Synthesis method of 5 alpha-androstane-2-ene-17-ketone

Abstract

The invention discloses a synthesis method of 5 [alpha]-androstane-2-ene-17-ketone. The 5 [alpha]-androstane-2-ene-17-ketone is used as a The invention provides a preparation method of 5 alpha-androstane-2-ene-17-ketone as shown in a formula I. The preparation method is characterized by comprising the following step: in a solvent, in the presence of proton base, triphenylphosphine and dimethyl azodicarboxylate (DEAD), epiandrosterone is subjected to an elimination reaction, and the 5 alpha-androstane-2-ene-17-ketone as shown in the formula I is obtained. The isomer produced by the preparation method provided by the invention is few in impurities, simple in post-treatment, low in price, mild in reaction condition and less in environmental damage, and the preparation method can be used for industrial production, and the used raw materials are bulk commodities. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for synthesizing 5α-androst-2-ene-17-one. Background Art

[0002] The present invention relates to a compound which is a key intermediate in the synthesis process of skeletal muscle relaxants rocuronium bromide, vecuronium bromide, pancuronium bromide and pipecuronium bromide. With the increase of market competition, the production cost of skeletal muscle relaxants is particularly important. In the whole production process, on the basis of the similarity of the subsequent processes, the content of the isomeric impurity 5α-androst-3-ene-17-one in 5α-androst-2-ene-17-one is crucial to the process yield of the whole skeletal muscle relaxant raw material, and plays a decisive role in the control of production costs.

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

[0004]

[0005] 5α-androst-3-ene-17-one, CAS number: 14935-81-0, structural formula as follows Ⅱ:

[0006]

[0007] The main technical schemes in the existing literature are to use epiandrosterone as the raw material, firstly sulfonylate epiandrosterone p-toluenesulfonate through p-toluenesulfonyl chloride, p-toluenesulfonate is eliminated in 2-methylpyridine / 2,6-dimethylpyridine at 90-100°C, concentrated to remove the solvent, and add water for crystallization. The compound of formula I is obtained through two-step reaction. We also use these schemes for production, and the obtained product will contain a large amount of isomeric impurities of formula II (about 30%).

[0008] Patent CN101058598 uses epiandrosterone as a raw material, first loads p-toluenesulfonic acid on silica gel to prepare a catalyst, and then refluxes and dehydrates in solvent benzene to obtain the compound of formula I. This solution uses benzene in the preparation process, which is highly toxic and very unfriendly to the environment, and is not suitable for industrialization.

[0009] Patent CN109678918 uses epiandrosterone as a raw material, and decolorizes at high temperature under the catalysis of protonic acid and lanthanum trifluoromethanesulfonate or ytterbium trifluoromethanesulfonate to obtain the compound of formula I. The trifluoromethanesulfonate used in this scheme is expensive, which is not conducive to cost control and is not suitable for industrial production. There is no mention of the residual isomer impurities.

[0010] Patent CN113637043 uses epiandrosterone as a raw material, reacts with p-dodecylbenzenesulfonyl chloride under the action of a catalyst to generate sulfonic acid esters, and then eliminates the reaction at a high temperature of 110-130°C in a 2-methylpyridine system, and then obtains a compound of formula I after recrystallization and purification, with a purity of 90%, which contains 5-7% of formula II isomers. In this scheme, p-dodecylbenzenesulfonyl chloride has lower atomic utilization efficiency than benzenesulfonyl chloride, and requires one more crystallization, and the purity of the obtained product is also low.

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

[0012] The technical problem to be solved by the present invention is that the existing preparation method of 5α-androst-2-ene-17-one has defects such as too high isomer impurities, expensive catalysts, and mild reaction conditions, and provides a preparation method of 5α-androst-2-ene-17-one. The preparation method of the present invention produces less isomer impurities, simple post-treatment, the raw materials used are all 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 invention provides a method for preparing 5α-androst-2-en-17-one as shown in formula I, which comprises the following steps: in a solvent, in the presence of a proton base, triphenylphosphine and dimethyl azodicarboxylate (DEAD), epiandrosterone undergoes an elimination reaction to obtain 5α-androst-2-en-17-one as shown in formula I;

[0014] .

