CN111285914A - Preparation method of obeticholic acid - Google Patents
Preparation method of obeticholic acid Download PDFInfo
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- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
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- 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
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Abstract
The invention relates to a preparation method of obeticholic acid, and particularly relates to a compound shown as a formula III, a preparation method of the compound, and a method for preparing obeticholic acid from the compound III. The method has the advantages of mild reaction conditions, few byproducts, simple and convenient operation, high total yield and the like, and is suitable for large-scale production.
Description
Technical Field
The invention relates to a preparation method of obeticholic acid.
Background
Obeticholic acid (shown in formula I) is a semisynthetic chenodeoxycholic acid derivative, and can be used for treating portal hypertension and liver diseases, including primary biliary cirrhosis, bile acid diarrhea, and non-alcoholic steatohepatitis. Obeticholic acid acts by activating the FXR receptor, a nuclear receptor, expressed primarily in the liver, intestine, kidney, which regulates the expression of genes associated with bile acid, fat and sugar metabolism, and also regulates immune responses. Activating FXR can inhibit bile acid synthesis and prevent toxic reaction caused by excessive accumulation of bile acid.
WO2002072598 discloses for the first time a process for the preparation of obeticholic acid by direct alkylation with iodoethane under strongly basic conditions to introduce an ethyl group, followed by reduction and deprotection of the carboxyl group to produce obeticholic acid. Due to the poor selectivity and low yield of direct alkylation with iodoethane, the synthesis process is difficult to scale up.
WO2006122977 improves the synthesis process, and the method comprises the steps of condensing and dehydrating a silicon-based protected enolate compound and acetaldehyde, and then carrying out palladium-carbon hydrogenation reduction and carbonyl reduction under an alkaline condition to obtain obeticholic acid. Although the synthesis process can realize scale-up synthesis, the process has the disadvantages of more by-products, difficult impurity control and low total synthesis yield.
CN05585603, CN05399793, CN06459136, CN06279335, CN07663221, CN07793463, WO2017184598, WO2018010651 and the like improve the preparation method of obeticholic acid, but the defects of low total synthesis yield, difficult impurity control and the like still exist.
Disclosure of Invention
Aiming at the defects in the existing synthetic method of obeticholic acid, the inventor finds that the purification efficiency of an intermediate in the synthetic process and the synthetic efficiency of obeticholic acid can be improved by protecting carboxyl of a compound V by using Wenreb amide through intensive research, so that the preparation method of obeticholic acid, which is few in byproducts, simple and convenient to operate, high in yield, low in synthetic cost and suitable for large-scale production, is provided.
The invention provides a new method for synthesizing obeticholic acid, which has the following reaction equation:
specifically, the synthesis method comprises the following steps:
1) the compound of the formula V is subjected to carboxyl protection reaction to obtain a compound shown as a formula IV;
2) the compound shown in the formula IV is subjected to reduction reaction to prepare a compound shown in a formula IIIa; further, carrying out configuration inversion on the compound IIIa under an alkaline condition to obtain a compound III;
3) the compound shown in the formula III is subjected to reduction reaction to prepare a compound shown in a formula II;
4) and removing the carboxyl protecting group from the compound in the formula II under the alkaline condition to obtain the obeticholic acid shown in the formula I.
In one preferred embodiment, the compound of formula V of step 1) is prepared by a carboxy protection reaction of a compound of formula V with dimethylhydroxylamine hydrochloride.
In a preferred embodiment, the reduction reaction in step 2) is catalyzed and hydrogenated by using a palladium carbon catalyst.
The invention also provides a compound shown as the formula IV,
the invention also provides a preparation method of the compound shown in the formula IV, the compound IV is prepared by performing carboxyl protection on the compound shown in the formula V, and the reaction equation is as follows:
in one preferred embodiment, the compound of formula IV is prepared by reacting compound V with dimethylhydroxylamine or a salt thereof to protect the carboxyl group.
In one preferred embodiment, the conditions for the carboxyl protection reaction comprise the addition of an organic base, a condensing agent and a condensation aid.
