A preparation method of obeticholic acid

Abstract

The present invention relates to a method for preparing obeticholic acid, and in particular to a compound as shown in formula III and a method for preparing the compound, as well as a method for preparing obeticholic acid by using compound III. The method has the advantages of mild reaction conditions, few by-products, simple operation, high total yield, etc., and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to a method for preparing obeticholic acid. Background Art

[0002] Obeticholic acid (as shown in Formula I) is a semisynthetic chenodeoxycholic acid derivative used to treat portal hypertension and liver diseases, including primary biliary cirrhosis, bile acid diarrhea, and non-alcoholic steatohepatitis. Obeticholic acid works by activating the FXR receptor, a nuclear receptor that is mainly expressed in the liver, intestines, and kidneys. It can regulate the expression of genes related to bile acid, fat, and sugar metabolism, and can also regulate immune responses. Activating FXR can inhibit bile acid synthesis and prevent toxic reactions caused by excessive accumulation of bile acids.

[0003]

[0004] WO2002072598 discloses for the first time a method for preparing obeticholic acid, which involves introducing an ethyl group by direct alkylation with iodoethane under strong alkaline conditions, followed by reduction and carboxyl deprotection to obtain obeticholic acid. Due to the poor selectivity and low yield of direct alkylation with iodoethane, this synthesis process is difficult to achieve scale-up synthesis.

[0005] WO2006122977 improves the above synthesis process, which is to prepare obeticholic acid by condensing and dehydrating a silicon-protected enol compound with acetaldehyde, followed by palladium-carbon hydrogenation reduction and carbonyl reduction under alkaline conditions. Although this synthesis process can achieve scale-up synthesis, it has many by-products, is difficult to control impurities, and has a low overall yield.

[0006] CN05585603, CN05399793, CN06459136, CN06279335, CN07663221, CN07793463, WO2017184598, WO2018010651 and the like have improved the preparation method of obeticholic acid, but there are still disadvantages such as low overall synthesis yield and difficulty in impurity control. Summary of the invention

[0007] In view of the shortcomings of the existing synthesis methods of obeticholic acid, the inventors have found through intensive research that by protecting the carboxyl group of compound V with Wenreb amide, the purification efficiency of intermediates in the synthesis process and the synthesis efficiency of obeticholic acid can be improved, thereby providing a method for preparing obeticholic acid with few by-products, simple operation, high yield, low synthesis cost, and suitable for large-scale production.

[0008] The present invention provides a new method for synthesizing obeticholic acid, and the reaction equation is as follows:

[0009]

[0010] Specifically, the synthesis method comprises the following steps:

[0011] 1) The compound of formula V is subjected to a carboxyl protection reaction to obtain a compound of formula IV;

[0012] 2) The compound of formula IV is subjected to a reduction reaction to obtain a compound of formula IIIa; further, compound IIIa is subjected to a configuration inversion under alkaline conditions to obtain compound III;

[0013] 3) The compound of formula III is subjected to reduction reaction to obtain a compound of formula II;

[0014] 4) The compound of formula II is subjected to alkaline conditions to remove the carboxyl protecting group to obtain obeticholic acid as shown in formula I.

[0015] In one preferred embodiment, in step 1), the compound of formula V is reacted with dimethylhydroxylamine hydrochloride through a carboxyl protection reaction.

[0016] In a preferred embodiment, the reduction reaction in step 2) is carried out by catalytic hydrogenation reduction using a palladium-carbon catalyst.

[0017] The present invention also provides a compound as shown in formula IV,

[0018]

[0019] The present invention also provides a method for preparing a compound as shown in formula IV. Compound IV is prepared by protecting the carboxyl group of a compound as shown in formula V. The reaction equation is as follows:

[0020]

[0021] In one preferred embodiment, the preparation method of the compound represented by formula IV is to carry out a carboxyl protection reaction of compound V and dimethylhydroxylamine or a salt thereof to obtain the compound.

