式(4)化合物、碱的摩尔比为1：(0～5)；和/或，所述式(4)化合物、Pd/C的质量比为1：(0.02～0.3)；和/或，所述第五溶剂选自甲醇、乙醇、丙醇、乙酸乙酯、丙酮、二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺中的一种或多种；和/或，所述碱选自碳酸钠、碳酸氢钠、氨水、4-甲氧基吡啶、吡啶、4-二甲氨基吡啶中的一种或多种；和/或，所述A环双键及侧链双键氢化还原反应的H2压强为1～40atm；和/或，所述A环双键及侧链双键氢化还原反应的温度为0～40℃；和/或，所述A环双键及侧链双键氢化还原反应的时间为1～48h。Wherein, the molar ratio of the compound of formula (4) and base is 1: (0-5); and/or the mass ratio of the compound of formula (4) and Pd/C is 1: (0.02-0.3); And/or, the fifth solvent is selected from one or more of methanol, ethanol, propanol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, N,N-dimethylformamide; and/or , the base is selected from one or more of sodium carbonate, sodium bicarbonate, ammonia, 4-methoxypyridine, pyridine, and 4-dimethylaminopyridine; and/or, the A ring double bond and side The H 2 pressure of the chain double bond hydrogenation reduction reaction is 1 to 40 atm; and/or the temperature of the A ring double bond and side chain double bond hydrogenation reduction reaction is 0 to 40°C; and/or the A ring double bond The hydrogenation and reduction reaction time of bonds and side chain double bonds is 1 to 48 hours.
  9. 如权利要求1所述的方法，其特征在于，所述步骤(f)中，所述A环羰基还原反应具体为：所述式(6)化合物、七水合三氯化铈在所述第六溶剂中，加入还原剂，发生A环羰基还原反应，得到式(5)化合物；The method of claim 1, wherein in step (f), the carbonyl reduction reaction of the A ring is specifically: the compound of formula (6), cerium trichloride heptahydrate in the sixth In the solvent, a reducing agent is added, and a reduction reaction of the carbonyl group of the A ring occurs to obtain the compound of formula (5);
    其中，所述式(6)化合物、七水合三氯化铈、还原剂的摩尔比为1：(0～2)：(1～5)；和/或，所述第六溶剂选自甲醇、乙酸乙酯、二氯甲烷、四氢呋喃、乙醇、水中的一种或多种；和/或，所述还原剂选自硼氢化钠、硼氢化钾、三叔丁氧基氢化铝锂中的一种或多种；和/或，所述A环羰基还原反应的温度为-40～30℃；和/或，所述A环羰基还原反应的时间为0.1～8h。Wherein, the molar ratio of the compound of formula (6), cerium trichloride heptahydrate, and the reducing agent is 1: (0～2): (1～5); and/or the sixth solvent is selected from methanol, One or more of ethyl acetate, methylene chloride, tetrahydrofuran, ethanol, and water; and/or the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, and lithium tri-tert-butoxyaluminum hydride. or more; and/or, the temperature of the A ring carbonyl reduction reaction is -40~30°C; and/or, the time of the A ring carbonyl reduction reaction is 0.1~8h.
  10. 如权利要求1所述的方法，其特征在于，所述步骤(g)中，所述酯化反应为：所述式(5)化合物、羟基保护试剂，在碱的作用下，在所述第七溶剂中发生酯化反应，得到式(7)化合物；The method of claim 1, wherein in step (g), the esterification reaction is: the compound of formula (5) and the hydroxyl protecting reagent are reacted in the first step under the action of a base. An esterification reaction occurs in seven solvents to obtain the compound of formula (7);
    其中，所述第七溶剂选自乙酸乙酯、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、甲苯、四氢呋喃、2-甲基四氢呋喃中的一种或多种；和/或，所述碱选自三乙胺、二异丙基乙基胺、咪唑、吡啶、4-二甲氨基吡啶DMAP中的一种或多种；和/或，所述式(5)化合物、羟基保护试剂、碱的摩尔比为1:(1～4):(0.05～5)；和/或，所述酯化反应的温度为0～50℃；和/或，所述酯化反应的时间为2～24h。Wherein, the seventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran; and/ Or, the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, and 4-dimethylaminopyridine DMAP; and/or, the compound of formula (5), The molar ratio of hydroxyl protecting reagent and base is 1:(1~4):(0.05~5); and/or the temperature of the esterification reaction is 0~50°C; and/or the temperature of the esterification reaction is The time is 2~24h.
