Process for the preparation of drospirenone 17-side chain intermediates

Abstract

The application discloses a preparation method of a drospirenone 17-position side chain intermediate, and the method is as follows: taking 3beta, 5-dihydroxy-6beta, 7beta, 15beta, 16beta-dimethylene-5beta-androstane-17-ketone shown in formula (II) as raw material, nucleophilic addition reaction of a structure 17-position carbonyl group and Grignard reagent obtains drospirenone intermediate 17alpha-(3-hydroxypropyl)-6beta, 7beta, 15beta, 16beta-dimethylene-5-beta-androstane-3beta, 5, 17beta-triol shown in formula (III), namely, the drospirenone 17-position side chain intermediate, and the reaction formula is as follows: the preparation method has the advantages of high efficiency, simple operation, low production cost, mild reaction condition, good reaction selectivity and the like.

Description

Technical Field

[0001] This invention relates to a method for preparing a drospirenone 17-position side chain intermediate, belonging to the field of pharmaceutical intermediate preparation technology. Background Technology

[0002] Drospirenone (Formula I), a derivative of 17α-spironolactone, is a fourth-generation progestin developed by Schering AG in Germany. It has progestin activity similar to natural progesterone and is used as a contraceptive and hormone replacement therapy for women. It can also prevent symptoms such as osteoporosis and hypertension in women. It has few side effects and is well tolerated. As a new generation of steroidal contraceptives with low toxicity, high efficacy, and few side effects, drospirenone is often used in combination with ethinylestradiol in clinical practice to form a combination tablet, namely drospirenone ethinylestradiol tablets, marketed as Yasmin. It is one of the best fourth-generation oral contraceptives currently available.

[0003]

[0004] Formula (III) 17α-(3-hydroxypropyl)-6β,7β,15β,16β-dimethylene-5β-androstane-3β,5,17β-triol is a key intermediate in the preparation of drospirenone. The main difficulty in synthesizing this intermediate lies in introducing a side chain structure at position 17. Currently reported synthetic routes are as follows: European patent EP0076189 discloses a method for introducing the side chain using propynyl alcohol, but propynyl alcohol is highly toxic and requires high-pressure catalytic hydrogenation, placing high demands on process conditions and equipment, making it unsuitable for industrial production. US patent US20160002284 discloses a method of first protecting the hydroxyl group in the introduced side chain structure with ethers, silane ethers, and acetals, and then removing the protecting group. This method is complex and costly. Summary of the Invention

[0005] The purpose of this invention is to provide a simple, efficient, safe and environmentally friendly method for preparing the 17-position side chain intermediate of drospirenone.

[0006] A method for preparing a drospirenone 17-position side chain intermediate specifically includes the following steps:

[0007] (1) 3-bromo-1-propanol, methyl magnesium bromide and an aprotic solvent are mixed and reacted to produce a solution of 3-bromopropane-1-ol magnesium bromide.

[0008] (2) The solution of 3-bromopropane-1-ol magnesium bromide obtained in step (1) is added dropwise to a mixture of metallic magnesium and aprotic organic solvent. An addition reaction is carried out under stirring to generate a Grignard reagent. Then, 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene-5β-androstan-17-one as shown in formula (II) is added to it to carry out a nucleophilic addition reaction. After the reaction is completed, the drospirenone intermediate 17α-(3-hydroxypropyl)-6β,7β,15β,16β-dimethylene-5β-androstan-3β,5,17β-triol as shown in formula (III) is obtained. This is the drospirenone 17-position side chain intermediate. Its reaction formula is as follows:

[0009]

[0010] Furthermore, the present invention also specifies that the molar ratio of methyl magnesium bromide to 3-bromo-1-propanol in step (1) is 1 to 1.5:1.

[0011] Furthermore, the present invention also specifies that the reaction in step (1) is carried out in a nitrogen atmosphere, the reaction temperature is -10 to 0°C, and the reaction time is 10 to 30 min.

[0012] Furthermore, the present invention specifies that the aprotic organic solvent in step (1) is one of the following: tetrahydrofuran or 2-methyltetrahydrofuran. The concentration of 3-bromo-1-propanol in the reaction system in step (1) is 0.2-1.0 mol / L.