[0022] In a preferred embodiment, the conditions of the carboxyl protection reaction include adding an organic base and a condensation agent and a condensation auxiliary agent.

[0023] In one preferred embodiment, the specific steps are:

[0024] At 10-30°C, compound V and an organic solvent are added to a reactor respectively, and nitrogen is used for protection. The temperature is controlled at 0-5°C, and dimethylhydroxylamine hydrochloride; an organic base including triethylamine, N,N-diisopropylethylamine, etc., preferably N,N-diisopropylethylamine; a condensing agent including dicyclohexylcarbodiimide (DCC), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt A condensation aid comprises 4-dimethylaminopyridine (DMAP), 1-hydroxy-7-azobenzotriazole (HOAT), 1-hydroxybenzotriazole (HOBT), preferably 1-hydroxybenzotriazole (HOBT); after stirring for 0.1 to 1 hour, heating to 20 to 25° C., continuing the reaction for 2 to 6 hours to obtain a reaction mixture, and further post-treating the reaction mixture to obtain a compound of formula IV.

[0025] In one preferred embodiment, the organic solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, etc., preferably dichloromethane.

[0026] The mass volume ratio of compound V to the organic solvent is 1 g:5 ml to 1 g:40 ml, preferably 1 g:20 ml.

[0027] Preferably, the post-treatment is: adding water to the reaction mixture, stirring, and then standing to separate the layers, extracting the aqueous layer with an organic solvent, combining the organic layers, washing the organic layers, concentrating the organic phase under reduced pressure, adding a solvent that is conducive to crystallization, replacing and concentrating, a large amount of white solid precipitates, filtering, washing, suction filtering, collecting the filter cake, and drying to obtain a white solid IV.

[0028] The solvents that are conducive to crystallization are dichloromethane, methyl tert-butyl ether, ethyl acetate, n-heptane, etc., preferably n-heptane.

[0029] Preferably, after a large amount of white solid is precipitated, n-heptane is added and stirred, and then filtered at 10-30° C., the filter cake is washed with n-heptane, filtered, and the filter cake is collected.

[0030] The mass volume ratio of the organic phase reduced pressure concentrate to the added solvent that facilitates crystallization is: 1 g:2 ml to 1 g:10 ml, preferably 1 g:4 ml.

[0031] The present invention also provides a compound as shown in formula IIIa or formula III,

[0032]

[0033] The present invention also provides a method for preparing a compound as shown in formula IIIa or formula III, wherein compound IIIa is prepared by a reduction reaction of a compound as shown in formula IV, and optionally, further, compound IIIa is treated under alkaline conditions and the configuration is reversed to obtain compound III, and the reaction equation is as follows:

[0034]

[0035] In a preferred embodiment, the reduction reaction is carried out by catalyzing a hydrogenation reaction with a palladium-carbon catalyst.

[0036] In one preferred embodiment, the catalytic hydrogenation reaction comprises the following specific steps:

[0037] At 15-30°C, compound IV, catalytic hydrogenation catalyst and organic solvent are added into a reactor, hydrogen is replaced, and the reaction is carried out under normal pressure. After post-treatment, IIIa is obtained.

[0038] Preferably, the catalytic hydrogenation catalyst is a palladium-carbon catalyst; preferably, the palladium-carbon catalyst is 10% Pd / C.

[0039] The organic solvent is methanol, ethanol, tetrahydrofuran, ethyl acetate, etc., preferably ethyl acetate.

[0040] Preferably, the post-treatment is as follows: after the reaction is complete, filtering, washing the filter cake with an organic solvent, concentrating the filtered mother liquor under reduced pressure, adding a solvent that is conducive to crystallization to continue concentrating, a large amount of white solid precipitates, washing, suction filtering, collecting the filter cake, and drying to obtain a white solid IIIa.

