A method for the synthesis of 5alpha-androst-2-ene-17-one

Abstract

The application discloses a synthesis method of 5alpha-androsta-2-ene-17-one. The application provides a preparation method of 5alpha-androsta-2-ene-17-one as shown in formula I, and the method is characterized in that the method comprises the following steps: in the presence of a proton base, triphenylphosphine and dimethyl azodicarboxylate (DEAD), androsterone is subjected to an elimination reaction in a solvent to obtain 5alpha-androsta-2-ene-17-one as shown in formula I. The preparation method has the advantages of less isomer impurities, simple post-treatment, cheap raw materials, mild reaction conditions, less damage to the environment and the like, and can be used for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing 5alpha-androst-2-ene-17-one. BACKGROUND

[0002] The present application relates to a key intermediate in the synthesis of skeletal muscle relaxants rocuronium, vecuronium, pancuronium and pipecuronium. With the increasing market competition, the production cost of skeletal muscle relaxants is particularly important. In the whole production process, on the basis of the similar follow-up process, the content of isomer impurity 5alpha-androst-3-ene-17-one in 5alpha-androst-2-ene-17-one is crucial to the process yield of the whole skeletal muscle relaxant drug substance, and plays a decisive role in controlling the production cost.

[0003] 5alpha-androst-2-ene-17-one, CAS No.: 963-75-7, structural formula as follows I:

[0004]

[0005] 5alpha-androst-3-ene-17-one, CAS No.: 14935-81-0, structural formula as follows II:

[0006]

[0007] The main technical scheme in the existing literature is to take epiandrosterone as raw material, first sulfonated by p-toluenesulfonyl chloride to get epiandrosterone p-toluenesulfonic acid ester, and then eliminate reaction in 2-methylpyridine / 2,6-dimethylpyridine at 90~100℃, concentrate to remove the solvent, and add water to crystallize. Through two-step reaction, compound I is obtained. We also use these schemes for production, and the product obtained contains a large amount of isomer impurity II (about 30%).

[0008] Patent CN101058598 takes epiandrosterone as raw material, first loads p-toluenesulfonic acid on silica gel to prepare catalyst, and then gets compound I by reflux dehydration in solvent benzene. In this preparation process, benzene is used, which is toxic and not friendly to the environment, and is not suitable for industrialization.

[0009] Patent CN109678918 takes epiandrosterone as raw material, and gets compound I by high-temperature decolorization under the catalysis of protonic acid and lanthanum triflate or ytterbium triflate. The triflate used in this scheme is expensive, which is not conducive to cost control and is not suitable for industrial production. It also does not mention the residual situation of isomer impurities.

[0010] Patent CN113637043 uses epiandrosterone as a raw material, reacts with p-dodecylbenzenesulfonyl chloride under the action of a catalyst to generate a sulfonic acid ester, then eliminates in a 2-methylpyridine system at a high temperature of 110-130℃, and after recrystallization purification, a compound of formula I is obtained, with a purity of 90%, and 5-7% of isomer II. In this scheme, p-dodecylbenzenesulfonyl chloride reduces the atomic utilization efficiency compared with benzenesulfonyl chloride, and needs to be recrystallized once, and the purity of the obtained product is also low.

[0011] Therefore, in order to solve the problems of excessive isomer impurities in 5α-androst-2-ene-17-one, harsh reaction conditions, and expensive catalysts in the prior art, there is an urgent need in the field to develop a simple, economical, and mild reaction condition method to prepare 5α-androst-2-ene-17-one with higher purity. SUMMARY

[0012] The technical problem to be solved by the present application is that the existing preparation method of 5α-androst-2-ene-17-one has the defects of excessive isomer impurities, expensive catalysts, and harsh reaction conditions, and a preparation method of 5α-androst-2-ene-17-one is provided. The preparation method produces less isomer impurities, the post-treatment is simple, the raw materials used are bulk commodities, the price is cheap, the reaction conditions are mild, the damage to the environment is small, and it can be used for industrial production.

[0013] The present application provides a preparation method of 5α-androst-2-ene-17-one as shown in formula I, which comprises the following steps: in the presence of a proton base, triphenylphosphine, and dimethyl azodicarboxylate (DEAD), epiandrosterone undergoes an elimination reaction to obtain 5α-androst-2-ene-17-one as shown in formula I;

[0014] .

[0015] The solvent can be a solvent commonly used in the field for such an elimination reaction, and can be selected from one or more of an ether solvent, a halogenated alkane solvent, and an aromatic hydrocarbon solvent, for example, an ether solvent or a halogenated alkane solvent.

[0016] The ether solvent is, for example, tetrahydrofuran and / or dioxane; the halogenated alkane solvent is, for example, dichloromethane; and the aromatic hydrocarbon solvent is, for example, toluene.

