CN112724187B - Method for preparing obeticholic acid intermediate through fixed bed reactor - Google Patents
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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 discloses a method for preparing an obeticholic acid intermediate by continuous hydrogenation in a fixed bed, which comprises the steps of reacting an obeticholic acid intermediate 1 with hydrogen in a fixed bed reactor filled with a catalyst; the structural formula of the obeticholic acid intermediate 1 is shown as (I); the catalyst is one or a mixture of more of palladium/carbon, palladium/aluminum oxide, platinum/carbon, platinum/aluminum oxide or nickel/silicon dioxide; the invention has the advantages of high reaction speed, high conversion rate, simple and safe operation process, low cost, continuous operation and capability of reducing the problem of three wastes.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing an obeticholic acid intermediate through a fixed bed reactor.
Background
Obeticholic acid, having the english name Obetix. Developed by the american pharmaceutical company Intercept, the first drug for the treatment of primary biliary cirrhosis and non-alcoholic fatty liver disease for 20 years, was approved by the U.S. FDA for marketing at the earliest 5.27.2016 and approved by the european union at 12.12.2016. The specific structural formula is as follows:
the related methods for preparing obeticholic acid intermediates reported at present all have a hydrogenation reaction step. The intermediate 1 reacts under the catalytic hydrogenation condition to obtain an intermediate 2 and a small amount of an intermediate 3, and the intermediate 2 is completely converted into the intermediate 3 under the alkaline condition. And the intermediate 3 is subjected to appropriate reaction steps to obtain obeticholic acid.
In the documents of US20140148428a1, WO20178053428a1, CN105294801A, CN108070014A, etc., palladium/carbon is used as a catalyst, and the reaction is carried out in batches and intermittently by using a dedicated high-pressure hydrogenation reactor. When the method is used for preparing the obeticholic acid intermediate, the safety problems of long reaction time, high cost, high safety risk of a high-pressure reaction kettle, complicated operation of filtering and recovering the catalyst and easiness in spontaneous combustion exist.
Disclosure of Invention
The purpose of the invention is as follows: the technical problem to be solved by the invention is to provide a method for preparing an obeticholic acid intermediate by continuous hydrogenation in a fixed bed, so as to solve the safety problems of long reaction time, high cost, high safety risk of a high-pressure reaction kettle, complicated operation of filtering and recovering a catalyst and easy spontaneous combustion in the prior art for preparing the obeticholic acid intermediate
The technical scheme is as follows: in order to solve the technical problems, the invention provides the following technical scheme:
a method for preparing an obeticholic acid intermediate through a fixed bed reactor is characterized in that obeticholic acid intermediate 1 is reacted with hydrogen in the fixed bed reactor filled with a catalyst;
the structural formula of the obeticholic acid intermediate 1 is shown as (I);
the catalyst is selected from palladium/carbon, palladium/aluminum oxide, platinum/carbon, platinum/aluminum oxide or nickel/silicon dioxide, preferably palladium/aluminum oxide;
in some embodiments, obeticholic acid intermediate 1 is dissolved in one or a mixture of methanol, ethanol, and aqueous sodium hydroxide.
In some embodiments, the concentration of obeticholic acid intermediate 1 is 5-10 w/w%.
A method for preparing obeticholic acid intermediate by continuous hydrogenation in a fixed bed comprises the following steps:
(1) filling a catalyst into a fixed bed reactor;
(2) dissolving the obeticholic acid intermediate 1 in an organic solvent, and simultaneously conveying the obeticholic acid intermediate 1 solution and hydrogen into a mixer to mix to obtain a mixed material;
(3) the mixed material is conveyed into a fixed bed reactor loaded with a catalyst to carry out hydrogenation reaction;
(4) and (3) conveying a reaction mixture flowing out of the fixed bed reactor to a gas-liquid separator to separate hydrogen, and intensively collecting and treating the liquid to obtain an obeticholic acid intermediate 2, wherein the structure of the obeticholic acid intermediate 2 is shown as a formula (II).
