CN112028956A - Method for synthesizing 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione - Google Patents

Abstract

The application relates to a method for synthesizing 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione, which uses 11-deoxycortisol as a raw material, selectively esterifies a secondary hydroxyl group at 17alpha position of the 11-deoxycortisol by means of chemical synthesis of a protecting group, and simultaneously retains a primary hydroxyl group at 21 position of the 11-deoxycortisol to keep the primary hydroxyl group without esterification, so as to obtain 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3, 20-dione. The method has the advantages that the intermediate product of 'one-kettle reaction' does not need to be separated and purified, is more suitable for large-scale industrial preparation, and has mild reaction conditions, high yield, simple post-treatment and the like.

Description

Method for synthesizing 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione

Technical Field

The application relates to the field of pharmaceutical chemistry, in particular to a method for synthesizing 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione (17 th position is alpha configuration (17 alpha), 17alpha-propio17- (1-oxopropoxy) pregn-4-ene-3,20-dione, also called 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3, 20-dione).

Background

21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione (object compound 1) is known to have an antiandrogenic effect and to have a wide variety of effects in various androgen-related therapeutic fields. The synthesis of the compound has been reported in the literature (Tetrahedron Letter,448,1961; Gazz. Chim. IT.63,431,1963) and U.S. Pat. No. 3,3152154, the target product is obtained under acidic condition after condensation reaction by using 11-deoxidized pinacol as raw material and ortho-ester in aprotic solvent, but the reaction route can produce a certain amount of isomer by-product of esterification of 21-primary alcohol, and the by-product and the target product have similar properties and are difficult to separate. There may also be an unreacted starting 11-deoxycortisol which has not been esterified at both the 17alpha and 21 hydroxyl groups. The mixture can be purified only by column chromatography and a small amount of preparation for biological experiments, and chemical synthesis industrial production and large-scale preparation cannot be realized.

In order to solve the problem of mass production of the target compound 1, there are reports of using a biological enzyme method to prepare the target product, such as CN103450304A, CN101743316B, CN103450304B, CN 104861023B. The bio-enzymatic method, reported in the literature (JACS, 75, 3489, 1953), provides the target compound 1 by obtaining intermediate products of 17 α and 21 double esterification of di-esterified 11-deoxycortisol, and hydrolyzing the ester bond at position 21 selectively with lipase.

The method well solves the problem of the selectivity of the esterification site of a target product, and uses the lipase of Candida as a biocatalyst, and the lipase can directionally decompose ester bonds. The target product 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione (CAS No.19608-29-8) was prepared by alcoholysis.

However, problems with the lipase method include: catalytic efficiency of the enzyme, maximum usage of enzyme substrate per unit amount, recycling activity problems of the enzyme, and enzyme catalytic reaction time. Under the condition of perfect chemical synthesis industrial system, the 17alpha hydroxyl is directionally selected and esterified by developing a chemical reaction method, and the synthesized target product can better and more quickly finish the industrial preparation of mass products of mass target products.

Disclosure of Invention

The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

In particular, the present application provides a method of synthesizing 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione, the method comprising:

taking 11-deoxidized cortisol as a raw material, protecting 21-hydroxyl, propionylating 17 alpha-hydroxyl, and finally removing a protecting group in an acid-ester solvent system to obtain a target compound 1

Wherein R may be

R₁May be selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₂May be selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₃May be selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇。

In the present application, the reactions for the synthesis of the intermediate product I, the intermediate product II and the target compound 1 can be carried out in the same vessel and without work-up.

In the present application, the intermediate I may be obtained by the following reaction:

wherein, the 11-deoxidized cortisol can react with a selective primary alcohol protective reagent to obtain the intermediate product I;

the selective primary alcohol protecting reagent may be selected from the group consisting of 4,4' -bismethoxytrityl chloride and 4-methoxytrityl chloride.

