CN112625077A - Preparation method of androst-2-ene-17-one and androst-2-ene-17-one - Google Patents
Preparation method of androst-2-ene-17-one and androst-2-ene-17-one Download PDFInfo
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- CN112625077A CN112625077A CN202011615984.6A CN202011615984A CN112625077A CN 112625077 A CN112625077 A CN 112625077A CN 202011615984 A CN202011615984 A CN 202011615984A CN 112625077 A CN112625077 A CN 112625077A
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- androst
- ene
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- epiandrosterone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
Abstract
The invention discloses a preparation method of androstane-2-alkene-17-ketone, which comprises the following steps: s01, taking organic solvent as solvent and acid as catalyst, the epiandrosterone generates mixed liquid with androstane-2-alkene-17-ketone through dehydration reaction. The product is obtained through one-step reaction, so that the reaction steps are shortened, the use of a large amount of organic alkali is avoided, and the process is more environment-friendly; the method avoids the use of silica gel and the like in large quantity, has better process operability, simple post-treatment and easy product separation, and greatly reduces the discharge amount of three wastes.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a preparation method of androst-2-ene-17-one and androst-2-ene-17-one.
Background
Androst-2-ene-17-one, alias rocuronium bromide intermediate LK-2, is a common intermediate for producing steroid hormone medicine. The compound is used as a raw material to produce various common muscle relaxation steroid hormone medicaments such as rocuronium bromide, vecuronium bromide and the like. Common muscle relaxation steroid hormone medicaments such as rocuronium bromide, vecuronium bromide and the like are important auxiliary medicaments for anesthesia in surgical operation in clinic.
The androst-2-ene-17-one is a common intermediate of the steroid hormone medicaments, and different bromine amine muscle relaxation steroid hormone medicaments are obtained through 6 steps of 17-enol esterification, double epoxidation, ring opening with different alicyclic amines, reduction, double esterification, bromomethyl amination and the like.
The existing preparation method of androst-2-ene-17-one is generally divided into two routes: (1) a two-step method: reacting with sulfonyl chloride under the action of alkali to obtain sulfonic ester, and then carrying out elimination reaction under a certain condition to obtain androstane-2-alkene-17-ketone. (2) A one-step method: preparing acidic solid-phase carrier catalyst with acid and adsorbent, and refluxing in organic solvent such as toluene to obtain androst-2-ene-17-one.
The two-step synthesis method mainly comprises (1) sulfonylating the 3-position hydroxyl of the epiandrosterone, and obtaining the 5 a-androst-2-ene-17-ketone (such as CN101225099A) through elimination reaction under the catalysis of organic amine (such as diisopropylethanolamine). (2) Firstly, preparing intermediate epiandrosterone sulfonate, and then obtaining 5 a-androst-2-ene-17-one (CN 101684139A; intermediate in fine chemical industry, 2013,43(3), 35; chemical reagent, 2009,31(7),568 and 570) by elimination under the action of methyl substituted pyridine compounds. (3) After the epiandrosterone sulfonate is prepared, DMF is directly used as a solvent to carry out high-temperature reflux to generate elimination reaction to obtain 5 a-androst-2-ene-17-one (J.Chem.Chem.China, 2008,18(1), 61-63). (4) After the preparation of the epiandrosterone sulfonate, an elimination reaction is realized by utilizing an acetic acid/sodium acetate system to obtain 5 a-androst-2-ene-17-one (Asian journel of chemistry, 2009,21(6), 4399-4403.).
The one-step synthesis method mainly comprises the following steps: (1) preparing sulfuric acid silica gel solid phase catalyst, and refluxing in toluene to prepare androst-2-ene-17-one. (2) Preparing MCM 41-sulfuric acid silica gel solid phase catalyst, and refluxing in toluene to prepare androst-2-ene-17-one. (3) Preparing strong acid-adsorbent solid-phase catalyst, and refluxing in toluene to prepare androst-2-ene-17-one.
The existing synthesis method has the following defects: in the two-step method, the reaction uses larger alkali amount, the waste liquid is difficult to treat, and the pressure on environmental protection is larger. In the one-step method, a large amount of silica gel or alumina and other adsorbents are used, so that on one hand, the amplification effect is easy to fail due to the heterogeneous reaction system during amplification, and on the other hand, the acid-silica gel adsorption catalyst is high in cost and uneconomical.
Therefore, the preparation method of the high-efficiency and environment-friendly androstane-2-alkene-17-ketone has important economic and social benefits.
Disclosure of Invention
Based on the problems, on one hand, the invention provides a preparation method of androst-2-ene-17-one, which can be used for preparing androst-2-ene-17-one and has the advantages of expanded production, environmental protection and low cost.
