CN112209982B - Preparation method of chenodeoxycholic acid - Google Patents
Preparation method of chenodeoxycholic acid Download PDFInfo
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Abstract
The invention relates to the technical field of drug synthesis, in particular to a preparation method of chenodeoxycholic acid. The invention develops a method for synthesizing chenodeoxycholic acid by taking hyodeoxycholic acid (3 alpha, 6 alpha-dihydroxy-5 beta-cholanic acid) as a raw material and carrying out 9-step reaction, wherein the reaction conditions of the steps are mild, the control is easy, the process is simple, the raw material source is wide, the price is low, the raw material is easy to obtain, the yield is high, the total yield can reach 61%, the synthesis cost is low, and the method is suitable for mass preparation and industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of chenodeoxycholic acid.
Background
Chenodeoxycholic acid (3 alpha, 7 alpha-dihydroxy-5 beta-cholanic acid, CDCA) is used as a steroid compound, is mainly extracted from animal bile, is clinically used for treating various cholelithiasis diseases and digestive tract diseases, and is also widely used for treating various liver diseases. In addition, chenodeoxycholic acid is a raw material for synthesizing ursodeoxycholic acid, obeticholic acid and other steroid compounds. Therefore, as the medicinal value is expanded and the demand for ursodeoxycholic acid and obeticholic acid is expanded, the demand for chenodeoxycholic acid is also increased.
The pig bile is a well-known pig viscera, most of the pig bile is discarded, and the pig bile contains abundant hyodeoxycholic acid (3 alpha, 6 alpha-dihydroxy-5 beta-cholanic acid, HDCA) actually, so that the synthesis of chenodeoxycholic acid or ursodeoxycholic acid by taking the hyodeoxycholic acid as a raw material has important industrial application value, and the current main synthetic route is as follows.
The first route is shown in figure 1, using hyodeoxycholic acid as raw material, after side chain carboxyl methyl esterification product, potassium dichromate oxidizes 6-hydroxyl into 6-carbonyl, then reacts with trimethylchlorosilane under the action of lithium diisopropylamide to generate enol-type silicon ether, immediately oxidizes the enol-type silicon ether with m-chloroperoxybenzoic acid or ozone to obtain 3 alpha, 7 alpha-dihydroxy-6-carbonyl-5 beta-cholanic acid methyl ester, reacts with benzene sulfonyl hydrazide, and uses NaBH4Reducing under acidic condition to obtain chenodeoxycholic acid methyl ester, and finally oxidizing by Jones and reducing by lithium-liquid ammonia to obtain ursodeoxycholic acid, wherein the total yield is about 16%. Although the process route only has 9 steps, the ultralow temperature reaction of LDA exists, the reaction condition is difficult to control, the total yield is lower and is only 16 percentThe industrialization value is not high.
And a second route, as shown in figure 2, synthesizing a 4-alkene-3-carbonyl structure compound by using hyodeoxycholic acid as a raw material, and then preparing a 5 beta-H configuration through steps of catalytic hydrogenation and the like, thereby forming an AB ring cis-structure. The reaction process comprises the steps of taking hyodeoxycholic acid as a raw material, obtaining a side chain carboxyl methyl esterification product, carrying out hydroxyl protection reaction with p-toluenesulfonyl chloride, carrying out elimination reaction under the action of potassium acetate to generate a 5, 6-bit double bond, carrying out deprotection under the action of potassium hydroxide to generate a 3-hydroxyl group, carrying out Oppenauer oxidation, then carrying out dehydrogenation by using tetrachlorobenzoquinone to obtain 4, 6-diene-3-carbonyl-methyl cholanate, carrying out epoxidation on the 6, 7-bit double bond by using m-chloroperoxybenzoic acid in a dichloromethane solution to obtain 6 alpha, 7 alpha-epoxy-3-carbonyl-4-alkene-methyl cholanate, carrying out Pd/C catalytic hydrogenation, finally carrying out Jones oxidation and lithium-liquid ammonia reduction to obtain ursodeoxycholic acid, wherein the total yield is 26%. Tetrachlorobenzoquinone used in the synthesis process route belongs to a limited used environmental pollutant, and aluminum isopropoxide is difficult to treat, so that the process route can cause great harm to the environment.
And a third route, as shown in fig. 3, heating and refluxing hyodeoxycholic acid serving as a raw material in a methanol system of concentrated sulfuric acid to obtain a side chain methyl esterification product, selectively oxidizing 6-position to obtain a 6-position carbonyl compound, then forming hydrazone with p-toluenesulfonyl hydrazide, performing elimination reaction under the action of lithium hydride to generate 6-position and 7-position double bonds, epoxidizing the 6-position and 7-position double bonds, and performing epoxy ring opening and hydrolysis under the action of lithium aluminum hydride to obtain chenodeoxycholic acid, wherein the total yield is 5.06%. The overall yield of the process route is low, and the process route uses lithium aluminum hydride to reduce epoxy, so that 24-site carboxyl is reduced into hydroxyl, and the process route has excessive byproducts and low yield.
And a fourth route, as shown in fig. 4, using hyodeoxycholic acid as a raw material, heating and refluxing in a methanol system of concentrated sulfuric acid to obtain a methyl esterification product, then selectively oxidizing 6 sites to generate a mono-oxidation product under the action of a Jones reagent, brominating 7 sites under the action of a bromination reagent, reducing 6 sites of carbonyl groups to methylene under the action of zinc and concentrated hydrochloric acid, and finally hydrolyzing under the action of alkali to obtain chenodeoxycholic acid, wherein the total yield is 18%. According to the process, selective oxidation of 6-hydroxy by adopting a Jones reagent is difficult to control, most of obtained products are 3, 6-hydroxy is oxidized into carbonyl, and the total yield is low.
Disclosure of Invention
The invention provides a preparation method of chenodeoxycholic acid, which is mild in reaction condition, simple in process, less in by-products, low in cost and suitable for industrial production, and aims to solve the problems that the existing method for synthesizing chenodeoxycholic acid or ursodesoxycholic acid by taking hyodeoxycholic acid as a raw material is difficult to control the reaction condition and low in total yield or is difficult to treat reactants so as to cause difficulty in realizing industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme.