[0015] The solvent may be a conventional solvent for this type of elimination reaction in the art, and may be selected from one or more of ether solvents, halogenated alkane solvents and aromatic hydrocarbon solvents, for example, ether solvents or halogenated alkane solvents.

[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 may be tetrahydrofuran or dichloromethane.

[0018] The volume-to-mass ratio of the solvent to epiandrosterone may be a conventional volume-to-mass ratio for this type of elimination reaction in the art, such as 2-10 ml / g, and another example is 5 ml / g.

[0019] The proton base can be a conventional proton base for this type of elimination reaction in the art, and can be selected from one or more of sodium hydrogen sulfide, 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), DABCO (triethylenediamine).

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

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

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

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

[0024] The reaction time of the elimination reaction may be the conventional reaction time of this type of elimination reaction in the art, which may be 8 to 30 hours, for example 12 to 20 hours, and for example 16 hours, 18 hours or 20 hours.

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

[0026] The raw materials of the preparation method can be composed of the solvent, epiandrosterone, proton base, triphenylphosphine and dimethyl azodicarboxylate. After the elimination reaction is completed, the post-treatment can be carried out through washing, extraction, concentration and pulping steps; the washing solvent can be dichloromethane and water; the extraction solvent can be dichloromethane; the pulping solvent can be ethanol.

[0027] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

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

[0029] The positive and progressive effects of the present invention are:

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

[0031] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0032] The present invention relates to an analytical method, wherein the HPLC purity detection method is as follows:

[0033] .

[0035] The reverse phase chiral detection method of the isomeric impurities of formula II is as follows:

[0036] .

[0038] Example 1

[0039] Add epiandrosterone (50g, 0.172mol), dichloromethane (250ml), triphenylphosphine (67.7g, 0.258mol) and DBU (31.4g, 0.206mol) to a 1000L three-necked reaction flask, start stirring, and cool to 0~10℃. Then slowly add DEAD (44.9g, 0.258mol) at 0~10℃, keep the temperature at 0~10℃ for 20h, and follow up with HPLC until epiandrosterone is completely consumed. After the reaction is completed, add dichloromethane (350ml) and water (250ml) to the reaction system, stir and separate. The aqueous phase is continuously extracted with dichloromethane (150ml), the organic phase is combined, and the organic phase is washed with water (250ml). Concentrate to remove dichloromethane, add ethanol (100ml) to the residue, slurry and disperse at room temperature, filter and rinse. After drying, 43.7 g of white solid 5 α -androst-2-en-17-one was obtained with a molar yield of 93.4%, a HPLC purity of 99.33%, and a reverse phase chiral purity of 99.44% (0.56% of the isomer impurity of Formula II).

[0040] Example 2

[0041] Add epiandrosterone (20g, 68.8mmol), tetrahydrofuran (100ml), triphenylphosphine (32.5g, 124.0mmol) and DABCO (11.6g, 103.2mmol) to a 500mL three-necked reaction bottle, start stirring, and cool to 0~10℃. Then slowly add DEAD (21.6g, 124.0mmol) at 0~10℃, keep the temperature at 0~10℃ for 16h, and follow up with HPLC until epiandrosterone is completely consumed. After the reaction is completed, add dichloromethane (150ml) and water (100ml) to the reaction system, stir and separate. The aqueous phase is continuously extracted with dichloromethane (100ml), the organic phase is combined, and the organic phase is washed with water (100ml). Concentrate to remove dichloromethane, add ethanol (50ml) to the residue, slurry and disperse at room temperature, filter and rinse. After drying, 17.1 g of white solid 5 α -androst-2-en-17-one was obtained with a molar yield of 91.2%, a HPLC purity of 98.87%, and a reverse phase chiral purity of 99.18% (0.82% of the isomer impurity of Formula II).