A preparation method of androst-2-ene-17-one comprises the steps of taking epiandrosterone as a raw material, carrying out dehydration reaction under the catalysis of acid, and carrying out post-treatment on the reaction to obtain androst-2-ene-17-one. The reaction formula is shown as the following formula I:
the reaction shown in the formula I is a decolorization reaction carried out in an organic solvent, and the androst-2-ene-17-ketone is generated in the reaction shown in the formula I.
Optionally, the method further comprises the steps of:
s02, washing the mixed solution with androst-2-ene-17-one with alkaline water, concentrating the organic phase under reduced pressure to recover the organic solvent, and concentrating under reduced pressure to obtain crude androst-2-ene-17-one;
s03, refining the crude androst-2-ene-17-one into a refined androst-2-ene-17-one.
Optionally, in the step S03, the crude androst-2-ene-17-one is refined into a refined androst-2-ene-17-one product by recrystallization.
Optionally, in the recrystallization, the recrystallization solvent is water, methanol, ethanol, isopropanol, or a mixture thereof.
Optionally, in S02, before the mixed solution with androst-2-en-17-one is washed with alkaline water, the mixed solution is cooled to 10-60 ℃.
In the S02, before the mixed solution with the androstane-2-alkene-17-ketone is washed by the alkaline water, the mixed solution is cooled to 20-30 ℃.
Optionally, the acid is a strong acid.
Alternatively, the strong acid is a strong acid that is not strongly oxidizing.
Alternatively, the strong acid is sulfuric acid, methane sulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, perchloric acid, or mixtures thereof.
Alternatively, in S01, the solvent for the dehydration reaction is toluene, chloroform, dioxane, tetrahydrofuran, DME, DMF, DMSO, or a mixture thereof.
Optionally, in S01, the ratio of epiandrosterone: the molar ratio of the catalyst is 1: 0.001-0.8.
Optionally, in S01, the ratio of epiandrosterone: the organic solvent molar ratio is 1 g: 1ml to 50 ml.
Alternatively, in the S01, the reaction temperature of the dehydration reaction is 60 to 160 ℃.
Alternatively, in the step S01, the dehydration reaction time is 3 to 48 hours.
Optionally, in S01, the reflux ratio of the dehydration reaction is 1% to 80%.
Optionally, in S01, the ratio of epiandrosterone: the molar ratio of the catalyst is 1: 0.001-0.3.
Optionally, in S01, the ratio of epiandrosterone: the organic solvent molar ratio is 1 g: 5ml to 30 ml.
Alternatively, in the step S01, the dehydration reaction time is 3 to 18 hours.
Optionally, in S01, the reflux ratio of the dehydration reaction is 20% to 50%.
In one aspect, the invention also provides an androst-2-en-17-one.
The technical scheme is as follows: androst-2-ene-17-one, which is prepared by the method, is disclosed.
The principle and the beneficial effects of the invention are as follows:
according to the invention, the naked acid is used as the catalyst to replace an acid-adsorbent solid-phase catalyst, so that on the first hand, failure of amplification effect caused by heterogeneous reaction system during amplification of reaction due to the use of a large amount of silica gel or aluminum oxide and other adsorbents is avoided; in the second aspect, the use of a large amount of organic alkali is avoided, so that the process is more environment-friendly; the use of silica gel and the like in large quantity is avoided, so that the process operability is better; in the third aspect, the production cost is reduced, and the economy is realized.
The invention also combines catalyst and reflux, on one hand, improves the yield of androst-2-ene-17-one, and on the other hand, improves the purity of androst-2-ene-17-one.
Drawings
FIG. 1 is an HPLC purity profile of example 1;
FIG. 2 is an HPLC purity profile of example 2;
FIG. 3 is an HPLC purity profile of example 2;
FIG. 4 is an HPLC purity profile of example 4;
FIG. 5 is an HPLC purity profile of example 5;
FIG. 6 is an HPLC purity profile of example 6;
FIG. 7 is an HPLC purity profile of example 7;
Detailed Description
The invention will be further explained with reference to the drawings.
The examples provided herein are merely to further illustrate the invention and should not be construed as limiting the invention in any way.
It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified, in the following.
In the present invention,% is a mass percentage unless otherwise specified.
In the invention, the calculation formula of the yield is as follows: yield ═ product weight 290/feedstock weight/272 x 100%.
In the present invention, HPLC refers to the English abbreviation of High Performance Liquid Chromatography (High Performance Liquid Chromatography), and the chromatographic conditions are as follows: a chromatographic column: octadecyl bonding silica gel column; detection wavelength: 210 nm; mobile phase: acetonitrile: 75:25 parts of water; the flow rate was 1.3 ml/min.