A preparation method of chenodeoxycholic acid takes hyodeoxycholic acid as a raw material and comprises the following steps:
(1) carrying out esterification reaction on hyodeoxycholic acid to generate a compound II;
(2) carrying out selective oxidation reaction on the compound II to generate a compound III;
(3) carrying out hydroxyl protection reaction on the compound III to generate a compound IV;
(4) carrying out carbonyl reduction reaction on the compound IV to generate a compound V;
(5) carrying out hydroxyl ester forming reaction on the compound V to generate a compound VI;
(6) carrying out elimination reaction on the compound VI to generate a compound VII;
(7) carrying out epoxidation reaction on the compound VII to generate a compound VIII;
(8) carrying out epoxy ring opening reaction on the compound VIII to generate a compound IX;
(9) hydrolyzing the compound IX to obtain chenodeoxycholic acid;
the structural formulas of the compounds II, III, IV, V, VI, VII, VIII and IX are respectively as follows in sequence:
preferably, the chenodeoxycholic acid preparation method has a synthesis circuit shown in figure 1, and comprises the following steps:
(1) under the catalytic action of acid, hyodeoxycholic acid reacts with R1OH is subjected to esterification reaction to generate a compound II;
(2) carrying out selective oxidation reaction on the compound II and an oxidant to generate a compound III;
(3) compounds III and R2COOH is subjected to hydroxyl protection reaction to generate a compound IV;
(4) carrying out carbonyl reduction reaction on the compound IV and metal hydride to generate a compound V;
(5) compounds V and R3SO3H or R3SO2Carrying out hydroxyl ester-forming reaction on Cl to generate a compound VI;
(6) carrying out elimination reaction on the compound VI and acetate to generate a compound VII;
(7) carrying out epoxidation reaction on the compound VII and an oxidant to generate a compound VIII;
(8) under the action of hydrogen and a catalyst, the compound VIII undergoes an epoxy ring-opening reaction to generate a compound IX;
(9) hydrolyzing the compound IX to obtain chenodeoxycholic acid;
the R is1Is substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl or alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 aryl or heteroaryl, (C1-C8 alkyl or aryl)3Silane radical, (C1-C8 alkyl)3Silane radical, (aryl radical)3A silane group;
the R is2Is substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl or alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 aryl or heteroaryl, (C1-C8 alkyl or aryl)3Silane radical, (C1-C8 alkyl)3Silane radical, (aryl radical)3A silane group;
the R is3Is substituted or unsubstituted C1-C10 alkyl or substituted or unsubstituted CSubstituted or unsubstituted C2-C10 alkenyl or alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 aryl or heteroaryl, (C1-C8 alkyl or aryl)3Silane radical, (C1-C8 alkyl)3Silane radical, (aryl radical)3A silane group.
The step (1) is preferably carried out under the following reaction conditions:
the acid may be selected from one or more of the following: concentrated sulfuric acid, concentrated hydrochloric acid, p-toluenesulfonic acid, phosphoric acid, boric acid, hydrobromic acid, hexafluorophosphoric acid and tetrafluoroboric acid; further preferably, the acid is concentrated hydrochloric acid.
The solvent is alcohol solvent, and can be one or more of methanol, ethanol, propanol, butanol, etc.; further preferably, the solvent is methanol.
Hyodeoxycholic acid and R1The molar ratio of OH is 1 (1-200); preferably 1: 20.
the reaction temperature is between room temperature and reflux temperature, and the preferred reaction temperature is reflux temperature; the reaction time is 1-48h, and the preferable reaction time is 2 h.
The step (2) is preferably carried out under the following reaction conditions:
the oxidant may be selected from one or more of the following: 2-iodoxybenzoic acid, iodobenzene diacetate, pyridinium chlorochromate, pyridinium dichromate, potassium hydrogen persulfate; further preferably, the oxidizing agent is 2-iodoxybenzoic acid.
The solvent can be any one or more of tert-butyl alcohol, acetonitrile, acetone, dichloromethane and water; further preferably, the solvent is tert-butanol.
The molar ratio of the compound II to the oxidizing agent is 1: 1-2; the preferred molar ratio is 1: 1.2.
the reaction temperature is from room temperature to reflux temperature; the preferred reaction temperature is reflux temperature; the reaction time is 1-48 h; the preferred reaction time is 1.5 h.
The step (3) is preferably carried out under the following reaction conditions:
reacting in an alkaline environment, wherein the alkali used in the alkaline environment is pyridine and/or triethylamine; further preferably, the base is triethylamine.
Compounds III and R2The molar ratio of COOH is 1: 1-5; preferably in a molar ratio of 1: 3.
The reaction temperature of the reaction is 0-room temperature, preferably room temperature; the reaction time is 1-24 h; preferably, it is 3.5 h.
The step (4) is preferably carried out under the following reaction conditions:
the solvent can be one or more of ethanol, methanol, dichloromethane and tetrahydrofuran; further preferably, the solvent is methanol.
The metal hydride can be sodium borohydride, potassium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride; further preferably, the metal hydride is sodium borohydride.
The molar ratio of the compound IV to the metal hydride is 1: 1-10; preferably in a molar ratio of 1: 5.
The reaction temperature is 0 ℃ to room temperature, and the preferable reaction temperature is 0 ℃; the reaction time is 1-24h, and the preferable reaction time is 2 h.
The step (5) is preferably carried out under the following reaction conditions:
the solvent is organic solvent, and can be selected from one of the following: pyridine, dichloromethane and triethylamine; further preferably, the solvent is pyridine.
Compounds V and R3SO3H (or R)3SO2Cl) is 1: 1-10; preferably in a molar ratio of 1: 5.
The reaction temperature is 0 ℃ to room temperature, and the preferable reaction temperature is room temperature; the reaction time is 1-48 h; the preferred reaction time is 24 h.