In one preferred embodiment, the specific steps are as follows:
respectively adding the compound V and an organic solvent into a reactor at 10-30 ℃, replacing and protecting with nitrogen, controlling the temperature to be 0-5 ℃, and respectively adding dimethylhydroxylamine hydrochloride; an organic base including triethylamine, N, N-diisopropylethylamine and the like, preferably N, N-diisopropylethylamine; a condensing agent comprising Dicyclohexylcarbodiimide (DCC), 2- (7-tolyltriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HATU), (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (EDCI), etc., preferably (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride); a condensation assistant comprises 4-Dimethylaminopyridine (DMAP), 1-hydroxy-7-azobenzotriazole (HOAT), 1-Hydroxybenzotriazole (HOBT), preferably 1-Hydroxybenzotriazole (HOBT); stirring for 0.1-1 hour, heating to 20-25 ℃, continuing to react for 2-6 hours to obtain a reaction mixture, and further carrying out post-treatment on the reaction mixture to obtain the compound shown in the formula IV.
In one preferred embodiment, the organic solvent is selected from tetrahydrofuran, methyltetrahydrofuran, dichloromethane, etc., preferably dichloromethane.
The mass-to-volume ratio of the compound V to the organic solvent is 1 g: 5 ml to 1 g: 40 ml, preferably 1 g: 20 ml.
Preferably, the post-treatment is: adding water into the reaction mixture, stirring, standing for layering, extracting the water layer with an organic solvent, combining the organic layers, washing the organic layer, concentrating the organic layer under reduced pressure, adding a solvent favorable for crystallization, performing displacement concentration, precipitating a large amount of white solid, filtering, washing, performing suction filtration, collecting a filter cake, and drying to obtain a white solid IV.
The solvent which is favorable for crystallization is dichloromethane, methyl tert-butyl ether, ethyl acetate, n-heptane and the like, and preferably n-heptane.
Preferably, after a large amount of white solid is precipitated, n-heptane is added and stirred, the mixture is filtered after stirring at 10-30 ℃, the filter cake is washed with n-heptane, filtered and collected.
The mass-volume ratio of the organic phase decompressed concentrate to the added solvent which is beneficial to crystallization is as follows: 1 g: 2 ml to 1 g: 10 ml, preferably 1 g: 4 ml.
The invention also provides a compound shown as the formula IIIa or III,
the invention also provides a preparation method of the compound shown in the formula IIIa or the formula III, the compound IIIa is prepared by the reduction reaction of the compound shown in the formula IV, optionally, the compound IIIa is further prepared by the configuration inversion after the treatment under the alkaline condition, and the reaction equation is as follows:
in one preferred embodiment, the reduction reaction is catalyzed by a palladium-carbon catalyst.
In a preferred embodiment, the catalytic hydrogenation reaction comprises the following specific steps:
and (3) adding the compound IV, a catalytic hydrogenation catalyst and an organic solvent into a reactor at 15-30 ℃, performing hydrogen replacement, reacting at normal pressure, and performing post-treatment to obtain IIIa.
Preferably, the catalytic hydrogenation catalyst is a palladium carbon catalyst; preferably, the palladium on carbon catalyst is 10% Pd/C.
The organic solvent is methanol, ethanol, tetrahydrofuran, ethyl acetate, etc., preferably ethyl acetate.
Preferably, the post-treatment is: and after the reaction is completed, filtering, washing a filter cake by using an organic solvent, concentrating the filtered mother liquor under reduced pressure, adding a solvent which is beneficial to crystallization, continuously concentrating, separating out a large amount of white solids, washing, performing suction filtration, collecting the filter cake, and performing suction drying to obtain a white solid IIIa.
The mass-volume ratio of the filtered mother liquor reduced pressure concentrate to the added solvent which is beneficial to crystallization is as follows: 1 g: 2 ml to 1 g: 10 ml, preferably 1 g: 4 ml. The solvent which facilitates crystallization is preferably n-heptane.
In a preferred embodiment, the compound III is prepared by the following steps:
adding a compound IIIa, alkali and an organic solvent into a reactor at 10-30 ℃, replacing and protecting with nitrogen, heating to 45-50 ℃, stirring and reacting for 0.1-2 hours, and carrying out aftertreatment on the obtained mixed solution to obtain a compound III.