In some embodiments, in step (2), the flow rate of the obeticholic acid intermediate 1 solution is selected from 0.1-1 mL/min, preferably 0.2-0.7 mL/min, more preferably 0.3-0.5 mL/min, and particularly optionally 0.2 mL/min, 0.3 mL/min 0.4 mL/min, 0.5 mL/min, 0.6 mL/min, or 0.7 mL/min.
In some embodiments, in step (3), the temperature of the hydrogenation reaction is 30 ℃ to 90 ℃, preferably 50 ℃ to 80 ℃, more preferably 70 ℃ to 80 ℃, and specifically may be selected from 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃ or 80 ℃.
In some embodiments, in the step (2), the input pressure of hydrogen is 0.5 to 4MPa, preferably 1 to 3MPa, more preferably 1.5 to 2.5MPa, and specifically may be selected from 1MPa, 1.5MPa, 2MPa, 2.5MPa, and 3 MPa.
In some embodiments, in step (4), the fixed bed reactor is selected from an axial adiabatic fixed bed reactor, a radial adiabatic fixed bed reactor, or a tubular fixed bed reactor, preferably a tubular fixed bed reactor.
Has the advantages that:
the method for preparing the obeticholic acid intermediate 2 by continuous hydrogenation of the fixed bed has the advantages of high reaction speed, high conversion rate, simple and safe operation process, low cost, continuous operation and capability of reducing the problem of three wastes.
Drawings
Fig. 1 is a process flow diagram for the continuous hydrogenation of obeticholic acid intermediate 1 to obeticholic acid intermediate 2.
Detailed Description
Unless otherwise indicated, terms referred to herein have the ordinary meaning in the art, such as palladium on carbon, palladium on alumina, platinum on carbon, platinum on alumina, and the like. The following examples are provided to illustrate the process, advantages and use of obeticholic acid intermediate 1 in the fixed bed continuous hydrogenation of obeticholic acid to obeticholic acid intermediate 2 of the present invention, but are not intended to limit the present invention.
Comparative example 1:
the method is implemented according to a palladium/carbon catalyst method reaction kettle technology. 100g of obeticholic acid intermediate 1 is put into a hydrogenation kettle, 500g of ethanol, 10g of palladium/carbon and 64g of 30% sodium hydroxide aqueous solution are added for dissolution and clarification, and after hydrogen replacement, the pressure of the hydrogenation kettle is controlled to be 0.2MPa, and the temperature is controlled to be 20-35 ℃ for reaction until all components are not changed. The reaction HPLC results are shown in Table 1.
TABLE 1HPLC TEST RESULTS FOR COMPARATIVE EXAMPLE 1
Comparative example 2:
the method is implemented according to a palladium/carbon catalyst method reaction kettle technology. 100g of obeticholic acid intermediate 1 is put into a hydrogenation kettle, 500g of ethanol, 10g of palladium/carbon and 64g of 30% sodium hydroxide aqueous solution are added for dissolution and clarification, and after hydrogen replacement, the pressure of the hydrogenation kettle is controlled to be 1MPa, and the temperature is controlled to be 20-35 ℃ for reaction until all components are not changed. The reaction HPLC results are shown in Table 2.
TABLE 2HPLC TEST RESULTS FOR COMPARATIVE EXAMPLE 2
Comparative example 3:
the method is implemented according to a palladium/carbon catalyst method reaction kettle technology. 100g of obeticholic acid intermediate 1 is put into a hydrogenation kettle, 500g of ethanol, 10g of palladium/carbon and 64g of 30% sodium hydroxide aqueous solution are added for dissolution and clarification, and after hydrogen replacement, the pressure of the hydrogenation kettle is controlled to be 1MPa, and the temperature is controlled to be 40-55 ℃ for reaction until all components are not changed. The reaction HPLC results are shown in Table 3.
TABLE 3HPLC TEST RESULTS FOR COMPARATIVE EXAMPLE 3
Example 1:
in the fixed bed hydrogenation reaction apparatus of the flow scheme shown in FIG. 1, a palladium/alumina catalyst was packed, the hydrogen pressure was adjusted to 2.5MPa, the feed rate of the solution of obeticholic acid intermediate 1 (5% by mass of ethanol solution, for example, 5g of obeticholic acid intermediate 1 was completely dissolved in 95 g of ethanol) was 0.4 mL/min, and the reaction was carried out at 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃ and 80 ℃ respectively, and the HPLC results of the respective components of the hydrogenation reaction are shown in Table 4.