The step (6) is preferably carried out under the following reaction conditions:
the acetate may be selected from one of the following: potassium acetate, sodium acetate, zinc acetate; further preferably, the acetate salt is potassium acetate.
The molar ratio of the compound VI to the potassium acetate is 1: 1-20; preferably, the molar ratio is 1: 10.
The reaction temperature is the reflux temperature; the reaction time is 1-24 h; the preferred reaction time is 4 h.
The solvent is a mixed solution of water and an organic solvent, and the organic solvent is selected from at least one of the following solvents: n, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide and dimethyl sulfoxide. Further preferably, the organic solvent is N, N-dimethylformamide.
The step (7) is preferably carried out under the following reaction conditions:
the oxidant can be one or more of m-chloroperoxybenzoic acid, a hydrogen peroxide solution with the mass fraction of 30 percent and monoperoxyphthalic acid; preferably, the oxidizing agent is m-chloroperoxybenzoic acid.
The solvent is dichloromethane or toluene; the preferred solvent is dichloromethane.
The molar ratio of the compound VII to the oxidant is 1: 1-20; preferably in a molar ratio of 1: 3.
The reaction temperature is 0 ℃ to room temperature, and the preferable reaction temperature is room temperature; the reaction time is 1-48 h; the preferred reaction time is 24 h.
The step (8) is preferably carried out under the following reaction conditions:
the catalyst may be selected from one or more of the following: palladium carbon with the mass percentage of 2-10%, palladium chloride, palladium hydroxide, palladium acetate and Raney nickel; further preferably, the catalyst is palladium on carbon with 10% by mass of palladium.
The solvent can be one or more of ethanol, methanol, pyridine, dioxane, isopropanol, tetrahydrofuran, and dichloromethane; preferably, the solvent is ethanol.
The pressure of the hydrogen is 0.1-2 MPa; preferably, the pressure of hydrogen is 0.45 MPa.
The mass ratio of the compound VIII to the catalyst is 1: 0.1-2; the preferred mass ratio is 1: 0.8.
The reaction temperature is between room temperature and reflux temperature, and the preferred reaction temperature is reflux temperature; the reaction time is 1-48h, and the preferable reaction time is 24 h.
The step (9) is preferably carried out under the following reaction conditions:
the base is an inorganic base selected from: one or more of sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate; further preferably, the base is sodium hydroxide.
The solvent is selected from one or more of methanol, tetrahydrofuran, ethanol, isopropanol, tert-butanol and water; further preferably, the solvent is a mixed solution of methanol and water in a volume ratio of 5: 1.
The molar ratio of the compound IX to the base is 1: 1-10; preferably in a molar ratio of 1: 6.
The reaction temperature is between room temperature and reflux temperature, and the preferred reaction temperature is reflux temperature; the reaction time is 1-24h, and the preferable reaction time is 2 h.
Compared with the prior art, the invention has the beneficial effects that:
the invention develops a method for synthesizing chenodeoxycholic acid by taking hyodeoxycholic acid as a raw material through 9-step reaction, the reaction conditions of each step are mild, the control is easy, the process is simple, the raw material sources are wide, the price is low, the chenodeoxycholic acid is easy to obtain, the yield is high, the total yield can reach 61%, and the method is suitable for large-scale preparation and industrial production.
Drawings
FIG. 1 is a synthesis scheme of a prior art for the synthesis of chenodeoxycholic acid methyl ester;
FIG. 2 is a synthesis scheme of ursodeoxycholic acid synthesis in the prior art;
FIG. 3 is one of the synthetic routes for the synthesis of chenodeoxycholic acid of the prior art;
FIG. 4 shows a second synthesis scheme for chenodeoxycholic acid synthesis in the prior art;
FIG. 5 is a scheme showing the synthesis of chenodeoxycholic acid according to the present invention.
Detailed Description
In order to more fully understand the technical contents of the present invention, the technical solutions of the present invention will be further described and illustrated with reference to the following specific embodiments.
The features, benefits and advantages of the present invention will become apparent to those skilled in the art from a reading of the present disclosure. The following examples are mainly intended to illustrate the specific implementation of the process of the present invention, and do not represent that the process of the present invention can be carried out only by the following examples, for example, in the case of the process for preparing compound IX by the epoxy ring-opening reaction of compound VIII under hydrogen pressurization and the action of a catalyst, the process of the present invention can be carried out under a hydrogen pressure of 0.1 to 2MPa, which is clearly illustrated in the summary of the invention, although the specific implementation is only exemplified by 0.45MPa and 1.5MPa, and does not represent that the reaction can be carried out only under a hydrogen pressure of 0.45MPa or 1.5MPa or limited to a range of 0.45 to 1.5MPa with respect to the hydrogen pressure. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, but are conventional products commercially available.
Example 1
The present embodiment provides a method for preparing chenodeoxycholic acid, wherein the synthetic route refers to fig. 5, and the method specifically includes the following steps:
(1) preparation of compound II by esterification of hyodeoxycholic acid
5.0g of hyodeoxycholic acid (12.8mmol) was dissolved in 25mL of methanol at room temperature, and 100. mu.L of concentrated hydrochloric acid (3.2mmol) was added thereto, followed by reflux reaction for 2 hours, whereby the reaction was terminated. After methanol was distilled off under reduced pressure, 50mL of ethyl acetate was added and dissolved, and the mixture was washed with a saturated sodium bicarbonate solution (10 mL. times.3) and a saturated sodium chloride solution (10 mL. times.3) in this order, and the ethyl acetate layer was collected. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered under suction, and ethyl acetate was removed by rotary evaporation to give 5.1g of a white solid with a yield of 98%.