A preparation method of androst-2-ene-17-one comprises the following steps:
s01, taking organic solvent as solvent and acid as catalyst, the epiandrosterone generates mixed liquid with androstane-2-alkene-17-ketone through dehydration reaction.
Optionally, the method further comprises the steps of:
s02, washing the mixed solution with androst-2-ene-17-one with alkaline water, concentrating the organic phase under reduced pressure to recover the organic solvent, and concentrating under reduced pressure to obtain crude androst-2-ene-17-one;
s03, refining the crude androst-2-ene-17-one into a refined androst-2-ene-17-one.
Example 1
Epiandrosterone (10mmol,2.9g), p-toluenesulfonic acid monohydrate (0.4mmol,0.78g) were added to a 100ml three-necked flask, toluene (58ml) was used as a solvent, and the mixture was heated to 110 ℃ for water-splitting reaction for 6 h. Washing the reacted mixed solution with androst-2-ene-17-one with 20ml of saturated sodium bicarbonate, drying (anhydrous sodium sulfate), carrying out reduced pressure distillation and concentration to obtain a yellow brown oily substance (crude androst-2-ene-17-one), and recrystallizing the crude androst-2-ene-17-one with 80% ethanol water solution to obtain 1.78g of refined androst-2-ene-17-one, wherein the yield is 65%, and the HPLC purity is 30.7% through detection.
The HPLC purity profile is shown in FIG. 1.
Example 2
Adding epiandrosterone (10mmol,2.9g) and p-toluenesulfonic acid monohydrate (0.4mmol,0.78g) into a 100ml three-necked bottle, taking toluene (58ml) as a solvent, heating to 110 ℃, carrying out water division reaction for 3h, carrying out reflux reaction for 3h, and continuing the water division reaction for about 3h at a reflux ratio of 33%. And (3) cooling the reacted mixed solution with the androst-2-ene-17-one to below 30 ℃, washing with 20ml of saturated sodium bicarbonate, drying (anhydrous sodium sulfate), carrying out reduced pressure distillation and concentration to obtain a light yellow solid (crude androst-2-ene-17-one), recrystallizing the crude androst-2-ene-17-one by using 80% ethanol water solution to obtain 2.36g of an androst-2-ene-17-one refined product, wherein the yield is 87%, and the HPLC purity is 98.2% by detection.
The HPLC purity profile is shown in FIG. 2.
Example 3:
adding epiandrosterone (0.1mol,29g) and 20% perchloric acid solution (0.003mmol,0.3g) into a 10L three-necked bottle, taking toluene (580ml) as a solvent, heating to 110 ℃, carrying out water diversion reaction for 3h, carrying out reflux reaction for 5 h, and continuing the water diversion reaction for about 2 h at a reflux ratio of 50%. Washing the reacted mixed solution with androst-2-ene-17-one with 0.2L saturated sodium bicarbonate, drying (anhydrous sodium sulfate), carrying out reduced pressure distillation and concentration to obtain a light yellow solid (crude androst-2-ene-17-one), and recrystallizing the crude androst-2-ene-17-one with 80% ethanol aqueous solution to obtain 25g of fine androst-2-ene-17-one product, wherein the yield is 92%, and the HPLC purity is 97.2% by detection.
The HPLC purity profile is shown in FIG. 3.
Example 4
The method and procedure of example 3 were followed except that the catalyst was adjusted to concentrated sulfuric acid, the amount of catalyst was adjusted to 10%, the yield of the fine androst-2-en-17-one product was 55%, and the HPLC purity was found to be 94.0%.
The HPLC purity profile is shown in FIG. 4.
Example 5:
the procedure of example 3 was followed except that the catalyst was adjusted to methanesulfonic acid, the amount of catalyst was adjusted to 15%, the yield of the fine androst-2-en-17-one product was 78%, and the HPLC purity was 96.8%.
The HPLC purity profile is shown in FIG. 5.
Example 6:
following the procedure of example 3, except that the catalyst was adjusted to methanesulfonic acid, the catalyst amount was adjusted to 5%, the yield of the fine androst-2-en-17-one product was 75%, and the HPLC purity was 95.2%
The HPLC purity profile is shown in FIG. 6.
