CN116497080A - Method for preparing deoxycortisone 17 alpha monoester and analogue thereof - Google Patents

Method for preparing deoxycortisone 17 alpha monoester and analogue thereof Download PDF

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CN116497080A
CN116497080A CN202310522328.9A CN202310522328A CN116497080A CN 116497080 A CN116497080 A CN 116497080A CN 202310522328 A CN202310522328 A CN 202310522328A CN 116497080 A CN116497080 A CN 116497080A
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deoxycortisone
analogues
reaction
substrate
monoester
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李爱涛
李倩
李明鹏
高成华
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Hubei University
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Hubei University
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Abstract

The invention relates to a method for preparing deoxycortisone 17 alpha monoester and analogues thereof, which comprises the following steps: dissolving deoxycortisone 17,21 diester as a substrate in an alcohol donor, and performing transesterification under the action of lipase to obtain deoxycortisone 17 alpha monoester and analogues thereof; the alcohol donor includes t-butanol, isopropanol, or isoamyl alcohol. The invention adopts the alcohol donor to dissolve the substrate, the alcohol donor plays the roles of dissolving the substrate by the organic solvent and participating in the reaction as the alcohol raw material, the reaction system is greatly simplified, the product separation is facilitated, the reaction system can not generate reverse reaction, the inclusion of the alcohol solvent and the substrate concentration is high, and the batch stability is good. The method has the advantages of high substrate concentration (up to 100-200 g/L), short reaction time, simple reaction system, easy separation of products and the like.

Description

Method for preparing deoxycortisone 17 alpha monoester and analogue thereof
Technical Field
The invention belongs to the technical field of bioengineering, and particularly relates to a method for preparing deoxycortisone 17 alpha monoester and analogues thereof.
Background
Acne is a chronic inflammatory skin disease of the pilosebaceous glands, the global incidence is about 9.4%, and in recent years, the incidence of acne tends to rise year by year. Acne not only causes physical discomfort to the patient but also is prone to psychological problems such as mood disorders, anxiety, and depressionDepression, etc., and thus should be positively treated for acne. At present, the treatment drugs for acne mainly comprise antibacterial drugs, vitamin A acid drugs, hormone drugs and the like. Since the us Food and Drug Administration (FDA) approved tretinoin to be marketed in 1982, innovative drugs for acne have been less developed. Month 8 of 2020, the FDA approved 1% Clascoterone (deoxycortisone 17 alpha monoester, trade name winlei) cream for the treatment of acne patients aged 12 and older. Clascoterone is a sterone propionate which is used as a local androgen receptor inhibitor and has a brand-new action mechanism. Clascoterone has the formula C 24 H 34 O 5 The molecular weight is 402g/mol, and the structural formula of Clascoterone is shown as the following formula a:
regarding the synthesis of Clascoterone, two methods are currently reported. The first is a chemical synthesis, according to the method of US3152154, in which a bis-hydroxylated substrate is mixed with an orthoester in an organic solvent (e.g. cyclohexane, DMF, etc.) under acid (e.g. p-toluene sulphonic acid) catalysis, and reacted to form a new orthoester. The new orthoesters are purified in a specific solvent (e.g., ethanol) and then hydrolyzed in aqueous ethanol to give the final product Clascoterone. However, the product synthesized by the route is not easy to extract and is also unstable, and the transfer of acyl from 17 to 21 is very easy to occur. The reaction process is shown in the following scheme b:
route b: method for chemical synthesis of Clascoterone (R) 1,2 ＝CH 3 ，C 2 H 5 ，C 3 H 7 )
The second synthesis method is a bioenzyme method, according to the method in patent WO2009/019138A2, a diester substrate is dissolved in an organic solvent (chloroform, toluene, tetrahydrofuran and acetonitrile), an alcohol solvent (methanol, ethanol, butanol, octanol) is added thereto as an alcohol donor, and Clascoterone is produced catalytically with a lipase (pancreatic lipase, candida cylindracea lipase, candida antarctica lipase B). The course of the reaction is shown in scheme c below. However, the method has the problems of low product concentration, complex reaction system, low conversion speed and the like, and the finally obtained reaction solution is a mixture, so that the product separation is difficult.