  11. 如权利要求1所述的方法，其特征在于，所述步骤(h)中，所述C环氧化反应为：所述式(7)化合物、N-羟基邻苯二甲酰亚胺NHPI、氧化剂在所述第八溶剂中，发生C环氧化反应，得到式(8)化合物；The method of claim 1, wherein in step (h), the C epoxidation reaction is: the compound of formula (7), N-hydroxyphthalimide NHPI, The oxidant undergoes C epoxidation reaction in the eighth solvent to obtain the compound of formula (8);
    其中，所述式(7)化合物、氧化剂、N-羟基邻苯二甲酰亚胺的摩尔比为1：(1-5)：(0～5)；和/或，所述氧化剂选自Na2Cr2O7、K2Cr2O7、重铬酸吡啶盐PDC、过氧化苯甲酰BPO、CrO3 中的一种或多种；和/或，所述第八溶剂选自甲苯、丙酮、水、二氯甲烷、N,N-二甲基甲酰胺、乙酸乙酯、N-甲基吡咯烷酮、乙酸中的一种或多种；和/或，所述C环氧化反应的温度为0～50℃；和/或，所述C环氧化反应的时间为10～48h。Wherein, the molar ratio of the compound of formula (7), oxidizing agent and N-hydroxyphthalimide is 1: (1-5): (0~5); and/or the oxidizing agent is selected from Na 2 Cr 2 O 7 , K 2 Cr 2 O 7 , pyridinium dichromate PDC, benzoyl peroxide BPO, CrO 3 One or more of; and/or, the eighth solvent is selected from toluene, acetone, water, methylene chloride, N,N-dimethylformamide, ethyl acetate, N-methylpyrrolidone, acetic acid One or more of them; and/or the temperature of the C epoxidation reaction is 0 to 50°C; and/or the time of the C epoxidation reaction is 10 to 48 hours.
  12. 如权利要求1所述的方法，其特征在于，所述步骤(i)中，所述C环氧化反应为：所述式(4)化合物、N-羟基邻苯二甲酰亚胺NHPI、氧化剂在所述第九溶剂中，发生氧化反应，得到式(9)化合物；The method of claim 1, wherein in step (i), the C epoxidation reaction is: the compound of formula (4), N-hydroxyphthalimide NHPI, The oxidizing agent undergoes an oxidation reaction in the ninth solvent to obtain the compound of formula (9);
    其中，式(4)化合物、氧化剂、N-羟基邻苯二甲酰亚胺NHPI的摩尔比为1：(1-10)：(0～5)；和/或，所述氧化剂选自Na2Cr2O7、K2Cr2O7、重铬酸吡啶盐PDC、过氧化苯甲酰BPO、CrO3中的一种或多种；和/或，所述第九溶剂选自甲苯、丙酮、水、二氯甲烷、N,N-二甲基甲酰胺、乙酸乙酯、N-甲基吡咯烷酮、乙酸中的一种或多种；和/或，所述C环氧化反应的温度为0～50℃；和/或，所述C环氧化反应的时间为10～48h。Wherein, the molar ratio of the compound of formula (4), oxidizing agent and N-hydroxyphthalimide NHPI is 1: (1-10): (0~5); and/or, the oxidizing agent is selected from Na 2 One or more of Cr 2 O 7 , K 2 Cr 2 O 7 , pyridinium dichromate PDC, benzoyl peroxide BPO, and CrO 3 ; and/or the ninth solvent is selected from toluene and acetone. , one or more of water, dichloromethane, N,N-dimethylformamide, ethyl acetate, N-methylpyrrolidone, and acetic acid; and/or, the temperature of the C epoxidation reaction is 0-50°C; and/or the C epoxidation reaction time is 10-48 hours.