[0041] The mass volume ratio of the filtered mother liquor under reduced pressure concentrate to the added solvent that is conducive to crystallization is: 1 g: 2 ml to 1 g: 10 ml, preferably 1 g: 4 ml. The solvent that is conducive to crystallization is preferably n-heptane.

[0042] In one preferred embodiment, the preparation method of compound III is:

[0043] At 10-30°C, compound IIIa, a base and an organic solvent are added into a reactor, replaced with nitrogen for protection, heated to 45-50°C, stirred for reaction for 0.1-2 hours, and the obtained mixed solution is post-treated to obtain compound III.

[0044] In one preferred embodiment, the base is selected from sodium hydroxide, potassium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, 1,8-diazabicycloundec-7-ene (DBU), triethylamine, tetramethylguanidine, etc., preferably sodium methoxide.

[0045] The organic solvent of the present invention is selected from N,N-dimethylformamide, methanol, ethanol, N,N-dimethylacetamide, ethyl acetate, tetrahydrofuran, etc., preferably tetrahydrofuran.

[0046] Preferably, the post-treatment is as follows: cooling the obtained reaction mixture to 20-25°C, taking another saturated citric acid aqueous solution and an organic solvent for extraction and adding them to another reactor, cooling it to 0-5°C, and dripping the reaction mixture into the reactor at 0-5°C. After the dripping is completed, stirring and standing to separate the layers, the aqueous layer is extracted once with an organic solvent for extraction, the organic layers are combined, and the organic layers are washed; drying, concentrating the dry oil under reduced pressure, and draining to obtain a foamy off-white solid compound III.

[0047] The organic solvent used for extraction is dichloromethane, ethyl acetate, tert-butyl methyl ether, preferably tert-butyl methyl ether.

[0048] The present invention also provides a method for preparing a compound as shown in formula IIIa or formula III, wherein the compound as shown in formula V is subjected to carboxyl protection to obtain a compound as shown in formula IV, and then subjected to reduction reaction to obtain IIIa. Optionally, the configuration of compound IIIa is further reversed under alkaline conditions to obtain compound III. The reaction equation is as follows:

[0049]

[0050] The reduction reaction is a hydrogenation reaction catalyzed by a palladium-carbon catalyst.

[0051] The present invention also provides a compound as shown in Formula II,

[0052]

[0053] The present invention also provides a method for preparing a compound as shown in formula II. Compound II is prepared by subjecting a compound as shown in formula III to a reduction reaction. The reaction equation is as follows:

[0054]

[0055] In a preferred embodiment, the reduction reaction is preferably carried out using sodium borohydride reduction.

[0056] In one preferred embodiment, the preparation method of the compound represented by formula II is:

[0057] The compound III is dissolved in an organic solvent at 10 to 30°C, and the mixture is added to a reactor. The mixture is replaced with nitrogen for protection. Stirring is started, and the temperature of the reaction solution is cooled to -10 to 0°C. A reducing agent is added. The mixture is stirred and reacted at -10 to 0°C for 0.5 to 2 hours. Compound II is obtained after post-treatment.

[0058] Preferably, the reducing agent is sodium borohydride.

[0059] Preferably, the organic solvent is methanol.

[0060] Preferably, the usage ratio of compound III to sodium borohydride is 5:1 to 2:1.

[0061] Preferably, the post-treatment is as follows: after the reaction is complete, saturated aqueous citric acid solution is added to quench, the quenched suspension is concentrated under reduced pressure to remove part of the organic solvent, then extracted with an organic solvent for extraction, the organic layers are combined, washed, concentrated under reduced pressure, ethyl acetate is added, stirred to precipitate a solid, stirred at 20-25°C for 30 minutes to 2 hours, cooled to 0-5°C, and stirred at 0-5°C for 1 hour to 5 hours, then filtered, and the filter cake is washed with cold ethyl acetate; after the suction filtration is completed, the filter cake is collected and dried to obtain a white solid II.

[0062] The preferred organic solvent is methanol. The organic solvent for extraction is tert-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane, etc., preferably dichloromethane. The crystallization solvent is preferably ethyl acetate.