Comparative example 1:
adding epiandrosterone (1mol,290g) and solid phase acid (5% p-toluenesulfonic acid silica gel, 145g) into a 100L three-necked bottle, taking toluene (5.8L) as a solvent, heating to 110 ℃, and carrying out water division reaction for 3 h. Reducing the temperature of the reacted mixed solution with androst-2-ene-17-one to be below 30 ℃, filtering, washing a filter cake with 300ml of toluene, combining filtrates, washing with 2L of saturated sodium bicarbonate, drying (anhydrous sodium sulfate), carrying out reduced pressure distillation and concentration to obtain a yellow oily substance (crude androst-2-ene-17-one), recrystallizing the crude androst-2-ene-17-one with 80% ethanol water solution to obtain refined androst-2-ene-17-one 232g, wherein the yield is 85%, and the HPLC purity is 85.8% by detection.
The HPLC purity profile is shown in FIG. 7.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of androst-2-ene-17-one comprises the following steps:
s01, taking organic solvent as solvent and acid as catalyst, the epiandrosterone generates mixed liquid with androstane-2-alkene-17-ketone through dehydration reaction.
2. The method of preparing androst-2-en-17-one according to claim 1 further comprising the steps of:
s02, washing the mixed solution with androst-2-ene-17-one with alkaline water, concentrating the organic phase under reduced pressure to recover the organic solvent, and concentrating under reduced pressure to obtain crude androst-2-ene-17-one;
s03, refining the crude androst-2-ene-17-one into a refined androst-2-ene-17-one.
3. The method for preparing androst-2-en-17-one according to claim 2, wherein in S03, the crude androst-2-en-17-one is refined into refined androst-2-en-17-one by recrystallization.
4. The method of claim 3, wherein the recrystallization solvent is water, methanol, ethanol, isopropanol, or a mixture thereof.
5. The method for preparing androst-2-en-17-one according to any one of claims 2-3 wherein the mixture is cooled to 10-60 ℃ before washing the mixture with androst-2-en-17-one with aqueous alkali in S02; optionally, in S02, before the mixed solution with androst-2-en-17-one is washed with alkaline water, the mixed solution is cooled to 20-30 ℃.
6. The method of producing androst-2-en-17-one according to any of claims 1-5 wherein the acid is a strong acid; alternatively, the strong acid is a strong acid that is not strongly oxidizing; alternatively, the strong acid is sulfuric acid, methane sulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, perchloric acid, or mixtures thereof.
7. The method for producing androst-2-en-17-one according to any one of claims 1-6 wherein the solvent for the dehydration reaction in S01 is toluene, chloroform, dioxane, tetrahydrofuran, DME, DMF, DMSO or a mixture thereof.
8. The method for producing androst-2-en-17-one according to any one of claims 1-7 wherein in S01 epiandrosterone: the molar ratio of the catalyst is 1: 0.001-0.8; or/and
in S01, epiandrosterone: the organic solvent molar ratio is 1 g: 1ml to 50 ml; or/and
in the S01, the reaction temperature of the dehydration reaction is 60-160 ℃; or/and
in the step S01, the time of dehydration reaction is 3-48 hours; or/and
in the S01, the reflux ratio of the dehydration reaction is 1-80%.
9. The method for producing androst-2-en-17-one according to any one of claims 1-8 wherein in S01 epiandrosterone: the molar ratio of the catalyst is 1: 0.001-0.3; or/and
in S01, epiandrosterone: the organic solvent molar ratio is 1 g: 5ml to 30 ml; or/and
in the S01, the reaction temperature of the dehydration reaction is 80-130 ℃; or/and
in the S01, the time of dehydration reaction is 3-18 hours; or/and
in the S01, the reflux ratio of the dehydration reaction is 20-50%.
10. An androst-2-en-17-one prepared by the process of any of claims 1-9.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113683655A (en) * | 2021-08-25 | 2021-11-23 | 福安药业集团重庆博圣制药有限公司 | Preparation method of rocuronium bromide intermediate |
| CN113788872A (en) * | 2021-11-03 | 2021-12-14 | 湖北共同药业股份有限公司 | Preparation method of androst-2-ene-17-one |
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| CN101684139A (en) * | 2008-09-27 | 2010-03-31 | 徐州师范大学 | Synthesis process of vecuronium bromide |
| CN109651473A (en) * | 2019-02-18 | 2019-04-19 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of androstane -2- alkene -17- ketone |
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| CN109678918A (en) * | 2019-01-24 | 2019-04-26 | 台州仙琚药业有限公司 | The preparation method of 5 α-androstane -2- alkene -17- ketone |
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Cited By (3)
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| CN113683655A (en) * | 2021-08-25 | 2021-11-23 | 福安药业集团重庆博圣制药有限公司 | Preparation method of rocuronium bromide intermediate |
| CN113788872A (en) * | 2021-11-03 | 2021-12-14 | 湖北共同药业股份有限公司 | Preparation method of androst-2-ene-17-one |
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