Route c: clascoterone (R) synthesized by traditional biological enzyme method 1,2 ＝CH 3 ，C 2 H 5 ，C 3 H 7 )
In order to solve the deficiencies of the two above methods, a new method for producing Clascoterone (deoxycortisone 17 a monoester) is needed.
Disclosure of Invention
The invention aims to overcome the technical defects, and provides a method for preparing deoxycortisone 17 alpha monoester and analogues thereof, which solves the technical problems that the preparation system of the deoxycortisone 17 alpha monoester in the prior art is complex and products are difficult to separate.
In order to achieve the technical purpose, the technical scheme provided by the invention is as follows:
a process for preparing deoxycortisone 17 alpha monoester and analogues thereof comprising the steps of:
dissolving deoxycortisone 17,21 diester as a substrate in an alcohol donor, and performing transesterification under the action of lipase to obtain deoxycortisone 17 alpha monoester and analogues thereof; the alcohol donor includes tert-butanol, isopropanol or isoamyl alcohol;
the structural formula of the deoxycortisone 17 alpha monoester and analogues thereof is shown in the following formula I:
wherein R is C1-C4 alkyl.
Compared with the prior art, the invention has the beneficial effects that:
the invention takes deoxycortisone 17,21 diester as a substrate, provides an alcohol donor to synthesize deoxycortisone 17 alpha monoester under the condition of lipase catalysis, wherein the alcohol donor is adopted to dissolve the substrate, and simultaneously plays roles of dissolving the substrate by an organic solvent and participating in the reaction as an alcohol raw material, so that the reaction system is greatly simplified, the product separation is facilitated, the reaction system does not generate reverse reaction, the inclusion of the alcohol solvent and the substrate concentration is high, and the batch stability is good. The method has the advantages of high substrate concentration (up to 100-200 g/L), short reaction time, simple reaction system, easy separation of products and the like.
Drawings
FIG. 1 is a schematic diagram of an apparatus for continuous flow microreactors;
FIG. 2 shows the kinetic data (A) for a continuous flow microreactor and the kinetic data (B) for a batch reactor according to the invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The traditional enzyme catalytic system is carried out in organic solvents such as toluene acetonitrile and the like, and higher reaction yield is obtained by adding an alcohol donor and strictly controlling reaction time.
In the traditional synthesis path, toluene is taken as an organic solvent, ethanol is added as an alcohol donor, and after catalytic reaction is carried out for 120 hours by candida cylindracea lipase CCL, the substrate conversion rate is about 73 percent. Repeated experiments have found that after 120 hours, as the reaction proceeds, the alcohol donor may volatilize, resulting in reverse reaction and reduced product yield. In addition, the final concentration of the substrate in the reaction system is only about 10-12 g/L. The types of the organic solvent, the alcohol donor and the enzyme are changed, the reaction time is adjusted, and the like, and the reaction effect is greatly different, but the batch stability of the reaction is poor. Thus, in general, the synthetic method has the problems of long reaction time, low efficiency and difficult separation of products. Meanwhile, the conditions such as the organic solvent, the alcohol donor, the enzyme type and the reaction time have great influence on the preparation of the deoxycortisone 17 alpha monoester.
The invention takes deoxycortisone 17, 21-diester as a substrate, and directly synthesizes deoxycortisone 17 alpha monoester (Clascoterone) under the catalysis of immobilized candida antarctica lipase B.
The innovation point of the invention is that the defect of the traditional method is solved by using a new enzyme catalysis system, and the reaction efficiency is greatly improved. The invention adopts the alcohol solvent to dissolve the substrate, thus the alcohol solvent can be used as an organic solvent and an alcohol donor, greatly simplifying the reaction system, and having the advantages of short reaction time, high reaction efficiency, high concentration of the substrate capable of reacting, good batch stability, easier product separation, and the like.
The preparation method specifically comprises the following steps:
after the diester substrate is dissolved in an alcohol donor, carrying out transesterification under the action of lipase to obtain deoxycortisone 17 alpha monoester and analogues thereof; the alcohol donor includes tert-butanol, isopropanol or isoamyl alcohol;
the structural formula of the deoxycortisone 17 alpha monoester and the analogue thereof is shown in the following formula I:
wherein R is C1-C4 alkyl; the single dashed line in the ring indicates the presence or absence of a double bond.