  13. 如权利要求1所述的方法，其特征在于，所述步骤(j)中，所述A环及侧链双键氢化还原反应为：所述式(9)化合物、雷尼镍、H2在所述第十溶剂中发生氢化还原反应，得到式(10)化合物；The method of claim 1, wherein in step (j), the hydrogenation and reduction reaction of the A ring and side chain double bonds is: the compound of formula (9), Raney nickel, H 2 in A hydrogenation reduction reaction occurs in the tenth solvent to obtain the compound of formula (10);
    其中，所述式(9)化合物、雷尼镍的质量比为1:(0.05～2)；和/或，所述第十溶剂选自四氢呋喃、1,4-二氧六环、乙酸乙酯、2-甲基四氢呋喃、异丙醇、甲基叔丁基醚、甲苯中的一种或多种；和/或，所述A环及侧链双键氢化还原反应的H2压强为1-60atm；和/或，所述A环及侧链双键氢化还原反应的温度为20～120℃；和/或，所述A环及侧链双键氢化还原反应的时间为1～12h。Wherein, the mass ratio of the compound of formula (9) to Raney Nickel is 1:(0.05~2); and/or the tenth solvent is selected from tetrahydrofuran, 1,4-dioxane, ethyl acetate , one or more of 2-methyltetrahydrofuran, isopropyl alcohol, methyl tert-butyl ether, and toluene; and/or, the H 2 pressure of the hydrogenation reduction reaction of the A ring and side chain double bonds is 1- 60 atm; and/or, the temperature of the hydrogenation reduction reaction of the A ring and the side chain double bond is 20 to 120°C; and/or, the time of the hydrogenation reduction reaction of the A ring and the side chain double bond is 1 to 12 hours.
  14. 如权利要求1所述的方法，其特征在于，所述步骤(k)中，所述酯化反应为：所述式(10)化合物、羟基保护试剂溶解在所述第十一溶剂中，在碱的作用下，发生酯化反应，得到式(8)化合物；The method of claim 1, wherein in step (k), the esterification reaction is: the compound of formula (10) and the hydroxyl protecting reagent are dissolved in the eleventh solvent, and Under the action of alkali, an esterification reaction occurs to obtain the compound of formula (8);
    其中，所述第十一溶剂选自乙酸乙酯、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、甲苯、四氢呋喃、2-甲基四氢呋喃中的一种或多种；和/或，所述碱选自三乙胺、二异丙基乙基胺、咪唑、吡啶、4-二甲氨基吡啶DMAP中的一种或多种；和/或，所述式(8)化合物、羟基保护试剂、碱的摩尔比为1:(1～4):(0.05～5)；和/或，所述酯化反应的温度为0～50℃；和/或，所述酯化反应的时间为2～24h。Wherein, the eleventh solvent is selected from one or more of ethyl acetate, dichloromethane, chloroform, N,N-dimethylformamide, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran; and /or, the base is selected from one or more of triethylamine, diisopropylethylamine, imidazole, pyridine, and 4-dimethylaminopyridine DMAP; and/or, the compound of formula (8) , the molar ratio of hydroxyl protecting reagent and base is 1:(1～4):(0.05～5); and/or, the temperature of the esterification reaction is 0～50°C; and/or, the esterification reaction The time is 2~24h.
  15. 如权利要求1所述的方法，其特征在于，所述步骤(l)中，所述C环双键氢化还原反应为：所述式(8)化合物、催化剂、H2在所述第十二溶剂中发生C环双键氢化还原反应，得到式(11)化合物；The method of claim 1, wherein in step (1), the C-ring double bond hydrogenation reduction reaction is: the compound of formula (8), catalyst, H 2 in the twelfth The C-ring double bond hydrogenation reduction reaction occurs in the solvent to obtain the compound of formula (11);
    其中，所述式(8)化合物、催化剂的质量比为1:(0.05～2)；和/或，所述催化剂选自雷 尼镍、钯碳、氧化铂、氢氧化钯中的一种或多种；和/或，所述第十二溶剂选自四氢呋喃、1,4-二氧六环、乙酸乙酯、2-甲基四氢呋喃、异丙醇、甲基叔丁基醚、甲苯、二甲苯中的一种或多种；和/或，所述双键氢化还原反应的H2压强为20-60atm；和/或，所述双键氢化还原反应的温度为70～120℃；和/或，所述双键氢化还原反应的时间为8～72h。Wherein, the mass ratio of the compound of formula (8) to the catalyst is 1:(0.05~2); and/or the catalyst is selected from the group consisting of One or more of nickel, palladium on carbon, platinum oxide, and palladium hydroxide; and/or, the twelfth solvent is selected from tetrahydrofuran, 1,4-dioxane, ethyl acetate, 2-methyl One or more of tetrahydrofuran, isopropyl alcohol, methyl tert-butyl ether, toluene, and xylene; and/or, the H 2 pressure of the double bond hydrogenation reduction reaction is 20-60 atm; and/or, The temperature of the double bond hydrogenation reduction reaction is 70-120°C; and/or the time of the double bond hydrogenation reduction reaction is 8-72 hours.