[0063] The present invention also provides a method for preparing obeticholic acid. The carboxyl protection of formula II is removed under alkaline conditions to obtain obeticholic acid as shown in formula I. The reaction equation is as follows:

[0064]

[0065] A preferred embodiment thereof, the preparation method thereof is as follows:

[0066] At 10-30°C, compound II, alkaline substance and organic solvent are added into the reactor, nitrogen replacement protection is performed, stirring is started, the temperature is raised to 70-90°C, stirring and reacting for 2-4 hours, and further post-processing is performed to obtain obeticholic acid.

[0067] Preferably, the alkaline substance is an aqueous sodium hydroxide solution.

[0068] Preferably, the organic solvent is methanol.

[0069] The mass volume ratio of compound II and sodium hydroxide aqueous solution is 1 g: 2 ml to 1 g: 10 ml, preferably 1 g: 3 ml. The concentration of sodium hydroxide aqueous solution is 10%, 15%, 30%, 40%, 50%, etc., preferably 30% sodium hydroxide aqueous solution.

[0070] Preferably, the post-treatment is as follows: after the reaction is completed, the temperature is lowered to 20-25°C, water is added, the reaction solution after adding water is concentrated under reduced pressure to remove part of the organic solvent, and then extracted with an organic solvent for extraction, the water layer is adjusted to a pH value of about 4-6 with a saturated citric acid aqueous solution, and then extracted with an organic solvent for extraction, the organic solvent is ethyl acetate, dichloromethane, tert-butyl methyl ether, etc., preferably tert-butyl methyl ether, the organic layers are combined, water is added for washing, and the mixture is concentrated under reduced pressure at below 40°C to obtain obeticholic acid (I) as a white solid. After concentration, a white foamy solid is obtained, which is stirred with dichloromethane for crystallization to obtain obeticholic acid (I) as a white solid.

[0071] In a preferred embodiment, the preparation method comprises the steps of subjecting the compound represented by formula III to carbonyl reduction to obtain the compound represented by formula II, and hydrolyzing the compound represented by formula II to prepare obeticholic acid, and the reaction equation is as follows:

[0072]

[0073] In a preferred embodiment, compound III is prepared by any of the aforementioned methods.

[0074] The following table shows the structural formula of the compounds involved in the examples:

[0075]

[0076] DETAILED DESCRIPTION

[0077] The present invention will be explained in detail below in conjunction with specific examples so that those skilled in the art can have a more comprehensive understanding of the present invention. The specific examples are only used to illustrate the technical solutions of the present invention and do not limit the present invention in any way.

[0078] Example 1: Preparation of Compound IV

[0079] At 20°C, 20.00 g of compound V (prepared according to the method in WO2006122977) and 400 ml of anhydrous dichloromethane were added to the reaction bottle. The reaction solution was cooled to 0°C, and 24.80 g of N,N-diisopropylethylamine, 9.37 g of dimethylhydroxylamine hydrochloride, 9.73 g of 1-hydroxybenzotriazole and 13.80 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added respectively. After the addition was completed, the mixture was stirred at 0°C for 0.5 hours, then the temperature was raised to 20°C, and the reaction was continued at 20°C with stirring for 4 hours. After treatment, 400 ml of water was added and stirred for 10 minutes, and then the mixture was allowed to stand for stratification. The organic layer was washed once with 400 ml of saturated citric acid aqueous solution and 400 ml of saturated brine respectively. After the organic phase was concentrated, it was stirred with ethyl acetate and n-heptane for crystallization, filtered, and the filter cake was collected and dried to obtain 21.86 g of white solid IV with a purity of 99.2% and a yield of 99.1%.

[0080] 1 H NMR (400MHz, CDCl3) δ6.13 (q, J = 7.0Hz, 1H), 3.69–3.62 (m, 3H), 3.63–3.47 (m, 1H), 3.13 (s, 3H), 2.5 3(dd,J=13.0,4.2Hz,1H),2.47–2.10(m,4H),2.04–1.52(m,12H),1.49–0.73(m,21H),0.60(s,3H).