In the present application, the intermediate II can be obtained by the following reaction:

wherein the propionylated agent may be selected from the group consisting of propionyl chloride, propionyl bromide, propionic anhydride, propionic acid, and propionate esters;

the reaction solvent for the propionylation may be selected from any one or more of dichloromethane, chloroform, carbon tetrachloride and pyridine;

the acid-binding agent for propionylation may be selected from any one or more of sodium hydroxide, pyridine, triethylamine and xylidine;

optionally, the catalyst for the propionylation may be 4-Dimethylaminopyridine (DMAP), pyridine, dicyclohexylcarbodiimide, or 1-ethyl- (3-dimethylaminopropyl) carbodiimide;

the reaction temperature of the propionylation may be 0 ℃ to 80 ℃;

the reaction time may be 4 hours to 12 hours.

In the present application, the propionylation can be carried out using propionic acid catalyzed by dicyclohexylcarbodiimide or 1-ethyl- (3-dimethylaminopropyl) carbodiimide.

In the present application, the target compound 1 can be obtained by the following reaction:

wherein the reaction may be carried out in an ester solvent using acid catalysis;

the mass percentage of the acid in the ester solvent may be 2% to 5%.

In the present application, the acid may be selected from protic and aprotic acids;

the ester solvent may be selected from any one or more of ethyl acetate, propyl acetate, ethyl propionate, propyl propionate, methyl formate, ethyl formate, methyl acetate, propyl formate, and methyl propionate.

In the present application, the acid may be selected from any one or more of trifluoroacetic acid, trichloroacetic acid, glacial acetic acid, and hydrochloric acid;

the ester is ethyl acetate.

In the present application, hydrochloric acid refers to a hydrochloric acid solution with a mass percentage between 0 and 35%.

In the present application, the reaction temperature for synthesizing the target compound 1 is-78 ℃ to 77 ℃; preferably, it is 0 ℃.

The present application also provides an intermediate product that is intermediate I or intermediate II:

wherein R may be

R₁May be selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₂May be selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₃May be selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇。

The application also provides the use of intermediate I and intermediate II in the synthesis of 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione

Wherein R may be

R₁May be selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₂May be selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₃May be selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇。

Preferably, intermediate I and intermediate II may each have the following structural formula:

in the present application, the method may further comprise recrystallizing the target compound 1, wherein the recrystallized solution system comprises: ethyl acetate-petroleum ether, ethanol-dichloromethane, ethanol-water or methanol-water.

In the present application, intermediate II may be prepared using other aliphatic acylating agents to react with intermediate I. In this case, the propyl group in the intermediate product may be a fatty alkyl group. 21-hydroxy-17- (1-oxofatty alkyloxy) pregn-4-ene-3,20-dione can be synthesized using the methods of the present application.

In this application, DMTr-Cl (or MMTr-Cl) is used as a selective primary alcohol protecting group and reacted with 11-deoxycortisol to give a DMTr (or MMTr) -protected intermediate at position 21. Using reaction conditions similar to the first step of protecting primary alcohol, the second step of esterifying 17alpha hydroxyl under the action of acylating reagent, and directly removing DMTr under the acidic condition in the same reaction vessel without post-treatment to obtain the target product. This procedure gives the target compound 1. The acylating agent is propionyl chloride or propionic anhydride.

The reaction route of the method is a three-step reaction, but actually, because the reaction solvent environment is the same, the reaction conditions of the first two steps are similar, the reaction conditions such as feeding sequence, temperature and the like are controlled in the same reaction solvent system by using a one-kettle reaction mode, and the intermediate obtained in the intermediate process does not need to be purified, namely, the three-step reaction is sequentially carried out in the same reaction container, and finally, the target compound 1 is obtained after the DMTr protective group is removed, and 21-bit hydroxyl is kept unesterified while propionyl esterification of 17-alpha-bit hydroxyl is carried out. The target product with higher purity is obtained after one-kettle reaction, and the target product with high yield and high purity can be obtained in a recrystallization mode.

Meanwhile, in order to better control the site selectivity and purity of the reaction and better optimize the one-kettle reaction condition, the applicant obtains pure products of reaction intermediate products one by one, the pure products of the intermediate reactants are all brand new compound entity structures which are not reported in documents, and comprise an intermediate product I and an intermediate product II, and in addition, the applicant carries out nuclear magnetism, mass spectrum and other structure confirmation, high-efficiency liquid phase purity confirmation and melting point determination on the two-step intermediate pure products in the one-kettle reaction.