[0017] The solvent can be tetrahydrofuran or dichloromethane.

[0018] The volume-to-mass ratio of the solvent to epiandrosterone can be a volume-to-mass ratio commonly used in the field for such an elimination reaction, for example, 2-10 ml / g, and for example, 5 ml / g.

[0019] The proton base can be one or more selected from the group consisting of sodium hydride, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (triethylenediamine) and potassium tert-butoxide, for example, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DABCO (triethylenediamine).

[0020] The molar ratio of epiandrosterone to the proton base can be 1: (1-2), for example, 1: (1.2-1.5).

[0021] The molar ratio of epiandrosterone to triphenylphosphine can be 1: (1-3), for example, 1:1.5 or 1:1.8.

[0022] The molar ratio of epiandrosterone to dimethyl azodicarboxylate can be 1: (1-3), for example, 1:1.5 or 1:1.8.

[0023] The reaction temperature of the elimination reaction can be -4-30°C, for example, 0-20°C, and further for example, 0-10°C.

[0024] The reaction time of the elimination reaction can be the reaction time of the elimination reaction in the art, which can be 8-30h, for example, 12-20h, and further for example, 16h, 18h or 20h.

[0025] The preparation method can comprise the following steps: mixing the solvent, epiandrosterone, proton base and triphenylphosphine, cooling to 0-10°C, and then adding dimethyl azodicarboxylate for reaction.

[0026] The raw materials of the preparation method can consist of the solvent, epiandrosterone, proton base, triphenylphosphine and dimethyl azodicarboxylate. The elimination reaction can be further treated by washing, extraction, concentration and slurry after the reaction is completed; the washing solvent can be dichloromethane and water; the extraction solvent can be dichloromethane; and the slurry solvent can be ethanol.

[0027] On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, thereby obtaining each preferred example of the present application.

[0028] The reagents and raw materials used in the present application are commercially available.

[0029] The positive progress effect of the present application is that:

[0030] The preparation method of 5 alpha -androst-2-ene-17-ketone provided by the application has better selectivity, less isomer impurities, high product yield and high purity (including HPLC purity and reverse chiral purity); only one step reaction is needed, the reaction condition is mild, high-temperature reaction is avoided, the reaction can be carried out at low temperature; and the post-treatment is simple, the raw materials used are bulk commodities, the price is cheap, the damage to the environment is small, and the method can be used for industrial production. DETAILED DESCRIPTION

[0031] The application will be further described by way of examples, but the application is not limited to the scope of the examples. In the following examples, the experimental methods not specified in the specific conditions are selected according to the conventional methods and conditions or according to the instructions of the commercial products.

[0032] The analysis method related to the application is as follows:

[0033]

[0034] The reverse chiral detection method of the isomer impurity of formula II is as follows:

[0035]

[0036] Example 1

[0037] A 1000L three-necked reaction flask was added with epiandrosterone (50g, 0.172mol), dichloromethane (250ml), triphenylphosphine (67.7g, 0.258mol) and DBU (31.4g, 0.206mol), and stirring was started, and the temperature was lowered to 0-10℃. Then DEAD (44.9g, 0.258mol) was slowly added at 0-10℃, and after the dropwise addition was completed, the reaction was carried out at 0-10℃ for 20h, and HPLC tracking detection was carried out until epiandrosterone was completely consumed. After the reaction was completed, dichloromethane (350ml) and water (250ml) were added to the reaction system, and stirring and liquid separation were carried out. The water phase was further extracted with dichloromethane (150ml), and the organic phases were combined and washed with water (250ml). Dichloromethane was removed by concentration, ethanol (100ml) was added to the residue, and the slurry was dispersed at room temperature, and then filtered and rinsed. Dry white solid 5 alpha -androst-2-ene-17-ketone 43.7g was obtained, the molar yield was 93.4%, the HPLC purity was 99.33%, and the reverse chiral purity was 99.44% (the isomer impurity of formula II was 0.56%).

[0038] Example 2

[0039] Into a 500 mL three-necked flask, add epiandrosterone (20 g, 68.8 mmol), tetrahydrofuran (100 mL), triphenylphosphine (32.5 g, 124.0 mmol) and DABCO (11.6 g, 103.2 mmol), start stirring, and cool to 0-10 °C. Then slowly add DEAD (21.6 g, 124.0 mmol) dropwise at 0-10 °C, and keep the temperature at 0-10 °C for 16 h after the addition. HPLC tracking detection is performed until epiandrosterone is completely consumed. After the reaction is completed, dichloromethane (150 mL) and water (100 mL) are added to the reaction system, and the mixture is stirred and separated. The aqueous phase is extracted with dichloromethane (100 mL), and the organic phases are combined and washed with water (100 mL). The dichloromethane is removed by concentration, and ethanol (50 mL) is added to the residue. The mixture is dispersed by stirring at room temperature, filtered, and rinsed. The white solid is dried to obtain 5 -androsta-2-ene-17-one, 17.1 g, a molar yield of 91.2%, an HPLC purity of 98.87%, and an enantiomeric purity of 99.18% (isomer impurity of formula II 0.82%).