In a preferred embodiment, the base is selected from sodium hydroxide, potassium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, 1, 8-diazabicycloundecen-7-ene (DBU), triethylamine, tetramethylguanidine, etc., preferably sodium methoxide.
The organic solvent is selected from N, N-dimethylformamide, methanol, ethanol, N, N-dimethylacetamide, ethyl acetate, tetrahydrofuran and the like, and tetrahydrofuran is preferred.
Preferably, the post-treatment is: cooling the obtained reaction mixed solution to 20-25 ℃, adding another saturated citric acid aqueous solution and an organic solvent for extraction into another reactor, cooling to 0-5 ℃, dropwise adding the reaction mixed solution into the reactor at 0-5 ℃, stirring, standing for layering, extracting the water layer once with the organic solvent for extraction, combining the organic layers, and washing the organic layers; drying, concentrating the dried oil under reduced pressure, and draining to obtain foamy off-white solid compound III.
The organic solvent for extraction is dichloromethane, ethyl acetate, tert-butyl methyl ether preferably tert-butyl methyl ether.
The invention also provides a preparation method of the compound shown in the formula IIIa or III, the compound shown in the formula IV is obtained by carboxyl protection of the compound shown in the formula V, then IIIa is obtained by reduction reaction, optionally, the compound IIIa is further overturned under the alkaline condition to obtain the compound III, and the reaction equation is as follows:
the reduction reaction is a palladium-carbon catalyst catalytic hydrogenation reaction.
The invention also provides a compound shown as a formula II,
the invention also provides a preparation method of the compound shown in the formula II, wherein the compound II is prepared by the reduction reaction of the compound shown in the formula III, and the reaction equation is as follows:
in a preferred embodiment, the reduction reaction is preferably performed by using sodium borohydride.
In a preferred embodiment, the compound of formula II is prepared by a process comprising:
dissolving the compound III in an organic solvent at 10-30 ℃, adding the organic solvent into a reactor, carrying out nitrogen replacement protection, starting stirring, cooling the temperature of the reaction solution to-10-0 ℃, adding a reducing agent, carrying out stirring reaction at-10-0 ℃ for 0.5-2 hours, and carrying out post-treatment to obtain a compound II.
Preferably, the reducing agent is sodium borohydride.
Preferably, the organic solvent is methanol.
Preferably, the ratio of the compound III to the sodium borohydride is 5: 1 to 2: 1.
Preferably, the post-treatment is: after the reaction is completed, adding saturated citric acid aqueous solution for quenching, decompressing and concentrating the quenched suspension to remove part of organic solvent, extracting by using the organic solvent for extraction, combining organic layers, washing, decompressing and concentrating, adding ethyl acetate, stirring to separate out solid, stirring at 20-25 ℃ for 30 minutes to 2 hours, cooling to 0-5 ℃, stirring at 0-5 ℃ for 1 hour to 5 hours, filtering, and washing a filter cake by using cold ethyl acetate; and after the suction filtration is finished, collecting a filter cake, and drying to obtain a white solid II.
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.
The invention also provides a preparation method of obeticholic acid, wherein the obeticholic acid shown in the formula I is prepared by removing carboxyl protection in the formula II under an alkaline condition, and the reaction equation is as follows:
in one preferred embodiment, the preparation method is as follows:
adding the compound II, an alkaline substance and an organic solvent into a reactor at 10-30 ℃, replacing and protecting with nitrogen, starting stirring, heating to 70-90 ℃, stirring for reacting for 2-4 hours, and further performing post-treatment to obtain obeticholic acid.
Preferably, the alkaline substance is an aqueous sodium hydroxide solution.
Preferably, the organic solvent is methanol.
The mass-to-volume ratio of the compound II to the aqueous solution of sodium hydroxide is 1 g: 2 ml to 1 g: 10 ml, preferably 1 g: 3 ml. The concentration of the aqueous sodium hydroxide solution is 10%, 15%, 30%, 40%, 50%, etc., preferably 30% aqueous sodium hydroxide solution.