[0013] Furthermore, the present invention further specifies that the molar ratio of 3-bromo-1-propanol in step (1) to metallic magnesium and 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene-5β-androstane-17-one shown in formula (II) in step (2) is (3.5-5):(7-10):1.

[0014] Furthermore, the present invention also specifies that both reactions in step (2) are carried out in a nitrogen atmosphere, the addition reaction temperature for preparing the Grignard reagent is 25-65℃, preferably 50-65℃, and the time is 1-2.5h; the nucleophilic addition reaction temperature is -5-10℃, preferably 0-5℃, and the time is 3-8h.

[0015] Furthermore, the present invention further specifies that the aprotic organic solvent in step (2) is one of the following: tetrahydrofuran, 2-methyltetrahydrofuran.

[0016] Furthermore, the present invention also defines the specific operational steps of the reaction in step (2):

[0017] S1: The mixture of metallic magnesium and aprotic organic solvent is first heated to 50-65℃ under nitrogen protection, and a few drops of 3-bromopropane-1-ol magnesium bromide solution are added dropwise. When bubbles begin to form on the surface of metallic magnesium, the reaction is initiated. At this time, the reaction system is moved to room temperature and stirred.

[0018] S2: Add the solution of magnesium bromide in 3-bromopropane-1-ol dropwise to the reaction system of step S1 again. After the addition is complete, heat the reaction solution to 50-65℃ and keep it at that temperature for 1-2.5 hours. Then, cool it to -5-10℃ after the reaction is complete and add 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene-5β-androstane-17-one as shown in formula (II) directly to it to carry out a nucleophilic addition reaction.

[0019] Furthermore, the present invention further specifies that the post-processing procedure involves adding ice water to the reaction system and stirring, extracting the reaction solution with ethyl acetate, washing with saturated brine, drying the organic layer with anhydrous sodium sulfate, concentrating it to dryness by vacuum distillation, and recrystallizing to obtain the target product.

[0020] Furthermore, the present invention also specifies that the solvent for recrystallization is selected from toluene, dichloromethane, chloroform, acetone or one or a mixture thereof.

[0021] Through the above-described techniques, the beneficial effects of this invention compared to existing technologies are as follows:

[0022] (1) The method for preparing the drospirenone 17-position side chain intermediate of the present invention is efficient, simple to operate, low in production cost, mild in reaction conditions and good in reaction selectivity.

[0023] (2) In the process of synthesizing the key intermediate of drospirenone, this invention requires the introduction of a three-carbon side chain, using 3-bromo-1-propanol as a raw material, which is low in cost and the first step reaction is simple. No initiator is required in the preparation of Grignard reagent, which reduces the generation of by-products, results in high reaction yield, and the preparation method is efficient; the raw materials are readily available and the production cost is low. Detailed Implementation

[0024] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0025] Example 1

[0026] (1) Under nitrogen protection, 3-bromo-1-propanol (974 mg, 7 mmol) and 10 ml of anhydrous tetrahydrofuran were added to a 50 ml reaction flask. After cooling to 0 °C, a tetrahydrofuran solution of methyl magnesium bromide with a concentration of 1 mol / L (7.3 ml, 7.3 mmol) was added. After the addition was complete, the mixture was stirred for 15 min to obtain a 3-bromopropane-1-ol magnesium bromide solution.

[0027] (2) The 3-bromopropane-1-ol magnesium bromide solution obtained in step (1) was added dropwise in two steps. In a separate 100 ml reaction flask, magnesium metal (336 mg, 14 mmol) and 8 ml of anhydrous tetrahydrofuran were added. Under nitrogen protection, the mixture was heated to 65 °C. 3–5 drops of the 3-bromopropane-1-ol magnesium bromide solution were added. When bubbles began to form on the surface of the magnesium metal, the reaction system was moved to room temperature and stirred. The remaining 3-bromopropane-1-ol magnesium bromide solution was then slowly added dropwise. After the addition was complete, the reaction mixture was kept at reflux temperature (approximately 65 °C) for 1 hour. The mixture was then cooled to 0–5 °C, and the 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene-5β- (as shown in formula (II)) was added. A 20 mL tetrahydrofuran solution of androstan-17-one (660 mg, 2 mmol) was added, and the reaction temperature was maintained at 0–2 °C with controlled dropping rate. The mixture was stirred for 4 h. After the reaction was complete, ice water was added to the reaction system and stirring was continued for 10 min. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and the organic layer was dried with anhydrous sodium sulfate. The crude product was concentrated by vacuum distillation and recrystallized with toluene to obtain 708 mg of the target product 17α-(3-hydroxypropyl)-6β,7β,15β,16β-dimethylene-5β-androstan-3β,5,17β-triol, with a yield of 90.6%. Its chemical structural formula is as follows:

[0028]

[0029] Characterization data: White solid, melting point: 186-188℃. 1 H NMR(400MHz,DMSO-d6)δ4.82(d,J=4.83Hz,1H),4.36(m,2H),4.12(s,1H),3.84(m,1H),3.4 2(m,2H),2.08(d,J=12.8Hz,1H),0.76(s,6H),1.82–0.60(22H),0.45(m,1H),0.15(m,1H); 13 C NMR(100MHz,DMSO-d6)δ81.1,73.2,67.2,66.4,64.2,62.5,53.2,44.1,42.8,40.4,36.9,34 .6,34.0,28.2,27.7,27.6,23.0,22.6,22.4,19.9,19.4,16.2,14.9,8.4; MS(ESI)m / z: Calcd for C 24 H 38 O4[M+Na] + 413.2667, found: 413.2668.

[0030] Example 2

[0031] (1) Under nitrogen protection, 3-bromo-1-propanol (9.74 g, 70 mmol) and 25 ml of anhydrous tetrahydrofuran were added to a 250 ml reaction flask. After cooling to 0 °C, a tetrahydrofuran solution of methyl magnesium bromide with a concentration of 1 mol / L (75 ml, 75 mmol) was added. After the addition was complete, the mixture was stirred for 30 min to obtain a 3-bromopropane-1-ol magnesium bromide solution.

[0032] (2) The 3-bromopropane-1-ol magnesium bromide solution obtained in step (1) is added dropwise in two steps. Take another 500ml reaction flask, add metallic magnesium (3.36g, 0.14mol), 20ml anhydrous tetrahydrofuran, purge with nitrogen, heat to 65℃, and add 6-10 drops of 3-bromopropane-1-ol magnesium bromide solution. When bubbles begin to form on the surface of the metallic magnesium, move the reaction system to room temperature and start stirring. Then continue to slowly add the remaining 3-bromopropane-1-ol magnesium bromide solution. After the addition is complete, keep the reaction solution at reflux temperature (i.e., about 65℃) for 2h, cool to 0-5℃, and then add 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene as shown in formula (II). An 80 mL tetrahydrofuran solution of 17α-(3-hydroxypropyl)-6β,7β,15β,16β-dimethylene-5β-androstane-3β,5,17β-triol was prepared. The reaction temperature was maintained at 0–2 °C by controlling the dropping rate. The mixture was stirred for 8 h. After the reaction was complete, ice water was added to the reaction system and stirring was continued for 10 min. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and the organic layer was dried with anhydrous sodium sulfate. The crude product was concentrated by vacuum distillation and recrystallized with toluene to obtain 7.1 g of the target product, 17α-(3-hydroxypropyl)-6β,7β,15β,16β-dimethylene-5β-androstane-3β,5,17β-triol, with a yield of 91.2%.

[0033] Example 3

[0034] The steps and methods of Example 1 were followed, except that the volume of the tetrahydrofuran solution of methyl magnesium bromide was increased in step (1) to make the molar ratio of methyl magnesium bromide to 3-bromo-1-propanol 1.5:1. The other operation steps were the same, and the target product 17α-(3-hydroxypropyl)-6β,7β,15β,16β-dimethylene-5β-androstane-3β,5,17β-triol 644 mg was finally obtained, with a yield of 82.4%.