[0040] Example 3

[0041] Into a 500 mL three-necked flask, add epiandrosterone (20 g, 68.8 mmol), tetrahydrofuran (100 mL), triphenylphosphine (27.1 g, 103.2 mmol) and DBU (15.7 g, 103.2 mmol), start stirring, and cool to 0-20 °C. Then slowly add DEAD (18.0 g, 103.2 mmol) dropwise at 0-20 °C, and keep the temperature at 0-20 °C for 20 h after the addition. HPLC tracking detection is performed until epiandrosterone is completely consumed. After the reaction is completed, dichloromethane (150 mL) and water (100 mL) are added to the reaction system, and the mixture is stirred and separated. The aqueous phase is extracted with dichloromethane (100 mL), and the organic phases are combined and washed with water (100 mL). The dichloromethane is removed by concentration, and ethanol (50 mL) is added to the residue. The mixture is dispersed by stirring at room temperature, filtered, and rinsed. The white solid is dried to obtain 5 -androsta-2-ene-17-one, 17.4 g, a molar yield of 92.8%, an HPLC purity of 99.1%, and an enantiomeric purity of 99.25% (isomer impurity of formula II 0.75%).

[0042] Example 4

[0043] 50 L reactor was charged with epiandrosterone (1.5 Kg, 5.16 mol), dichloromethane (7.5 L), triphenylphosphine (2.03 Kg, 7.74 mol) and DBU (0.94 Kg, 6.2 mol), and stirring was started. The temperature was lowered to 0-10 °C. Then DEAD (1.35 Kg, 7.74 mol) was slowly added at 0-10 °C. After the addition was completed, the reaction was maintained at 0-10 °C for 18 h. HPLC tracking detection was performed until the epiandrosterone was completely consumed. After the reaction was completed, dichloromethane (10.5 L) and water (7.5 L) were added to the reaction system, and the mixture was stirred and separated. The water phase was extracted with dichloromethane (5 L), and the organic phases were combined and washed with water (7.5 L). Dichloromethane was removed by concentration, and ethanol (3 L) was added to the residue. The mixture was dispersed at room temperature, filtered and rinsed. The white solid 5 -androsta-2-ene-17-one was obtained by drying, with a molar yield of 94.7%, an HPLC purity of 99.62%, and an enantiomeric purity of 99.37% (0.63% of isomer impurities of formula II). 1 HNMR (CDCI3): δH= 0.76 (1H, m), 0.78 (3H, s), 0.87 (3H, s), 0.91-1.02 (1H, m), 1.17 (1H, m), 1.19 (1H, m), 1.36 (1H, m), 1.38 (1H, m), 1.44 (2H, m), 1.45 (2H, m), 1.55 (2H, m), 1.57 (1H, m), 1.68 (1H, m), 1.78 (2H, m), 1.79 (2H, m), 2.02-2.13 (1H, m), 2.38-2.48 (1H, m), 5.55-5.63 (2H, m).

[0044] Comparative Example 1

[0045] A 500 mL three-necked reaction flask was charged with epiandrosterone (30 g, 0.103 mol), dichloromethane (60 ml) and pyridine (32.7 g, 0.413 mol), and stirring was started while the temperature was lowered to 0-30 °C. p-Toluenesulfonic acid chloride (29.4 g, 0.155 mol) was added, and the reaction was maintained at 20-30 °C for 6 h until the epiandrosterone was completely converted. After the reaction was completed, dichloromethane (120 ml) was added, and 10% sodium bicarbonate solution (120 ml) was added dropwise. The mixture was extracted and separated, and the organic phase was washed with water. Dichloromethane was concentrated, and ethanol was added to the mixture. The mixture was filtered and rinsed. The epiandrosterone p-toluenesulfonate was obtained by drying, with a molar yield of 92.1%.

[0046] Take epiandrosterone p-toluenesulfonic acid ester (28.0 g, 0.063 mol) and 2-methylpyridine (40.0 g) into a reaction bottle, and heat to 95-100°C for 48 h until the reaction is completed. Concentrate to remove 2-methylpyridine, slowly add water (60 ml), and drop in dilute sulfuric acid to adjust the system pH to 5-6. Cool to 10-20°C, and stir for 12 h. Filter, and rinse with water. Dry to obtain off-white 5α-androsta-2-ene-17-one 15.1 g, with a molar yield of 88.1%, HPLC purity of 98.3%, and reverse chiral purity of 68.31% (isomer impurity of formula II 31.69%).