Preferably, the mass ratio of lipase to diester substrate is (1-3): 1.
preferably, the concentration of diester substrate dissolved in the alcohol donor is 1-100 mg/mL.
Preferably, the temperature of the transesterification reaction is 40-60 ℃; further preferably 45 to 55 ℃.
Preferably, the transesterification reaction time is from 0.5h to 48h.
Preferably, in order to further complete the reaction and increase the reaction efficiency, the present invention first attempts to perform the reaction in a continuous flow microreactor, shortening the reaction time and increasing the reaction efficiency. The continuous flow microreactor comprises a propulsion system, a heating and heat-preserving micro-pipeline and a collecting device which are connected in sequence, wherein the propulsion system is used for propelling a reaction substrate into the micro-pipeline; the micro-pipeline can be heated and kept at a temperature so that the reaction can be normally carried out; the collection device is used for collecting the product at the outlet of the micro-pipeline.
Preferably, the alcohol donor is isopropanol and the transesterification reaction time is 30 to 150 minutes, more preferably 45 to 130 minutes, during the reaction in the continuous flow microreactor.
Preferably, the diameter of the micro-pipeline is 1-3 mm, and the length is 1-2 m; the flow rate of the reaction solution in the micro-pipeline is 0.03-0.1 mL/min.
Preferably, the diester substrate has the structural formula II:
wherein R' and R are each independently C1-C4 alkyl.
The lipase is commercially immobilized lipase, including Novozyme 435, lipozyme TL IM, lipozyme RM IM, IM-100, calB imo 8806 TM 、CalB immo Plus TM 。
The principles and features of the present invention are further described below with reference to the following examples, which are provided to illustrate the invention and are not intended to limit the scope of the invention. The experimental methods used in the following examples are all conventional in the art unless otherwise specified. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1
In a 25mL reaction flask, 5mL of t-butanol, 0.5g of deoxycortisone 17, 21-diester (R is ethyl and R' is methyl), 1g of commercially immobilized lipase CALB were added. The reaction was placed in a shaker at 220rpm and 50 ℃. Samples were taken and tested every 4 hours, and samples were collected and tested after 48 hours. After liquid phase detection, the substrate conversion rate is about 98% after 48 hours under the condition.
Example 2 (investigating the influence of different enzyme amounts on conversion)
Example 2 differs from example 1 only in that: the mass ratio of enzyme to substrate was adjusted as shown in Table 1 below, and the other steps and conditions were the same as in example 1.
Table 1: substrate conversion at different enzyme levels
From the data in Table 1, it is understood that the substrate conversion rate and the enzyme amount are related to each other under the same conditions, and that the substrate conversion rate is higher as the enzyme amount is larger. However, the increase in conversion rate becomes less and less pronounced with increasing enzyme amount. Considering the factors such as enzyme cost and the influence of the enzyme on a reaction system, the mass ratio of the enzyme to the substrate is preferably (1-3): 1, the optimal ratio of enzyme to substrate is 2:1.
example 3: examine the effect of different temperatures on conversion
Example 3 differs from example 1 only in that: the reaction temperature was adjusted, and the reaction conditions and other steps were the same as in example 1, as shown in Table 2 below.
Table 2: substrate conversion at different temperatures
From the data in Table 2, the effect of temperature on the conversion of the reaction was large. Under the same conditions, the conversion rate of the reaction at 50℃is the highest, and the reaction temperature of the present invention is preferably 45 to 55℃and most preferably 50℃in view of energy consumption and enzyme activity.
Example 4: influence of different alcohol donors on the reaction.
Example 4 differs from example 1 only in that: the types of alcohol donors (also solvents) were adjusted, and the procedure and conditions were the same as in example 1, except that the types of alcohol donors (also solvents) were as shown in Table 3 below.
Table 3: substrate conversion of the reaction under different alcohol donor conditions
Note that: when methanol or ethanol is used as the solvent and the alcohol donor, the reaction fails to detect the target product.
From the data in Table 3, the reaction has a preference for alcohol donors, where the conversion is best t-amyl alcohol, followed by t-butyl alcohol, isopropyl alcohol and isoamyl alcohol, but since t-amyl alcohol is more expensive, the cost is greatly increased, and so in subsequent experiments it is chosen to be carried out in lower priced and better converted t-butyl alcohol and isopropyl alcohol.