[0042] Example 3

[0043] Add epiandrosterone (20g, 68.8mmol), tetrahydrofuran (100ml), triphenylphosphine (27.1g, 103.2mmol) and DBU (15.7g, 103.2mmol) to a 500mL three-necked reaction bottle, start stirring, and cool to 0~20℃. Then slowly add DEAD (18.0g, 103.2mmol) at 0~20℃, keep the temperature at 0~20℃ for 20h, and follow up with HPLC until epiandrosterone is completely consumed. After the reaction is completed, add dichloromethane (150ml) and water (100ml) to the reaction system, stir and separate. The aqueous phase is continuously extracted with dichloromethane (100ml), the organic phase is combined, and the organic phase is washed with water (100ml). Concentrate to remove dichloromethane, add ethanol (50ml) to the residue, slurry and disperse at room temperature, filter and rinse. After drying, 17.4 g of white solid 5 α -androst-2-en-17-one was obtained with a molar yield of 92.8%, a HPLC purity of 99.1%, and a reverse phase chiral purity of 99.25% (0.75% of the isomer impurity of Formula II).

[0044] Example 4

[0045] Add epiandrosterone (1.5Kg, 5.16mol), dichloromethane (7.5L), triphenylphosphine (2.03Kg, 7.74mol) and DBU (0.94Kg, 6.2mol) to a 50L reactor, start stirring, and cool to 0~10℃. Then slowly add DEAD (1.35Kg, 7.74mol) at 0~10℃, keep the temperature at 0~10℃ for 18h, and follow up with HPLC until epiandrosterone is completely consumed. After the reaction is completed, add dichloromethane (10.5L) and water (7.5L) to the reaction system, stir and separate. The aqueous phase is continuously extracted with dichloromethane (5L), the organic phases are combined, and the organic phases are washed with water (7.5L). Concentrate to remove dichloromethane, add ethanol (3L) to the residue, slurry and disperse at room temperature, filter and rinse. After drying, 1.33 kg of white solid 5 α -androst-2-en-17-one was obtained with a molar yield of 94.7%, a HPLC purity of 99.62%, and a reverse phase chiral purity of 99.37% (0.63% of the isomer impurity of Formula II). 1 HNMR (CDCl3): 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).

[0046] Comparative Example 1

[0047] Add epiandrosterone (30g, 0.103mol), dichloromethane (60ml) and pyridine (32.7g, 0.413mol) to a 500mL three-necked reaction bottle, start stirring and cool to 0~30℃. Add p-toluenesulfonic acid chloride (29.4g, 0.155mol), keep warm at 20~30℃ and stir for 6h until epiandrosterone is completely converted. After the reaction is completed, add dichloromethane (120ml), add 10% sodium bicarbonate solution (120ml) dropwise, extract and separate, and wash the organic phase with water. Concentrate dichloromethane, pulp with ethanol, filter and rinse. Dry to obtain 42.2g of epiandrosterone p-toluenesulfonate with a molar yield of 92.1%.

[0048] Add epiandrosterone p-toluenesulfonate (28.0 g, 0.063 mol) and 2-methylpyridine (40.0 g) to the reaction bottle, heat to 95-100 ° C and react for 48 hours until the reaction is completed. Concentrate to remove 2-methylpyridine, slowly add water (60 ml), and drop dilute sulfuric acid to adjust the system pH to 5-6. Cool to 10-20 ° C, keep warm and stir, filter, and rinse with water. Dry to obtain 15.1 g of off-white 5 α -androst-2-ene-17-one, with a molar yield of 88.1%, HPLC purity of 98.3%, and reverse chiral purity of 68.31% (31.69% of isomer impurities of formula II).

[0049] Comparative Example 2

[0050] Add epiandrosterone (30g, 0.103mol), anhydrous phosphorus pentoxide (16.1g, 0.11mol), methanesulfonic acid (15.8g, 0.165mol) and dichloromethane (300ml) to a 1L reaction bottle. Turn on stirring and heat to reflux for 17h. Bring the reaction solution to room temperature, add water (500ml) and dichloromethane (200ml), stir and separate, wash the organic phase twice with 5% sodium bicarbonate solution (250ml), and wash twice with purified water (250ml). Dry over anhydrous sodium sulfate, filter, concentrate and dry to obtain 23.9g of off-white 5 α -androst-2-ene-17-one, with a molar yield of 85.3%. HPLC purity is 93.8%, and reverse chiral purity is 93.2% (6.8% impurity of isomer of formula II).