[0047] Comparative Example 2

[0048] Take epiandrosterone (30 g, 0.103 mol), anhydrous phosphorus pentoxide (16.1 g, 0.11 mol), methane sulfonic acid (15.8 g, 0.165 mol), and dichloromethane (300 ml) into a 1L reaction bottle. Start stirring, and heat to reflux for 17 h. Cool the reaction liquid to room temperature, add water (500 ml) and dichloromethane (200 ml), stir and separate, wash the organic phase twice with 5% sodium bicarbonate solution (250 ml), and purify with water (250 ml) twice. Dry with anhydrous sodium sulfate, filter, and concentrate to dryness to obtain off-white 5α-androsta-2-ene-17-one 23.9 g, with a molar yield of 85.3%, HPLC purity of 93.8%, and reverse chiral purity of 93.2% (isomer impurity of formula II 6.8%).

[0049] Comparative Example 3

[0050] Take epiandrosterone (20 g, 68.8 mmol), triethylamine (13.9 g, 137.6 mol), and dichloromethane (80 ml) into a 500 ml reaction bottle, and start stirring. Add DMAP (3 g), control the temperature to 0-25°C, slowly add p-dodecylbenzenesulfonyl chloride (35.6 g, 103.2 mmol), control the temperature to 30-40°C for 12 h until the epiandrosterone is completely reacted, concentrate, and slurry in ethanol. Dry to obtain epiandrosterone p-dodecylbenzenesulfonic acid ester 39.5 g.

[0051] 250ml reaction bottle is added epichlorohydrin (38.5g, 61.2mmol) and 2-methylpyridine (60g). Heating to 110°C for 68h until the reaction is complete, concentrated to remove 2-methylpyridine, slowly add water (80ml), drop in dilute sulfuric acid to adjust pH = 5~6, cooling filtration, to obtain 5 α -androst-2-ene-17-ketone crude product. The crude product is treated with 95% methanol (100ml) hot slurry, cooling 0~10℃, 4h, stirring, filtration, ethanol rinse. After drying, white 5 α -androst-2-ene-17-ketone pure product 13.5g, molar yield 81.7%. HPLC purity 99.28%, enantiomeric purity 82.3% (isomer impurities 17.7% of formula II).

Claims

1. A process for the preparation of 5α-androst-2-ene-17-one as shown in formula I, characterized in that, It comprises the following steps: In the solvent, in the presence of a proton base, triphenylphosphine, dimethyl azodicarboxylate, epieondrosterone undergoes an elimination reaction to obtain 5α-androst-2-ene-17-one as shown in formula I; The solvent is tetrahydrofuran or dichloromethane; The proton base is 1,8-diazabicyclo[5.4.0]undec-7-ene or triethylenediamine.

2. The process for the preparation of 5α-androst-2-ene-17-one according to claim 1, of the formula I, characterized in that, It meets one or more of the following conditions: (1) The volume-mass ratio of the solvent to epieondrosterone is 2-10 ml / g; (2) The molar ratio of epieondrosterone to proton base is 1:(1-2); (3) The molar ratio of epieondrosterone to triphenylphosphine is 1:(1-3); (4) The molar ratio of epieondrosterone to dimethyl azodicarboxylate is 1:(1-3); (5) The reaction temperature of the elimination reaction is -4℃-30℃; (6) The reaction time of the elimination reaction is 8-30h.

3. The method for preparing 5α-androst-2-en-17-one as shown in Formula I according to claim 2, characterized in that, It meets one or more of the following conditions: (1) The volume-mass ratio of the solvent to epieondrosterone is 5 ml / g; (2) The molar ratio of epieondrosterone to proton base is 1:(1.2-1.5); (3) The molar ratio of epieondrosterone to triphenylphosphine is 1:1.5 or 1:1.8; (4) The molar ratio of epieondrosterone to dimethyl azodicarboxylate is 1:1.5 or 1:1.8; (5) The reaction temperature of the elimination reaction is 0-20℃; (6) The reaction time of the elimination reaction is 12-20h.

4. The method for preparing 5α-androst-2-en-17-one as shown in Formula I according to claim 2, characterized in that, The reaction temperature of the elimination reaction is 0-10℃.

5. The method for preparing 5α-androst-2-en-17-one as shown in Formula I according to claim 2, characterized in that, The reaction time of the elimination reaction is 16h, 18h or 20h.

6. The method for preparing 5α-androst-2-en-17-one as shown in Formula I according to claim 1, characterized in that, It comprises the following steps: After mixing the solvent, epieondrosterone, proton base and triphenylphosphine, cooling to 0-10℃, dimethyl azodicarboxylate is added for reaction.

7. The method for preparing 5α-androst-2-en-17-one as shown in Formula I according to claim 1, characterized in that, The raw materials of the preparation method consist of the solvent, epieondrosterone, proton base, triphenylphosphine and dimethyl azodicarboxylate.

Images