The method solves the problem that the target product can generate propionyl migration isomerization under the acidic condition, so that the method can remove the DMTr protecting group of the 21-position hydroxyl of the intermediate II from trifluoroacetic acid (or other protonic acid conditions) in the last step in the synthesis process to obtain the target compound 1, and simultaneously can not cause the propionyl migration isomerization problem of the target compound 1 under the acidic condition. After recrystallization, the final product has no isomerized by-product detected by High Performance Liquid Chromatography (HPLC), and no isomerized by-product is detected by liquid mass spectrometry (LCMS).

The literature reports isomerization of the target compound 1 by propionyl migration under protonic acidic conditions (Tetrahedron Letter,448,1961; gazz. Chim. IT.63,431,1963), wherein isomerization is completed by six-membered ring mechanism after protonation of the carbonyl group of the target compound 1 under acidic conditions, and an isomerization byproduct 2 is generated by propionyl migration.

Because the removal of the DMTr protecting group is accomplished under acidic conditions. The final process of removing the protecting group in the process of preparing the target product by using DMTr-Cl to protect primary alcohol needs to be completed in an acidic environment, and the target compound 1 is subjected to isomerization and migration in the acidic environment for removing the protecting group, so that an isomerization byproduct 2 is generated. Accordingly, the target compound 1 with high purity cannot be produced by this method. At present, no report related to the preparation of the compounds by using DMTr-Cl protection means is found.

The method removes the DMTr protecting group of the primary alcohol under the acidic condition and does not cause the isomerization side reaction of the target compound 1.

Neither intermediate product I nor intermediate product II of this application is reported in the literature. The present application uses an ester solution system to perform the reaction while removing the DMTr protection. The ester solution system is utilized to have a large number of ester carbonyl groups competing for hydrogen ion protonation with the ester carbonyl group of the target compound 1. This prevents the ester carbonyl at the 17 α position of the objective compound 1 from protonating, and a side reaction of propionyl group migration at the 17 α position is cleaved.

The applicant completely blocks the occurrence of isomerization of the target compound 1 during the preparation process in an acidic environment by optimizing the solvent environment, optimizing the temperature, and using and kinds of acids.

The method has high yield, and the preparation mode of a pure chemical synthesis method is more convenient. Compared with the existing chemical synthesis technology, the method can avoid the defect that the final target product can be obtained only by using a column chromatography method when the generated isomerization byproducts are separated. Compared with the existing biological enzyme synthesis technology, the chemical synthesis method can synthesize the target product more efficiently and conveniently. The enzyme preparation has high requirements on equipment, the enzyme is sensitive to the environmental temperature, and the enzyme has the problems of catalytic efficiency and the like. So that the method for synthesizing the target product by the pure chemical synthesis method has high technical value and practical value. Under the same conditions, the feeding amount in the embodiment is amplified by 100 times, and the reaction result is basically consistent with that of a small amount.

Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. The objectives and other advantages of the application may be realized and attained by the structure particularly pointed out in the written description.

Detailed Description

Hereinafter, embodiments of the present application will be described in detail to make objects, technical solutions and advantages of the present application more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.

Examples

The starting material 11-deoxycortisol used in the examples was purchased from: shanghai Bide pharmaceutical science and technology, Inc.; the other reagents are all common commercial reagents; the nuclear magnetic resonance hydrogen spectrometer comprises: BRUKER AVANCE III HD 600MHz nuclear magnetic resonance spectrometer, germany; the mass spectrometer is as follows: shimadzu LC-MS 2020, Japan; the melting point instrument is as follows: mettler Toledo MP 90 melting point apparatus, switzerland.