  16. 如权利要求1所述的方法，其特征在于，所述步骤(m)中，所述C环羰基还原反应为：所述式(11)化合物在所述第十三溶剂中，加入还原剂，发生C环羰基还原反应，得到式(12)化合物；The method of claim 1, wherein in step (m), the C ring carbonyl reduction reaction is: adding a reducing agent to the compound of formula (11) in the thirteenth solvent, The C ring carbonyl reduction reaction occurs to obtain the compound of formula (12);
    其中，所述式(11)化合物、还原剂的摩尔比为1：(1～5)；和/或，所述第十三溶剂选自乙醇、甲醇、乙酸乙酯、二氯甲烷、四氢呋喃中的一种或多种；和/或，所述还原剂选自硼氢化钠、硼氢化钾、三叔丁氧基氢化铝锂中的一种或多种；和/或，所述C环羰基还原反应的温度为-10～30℃；和/或，所述C环羰基还原反应的时间为0.5～24h。Wherein, the molar ratio of the compound of formula (11) to the reducing agent is 1: (1-5); and/or the thirteenth solvent is selected from ethanol, methanol, ethyl acetate, dichloromethane, and tetrahydrofuran. One or more of; and/or, the reducing agent is selected from one or more of sodium borohydride, potassium borohydride, lithium tri-tert-butoxyaluminum hydride; and/or, the C ring carbonyl The temperature of the reduction reaction is -10~30°C; and/or the time of the reduction reaction of the C ring carbonyl group is 0.5~24h.
  17. 如权利要求1所述的方法，其特征在于，所述步骤(n)中，所述水解反应为：所述式(12)化合物在所述第十四溶剂中，在碱的作用下，发生水解反应，得到脱氧胆酸；The method of claim 1, wherein in step (n), the hydrolysis reaction is: the compound of formula (12) occurs in the fourteenth solvent under the action of a base. Hydrolysis reaction yields deoxycholic acid;
    其中，式(12)化合物、碱的摩尔比为1：(1～5)；和/或，所述第十四溶剂选自1,4-二氧六环、四氢呋喃、2-甲基四氢呋喃、异丙醇、叔丁醇、甲醇、乙醇、二氯甲烷、水中的一种或多种；和/或，所述碱选自叔丁醇钠、叔丁醇钾、乙醇钠、甲醇钠、氢氧化钠、氢氧化钾、氢氧化锂、氢氧化锂一水合物中的一种或多种；和/或，所述水解反应的温度为20～80℃；和/或，所述水解反应的时间为3～24h。Wherein, the molar ratio of the compound of formula (12) and the base is 1: (1-5); and/or the fourteenth solvent is selected from 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, One or more of isopropyl alcohol, tert-butyl alcohol, methanol, ethanol, methylene chloride, and water; and/or the base is selected from sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium methoxide, hydrogen One or more of sodium oxide, potassium hydroxide, lithium hydroxide, and lithium hydroxide monohydrate; and/or the temperature of the hydrolysis reaction is 20-80°C; and/or the temperature of the hydrolysis reaction The time is 3~24h.
  18. 如权利要求1所述的方法，其特征在于，所述步骤(o)中，所述A环双键及侧链双键氢化还原反应为：所述式(3)化合物在所述第十五溶剂中，在Pd/C、碱和氢气的作用下，发生氢化还原反应，得到式(14)化合物；The method of claim 1, wherein in step (o), the hydrogenation and reduction reaction of the A ring double bond and the side chain double bond is: the compound of formula (3) is reacted in the fifteenth In the solvent, under the action of Pd/C, alkali and hydrogen, a hydrogenation reduction reaction occurs to obtain the compound of formula (14);
    其中，所述式(3)化合物、碱的摩尔比为1：(0～5)；和/或，所述式(3)化合物、Pd/C的质量比为1：(0.02～0.3)；和/或，所述第十五溶剂选自甲醇、乙醇、丙醇、乙酸乙酯、丙酮、二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺中的一种或多种；和/或，所述碱选自碳酸钠、碳酸氢钠、氨水、4-甲氧基吡啶、吡啶、4-二甲氨基吡啶中的一种或多种；和/或，所述A环双键及侧链双键氢化还原反应的H2压强为1～40atm；和/或，所述A环双键及侧链双键氢化还原反应的温度为0～40℃；和/或，所述A环双键及侧链双键氢化还原反应的时间为1～48h。Wherein, the molar ratio of the compound of formula (3) and base is 1: (0-5); and/or the mass ratio of the compound of formula (3) and Pd/C is 1: (0.02-0.3); And/or, the fifteenth solvent is selected from one or more of methanol, ethanol, propanol, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, N,N-dimethylformamide; and/or Or, the base is selected from one or more of sodium carbonate, sodium bicarbonate, ammonia, 4-methoxypyridine, pyridine, and 4-dimethylaminopyridine; and/or, the A ring double bond and The H 2 pressure of the side chain double bond hydrogenation reduction reaction is 1 to 40 atm; and/or the temperature of the A ring double bond and side chain double bond hydrogenation reduction reaction is 0 to 40°C; and/or the A ring The hydrogenation and reduction reaction time of double bonds and side chain double bonds is 1 to 48 hours.