[0035] Example 4

[0036] The steps and methods of Example 1 were followed, except that the amount of 3-bromo-1-propanol was increased in step (1) so that the molar ratio of 3-bromo-1-propanol to 3β,5-dihydroxy-6β,7β,15β,16β-dimethylene-5β-androstan-17-one in step (2) was 5:1. The other operating steps were the same, and 720 mg of the target product 17α-(3-hydroxypropyl)-6β,7β,15β,16β-dimethylene-5β-androstan-3β,5,17β-triol was obtained with a yield of 92.3%.

[0037] Example 5.

[0038] Following the steps and methods of Example 1, the only difference was that the solvent tetrahydrofuran in the entire system of steps (1)-(2) was replaced with an equal volume of 2-methyltetrahydrofuran. The other operating steps were the same, and 698 mg of the target product 17α-(3-hydroxypropyl)-6β,7β,15β,16β-dimethylene-5β-androstane-3β,5,17β-triol was obtained, with a yield of 89.4%.

[0039] Example 6

[0040] Following the steps and methods of Example 1, the only difference being that the nucleophilic addition reaction temperature in step (2) was increased to 10°C, while the other operating steps were the same, 610 mg of the target product 17α-(3-hydroxypropyl)-6β,7β,15β,16β-dimethylene-5β-androstane-3β,5,17β-triol was obtained, with a yield of 78.1%.

[0041] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.

Claims

1. A method for preparing a drospirenone 17-position side chain intermediate, characterized in that... The drospirenone 17-position side chain intermediate is a compound represented by formula (III), and its preparation method specifically includes the following steps: (1) 3-bromo-1-propanol, methyl magnesium bromide and an aprotic solvent are mixed and reacted to produce a solution of 3-bromopropane-1-ol magnesium bromide; (2) The solution of 3-bromopropane-1-ol magnesium bromide obtained in step (1) was added dropwise to a mixture of metallic magnesium and aprotic organic solvent. An addition reaction was carried out under stirring to generate a Grignard reagent. Then, the compound shown in formula (II) was added to the mixture to carry out a nucleophilic addition reaction. After the reaction was completed, the drospirenone 17-side chain intermediate shown in formula (III) was obtained after post-treatment. The reaction formula is as follows: 。 2. The method for preparing the drospirenone 17-position side chain intermediate according to claim 1, characterized in that... In step (1), the molar ratio of methyl magnesium bromide to 3-bromo-1-propanol is 1 to 1.5:

1.

3. The method for preparing the drospirenone 17-position side chain intermediate according to claim 1, characterized in that... In step (1), the reaction is carried out in a nitrogen atmosphere, the temperature is -10 to 0℃, and the reaction time is 10 to 30 min.

4. The method for preparing the drospirenone 17-position side chain intermediate according to claim 1, characterized in that... In step (1), the aprotic organic solvent is one of the following: tetrahydrofuran or 2-methyltetrahydrofuran; the concentration of 3-bromo-1-propanol in the reaction system in step (1) is 0.2-1.0 mol / L.

5. The method for preparing the drospirenone 17-position side chain intermediate according to claim 1, characterized in that... In step (1), the molar ratio of 3-bromo-1-propanol to magnesium metal and the compound represented by formula (II) in step (2) is (3.5~5):(7~10):

1.

6. The method for preparing the drospirenone 17-position side chain intermediate according to claim 1, characterized in that... In step (2), both reactions are carried out in a nitrogen atmosphere. The addition reaction temperature for preparing the Grignard reagent is 25~65℃ and the reaction time is 1~2.5 h. The nucleophilic addition reaction temperature is -5~10℃ and the reaction time is 3~8 h.

7. The method for preparing the drospirenone 17-position side chain intermediate according to claim 1, characterized in that... In step (2), the aprotic organic solvent is one of the following: tetrahydrofuran or 2-methyltetrahydrofuran.

8. The method for preparing the drospirenone 17-position side chain intermediate according to any one of claims 1-7, characterized in that... The post-processing procedure is as follows: ice water is added to the reaction system and stirred. The reaction solution is extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated to dryness by vacuum distillation, and recrystallized to obtain the target product.

9. The method for preparing the drospirenone 17-position side chain intermediate according to claim 8, characterized in that... The solvent used for recrystallization is selected from one or more mixed solvents selected from toluene, dichloromethane, chloroform, and acetone.

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