Example 1

Preparation of intermediate I

Wherein R is DMTr

Dissolving the compound 11-deoxycortisol (1.04g,3.0mmol,1eq.) in 10mL of anhydrous pyridine, dissolving dried DMTrCl (1.2-1.5eq) in 5mL of anhydrous dichloromethane, dropwise adding a dichloromethane solution of DMTrCl into the reactant solution at room temperature, and reacting for 4 hours at room temperature; the reaction was quenched with methanol and the solvent was evaporated to dryness with an oil pump to give intermediate I in 85% yield (the next reaction was carried out without work-up, the solvent environment and catalyst were similar to the reaction of this step).

¹HNMR(600MHz,CDCl₃)(ppm)7.25-7.31(m,5H,H-DMTr),7.15-7.18(m,4H,H-DMTr),6.81-6.84(m,4H,H-DMTr),5.73(1H,s,H-4),4.65(1H,dd,J＝19.8,4.8Hz,H-21),4.30(1H,dd,J＝19.8,4.8Hz,H-21),3.80(6H,s),2.71(s,1H,17-OH),2.66-2.71(m,1H,H-16β),2.27-2.45(m,4H),1.19(3H,s,H-19),0.96-1.87(m,14H),0.72(s,3H,H-18).

MS⁺303(DMTr protecting group fragment), 649[ M + H]⁺

Melting point: 95-97 deg.C

Example 2:

preparation of intermediate II

Wherein R is DMTr

Under the protection of nitrogen, dissolving the intermediate product I (1eq.) in 5mL of anhydrous dichloromethane, adding DMAP (0.1eq.) into the solution, dropwise adding triethylamine (1.2eq.) and propionic anhydride or propionyl chloride (1.2eq.), reacting at 40 ℃ for 12 hours after dropwise adding, and evaporating the solvent to obtain an intermediate product II.

Or under the protection of nitrogen, dissolving the intermediate product I (1eq.) in 5mL of anhydrous pyridine, adding DMAP (0.1eq.) into the solution, dropwise adding triethylamine (1.2eq.) and propionic anhydride or propionyl chloride (1.2eq.), reacting at 80 ℃ for 4 hours after dropwise adding, and evaporating the solvent to obtain an intermediate product II. (the reaction in the step can be directly carried out for the next step of removing DMTr protecting group to obtain the reaction after solvent evaporation without strict purification post-treatment)

¹HNMR(600MHz,CDCl₃)(ppm)7.26-7.32(m,5H,H-DMTr),7.14-7.18(m,4H,H-DMTr),6.81-6.84(m,4H,H-DMTr),5.72(1H,s,H-4),4.65(1H,dd,J＝19.8,4.8Hz,H-21),4.30(1H,dd,J＝19.8,4.8Hz,H-21),3.81(6H,s),2.66-2.71(m,1H,H-16β),2.35(m,2H,-CH₂CH₃),2.27-2.45(m,4H),1.19(3H,s,H-19),1.15(t,3H,J＝7.8Hz,-CH₂CH₃),0.96-1.87(m,14H),0.72(s,3H,H-18)；

MS⁺:303(DMTr protecting group fragment), 727[ M + Na [)]⁺,768[M+Na+CH₃CN]⁺。

Example 3:

preparation of target Compound 1 (21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3, 20-dione)

Dissolving the concentrated intermediate product II in an ethyl acetate solution, slowly dropwise adding 0.5M hydrochloric acid solution or 2% trifluoroacetic acid-ethyl acetate solution at 0 ℃, reacting for 5 minutes at 0 ℃, removing DMTr protective groups, adding 5% sodium bicarbonate aqueous solution at 0 ℃, stirring, neutralizing acid in a reaction system, washing an ethyl acetate organic layer twice by using 5% sodium bicarbonate aqueous solution, removing acid and other water-soluble impurities in the ethyl acetate organic layer, drying the ethyl acetate organic layer by anhydrous sodium sulfate, evaporating to remove part of ethyl acetate solvent, adding petroleum ether into the remaining small amount of ethyl acetate solution, and recrystallizing in a system with 10 times of solvent amount of ethyl acetate-petroleum ether (5: 1) to obtain a target product with high purity of 90%. The total yield from 11-deoxycortisol is up to 70%. The final product was free of isomerized by-products by HPLC and was not found by LCMS.

