WO2023207268A1 - Procédé de synthèse d'acide désoxycholique d'origine végétale - Google Patents

Procédé de synthèse d'acide désoxycholique d'origine végétale 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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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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    • 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

L'invention concerne un procédé de synthèse d'acide désoxycholique qui permet la synthèse de l'acide désoxycholique à partir de 9-OH-BA d'origine végétale en tant que matériau de départ et comprenant les étapes suivantes : réaction d'oxydation de chaîne latérale ; réaction de Wittig ou de Wittig-Horner ; réaction de déshydratation ; réaction d'hydrogénation ; réaction d'estérification ; réaction de C époxydation ; réaction de réduction de carbonyle ; réaction d'hydrolyse et analogues.
PCT/CN2023/076722 2022-04-26 2023-02-17 Procédé de synthèse d'acide désoxycholique d'origine végétale WO2023207268A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106146593A (zh) * 2015-04-14 2016-11-23 南京诺瑞特医药科技有限公司 一种制备去氧胆酸的方法
CN112341516A (zh) * 2020-11-14 2021-02-09 湖南科瑞生物制药股份有限公司 5,6-环氧类固醇类化合物及其制备方法和应用
CN114716497A (zh) * 2021-01-05 2022-07-08 苏州盛迪亚生物医药有限公司 一种制备脱氧胆酸的方法
CN115466300A (zh) * 2022-10-18 2022-12-13 湖南科瑞生物制药股份有限公司 一种胆酸中间体a7及其合成方法
CN115611962A (zh) * 2022-10-18 2023-01-17 湖南科瑞生物制药股份有限公司 胆酸的合成方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106146593A (zh) * 2015-04-14 2016-11-23 南京诺瑞特医药科技有限公司 一种制备去氧胆酸的方法
CN112341516A (zh) * 2020-11-14 2021-02-09 湖南科瑞生物制药股份有限公司 5,6-环氧类固醇类化合物及其制备方法和应用
CN114716497A (zh) * 2021-01-05 2022-07-08 苏州盛迪亚生物医药有限公司 一种制备脱氧胆酸的方法
CN115466300A (zh) * 2022-10-18 2022-12-13 湖南科瑞生物制药股份有限公司 一种胆酸中间体a7及其合成方法
CN115611962A (zh) * 2022-10-18 2023-01-17 湖南科瑞生物制药股份有限公司 胆酸的合成方法

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