The structural characterization data for compound II is as follows:
1H NMR(400MHz,CDCl3)δ4.04(dt,J＝12.0,4.7Hz,1H),3.65(s,3H),3.59(dt,J＝10.6,4.6Hz,1H),0.90(d,J＝6.7Hz,6H),0.63(s,3H)。
13C NMR(101MHz,CDCl3)δ174.74,71.58,68.07,56.15,55.94,51.48,48.42,42.85,39.95,39.84,35.96,35.57,35.34,35.01,34.85,31.07,30.97,30.23,29.21,28.10,24.19,23.48,20.76,18.25,12.02。
HRMS:Calcd for C25H42O4 406.3083,Found 429.2976[M+Na]+。
(2) selective oxidation reaction of compound II to prepare compound III
6.5g of 2-iodoxybenzoic acid (23.2mmol) were dissolved in 80mL of tert-butanol, and 8.0g of Compound II (19.7mmol) were added and the reaction was refluxed at 85 ℃ for about 1.5 h. After the reaction, insoluble matter was removed by suction filtration, and t-butanol was evaporated and dissolved in 100mL of ethyl acetate. After washing with a 10% sodium sulfite solution (50 mL. times.3) and a saturated sodium chloride solution (50 mL. times.3) in this order, the organic layer was collected and dried over anhydrous magnesium sulfate. Suction filtration, ethyl acetate evaporation and column chromatography purification gave 6.8g of a white solid with a yield of 85%.
The structural characterization data for compound III is as follows:
1H NMR(400MHz,CDCl3)δ3.65(s,3H),3.60(dd,J＝10.5,5.3Hz,1H),0.91(d,J＝6.4Hz,3H),0.82(s,3H),0.63(s,3H)。
13C NMR(101MHz,CDCl3)δ213.84,174.64,70.11,59.41,56.83,55.82,51.48,43.10,42.89,40.02,39.61,37.96,37.06,35.27,34.87,34.38,31.05,30.91,29.85,27.97,23.95,23.15,20.84,18.23,11.95。
HRMS:Calcd for C25H40O4 404.2927,Found 427.2814[M+Na]+。
(3) compound IV is prepared by hydroxyl protection reaction
0.5004g of Compound III (1.2mmol) was dissolved in 15mL of ethyl acetate at room temperature, 0.0150g of 4-dimethylaminopyridine (0.1mmol) was added, 425. mu.L of triethylamine (3.1mmol) and 375. mu.L of acetic anhydride (4.0mmol) were added, and the reaction was stirred for 3.5 hours to complete. The pH was adjusted to neutral by adding 0.5mol/L dilute hydrochloric acid, and after washing with water (8 mL. times.3), the mixture was washed with a saturated sodium chloride solution (8 mL. times.3). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered under suction, and rotary evaporated to remove ethyl acetate, whereby 0.5402g of a white solid was obtained in a yield of 98%.
Structural characterization data for compound IV are as follows:
1H NMR(400MHz,CDCl3)δ4.76-4.66(m,1H),3.69(s,3H),2.05(s,3H),0.95(d,J＝6.4Hz,3H),0.87(s,3H),0.68(s,3H)。
13C NMR(101MHz,CDCl3)δ212.79,174.61,170.25,72.40,59.10,56.84,55.88,51.50,43.12,42.89,42.79,39.93,39.60,37.95,37.10,35.28,34.14,31.06,30.93,27.98,26.19,23.94,23.13,21.28,20.85,18.25,11.97。
HRMS:Calcd for C27H42O5 446.3032,Found 469.2930[M+Na]+。
(4) compound IV is subjected to hydroxyl reduction reaction to prepare compound V
Dissolving 2.5g of compound IV (5.6mmol) in 50mL of methanol, slowly adding 1.1g of sodium borohydride (28.0mmol) at 0 ℃ in an ice bath, reacting for 0.5h, naturally heating to room temperature, continuing to react for 2h, and finishing the reaction. The reaction was stopped by adding acetic acid, removing methanol by rotary evaporation, dissolving the product with 50mL of ethyl acetate, adjusting the pH to neutral with saturated sodium bicarbonate solution, and collecting the ethyl acetate layer. The ethyl acetate layer was then washed with a saturated sodium chloride solution (20 mL. times.3), and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed by filtration, the organic phase was collected, and the solvent was removed by distillation under the reduced pressure to obtain 2.5g of a white solid with a yield of 100%.
The structural characterization data for compound V is as follows:
1H NMR(600MHz,CDCl3)δ4.71-4.64(m,1H),3.73(s,1H),3.65(s,3H),2.01(s,3H),1.10(s,3H),0.90(d,J＝6.5Hz,3H),0.66(s,3H)。
13C NMR(151MHz,CDCl3)δ174.77,170.63,73.75,72.88,56.31,55.98,51.50,48.42,42.78,40.67,40.02,35.46,35.37,34.52,34.36,32.26,31.07,31.00,30.70,28.16,26.21,25.52,24.19,21.42,20.60,18.28,12.07。
HRMS:Calcd for C27H44O5 448.3189,Found 471.3082[M+Na]+。
(5) hydroxyl protection reaction of compound V to prepare compound VI
0.5000g of compound V (1.1mmol) is dissolved in 10mL of pyridine, 1.1572g of p-methoxybenzenesulfonyl chloride (5.6mmol) is slowly added under ice bath, and after reaction for 4h under ice bath, the temperature is naturally raised to room temperature for reaction for 24 h. After the reaction, pyridine was removed by rotary evaporation, 15mL of ethyl acetate was added to dissolve the product, and the ethyl acetate layer was washed with a saturated sodium bicarbonate solution (5 mL. times.3) and a saturated sodium chloride solution (5 mL. times.3) in this order, and then dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration, the organic phase was collected, and the solvent was removed by distillation under the reduced pressure to obtain 0.6613g of a white solid with a yield of 99%.