¹HNMR(600MHz,CDCl₃)(ppm):5.75(s,1H,H-4),4.28(d,1H,J＝18.0Hz,H-21),4.23(d,1H,J＝18.0Hz,H-21),3.05(s,1H,21-OH),2.81-2.86(m,1H,H-16β),2.34-2.46(m,3H),2.35(m,2H,-CH₂CH₃),2.28-2.33(m,1H),2.03-2.07(m,1H),1.86-1.94(m,2H),1.67-1.77(m,3H),1.55-1.64(m,3H),1.35-1.46(m,3H),1.19(s,3H,H-19),1.15(t,3H,J＝7.8Hz,-CH₂CH₃),1.08-1.11(m,1H),1.00-1.05(m,1H),0.69(s,3H,H-18)；

MS⁺：403[M+H]⁺，444[M+H+CH₃CN]⁺

Melting point: 128-130 ℃.

Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.

Claims (11)

1. A method of synthesizing 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione, the method comprising:

taking 11-deoxidized cortisol as a raw material, protecting 21-hydroxyl, propionylating 17 alpha-hydroxyl, and finally removing a protecting group in an acid-ester solvent system to obtain a target compound 1

Wherein R is

R₁Selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₂Selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₃Selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇。

2. The method of claim 1, wherein the reactions for synthesizing intermediate I, intermediate II, and target compound 1 are performed in the same vessel and without work-up.

3. The process according to claim 1 or 2, wherein the intermediate product I is obtained by the reaction:

wherein, the intermediate product I is obtained by the reaction of 11-deoxidized cortisol and a selective primary alcohol protective reagent;

the selective primary alcohol protecting reagent is preferably selected from the group consisting of 4,4' -bismethoxytrityl chloride and 4-methoxytrityl chloride.

4. The process according to claim 1 or 2, wherein the intermediate product II is obtained by the reaction:

wherein the propionylated agent is selected from the group consisting of propionyl chloride, propionyl bromide, propionic anhydride, propionic acid, and propionate esters;

the reaction solvent for the propionylation is selected from any one or more of dichloromethane, chloroform, carbon tetrachloride and pyridine;

the acid-binding agent for propionylation is selected from any one or more of sodium hydroxide, pyridine, triethylamine and xylidine;

optionally, the catalyst for the propionylation is 4-dimethylaminopyridine, pyridine, dicyclohexylcarbodiimide or 1-ethyl- (3-dimethylaminopropyl);

the reaction temperature of the propionylation is 0 ℃ to 80 ℃;

the reaction time is 4 to 12 hours.

5. The process according to claim 4, wherein the propionylation is carried out using propionic acid catalyzed by dicyclohexylcarbodiimide or 1-ethyl- (3-dimethylaminopropyl) carbodiimide.

6. The method according to claim 1 or 2, the target compound 1 being obtained by the reaction:

wherein the reaction is carried out in an ester solvent using acid catalysis;

the mass percentage of the acid in the ester solvent is 2% to 5%.

7. The method of claim 6, wherein the acid is selected from the group consisting of protic and aprotic acids;

the ester is selected from any one or more of ethyl acetate, propyl acetate, ethyl propionate, propyl propionate, methyl formate, ethyl formate, methyl acetate, propyl formate and methyl propionate.

8. The process according to claim 7, wherein the acid is selected from any one or more of trifluoroacetic acid, trichloroacetic acid, glacial acetic acid and hydrochloric acid;

the ester is ethyl acetate.

9. The method according to any one of claims 6 to 8, wherein the reaction temperature for synthesizing the target compound 1 from the intermediate product II is from-78 ℃ to 77 ℃; preferably, it is 0 ℃.

10. An intermediate product which is intermediate I or intermediate II:

wherein R is

R₁Selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₂Selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₃Selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇。

11. Use of intermediate I and intermediate II in the synthesis of 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione

Wherein R is

R₁Selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₂Selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇；R₃Selected from: H. OCH (OCH)₃、OC₂H₅And OC₃H₇。