[0051] Comparative Example 3

[0052] Add epiandrosterone (20 g, 68.8 mmol), triethylamine (13.9 g, 137.6 mol) and dichloromethane (80 ml) to 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 and react for 12 h until the epiandrosterone reacts completely, concentrate, ethanol slurry, and dry to obtain 39.5 g of epiandrosterone p-dodecylbenzenesulfonate.

[0053] Add epiandrosterone p-dodecylbenzenesulfonate (38.5 g, 61.2 mmol) and 2-methylpyridine (60 g) to a 250 ml reaction bottle. Heat to 110 ° C for 68 h until the reaction is completed, concentrate to remove 2-methylpyridine, slowly add water (80 ml), add dilute sulfuric acid to adjust the pH value to 5-6, cool and filter to obtain crude 5 α -androst-2-ene-17-one. The crude product was hot-beaten with 95% methanol (100 ml), cooled to 0-10 ° C, stirred for 4 h, filtered, and rinsed with ethanol. After drying, 13.5 g of off-white pure 5 α -androst-2-ene-17-one was obtained with a molar yield of 81.7%. HPLC purity was 99.28%, and reverse phase chiral purity was 82.3% (17.7% of isomer impurities of formula II).

Claims

1. A method for preparing 5α-androst-2-ene-17-one as shown in formula I, characterized in that: It includes the following steps: In a solvent, in the presence of a proton base, triphenylphosphine, and dimethyl azodicarboxylate, epiandrosterone undergoes an elimination reaction to obtain 5α-androst-2-en-17-one as shown in formula I; 。 2. The method for preparing 5α-androst-2-ene-17-one as shown in formula I according to claim 1, characterized in that: The proton base is selected from one or more of sodium hydride, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine and potassium tert-butoxide.

3. The method for preparing 5α-androst-2-ene-17-one as shown in formula I according to claim 2, characterized in that: The proton base is 1,8-diazabicyclo[5.4.0]undec-7-ene or triethylenediamine.

4. The method for preparing 5α-androst-2-ene-17-one as shown in formula I according to claim 1, characterized in that: The solvent is selected from one or more of ether solvents, halogenated alkane solvents and aromatic hydrocarbon solvents.

5. The method for preparing 5α-androst-2-ene-17-one as shown in formula I according to claim 4, characterized in that: The solvent is selected from ether solvents or halogenated alkane solvents.

6. The method for preparing 5α-androst-2-ene-17-one as shown in formula I according to claim 4, characterized in that: It meets one or more of the following conditions: (1) The ether solvent is tetrahydrofuran and / or dioxane; (2) The halogenated alkane solvent is dichloromethane; (3) The aromatic hydrocarbon solvent is toluene.

7. The method for preparing 5α-androst-2-ene-17-one as shown in formula I according to claim 1, characterized in that: The solvent is tetrahydrofuran or dichloromethane.

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

9. The method for preparing 5α-androst-2-ene-17-one as shown in formula I according to claim 8, characterized in that: It meets one or more of the following conditions: (1) The volume mass ratio of the solvent to epiandrosterone is 5 ml / g; (2) The molar ratio of epiandrosterone to proton base is 1:(1.2-1.5); (3) The molar ratio of epiandrosterone to triphenylphosphine is 1:1.5 or 1:1.8; (4) The molar ratio of epiandrosterone to dimethyl azodicarboxylate is 1:1.5 or 1:1.8; (5) The reaction temperature of the elimination reaction is 0 to 20°C; for example, 0 to 10°C; (6) The reaction time of the elimination reaction is 12 to 20 hours, for example, 16 hours, 18 hours or 20 hours.

10. The method for preparing 5α-androst-2-ene-17-one as shown in formula I according to claim 1, characterized in that: It meets one or both of the following conditions: (1) The preparation method comprises the following steps: mixing the solvent, epiandrosterone, a proton base and triphenylphosphine, cooling the mixture to 0-10°C, and then adding dimethyl azodicarboxylate for reaction; (2) The raw materials of the preparation method may consist of the solvent, epiandrosterone, a proton base, triphenylphosphine and dimethyl azodicarboxylate.

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