The structural characterization data for compound VI is as follows:
1H NMR(400MHz,CDCl3)δ7.75(d,J＝7.8Hz,2H),7.33(d,J＝8.0Hz,2H),4.64-4.52(m,1H),4.41(s,1H),3.65(s,3H),3.81(s,3H),1.99(s,3H),1.01(s,3H),0.89(d,J＝6.3Hz,3H),0.62(s,3H)。
13C NMR(101MHz,CDCl3)δ174.70,170.41,144.52,134.53,130.22,129.81,127.59,127.05,83.62,72.96,55.91,55.88,51.50,45.65,42.76,40.06,39.83,35.32,34.92,34.30,32.04,31.63,31.05,30.96,30.83,28.08,26.06,25.01,23.92,21.64,21.33,20.40,18.24,12.04。
(6) preparation of compound VII by elimination reaction of compound VI
0.6191g of Compound VI (1.0mmol) was dissolved in 15mL of N, N-dimethylformamide and 2mL of water, and 1.008g of potassium acetate (10.2mmol) was added thereto, followed by reflux reaction for 4 hours. After the reaction, the solvent was removed by rotary evaporation, 20mL of ethyl acetate was added to dissolve the product, and the ethyl acetate layer was washed with a saturated sodium bicarbonate solution (5 mL. times.3) and a saturated sodium chloride solution (5 mL. times.3), followed by addition of anhydrous magnesium sulfate and drying. Anhydrous magnesium sulfate was removed by filtration, an organic phase was collected, the solvent was removed by distillation under the reduced pressure, and column chromatography purification was performed to obtain 0.3972g of a white solid with a yield of 90%.
Structural characterization data for compound VII are as follows:
1H NMR(600MHz,CDCl3)δ5.49(ddd,J＝9.9,4.8,2.5Hz,1H),5.44(d,J＝10.1Hz,1H),4.70-4.63(m,1H),3.66(s,3H),2.02(s,3H),0.92(d,J＝6.5Hz,3H),0.85(s,3H),0.68(s,3H)。
13C NMR(151MHz,CDCl3)δ174.68,170.59,130.31,128.29,73.60,55.85,54.76,51.44,43.58,43.38,40.13,39.83,37.62,35.91,35.34,34.08,33.28,31.09,31.03,28.25,26.61,23.87,22.62,21.38,20.58,18.27,12.04。
HRMS:Calcd for C27H42O4 430.3083,Found 453.2976[M+Na]+。
(7) epoxidation reaction is carried out on the compound VII to prepare a compound VIII
Under ice-bath, 1.1g of m-chloroperoxybenzoic acid (6.4mmol) was dissolved in 20mL of dichloromethane, 1.0g of compound VII (2.3mmol) was added, and the mixture was allowed to react at room temperature for 24 hours. After completion of the reaction, the reaction mixture was washed with a saturated sodium bicarbonate solution (5 mL. times.3), a saturated sodium sulfite solution (5 mL. times.3) and a saturated sodium chloride solution (5 mL. times.3) in this order, and the organic layer was collected and dried over anhydrous magnesium sulfate. Filtration by suction and evaporation of ethyl acetate gave 1.0g of a white solid with a yield of 96%.
The structural characterization data for compound VIII is as follows:
1H NMR(600MHz,CDCl3)δ4.73-4.65(m,1H),3.66(s,3H),3.12-3.06(m,2H),2.02(s,3H),0.91(d,J＝6.5Hz,3H),0.83(s,3H),0.69(s,3H)。
13C NMR(151MHz,CDCl3)δ174.65,170.73,72.91,55.62,55.18,54.01,51.81,51.45,43.21,40.22,39.69,35.81,35.36,34.78,33.87,32.55,31.07,31.01,29.51,28.31,26.27,23.91,23.47,21.37,20.24,18.23,11.94。
HRMS:Calcd for C27H42O5 446.3032,Found 469.2928[M+Na]+。
(8) epoxy ring opening reaction of compound VIII to prepare compound IX
In a medium pressure hydrogenation reactor, 0.3000g of compound VIII (0.1mmol) was dissolved in 15mL of ethanol, and 0.2500g of 10% palladium on carbon (10% by mass of palladium in the palladium on carbon catalyst) was added, and the reaction was carried out under the above conditions at a hydrogen pressure of 0.45MPa and a reaction temperature of 90 ℃ for 24 hours. After the reaction, celite was added, 10% palladium on carbon was removed by suction filtration, ethanol was evaporated, the residue was dissolved in 15mL of ethyl acetate, and the solution was washed with a saturated sodium chloride solution (5 mL. times.3), and the organic layer was collected and dried over anhydrous magnesium sulfate. Suction filtration, evaporation of ethyl acetate and purification by column chromatography gave 0.2713g of a white solid with a yield of 90%.
Structural characterization data for compound IX is as follows:
1H NMR(400MHz,CDCl3)δ4.61-4.51(m,1H),3.88-3.81(m,1H),3.65(s,3H),2.00(s,3H),0.95-0.88(m,6H),0.65(s,3H)。
13C NMR(151MHz,CDCl3)δ174.76,170.81,74.39,68.49,55.80,51.51,50.44,42.71,41.20,39.59,39.40,35.38,35.31,35.08,34.99,34.41,32.80,31.04,30.99,28.15,26.71,23.71,22.73,21.49,20.59,18.26,11.77。
HRMS:Calcd for C27H44O5 448.3189,Found 471.3082[M+Na]+。
(9) compound IX is hydrolyzed to prepare chenodeoxycholic acid I
0.0500g of Compound IX (0.1mmol) was dissolved in a mixed solution of 5mL of methanol and 400. mu.L of water, and 0.0250g of sodium hydroxide (0.6mmol) was added thereto, followed by reaction under reflux for 2 hours. After completion of the reaction, methanol was distilled off, and the mixture was dissolved in 5mL of ethyl acetate, washed with acid to neutrality, then washed with a saturated sodium chloride solution (2 mL. times.3), and the organic layer was collected and dried over anhydrous magnesium sulfate. And (4) performing suction filtration, evaporating to remove ethyl acetate, adding diethyl ether to ensure that the oily liquid is just dissolved, dropwise adding n-hexane into the oily liquid, and separating out white solid. Suction filtration gave 0.0427g of a white solid in 97% yield.
The structural characterization data of chenodeoxycholic acid I are as follows:
1H NMR(400MHz,CDCl3)δ3.90-3.78(m,1H),3.53-3.45(m,1H),0.94(d,J＝6.5Hz,3H),0.91(s,3H),0.66(s,3H).