Preferably, the post-treatment is: after the reaction is finished, cooling to 20-25 ℃, adding water, concentrating the reaction solution after adding water under reduced pressure to remove part of organic solvent, extracting by using organic solvent for extraction, adjusting the pH value of the water layer to about 4-6 by using saturated citric acid aqueous solution, then adding organic solvent for extraction, wherein the organic solvent is ethyl acetate, dichloromethane, tert-butyl methyl ether and the like, preferably tert-butyl methyl ether, combining the organic layers, adding water for washing, concentrating under reduced pressure at the temperature of below 40 ℃, and concentrating under reduced pressure to obtain the obeticholic acid (I) white solid. Concentrating to obtain white foamy solid, stirring with dichloromethane, and crystallizing to obtain obeticholic acid (I) white solid.
In a preferred embodiment, the preparation method comprises the steps of reducing the compound shown in the formula III through carbonyl to obtain a compound shown in the formula II, and hydrolyzing the compound shown in the formula II to prepare obeticholic acid, wherein the reaction equation is as follows:
in a preferred embodiment, compound III is prepared by any of the methods described above.
The following table shows the structural formulae of the compounds mentioned in the examples
Detailed Description
The present invention will be explained in detail below with reference to specific examples so that those skilled in the art can more fully understand the present invention, and the specific examples are only for illustrating the technical scheme of the present invention and do not limit the present invention in any way.
Example 1: preparation of Compound IV
20.00 g of compound V (prepared according to the method of WO2006122977) and 400 ml of anhydrous dichloromethane were added to the reaction flask, respectively, at 20 ℃. The reaction solution was cooled to 0 ℃ 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 complete, the mixture was stirred at 0 ℃ for 0.5 hour, then warmed to 20 ℃ and stirred at 20 ℃ for 4 hours. Adding 400 ml of water into the post-treatment, stirring for 10 minutes, standing for layering, washing an organic layer once by using 400 ml of saturated citric acid aqueous solution and 400 ml of saturated saline solution respectively, concentrating an organic phase, stirring and crystallizing by using ethyl acetate and n-heptane, filtering, collecting a filter cake, and drying to obtain 21.86 g of white solid IV with the purity of 99.2 percent and the yield of 99.1 percent
1H 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).
MS(ESI+)：C28H45NO4，[M+H]：460.3
Example 2: preparation of Compound III
21.00 g of Compound IV, 10.50 g of 10% Pd/C (66.7% water) and 420 ml of ethyl acetate were introduced into a reaction flask at 20 ℃ and replaced with hydrogen. Stirring and reacting at 20 ℃ for 18 hours, filtering, concentrating the filtered mother liquor, stirring and crystallizing by using ethyl acetate and n-heptane, filtering, and collecting a filter cake to obtain a white solid compound IIIa.
The above compound IIIa, 7.95 g of sodium methoxide and 300 ml of tetrahydrofuran were added to the reaction flask. Heating the reaction solution to 45 ℃, stirring and reacting for 1 hour, cooling the reaction solution to 20 ℃, dropwise adding the reaction solution into a reaction bottle filled with 200 ml of saturated citric acid aqueous solution and 200 ml of tert-butyl methyl ether, controlling the temperature at 0 ℃ during dropwise adding, standing and layering after the dropwise adding is finished, and washing the organic layer once with 300 ml of water, 300 ml of saturated sodium bicarbonate aqueous solution and 300 ml of saturated saline solution respectively. Drying and concentrating to obtain 20.10 g of white solid compound III with purity of 98.9% and yield of 95.2%
1H 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).
MS(ESI+)：C28H47NO4，[M+H]：462.3
Example 6: preparation of Compound II
At 20 ℃, respectively adding 10.00 g of compound III and 300 ml of methanol into a reaction bottle, cooling to-10 ℃, adding 2.50 g of sodium borohydride in batches at the temperature, finishing the addition, and stirring at-10 ℃ for reaction for 1 hour to complete the reaction. Quenched by addition of 200 ml of saturated aqueous citric acid, concentrated to remove a portion of methanol, extracted twice with 200 ml of dichloromethane, the organic layers combined and washed once with 200 ml of saturated brine. Concentrating, adding 80 ml ethyl acetate, stirring to separate out solid, filtering, collecting filter cake, and oven drying to obtain 10.11 g white solid compound II with purity of 98.3% and yield of 94.9%
1H 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).
