Preparation method of high-purity steroid androgen receptor inhibitor

Abstract

According to the present invention, the 21-hydroxy-17-(propionate) pregna-4-ene-3, 20-diketone is the effective androgen receptor inhibitor, and can be used as the androgen receptor inhibitor. The development of a high-purity synthesis process for preparing the compound has important significance. The preparation method comprises the following steps: by taking 21-hydroxy-17-(propionate) pregna-4-ene-3, 20-diketone containing isomer impurities as a raw material, selectively etherifying 21-hydroxyl silicon by using a silicon protecting group, so as to obtain an intermediate compound 3; the compound 3 is further converted to obtain a target compound 1, and a high-purity target product can be prepared by recrystallization. The synthesis process has the advantages of mild reaction conditions, high yield, simple post-treatment and the like.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis process development, and specifically relates to a method for preparing a high-purity steroidal androgen receptor inhibitor. Background Art

[0002] 21-Hydroxy-17-(propionate)pregn-4-ene-3,20-dione (structural formula shown below) is an effective androgen receptor inhibitor, widely used in the treatment of acne in adults and children over 12 years old. It was approved for marketing by the U.S. Food and Drug Administration in August 2020.

[0003]

[0004] Currently, the public document Tetrahedron Lett. 1961, 2, 448-451 and US Pat. No. 3152154 report the use of 17, 21-dihydroxy compounds as raw materials, the condensation of orthoesters to obtain cyclic ester condensation products; and then hydrolysis under acidic conditions to open the ring to obtain the target product. However, this reaction route will produce a certain amount of 21-propionate esterified isomer by-products. Since the by-products and the target compounds have similar properties, and the main product can be converted into 21-propionate esterified isomer by-products in protic solvents under acidic and alkaline conditions. The main product is difficult to separate and purify by conventional methods such as column chromatography and recrystallization; it is not conducive to industrial production.

[0005]

[0006] In order to solve the problem of obtaining high-purity 21-hydroxy-17-(propionate) pregnane-4-ene-3,20-dione in industrial production, many literatures have reported methods of selectively hydrolyzing 17,21-dihydroxy ester precursors by bioenzyme catalysis. For example, Tetrahedron Lett. 2008, 49, 4610–4612, CN 114410727, CN 116497080, CN104861023B, CN 103450304B

[0007] However, the main problems of bio-enzyme selective hydrolysis include: the immobilization of enzyme catalysts and the resulting catalytic activity, the problem of enzyme catalytic reaction time, and the problem of separation and purification of products after hydrolysis. In addition, the production cost of enzyme-catalyzed selective hydrolysis is high and lacks market competitiveness.

[0008] Patent document CN 112028956 reports that 17,21-dihydroxy compound is used as raw material, 21-hydroxyl group is etherified by large sterically hindered alkoxy protecting group, 17-hydroxyl group is esterified by propionate, and finally the protecting group is removed to obtain the target product. The implementation case of this patent can only obtain the target product with a purity of 90%, and subsequent purification is required to obtain a product that meets the quality requirements of raw materials. Summary of the invention

[0009] In order to solve the problems existing in the prior art, the present invention designs a new synthetic method for preparing high-purity 21-hydroxy-17-(propionate) pregnane-4-ene-3,20-dione with mild reaction conditions, good selectivity and simple purification operation process.

[0010] The technical solution of the present invention comprises two-step reaction:

[0011] The first step is 21-hydroxysilyl etherification reaction:

[0012] The chemical reaction equation is as follows:

[0013] The 17,21-cyclic ester was hydrolyzed by the method reported in US3152154 to obtain compound 1, which contained the main impurity compound 2, and the purity of compound 1 was 96%. Compound 3 was synthesized using this as a raw material.

[0014] Compound 1 (purity 96%) and reaction solvent were added to a reaction flask and stirred to dissolve, and then tert-butyldimethylsilyl chloride was added to the reaction flask in a certain proportion, and stirred to react at a certain temperature until the raw material was completely converted. The product was poured into ice water and stirred to crystallize, and the solvent was filtered to remove compound 3.

[0015] Preferably, the equivalent of TBSCl in the reaction is 1-1.3 equivalents.

[0016] Preferably, the solvent in the reaction is at least one of N,N-dimethylformamide and N,N-dimethylacetamide, the temperature is from room temperature to 60° C., and the reaction time is from 12 to 24 hours.

[0017] The second step is 21-hydroxyl deprotection reaction:

[0018] The chemical reaction equation is as follows:

[0019] Compound 3 was added to a reaction flask at a certain temperature, and a solvent was added and stirred evenly. A certain proportion of a deprotecting agent was added, and the reaction was stirred at room temperature until the raw material was completely converted. The reaction solution was cooled and poured into ice water, and the solid was rapidly stirred to precipitate, and the compound 1 was obtained by filtration.

[0020] Preferably, the deprotecting agent in the reaction is tetrabutylammonium fluoride, potassium fluoride, acetic acid, 10% dilute hydrochloric acid

[0021] Preferably, in the reaction, the molar ratio of compound 3 to the deprotecting agent is 1:1 to 1:3.

[0022] Preferably, the solvent in the second step reaction is at least one of tetrahydrofuran, ethyl acetate, toluene and acetonitrile. DETAILED DESCRIPTION

[0023] The present invention will be further described below in conjunction with specific embodiments.

[0024] The following examples may enable those skilled in the art to better understand the present invention. However, the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention in any way.