Example 5: reaction in a continuous flow apparatus.
The continuous flow microreactor means are arranged according to the conditions required for the reaction. The substrate is fully contacted with the enzyme and the alcohol donor in the micro-pipeline of the continuous flow micro-reactor, so that the mass transfer efficiency is greatly improved, and the reaction rate and the substrate conversion rate are greatly improved.
As shown in fig. 1, the continuous flow microreactor device consists of a left propulsion system 1, a middle micro-pipeline 2 which can be heated and insulated and a right collection device 3, and the three devices are connected in sequence. Wherein lipase CALB is placed in the micro-pipeline 2, and the micro-pipeline 2 can be placed in a water bath environment for heating and heat preservation to enable the reaction to normally run; the propulsion system 1 is used for pushing a reaction liquid obtained by dissolving a substrate in an alcohol donor into the micro-pipeline 2 and pushing the reaction liquid in the micro-pipeline 2 to advance; the reaction liquid is reacted after contacting with lipase CALB in the micro-pipeline, and the collecting device 3 is used for collecting the product.
Table 4: reaction Effect in continuous flow microreactors
From the data in Table 4, it can be seen that in a continuous flow microreactor, substrate conversion is related to both enzyme quantity and microchannel length and flow rate, probably because flow rate affects the residence time of the substrate in the microchannels, and thus the contact of the enzyme with the substrate. The specific relation is that the more enzyme amount is, the longer the micro-pipeline is, the slower the flow speed is, and the higher the substrate conversion rate is under the same other conditions. Meanwhile, it should be noted that isopropanol is used as a solvent in continuous flow microreactors instead of t-butanol because t-butanol has a low freezing point and tends to clog the microchannels.
And the results showed that the apparent rate constant of the reaction was increased by a factor of 58 in the microreactor. Further shortening the reaction time and improving the reaction efficiency. When the continuous flow microreactor is used for reaction, the substrate conversion rate reaches 100% under certain conditions.
Wherein the apparent rate constants are fitted with first order reaction kinetics as follows:
-ln(1-X t )＝k app t
wherein Xt is the substrate conversion, k, at a residence time of t app Is the apparent rate constant. With further increases in temperature, the apparent reaction rate does not change much. In general, the reaction rate depends on two factors, the efficiency of the enzyme and the mass transfer rate.
As shown in FIG. 2, the kinetic data (A) of the continuous flow microreactor of the present invention was compared to the kinetic data (B) of the batch reactor, and the reaction rate in the continuous flow microreactor of the present invention was much faster than that in the batch reactor at 50 ℃. The apparent reaction rate of the continuous flow microreactor of the invention is 58 times that of the batch reactor. The better performance of the continuous flow microreactor of the invention can be attributed to two factors (1) in the closed volume of the continuous flow microreactor, the reactants are forced to contact enzyme active sites, i.e., the transport path of the substrate in the continuous flow microreactor is much smaller than that of the batch reactor; (2) Since the surface area to volume ratio in a continuous flow microreactor is much higher than in a batch reactor, the substrate can in any case be contacted with more enzyme active sites. In batch reactors, similar effects can be achieved by adding more enzyme, but this creates other problems. For example, low enzyme utilization results in higher costs and more enzyme particle breakage during mixing. Furthermore, a significant advantage of the present invention using a continuous flow microreactor is that the conversion of diester substrates can reach 100%, which is difficult to achieve with batch reactors.
Example 6: the invention is applicable to Clascoterone analogues.
Example 6 differs from example 1 only in that: the substrate species were adjusted so that the product structures are shown in the following formulas 1 to 7, and other steps and conditions were the same as in example 1.
The effect of this system in catalyzing the production of the corresponding diester to the Clascoterone analogs of formulas 1-7 below was examined and the results are shown in Table 5.
Table 5: catalytic production of Clascoterone analogues in the inventive System
Example 7: influence of different commercial immobilized lipases.
Example 7 differs from example 1 only in that: the lipase types were adjusted, and the other steps and conditions were the same as those in example 1, as shown in Table 6 below.
Detect differentThe commercial immobilized lipase CALB produced by manufacturers has application effect in the system of the invention. Wherein Novozyme 435, lipozyme TL IM, lipozyme RM IM are available from Denmark Norwegian Co., ltd., IM-100 is available from Shang Ke biological medicine (Shanghai), calB imo 8806 TM 、CalB immo Plus TM Purchased from boulder, uk.