Table 4 example 1HPLC assay results
Example 2:
in the fixed bed hydrogenation reaction apparatus of the flow scheme shown in fig. 1, a palladium/alumina catalyst is filled, the reaction temperature is controlled at 80 ℃, the feeding rate of the solution of obeticholic acid intermediate 1 (5% by mass of ethanol solution, for example, 5g of obeticholic acid intermediate 1 is completely dissolved in 95 g of ethanol) is controlled at 0.4 mL/min, the hydrogen pressure is adjusted to 0.5MPa, 1.0MPa, 1.5MPa, 2.0MPa, 2.5MPa, 3.0MPa, 3.5MPa and 4.0MPa respectively, and the HPLC results of each component of the hydrogenation reaction are shown in table 5.
Table 5 example 2HPLC assay results
Example 3:
in the fixed bed hydrogenation reaction apparatus of the flow scheme shown in fig. 1, a palladium/alumina catalyst is filled, the reaction temperature is controlled at 80 ℃, and the feeding rates of a solution of obeticholic acid intermediate 1 (5% by mass of an ethanol solution, for example, 5g of obeticholic acid intermediate 1 is completely dissolved in 95 g of ethanol) with the hydrogen pressure adjusted to 2.5MPa are respectively 0.2 mL/min, 0.3 mL/min, 0.4 mL/min, 0.5 mL/min, 0.6 mL/min and 0.7 mL/min, and the HPLC results of the components of the hydrogenation reaction are shown in table 6.
Table 6 example 3HPLC assay results
Example 4:
in the fixed bed hydrogenation reaction apparatus of the flow shown in fig. 1, palladium/carbon, palladium/alumina, platinum/carbon, platinum/alumina, and nickel/silica catalysts were charged, respectively, and the reaction was carried out under the conditions of a hydrogen pressure of 2.5MPa, a feeding rate of 0.4 mL/min of obeticholic acid intermediate 1 solution (5% by mass of ethanol solution, for example, 5g of obeticholic acid intermediate 1 was completely dissolved in 95 g of ethanol), and a temperature of 80 ℃, and HPLC results of each component of the hydrogenation reaction are shown in table 7.
Table 7 example 4HPLC assay results
Claims (2)
1. A method for preparing an obeticholic acid intermediate through a fixed bed reactor is characterized in that obeticholic acid intermediate 1 is reacted with hydrogen in the fixed bed reactor filled with a catalyst;
the structural formula of the obeticholic acid intermediate 1 is shown as (I);
the catalyst is palladium/aluminum oxide;
（Ⅰ）；
the method comprises the following steps:
(1) filling a catalyst into a fixed bed reactor;
(2) dissolving the obeticholic acid intermediate 1 in an organic solvent, and simultaneously conveying the obeticholic acid intermediate 1 solution and hydrogen into a mixer to mix to obtain a mixed material;
(3) the mixed material is conveyed into a fixed bed reactor loaded with a catalyst to carry out hydrogenation reaction;
(4) conveying a reaction mixture flowing out of the fixed bed reactor to a gas-liquid separator for separating hydrogen, and intensively collecting and treating liquid to obtain an obeticholic acid intermediate 2, wherein the structural formula of the obeticholic acid intermediate 2 is shown as a formula (II);
formula (II);
the obeticholic acid intermediate 1 is dissolved in hexanol;
the concentration of the obeticholic acid intermediate 1 is 5 w/w%;
in the step (2), the flow rate of the obeticholic acid intermediate 1 solution is selected from 0.2-0.4 mL/min,
in the step (3), the temperature of the hydrogenation reaction is 80 ℃,
in the step (2), the input pressure of hydrogen is 2.5 MPa.
2. The method for preparing an obeticholic acid intermediate product through a fixed bed reactor according to claim 1, wherein in the step (4), the fixed bed reactor is selected from an axial adiabatic fixed bed reactor, a radial adiabatic fixed bed reactor or a tubular fixed bed reactor.
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