[0025] Example 1

[0026] A method for preparing a high-purity steroidal androgen receptor inhibitor comprises the following two steps:

[0027] The first step is 21-hydroxysilyl etherification reaction:

[0028] Compound 1 (purity 96%) (0.1 mol, 40.2 g), imidazole (0.15 mol, 10.2 g) 200 mL N, N-dimethylformamide were added to a 500 mL reaction bottle and magnetically stirred to dissolve. The reaction solution was added dropwise to the reaction bottle with tert-butyldimethylsilyl chloride (0.12 mol, 18.0 g). The reaction was stirred at room temperature for 18 hours, and the raw material was completely converted by TLC detection. The reaction solution was poured into 1000 mL ice water and stirred rapidly to precipitate solids, and the solvent was filtered to remove the white solid. The filtered white solid was recrystallized with 200 mL tetrahydrofuran and dried under vacuum at room temperature to obtain 44.9 g of compound 3 with a yield of 87%.

[0029] The second step is 21-hydroxyl deprotection reaction:

[0030] Add (0.05mol, 25.8g) of compound 3 to a 500mL reaction flask, add 150mL of tetrahydrofuran and stir to dissolve. Add (0.05mol, 13.1g) of tetrabutylammonium fluoride to the reaction flask, stir and react at room temperature for 12 hours, and the raw material has been completely converted by TLC detection. The reaction solution is cooled to room temperature, slowly poured into 500mL of deionized water, extracted with ethyl acetate, and the organic phase is collected. After drying, the solvent is removed by decompression and concentrated to obtain a large amount of white solid. The obtained white solid is recrystallized with 300mL of methyl tert-butyl ether, and the white solid compound obtained by filtration is vacuum dried to obtain 18.1g of the target compound, with a yield of 90%.

[0031] Example 2

[0032] A method for preparing a high-purity steroidal androgen receptor inhibitor comprises the following two steps:

[0033] The first step is 21-hydroxysilyl etherification reaction:

[0034] Compound 1 (purity 96%) (0.1 mol, 40.2 g), imidazole (0.2 mol, 13.6 g) 200 mL N, N-dimethylacetamide were added to a 500 mL reaction bottle and magnetically stirred to dissolve. The reaction solution was added dropwise to the reaction bottle with (0.2 mol, 30.0 g) tert-butyldimethylsilyl chloride. The reaction was stirred at 50 ° C for 2 hours. TLC detected that the raw material had been completely converted. The reaction solution was poured into 1000 mL of ice water and stirred rapidly to precipitate solids. The solvent was filtered to remove the white solid, which was recrystallized with 200 mL of tetrahydrofuran and dried in vacuo at room temperature to obtain 48.0 g of compound 3 with a yield of 93%.

[0035] The second step is 21-hydroxyl deprotection reaction:

[0036] Add (0.1 mol, 51.6 g) of compound 3 to a 500 mL reaction flask, add 150 mL of tetrahydrofuran and stir to dissolve. Add (5.0 mmol, 0.28 mL) of glacial acetic acid to the reaction flask, stir and react at 60°C for 12 hours, and the raw material has been completely converted by TLC. The reaction solution was cooled to room temperature, and a large amount of white solid was obtained after decompression and concentration to remove part of the solvent. The white solid compound obtained by filtration was vacuum dried to obtain 32.7 g of the target compound, with a yield of 81%, and a purity of >99.8% detected by HPLC.

[0037] Characterization data of compound 3:

[0038] 1 HNMR (400MHz, CDCl3) δ5.74(s,1H),4.35(q,J=17.2Hz,1H),2.85(ddd,J=14.9,11.2,1.7Hz,1H),2.48–2.27(m,6H),2.08–2.02(m,1H),1.93–1.60(m ,10H),1.49–1.41(m,1H),1.38–1.31(m,1H),1.19(s,3H),1.14(t,J=7.6H z,3H),1.06–0.98(m,1H),0.91(s,9H),0.71(s,3H),0.09(d,J=7.6Hz,6H).

[0039] Characterization data of compound 4:

[0040] 1 HNMR(400MHz,CDCl3)δ5.75(s,1H),4.32–4.21(m,2H),3.49(s,1H),2.87–2.81(m,1H),2.48–2.29(m,6H),2.07–2.04(m,1H),1.95–1.55(m,9H),1.48–1.36(m,2H),,1.19(s,3H),1.16–1.13(m,4H),1.06–0.98(m,1H),0.69(s,3H).

Claims

1. Preparation of high-purity steroidal androgen receptor inhibitor 21-hydroxy-17-(propionate) pregnane-4-ene-3,20-dione (Compound 1), characterized in that: Prepared by the following reaction:

2. The synthesis method according to claim 1, characterized in that In the reaction, the deprotecting reagents are tetrabutylammonium fluoride, potassium fluoride, acetic acid, and 10% dilute hydrochloric acid.

3. The synthesis method according to claim 1, characterized in that The molar ratio of the compound 1 to the deprotecting agent is 1:1 to 1:

3.

4. The synthesis method according to claim 1, characterized in that The solvent in the reaction is at least one of tetrahydrofuran, ethyl acetate, toluene and acetonitrile.

5. The synthesis method according to claim 1, characterized in that The reaction temperature is room temperature.

6. The synthesis method according to claim 1, characterized in that Compound 3 was prepared by the following reaction:

7. The synthesis method according to claim 6, characterized in that The equivalent of tert-butyldimethylsilyl chloride in the reaction for synthesizing compound 3 is 1.0-1.3 equivalents.

8. The synthesis method according to claim 6, characterized in that The solvent in the reaction for synthesizing compound 3 is at least one of N,N-dimethylformamide and N,N-dimethylacetamide.

9. The synthesis method according to claim 6, characterized in that The reaction temperature in the reaction for synthesizing compound 3 is from room temperature to 60° C., and the reaction time is from 12 to 24 hours.

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