[0081] MS(ESI+):C28H45NO4,[M+H]:460.3

[0082] Example 2: Preparation of Compound III

[0083] At 20°C, 21.00 g of compound IV, 10.50 g of 10% Pd / C (containing 66.7% water) and 420 ml of ethyl acetate were added to a reaction flask and replaced with hydrogen. The mixture was stirred at 20°C for 18 hours, filtered, and the mother liquor was concentrated and crystallized by stirring with ethyl acetate and n-heptane, filtered, and the filter cake was collected to obtain a white solid compound IIIa.

[0084] Add the above compound IIIa, 7.95 g of sodium methoxide and 300 ml of tetrahydrofuran to a reaction flask. Heat the reaction solution to 45°C, stir and react for 1 hour, cool the reaction solution to 20°C, and then drop it into a reaction flask containing 200 ml of saturated citric acid aqueous solution and 200 ml of tert-butyl methyl ether. The temperature is controlled at 0°C during the dropwise addition. After the dropwise addition is completed, stand the mixture to separate into layers. Wash the organic layer once with 300 ml of water, 300 ml of saturated sodium bicarbonate aqueous solution and 300 ml of saturated brine. Dry and concentrate to obtain 20.10 g of white solid compound III with a purity of 98.9% and a yield of 95.2%.

[0085] 1 H NMR (400MHz, CDCl3) δ6.13 (q, J = 7.0Hz, 1H), 3.69–3.62 (m, 3H), 3.63–3.47 (m, 1H), 3.13 (s, 3H), 2.5 3(dd,J=13.0,4.2Hz,1H),2.47–2.10(m,4H),2.04–1.52(m,12H),1.49–0.73(m,21H),0.60(s,3H).

[0086] MS(ESI+):C28H47NO4,[M+H]:462.3

[0087] Example 6: Preparation of Compound II

[0088] 20 ℃, respectively, add 10.00 g of compound III and 300 ml of methanol to the reaction bottle, cool to -10 ℃, add 2.50 g of sodium borohydride in batches at this temperature, add the materials, and stir the reaction at -10 ℃ for 1 hour, and the reaction is complete. Add 200 ml of saturated citric acid aqueous solution to quench, concentrate to remove part of the methanol, then extract twice with 200 ml of dichloromethane, combine the organic layers, add 200 ml of saturated brine to wash once. After concentration, add 80 ml of ethyl acetate, stir to precipitate solids, collect the filter cake by suction, and dry to obtain 10.11 g of white solid compound II with a purity of 98.3% and a yield of 94.9%.

[0089] 1 H NMR (400MHz, CDCl3) δ6.13 (q, J = 7.0Hz, 1H), 3.69–3.62 (m, 3H), 3.63–3.47 (m, 1H), 3.13 (s, 3H), 2.5 3(dd,J=13.0,4.2Hz,1H),2.47–2.10(m,4H),2.04–1.52(m,12H),1.49–0.73(m,21H),0.60(s,3H).

[0090] MS(ESI+):C28H49NO4,[M+H]:464.3

[0091] Example 7: Preparation of obeticholic acid (I)

[0092] At 20°C, 4.00 g of compound II, 10 ml of 30% sodium hydroxide aqueous solution and 40 ml of methanol were added to a 100 ml reaction bottle, the temperature was raised to 80°C, and the reaction was stirred at 80°C for 3 hours to complete the reaction. The temperature was lowered to 20°C, 80 ml of water was added, and part of the methanol was removed by concentration. The mixture was extracted twice with 80 ml of tert-butyl methyl ether, the pH value of the aqueous layer was adjusted to 4, and then 80 ml of tert-butyl methyl ether was added to extract twice, the organic layers were combined, and 100 ml of water was added to wash once. After concentration, a white foamy solid was obtained, which was stirred and crystallized with dichloromethane to obtain 3.62 g of the product obeticholic acid (I) as a white solid with a purity of 99.9% and a yield of 96.7%.