13C NMR(151MHz,CDCl3)δ178.43,72.06,68.60,55.79,50.44,42.72,41.46,39.83,39.62,39.42,35.39,35.31,35.05,34.58,32.83,30.80,30.62,29.71,28.17,23.71,22.77,20.58,18.25,11.79.
HRMS:Calcd for C24H40O4 392.2927,Found 391.2864[M-H]-。
the spectrum of chenodeoxycholic acid I obtained by the present example is completely identical to the spectrum of a chenodeoxycholic acid standard substance.
Examples 2 to 15
Examples 2 to 15 each provide a method for preparing chenodeoxycholic acid, and examples 2 to 15 refer to the method for preparing the same in example 1, except for the step (2), which is specifically as follows:
the oxidizing agent was dissolved in 80mL of the solvent in proportion according to the reaction conditions shown in Table 1 below, and 8.0g of Compound II (19.7mmol) was added to carry out the reaction. After the reaction, insoluble matter was removed by suction filtration, and t-butanol was evaporated and dissolved in 100mL of ethyl acetate. After washing with a 10% sodium sulfite solution (50 mL. times.3) and a saturated sodium chloride solution (50 mL. times.3) in this order, the organic layer was collected and dried over anhydrous magnesium sulfate. And (4) carrying out suction filtration, evaporating to remove ethyl acetate, carrying out column chromatography purification, and collecting a product compound III.
TABLE 1 reaction conditions and results of step (2) in examples 2-15
From the experimental results of examples 2 to 15, it can be seen that, among the reaction effects of the five oxidizing agents on the selective oxidation of the 6-hydroxyl, 2-iodoxybenzoic acid is the oxidizing agent with the best selective oxidation effect, the selectivity is strong, and the yield of the obtained target product is high. 2-iodoxybenzoic acid is used as an oxidant, and the influence of the dosage of the oxidant, the reaction temperature and the reaction time on the reaction effect is as follows: the molar ratio of the compound II to the oxidizing agent is 1: 1.2 is the optimum oxidant ratio, when the molar ratio is lower than 1: 1.2, the raw materials are not completely reacted; when the molar ratio is higher than 1: 1.2, with the increase of the oxidant, the generated by-products of 3-position and 6-position hydroxyl double oxidation are increased, and the yield of the obtained target product is reduced; when the oxidation reaction is carried out at room temperature, the oxidation reaction speed is slow, and the reaction can be completed within at least 24 hours; when the oxidation reaction is carried out at the reflux temperature, the reaction speed is obviously accelerated; the oxidation reaction can be carried out for 1.5h at the reflux temperature, namely the reaction is complete, the generated by-products of 3-position and 6-position hydroxyl double oxidation are increased along with the extension of the reaction time, and the yield of the obtained target product is reduced.
Example 16
This example provides a process for the preparation of chenodeoxycholic acid, which is referred to the process of example 1, with the only difference that: in the step (1), the catalyst is concentrated sulfuric acid.
5.0g of hyodeoxycholic acid (12.8mmol) was dissolved in 25mL of methanol at room temperature, and 170. mu.L of concentrated sulfuric acid (3.2mmol) was added thereto, followed by reflux reaction for 2 hours to complete the reaction. After methanol was distilled off under reduced pressure, 50mL of ethyl acetate was added and dissolved, and the mixture was washed with a saturated sodium bicarbonate solution (10 mL. times.3) and a saturated sodium chloride solution (10 mL. times.3) in this order, and the ethyl acetate layer was collected. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered under suction, and ethyl acetate was removed by rotary evaporation to give 5.1g of a white solid with a yield of 98%.
Example 17
This example provides a process for the preparation of chenodeoxycholic acid, which is referred to the process of example 1, with the only difference that: in step (3), the compounds III and R2The molar ratio of COOH was 1: 2.2, the amount of acetic anhydride was 2.7 mmol.
0.5000g of Compound III (1.2mmol) was dissolved in 15mL of ethyl acetate at room temperature, 0.0150g of 4-dimethylaminopyridine (0.1mmol) was added, 425. mu.L of triethylamine (3.1mmol) and finally 255. mu.L of acetic anhydride (2.7mmol) were added, and the reaction was stirred for 3.5 hours to terminate. The pH was adjusted to neutral by adding 0.5mol/L dilute hydrochloric acid, and after washing with water (8 mL. times.3), the mixture was washed with a saturated sodium chloride solution (8 mL. times.3). The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered under suction, and rotary evaporated to remove ethyl acetate, whereby 0.5303g of a white solid was obtained in 96% yield.
Example 18
This example provides a process for the preparation of chenodeoxycholic acid, which is referred to the process of example 1, with the only difference that: in the step (4), the metal hydride is potassium borohydride.
2.5g of compound IV (5.6mmol) is dissolved in 50mL of methanol, 1.5g of potassium borohydride (28.0mmol) is slowly added under ice bath at 0 ℃, then the temperature is naturally raised to room temperature for reaction for 2h, and the reaction is finished. The reaction was stopped by adding acetic acid, removing methanol by rotary evaporation, dissolving the product with 50mL of ethyl acetate, adjusting the pH to neutral with saturated sodium bicarbonate solution, and collecting the ethyl acetate layer. The ethyl acetate layer was then washed with a saturated sodium chloride solution (20 mL. times.3), and dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration, the organic phase was collected, the solvent was removed by distillation under the reduced pressure, and column chromatography purification was carried out to obtain 1.7g of a white solid with a yield of 68%.
Example 19
This example provides a process for the preparation of chenodeoxycholic acid, which is referred to the process of example 1, with the only difference that: in the step (5), the reaction solvent is dichloromethane, and the catalyst is pyridine.