MS(ESI+)：C28H49NO4，[M+H]：464.3
Example 7: preparation of obeticholic acid (I)
At 20 ℃, 4.00 g of compound II, 10 ml of 30% aqueous sodium hydroxide solution and 40 ml of methanol were added to a 100 ml reaction flask, heated to 80 ℃, and stirred at 80 ℃ for reaction for 3 hours, and the reaction was completed. The temperature is reduced to 20 ℃, 80 ml of water is added, partial methanol is removed by concentration, the mixture is extracted twice by 80 ml of tert-butyl methyl ether, the pH value of the water layer is adjusted to 4, then 80 ml of tert-butyl methyl ether is added for extraction twice, the organic layers are combined, and 100 ml of water is added for washing once. Concentrating to obtain white foamy solid, stirring with dichloromethane for crystallization to obtain 3.62 g product obeticholic acid (I) white solid with purity of 99.9% and yield of 96.7%
1H 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)
Past route control (WO 2006122977):
EXAMPLE 8 preparation of 3 α -hydroxy-6-ethylidene-7-keto-5 β -cholan-24-oic acid (1b)
Adding 2.80 g of 3 α -hydroxy-6-ethylidene-7-keto-5 β -cholane-24-oic acid methyl ester (1a) into a reaction bottle, then respectively adding 28 ml of 30% sodium hydroxide aqueous solution and 28 ml of methanol into the reaction bottle, heating to 80 ℃, stirring at 80 ℃ for 2 hours, cooling to 20 ℃, adding 80 ml of water after the reaction is finished, concentrating to remove part of methanol, extracting twice with 80 ml of tert-butyl methyl ether, adjusting the pH value of a water layer to 4, then adding 80 ml of tert-butyl methyl ether for extracting twice, combining organic layers, adding 100 ml of water for washing once, concentrating to obtain a white foam solid, stirring and crystallizing with dichloromethane to obtain 2.50 g of 3 α -hydroxy-6-ethylidene-7-keto-5 β -cholane-24-oic acid, wherein the purity is 96.5%, and the yield is 92.3%.
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＝5.02，10.29Hz，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).
EXAMPLE 9 preparation of 3 α -hydroxy-6 α -ethyl-7-keto-5 β -cholan-24-oic acid (1c)
Adding 2.50 g of 3 α -hydroxy-6-ethylene-7-keto-5 β -cholane-24-acid into a hydrogenation reaction device, then respectively adding 25 ml of water, 1 ml of 50% sodium hydroxide aqueous solution and 0.50g of catalyst containing 10% palladium carbon into the hydrogenation reaction device, respectively carrying out displacement reaction by using nitrogen and hydrogen, then applying 5 bar of hydrogen pressure, heating the reaction liquid to 100 ℃, stirring at 100 ℃ for reaction for 3 hours, after the reaction is finished, cooling the reaction liquid to 40-50 ℃, filtering to remove the catalyst, adding 2g of 85% phosphoric acid and 10 ml of ethyl acetate into the filtered filtrate, after the reaction is finished and stirred for 1 hour at 40-50 ℃, cooling the reaction mixture to 0-30 ℃ for crystallization, filtering the precipitated solid part, washing by using ethyl acetate, drying to obtain 1.61g of 3 α -hydroxy-6 α -ethyl-7-keto-5 β -24-cholane-24-acid, wherein the purity is 63.2%, and the yield is 95.7%.
1H 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).
EXAMPLE 10 preparation of 3 α, 7 α -dihydroxy-6 α -ethyl-5 β -cholan-24-oic acid (I)
Adding 0.80 g of 3 α -hydroxy-6 α -ethyl-7-keto-5 β -cholane-24-acid into a reaction bottle at 20 ℃, respectively adding 6.4 ml of water and 0.8 ml of 50% sodium hydroxide aqueous solution into the reaction bottle, then adding 0.1g of sodium borohydride into the reaction bottle, after the addition is finished, heating the reaction solution to 100 ℃, stirring and reacting for 3 hours at 100 ℃, cooling the reaction solution to 30-50 ℃, adjusting the pH value to acidity by using saturated citric acid aqueous solution, adding 40 ml of n-butyl acetate for extraction, taking an n-butyl acetate layer, slowly cooling the n-butyl acetate layer to 15-20 ℃ for crystallization, filtering the precipitated solid part, washing by using the n-butyl acetate, drying and drying to obtain 0.60g of 3 α, 7 α -dihydroxy-6 α -ethyl-5 β -cholane-24-acid, wherein the purity is 98.1%, and the yield is 74.6%.