[0093] 1 H NMR (400MHz, CDCl3) δ6.13 (q, J = 7.0Hz, 1H), 3.69–3.62 (m, 3H), 3.63–3.47 (m, 1H), 3.13 (s, 3H), 2. 53(dd,J=13.0,4.2Hz,1H),2.47–2.10(m,4H),2.04–1.52(m,12H),1.49–0.73(m,21H),0.60(s,3H)

[0094] Previous route comparison (WO2006122977):

[0095]

[0096] Example 8: Preparation of 3α-hydroxy-6-ethylidene-7-keto-5β-cholane-24-oic acid (1b)

[0097] At 20°C, 2.80 g of 3α-hydroxy-6-ethylidene-7-keto-5β-cholane-24-acid methyl ester (1a) was added to a reaction flask, and then 28 ml of 30% sodium hydroxide aqueous solution and 28 ml of methanol were added to the reaction flask respectively, and the temperature was raised to 80°C, and the reaction was stirred at 80°C for 2 hours to complete the reaction. The temperature was lowered to 20°C, 80 ml of water was added, and part of the methanol was removed by concentration. The mixture was extracted twice with 80 ml of tert-butyl methyl ether, the pH value of the water layer was adjusted to 4, and then 80 ml of tert-butyl methyl ether was added to extract twice, the organic layers were combined, and 100 ml of water was added to wash once. After concentration, a white foamy solid was obtained, which was stirred and crystallized with dichloromethane to obtain 2.50 g of 3α-hydroxy-6-ethylidene-7-keto-5β-cholane-24-acid. The purity was 96.5%, and the yield was 92.3%.

[0098] 1H NMR (400MHz, CDCl3) δ6.19 (q, J=7.36Hz, 1H), 3.60-3.74 (m, 1H), 2.58 (dd, J=4.02, 13.05Hz, 1H), 2.40 (tt, J=5.02, 10.2 9Hz,3H),2.19-2.32(m,2H),1.61-2.06(m,10H),1.04-1.54(m,14H),1.01(s,3H),0.95(d,J=6.53Hz,3H),0.65(s,3H).

[0099] Example 9: Preparation of 3α-hydroxy-6α-ethyl-7-keto-5β-cholane-24-oic acid (1c)

[0100] At 20°C, 2.50 g of 3α-hydroxy-6-ethylidene-7-keto-5β-cholane-24-acid was added to a hydrogenation reaction device, and then 25 ml of water, 1 ml of 50% sodium hydroxide aqueous solution and 0.50 g of 10% palladium carbon catalyst were added to the hydrogenation reaction device, and nitrogen and hydrogen were used to replace the reaction, and then 5 bar of hydrogen pressure was applied, and the reaction solution was heated to 100°C and stirred at 100°C for 3 hours to complete the reaction. The reaction solution was cooled to 40 to 50 degrees, filtered to remove the catalyst, and 2 g of 85% phosphoric acid and 10 ml of ethyl acetate were added to the filtered filtrate. After the addition was completed and stirred at 40 to 50 degrees for 1 hour, the reaction mixture was cooled to between 0 and 30 degrees for crystallization, and the precipitated solid part was filtered, washed with ethyl acetate, and dried to obtain 1.61 g, 3α-hydroxy-6α-ethyl-7-keto-5β-cholane-24-acid. The purity is 95.2% and the yield is 63.7%.

[0101] 1 H NMR (400MHz, CDCl3) δ3.49-3.60(m,1H),2.70(q,J=6.02Hz,1H),2.12-2.45(m,4H),1.65-2.02(m,9H ),1.29-1.52(m,6H),1.05-1.24(m,8H),0.93(d,J=6.53Hz,5H),0.81(t,J=7.53Hz,3H),0.66(s,3H).