0.5000g of compound V (1.1mmol) is dissolved in 10mL of dichloromethane, 1.1572g of p-methoxybenzenesulfonyl chloride (5.6mmol) and 450. mu.L of pyridine (5.6mmol) are slowly added under ice bath, and after reaction for 4 hours under ice bath, the temperature is naturally raised to room temperature for reaction for 24 hours. After the reaction, the solvent was removed by rotary evaporation, 15mL of ethyl acetate was added to dissolve the product, and the ethyl acetate layer was washed with a saturated sodium bicarbonate solution (5 mL. times.3) and a saturated sodium chloride solution (5 mL. times.3) in this order, and then dried over anhydrous magnesium sulfate. The anhydrous magnesium sulfate was removed by filtration, the organic phase was collected, the solvent was removed by distillation under the reduced pressure, and column chromatography purification was performed to obtain 0.3829g of a white solid with a yield of 58%.
Example 20
This example provides a process for the preparation of chenodeoxycholic acid, which is referred to the process of example 1, with the only difference that: in the step (6), the reaction solvent is hexamethylphosphoric triamide.
0.6004g of Compound VI (1.0mmol) was dissolved in 15mL of hexamethylphosphoric triamide, 1.0081g of potassium acetate (10.2mmol) was added, and the reaction was refluxed for 12 hours. After the reaction, the solvent was removed by rotary evaporation, 20mL of ethyl acetate was added to dissolve the product, and the ethyl acetate layer was washed with a saturated sodium bicarbonate solution (5 mL. times.3) and a saturated sodium chloride solution (5 mL. times.3), followed by addition of anhydrous magnesium sulfate and drying. Anhydrous magnesium sulfate was removed by filtration, an organic phase was collected, the solvent was removed by distillation under the reduced pressure, and column chromatography purification was performed to obtain 0.1414g of a white solid with a yield of 33%.
Example 21
This example provides a process for the preparation of chenodeoxycholic acid, which is referred to the process of example 1, with the only difference that: in the step (7), the oxidant is monoperoxyphthalic acid.
(1) Preparation of monoperoxyphthalic acid
17.5g of phthalic anhydride (0.1mmol) was added to 105mL of diethyl ether, 30mL of a 30% aqueous hydrogen peroxide solution (1.0mmol) was added dropwise thereto, and the reaction was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was washed with a 40% ammonium sulfate solution (40 mL. times.3), dried over anhydrous magnesium sulfate was added thereto, and the anhydrous magnesium sulfate was removed by suction filtration, and the solution was refrigerated at 4 ℃ for further use.
(2) Epoxidation reaction
Dissolving 1.0g of compound VII in 15mL of toluene, adding 5mL of ether solution of monoperoxyphthalic acid, removing ether under reduced pressure, and stirring at room temperature for reaction for 4 hours; then adding 5mL of ether solution of monoperoxyphthalic acid, decompressing and pumping off the ether, and stirring and reacting for 4 hours at room temperature; after addition of 5mL of an ether solution of monoperoxyphthalic acid, the ether was removed under reduced pressure and the reaction was continued at room temperature for 4 hours. After completion of the reaction, a 10% sodium carbonate solution was added to dissolve the white solid, and the organic layer was washed with a saturated sodium carbonate solution (5 mL. times.3) and a saturated sodium chloride solution (5 mL. times.3) in this order, and then the organic layer was collected and dried over anhydrous magnesium sulfate. Suction filtration and evaporation of the solvent gave 1.0g of a white solid in 96% yield.
Example 22
This example provides a process for the preparation of chenodeoxycholic acid, which is referred to the process of example 1, with the only difference that: in the step (7), the reaction solvent is pyridine.
1.1g of m-chloroperoxybenzoic acid (6.4mmol) was dissolved in 15mL of toluene, and 1.0g of compound VII (2.3mmol) was added thereto, followed by reflux reaction for 3 hours. After completion of the reaction, the reaction mixture was cooled, and washed with a 10% sodium hydroxide solution (5 mL. times.3) and a saturated sodium chloride solution (5 mL. times.3) in this order, and the organic layer was collected and dried over anhydrous magnesium sulfate. The toluene was evaporated off by suction filtration to give 1.0g of a white solid with a yield of 96%.
Examples 23 to 27
Examples 23 to 27 each provide a method for producing chenodeoxycholic acid, and examples 23 to 27 refer to the production method of example 1, except for the step (8), specifically as follows:
0.3000g of Compound VIII (0.1mmol) was dissolved in 15mL of a solvent in an autoclave according to the reaction conditions shown in Table 2 below, 0.2500g of a catalyst was added, and the reaction was carried out for 12 hours under the conditions shown in Table 2 with the hydrogen pressure and the reaction temperature set. After the reaction, celite was added, 10% Pd/C was removed by suction filtration, ethanol was evaporated, the residue was dissolved in 15mL of ethyl acetate, the solution was washed with a saturated sodium chloride solution (5 mL. times.3), and the organic layer was collected and dried over anhydrous magnesium sulfate. And (4) carrying out suction filtration, evaporating to remove ethyl acetate, carrying out column chromatography purification, and collecting a product compound IX.
TABLE 2 reaction conditions and results of step (8) in examples 23-27
| Examples | Solvent(s) | Reaction temperature | Reaction time | Reaction pressure | Catalyst and process for preparing same | Results of the reaction |
| 23 | Methanol | 70℃ | 24h | 0.45 |
10% Palladium on carbon | Is not reacted |
| 24 | Methylene dichloride | 50℃ | 24h | 0.45 |
10% Palladium on carbon | Is not reversedShould be taken |
| 25 | Dioxane (dioxane) | RT | 24h | 0.45 |
10% Palladium on carbon | Complete reaction and more by-products |
| 26 | Ethanol | 90℃ | 24h | 0.45MPa | 5% Palladium on carbon | 37％ |
| 27 | Ethanol | 90℃ | 24h | 1.5 |
10% Palladium on carbon | 50％ |
From the experimental results of examples 23-27, it can be seen that 10% palladium on carbon is the better catalyst, and the reaction effect is better than that of 5% palladium on carbon; when the hydrogen pressure is 0.45MPa, the reaction effect is good, and when the pressure is increased to 1.5MPa, a by-product is generated in the reaction, and the reaction yield is reduced.