1H 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)
Comparison of the method of the present invention with the conventional method (WO 2006122977):
compared with the prior method (WO2006122977), the method of the invention has the following advantages:
1. the total synthesis yield is high: the total yield of the previous method was: 43.9% (92.3% x 63.7% x 74.6%); in contrast, the overall yield of the process of the invention was 87.4% (95.2% x 94.9% x 96.7%).
2. The crystallization and purification effects are good: in the previous method, the crystallization process of the intermediate 1c (example 9) is unstable, oil substances are often separated out, and the repeatability of crystallization conditions is poor, so that the impurity removal effect is poor and the yield is low; the intermediate crystallization condition of the method is stable and the repeatability is good, so that the impurity removal effect is good and the yield is high.
3. The purity of the intermediate and the final product is high: the purity of the intermediate in the prior method is respectively as follows: 96.5% and 95.2%, the purity of the final product is 98.1%; compared with the prior art, the purity of the intermediate of the method is respectively as follows: 99.2%, 98.9% and 98.3%, the purity of the final product is 99.9%.
4. The method has the following industrialized practicability: according to the preparation method of the present invention, obeticholic acid useful as a pharmaceutical can be produced practically and efficiently on a large scale.
The present invention is not limited to the above-described embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention are intended to be equivalent substitutions and should be included within the scope of the present invention.
Claims (10)
1. A compound with a structure shown as a formula III or IIIa,
2. a preparation method of a compound shown in formula IIIa or III is characterized in that a compound shown in formula IV is obtained by carboxyl protection of a compound shown in formula V, and then the compound IIIa is obtained by reduction, optionally, the compound IIIa is further subjected to configuration inversion under an alkaline condition to obtain a compound III, and the reaction equation is as follows:
preferably, the carboxyl protection is carboxyl protection by condensation reaction of carboxyl and dimethylhydroxylamine hydrochloride.
3. A compound as shown in formula IV
4. A preparation method of a compound shown in a formula IV is characterized in that the compound shown in a formula V is prepared after carboxyl protection, and the reaction equation is as follows:
5. a preparation method of a compound shown in formula IIIa or III is characterized in that IIIa is prepared by carrying out reduction reaction on a compound shown in formula IV, optionally, further, the compound IIIa is inverted in configuration under an alkaline condition to obtain a compound III, and the reaction equation is as follows:
the reduction reaction is preferably catalytic hydrogenation reduction by a palladium-carbon catalyst.
6. A compound as shown in formula II
7. A preparation method of a compound shown in a formula II is characterized in that the compound shown in a formula III is prepared by carbonyl reduction reaction, and the reaction equation is as follows:
the reduction reaction is preferably carried out using sodium borohydride.
8. The preparation method of obeticholic acid is characterized by comprising the steps of reducing a compound shown in a formula III through carbonyl to obtain a compound shown in a formula II, and hydrolyzing the compound shown in the formula II to prepare obeticholic acid, wherein the reaction equation is as follows:
9. the method for preparing obeticholic acid according to claim 8, further comprising the step of preparing the compound represented by formula III according to claim 5.
10. The method for preparing obeticholic acid according to claim 8, further comprising the step of preparing the compound represented by formula III according to claim 2.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811507049.0A CN111285914B (en) | 2018-12-10 | 2018-12-10 | Preparation method of obeticholic acid |
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| CN105669811B (en) * | 2014-11-17 | 2020-09-04 | 正大天晴药业集团股份有限公司 | New 7-keto-6 beta-alkyl cholanic acid derivative in preparation of obeticholic acid and application thereof in medical field |
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