  19. 如权利要求1所述的方法，其特征在于，所述步骤(p)中，所述脱水反应为：所述式(14)化合物、乙酸酐、酸在所述第十六溶剂中发生脱水反应，得到式(6)化合物；The method of claim 1, wherein in step (p), the dehydration reaction is: the compound of formula (14), acetic anhydride, and acid undergo a dehydration reaction in the sixteenth solvent , obtain the compound of formula (6);
    其中，所述式(14)化合物、乙酸酐、酸的摩尔比为1：(0～8)：(0.01～4)；和/或，所述酸选自对甲基苯磺酸、硫酸、三氟化硼乙酸络合物中的一种或多种；和/或，所述第十六溶剂 选自二氯甲烷、乙酸乙酯、氯仿、1,2-二氯乙烷、水中的一种或多种；和/或，所述脱水反应的温度为-40℃～80℃；和/或，所述脱水反应的时间为0.5～10h。Wherein, the molar ratio of the compound of formula (14), acetic anhydride and acid is 1: (0~8): (0.01~4); and/or the acid is selected from p-toluenesulfonic acid, sulfuric acid, One or more boron trifluoride acetic acid complexes; and/or the sixteenth solvent One or more selected from dichloromethane, ethyl acetate, chloroform, 1,2-dichloroethane, and water; and/or, the temperature of the dehydration reaction is -40°C to 80°C; and/or , the dehydration reaction time is 0.5 to 10h.
  20. 一种化合物，其特征在于，所述化合物的结构分别如式(2)、(3)、(4)、(6)、(7)、(8)、(9)、(11)、(12)化合物所示：

    A compound, characterized in that the structure of the compound is as follows: formula (2), (3), (4), (6), (7), (8), (9), (11), (12) ) compound shown:

PCT/CN2023/076722 2022-04-26 2023-02-17 Synthesis method of plant-derived deoxycholic acid WO2023207268A1 (en)

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* Cited by examiner, † Cited by third party
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CN106146593A (en) * 2015-04-14 2016-11-23 南京诺瑞特医药科技有限公司 A kind of method preparing deoxycholic acid
CN112341516A (en) * 2020-11-14 2021-02-09 湖南科瑞生物制药股份有限公司 5, 6-epoxy steroid compound and preparation method and application thereof
CN114716497A (en) * 2021-01-05 2022-07-08 苏州盛迪亚生物医药有限公司 Method for preparing deoxycholic acid
CN115466300A (en) * 2022-10-18 2022-12-13 湖南科瑞生物制药股份有限公司 Cholic acid intermediate A7 and synthesis method thereof
CN115611962A (en) * 2022-10-18 2023-01-17 湖南科瑞生物制药股份有限公司 Method for synthesizing cholic acid

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106146593A (en) * 2015-04-14 2016-11-23 南京诺瑞特医药科技有限公司 A kind of method preparing deoxycholic acid
CN112341516A (en) * 2020-11-14 2021-02-09 湖南科瑞生物制药股份有限公司 5, 6-epoxy steroid compound and preparation method and application thereof
CN114716497A (en) * 2021-01-05 2022-07-08 苏州盛迪亚生物医药有限公司 Method for preparing deoxycholic acid
CN115466300A (en) * 2022-10-18 2022-12-13 湖南科瑞生物制药股份有限公司 Cholic acid intermediate A7 and synthesis method thereof
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