Example 28
This example provides a process for the preparation of chenodeoxycholic acid, which is referred to the process of example 1, with the only difference that: in the step (9), the inorganic base is potassium hydroxide.
0.0506g of Compound IX (0.1mmol) was dissolved in a mixed solution of 5mL of methanol and 400. mu.L of water, and 0.0337g of potassium hydroxide (0.6mmol) was added thereto, followed by reflux reaction for 2 hours. After completion of the reaction, methanol was distilled off, and the mixture was dissolved in 5mL of ethyl acetate, washed with acid to neutrality, then washed with a saturated sodium chloride solution (2 mL. times.3), and the organic layer was collected and dried over anhydrous magnesium sulfate. And (4) performing suction filtration, evaporating to remove ethyl acetate, adding diethyl ether to ensure that the oily liquid is just dissolved, dropwise adding n-hexane into the oily liquid, and separating out white solid. Filtration with suction gave 0.0416g of a white solid in 95% yield.
In conclusion, the hyodeoxycholic acid is used as a reaction raw material, so that waste can be utilized, the synthesis cost is reduced, and the raw material source is wide and sufficient in supply. And the yield of the chenodeoxycholic acid obtained by the steps is high and can reach 61%, and the method is suitable for large-scale preparation. The preparation method is simple to operate, high in repeatability and certain in practicability.
The technical contents of the present invention are further illustrated by the examples, so as to facilitate the understanding of the reader, but the embodiments of the present invention are not limited thereto, and any technical extension or re-creation based on the present invention is protected by the present invention.
Claims (6)
1. A preparation method of chenodeoxycholic acid takes hyodeoxycholic acid as a raw material, and is characterized by comprising the following steps:
(1) under the catalytic action of acid, hyodeoxycholic acid reacts with R1OH is subjected to esterification reaction to generate a compound II;
(2) carrying out selective oxidation reaction on the compound II and an oxidant to generate a compound III;
(3) compounds III and R2COOH is subjected to hydroxyl protection reaction to generate a compound IV;
(4) carrying out carbonyl reduction reaction on the compound IV and metal hydride to generate a compound V;
(5) compounds V and R3SO3H or R3SO2Carrying out hydroxyl ester-forming reaction on Cl to generate a compound VI;
(6) carrying out elimination reaction on the compound VI and acetate to generate a compound VII;
(7) carrying out epoxidation reaction on the compound VII and an oxidant to generate a compound VIII;
(8) under the action of hydrogen and a catalyst, the compound VIII undergoes an epoxy ring-opening reaction to generate a compound IX;
(9) hydrolyzing the compound IX to obtain chenodeoxycholic acid;
the structural formulas of the compounds II, III, IV, V, VI, VII, VIII and IX are respectively as follows in sequence:
wherein, R is1、R2And R3Are all selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl or alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 aryl or heteroaryl, (C1-C8 alkyl or aryl)3Silane radical, (C1-C8 alkyl)3Silane radical, (aryl radical)3Any of silane groups;
in the step (2), the oxidant is 2-iodoxybenzoic acid; the solvent is one or more of tert-butyl alcohol, acetonitrile, acetone, dichloromethane and water; the molar ratio of the compound II to the oxidant is 1: 1.2, the reaction temperature is the reflux temperature, and the reaction time is 1.5 h;
in the step (7), the oxidant is one or more of m-chloroperoxybenzoic acid, a hydrogen peroxide aqueous solution with the mass fraction of 30% and monoperoxyphthalic acid; the solvent is one or more of dichloromethane and toluene; the reaction temperature is 0 ℃ to room temperature; the reaction time is 1-48 h;
in the step (8), the catalyst is palladium-carbon with the mass percent of palladium being 10%; the solvent is one or more of ethanol, methanol, pyridine, dioxane, isopropanol, tetrahydrofuran and dichloromethane; the pressure of hydrogen is 0.45MPa, the reaction temperature is the reflux temperature, and the reaction time is 24 h.
2. The method for preparing chenodeoxycholic acid according to claim 1, wherein the reaction conditions of step (1) are: the acid is selected from one or more of concentrated sulfuric acid, concentrated hydrochloric acid, p-toluenesulfonic acid, phosphoric acid, boric acid, hydrobromic acid, hexafluorophosphoric acid and tetrafluoroboric acid; the solvent is selected from one or more of methanol, ethanol, propanol and butanol; the reaction temperature is from room temperature to reflux temperature, and the reaction time is 1-48 h.
3. The method for preparing chenodeoxycholic acid according to claim 1, wherein the reaction conditions of step (3) are: reacting in an alkaline environment, wherein the alkali used in the alkaline environment is pyridine and/or triethylamine; the reaction temperature is 0-room temperature; the reaction time is 1-24 h.
4. The method for preparing chenodeoxycholic acid according to claim 1, wherein the reaction conditions of step (4) are: the solvent is selected from one or more of ethanol, methanol, dichloromethane and tetrahydrofuran; the metal hydride is sodium borohydride, potassium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; the reaction temperature is 0 ℃ to room temperature; the reaction time is 1-24 h.
5. The method for preparing chenodeoxycholic acid according to claim 1, wherein the reaction conditions of step (5) are: the solvent is selected from pyridine, dichloromethane or triethylamine; the reaction temperature is 0 ℃ to room temperature; the reaction time is 1-48 h.
6. The method for preparing chenodeoxycholic acid according to claim 1, wherein the reaction conditions of step (6) are: the acetate is selected from potassium acetate, sodium acetate or zinc acetate; the reaction temperature is the reflux temperature; the reaction time is 1-24 h; the solvent is a mixed solution of water and an organic solvent, and the organic solvent is selected from one or more of N, N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide and dimethyl sulfoxide.
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| CN108794557A (en) * | 2018-03-09 | 2018-11-13 | 山东睿鹰先锋制药有限公司 | A kind of preparation method of chenodeoxycholic acid and intermediate |
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| CN106831923A (en) * | 2017-03-15 | 2017-06-13 | 眉山市新功生物科技有限公司 | A kind of preparation method of chenodeoxycholic acid |
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