[0102] Example 10: Preparation of 3α,7α-dihydroxy-6α-ethyl-5β-cholane-24-oic acid (I)

[0103] 20 ℃, 0.80 grams of 3α-hydroxy-6α-ethyl-7-keto-5β-cholane-24-acid is added to a reaction flask, and then 6.4 milliliters of water and 0.8 milliliters of 50% sodium hydroxide aqueous solution are added to the reaction flask, and then 0.1g of sodium borohydride is added to the reaction flask. After the addition is completed, the reaction solution is heated to 100 degrees, and stirred at 100 degrees for 3 hours to complete the reaction. The reaction solution is cooled to 30 to 50 degrees, and the pH value is adjusted to acidity using saturated citric acid aqueous solution, 40 milliliters of n-butyl acetate is added for extraction, the n-butyl acetate layer is taken, and the n-butyl acetate layer is slowly cooled to between 15 and 20 degrees for crystallization, the precipitated solid part is filtered, washed with n-butyl acetate, and dried to obtain 0.60g of 3α, 7α-dihydroxy-6α-ethyl-5β-cholane-24-acid. The purity is 98.1%, and the yield is 74.6%.

[0104] 1 H NMR (400MHz, CDCl3) δ6.13 (q, J = 7.0Hz, 1H), 3.69–3.62 (m, 3H), 3.63–3.47 (m, 1H), 3.13 (s, 3H), 2. 53(dd,J=13.0,4.2Hz,1H),2.47–2.10(m,4H),2.04–1.52(m,12H),1.49–0.73(m,21H),0.60(s,3H)

[0105] Comparison between the method of the present invention and the prior art method (WO2006122977):

[0106] Compared with the previous method (WO2006122977), the method of the present invention has the following advantages:

[0107] 1. High total yield of synthesis: The total yield of the previous method is 43.9% (92.3% x 63.7% x 74.6%); in comparison, the total yield of the method of the present invention is 87.4% (95.2% x 94.9% x 96.7%).

[0108] 2. Good crystallization and purification effect: In the previous method, the crystallization process of intermediate 1c (Example 9) is unstable, oily substances are often precipitated, and the crystallization conditions are not repeatable, resulting in poor impurity removal effect and low yield; the intermediate crystallization conditions of the method of the present invention are stable and repeatable, resulting in good impurity removal effect and high yield.

[0109] 3. High purity of intermediates and final products: The purity of the intermediates in the previous methods was 96.5% and 95.2%, respectively, and the purity of the final product was 98.1%. In comparison, the purity of the intermediates in the method of the present invention was 99.2%, 98.9% and 98.3%, respectively, and the purity of the final product was 99.9%.

[0110] 4. The method of the present invention has industrial applicability: According to the preparation method of the present invention, obeticholic acid that can be used in medicine can be produced on a large scale in a practical and efficient manner.

[0111] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement modes and shall be included in the protection scope of the present invention.

Claims

1. A compound as shown in formula IV 2. A method for preparing obeticholic acid, characterized in that: The following steps are involved: (1) the compound of formula V is subjected to a carboxyl protection reaction to obtain a compound of formula IV; (2) The compound of formula IV is then subjected to a reduction reaction to obtain a compound of formula IIIa; further, compound IIIa is subjected to a configuration inversion under alkaline conditions to obtain compound III, wherein the reduction reaction is a palladium-carbon catalyst-catalyzed hydrogenation reduction; the base used in the alkaline conditions is sodium methoxide; (3) the compound of formula III is subjected to carbonyl reduction reaction to obtain the compound of formula II, wherein the reduction reaction is carried out using sodium borohydride; (4) removing the carboxyl protecting group from the compound of formula II under alkaline conditions to obtain obeticholic acid as shown in formula I, wherein the carboxyl protection is performed by condensation reaction of the carboxyl group and dimethylhydroxylamine hydrochloride, and the base used in the alkaline conditions is sodium hydroxide;

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