Table 6: reaction Effect of different commercially immobilized lipases in the System of the invention
As shown in Table 6, the effect of the manufacturer source of the immobilized CALB enzyme is not great, which indicates that the lipase source of the reaction system of the invention is wide and the substrate conversion rate is stable.
In summary, the invention uses tertiary butanol and the like as solvents, the substrate concentration is 100g/L, immobilized Candida Antarctica Lipase B (CALB) is used for catalytic reaction, the substrate conversion rate is more than 80% after 24 hours at the temperature of 50 ℃, and the conversion rate is more than 98% after 48 hours. After a large number of repeated experiments prove that the reaction system can not generate reverse reaction, and the substrate transfer rate can not be reduced after the reaction time is prolonged. The system has high inclusion of alcohol solvent and substrate concentration and high batch stability. The optional alcohol solvents include isopropanol, isobutanol, tertiary butanol, and isoamyl alcohol, and the conversion rate of about 80% can be achieved in the reaction system under the condition that the substrate concentration reaches 200g/L and under the other conditions under the same conditions. The system has the advantages of short reaction time, high reaction efficiency, high concentration of the reactive substrate, good batch stability, easier product separation and the like, and has great industrial value.
The above-described embodiments of the present invention do not limit the scope of the present invention. Any other corresponding changes and modifications made in accordance with the technical idea of the present invention shall be included in the scope of the claims of the present invention.

Claims (10)

1. A process for preparing deoxycortisone 17 alpha monoester and analogues thereof comprising the steps of:
dissolving deoxycortisone 17,21 diester as a substrate in an alcohol donor, and performing transesterification under the action of lipase to obtain deoxycortisone 17 alpha monoester and analogues thereof; the alcohol donor includes tert-butanol, isopropanol or isoamyl alcohol;
the structural formula of the deoxycortisone 17 alpha monoester and the analogue thereof is shown in the following formula I:
wherein R is C1-C4 alkyl.
2. The method for preparing deoxycortisone 17 alpha monoester and analogues thereof according to claim 1, wherein the mass ratio of lipase to substrate is (1-3): 1.
3. the method of preparing deoxycortisone 17 a monoester and analogues thereof according to claim 1, wherein the concentration of substrate dissolved in the alcohol donor is 1-100 mg/mL.
4. The process for preparing deoxycortisone 17 alpha monoester and its analogues according to claim 1, wherein the transesterification reaction is carried out at a temperature of 40-60 ℃.
5. The method for preparing deoxycortisone 17 alpha monoester and its analogues according to claim 1, wherein the transesterification reaction time is 0.5 h-48 h.
6. The process for the preparation of deoxycortisone 17 alpha monoester and analogues thereof according to claim 1, characterized in that the transesterification reaction is carried out in a continuous flow microreactor comprising a propulsion system, a microchannel and a collecting device connected in sequence, the propulsion system being adapted to drive the reaction liquid into the microchannel and towards the collecting device, the reaction liquid being obtained by dissolution of the substrate in the alcohol donor; the lipase is placed in the micro-channels, and the collecting device is used for collecting reaction products.
7. The method for preparing deoxycortisone 17 alpha monoester and analogues thereof according to claim 6, wherein the micro-channels are heated and kept in a water bath environment when being carried out in a continuous flow micro-reactor, the alcohol donor is isopropanol, and the transesterification reaction time is 30-150 min.
8. The method for preparing deoxycortisone 17 alpha monoester and its analogues according to claim 6, wherein the micro-pipe has a diameter of 1-3 mm and a length of 1-2 m; the flow rate of the reaction solution in the micro-pipeline is 0.03-0.1 mL/min.
9. The process for preparing deoxycortisone 17 a monoester and its analogues as claimed in claim 1, wherein the structural formula of the deoxycortisone 17,21 diester is as follows:
wherein R' and R are each independently C1-C4 alkyl.
10. The method of preparing deoxycortisone 17 a monoester and analogues thereof according to claim 1, wherein the lipase is a commercially immobilized lipase.
CN202310522328.9A 2023-05-06 2023-05-06 Method for preparing deoxycortisone 17 alpha monoester and analogue thereof Pending CN116497080A (en)

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