CN114395007B - Preparation method of mesterone - Google Patents
Preparation method of mesterone Download PDFInfo
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- CN114395007B CN114395007B CN202111635894.8A CN202111635894A CN114395007B CN 114395007 B CN114395007 B CN 114395007B CN 202111635894 A CN202111635894 A CN 202111635894A CN 114395007 B CN114395007 B CN 114395007B
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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
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
- C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Abstract
A preparation method of mesterone takes epiandrosterone as a raw material and comprises the following steps: 1) Performing oxidation reaction, dissolving the compound I in dichloromethane, adding a sodium bicarbonate aqueous solution, and dropwise adding a sodium hypochlorite solution at 20-25 ℃ to obtain a compound II; 2) Performing etherification reduction hydrolysis reaction, dissolving the compound II in methanol, controlling the temperature to be 20-25 ℃, and adding p-toluenesulfonic acid to react until the compound III is completely obtained; 3) Carrying out debromination reaction, adding a compound V and hydrochloric acid ethanol into dichloromethane for dissolution, and adding bromine at 10-15 ℃; reacting for 2 hours at the temperature of 15-20 ℃, and reacting for 2 hours at the temperature of 25-30 ℃ until the reaction is completed to obtain a compound VII; 4) Performing Grignard reaction, namely adding a compound VII into tetrahydrofuran, cooling, adding cuprous chloride, slowly adding methyl magnesium chloride at 0-5 ℃, and keeping the temperature at 5-10 ℃ for reaction till the reaction is complete; obtaining a mesterone crude product; and refining to obtain mesterone.
Description
Technical Field
The invention relates to a preparation method of an androstane compound.
Background
Mesterone (CAS: 1424-00-6, alternative names: medroxytestosterone, androstanolone) is the oldest protein-assimilating androgenic steroid on the market. Can be used for treating male hypogonadism and oligospermia infertility.
The existing mesterone preparation method has two main routes, wherein the first route is as follows: ADD (androstenedione) is subjected to 7-step synthesis reaction to generate mesterone. The reaction route using ADD as starting material is as follows:
the problem of the route is that the ADD is obtained by fermenting 4AD (androstenedione) and then forming double bonds at 1,2 positions, so that the cost of the ADD is high, the process economy of the whole route is affected, and in addition, the 1, 2-position epoxy and the ring-opening reaction have certain dangerousness and the yield is not ideal, so the whole economy is not high.
In the second route, epiandrosterone is used as a raw material, and the raw material is subjected to oxidation, etherification reduction hydrolysis, debromination and Grignard refining to generate mesterone.
The reaction route is as follows:
in the route, the epiandrosterone as a raw material can be synthesized and prepared by 4AD, and chromic anhydride or hydrogen peroxide and the like are used as oxidants in the oxidation reaction. However, chromic anhydride or hydrogen peroxide are dangerous, the former is easy to cause environmental pollution, and the latter has high explosion risk. In the etherification-reduction-acidolysis reaction, the traditional process is that after the etherification reaction is finished, methanol is concentrated firstly, and then solid-liquid separation is carried out, but etherified substances are poor in stability and easy to decompose, and must be put into the next reduction reaction as soon as possible, so that the problems of material loss, mother liquor increase and the like in the intermediate process desolventization can be caused by adopting a step-by-step synthesis mode. In the above-mentioned debromination reaction, it has been found through research that the prior art has a problem of incomplete reaction, and about 10% of raw materials can not be completely reacted, thereby affecting the total yield of the product. Based on the above problems in the prior art, it is an urgent need in the art to improve the preparation method of mesterone using epiandrosterone as the starting material to increase the total yield of the reaction.
Disclosure of Invention
In order to solve the above problems in the prior art, we provide the following technical solutions:
a preparation method of mesterone takes epiandrosterone as a raw material, and prepares mesterone through oxidation reaction, etherification reduction hydrolysis reaction, upper debromination reaction, grignard reaction and refining: the reaction formula is as follows
The steps specifically include:
1) Oxidation reaction
Dissolving epiandrosterone (compound I) in dichloromethane, adding a sodium bicarbonate aqueous solution, cooling to 20-25 ℃, dropwise adding a sodium hypochlorite solution, controlling the adding time to be 1-1.5 h, keeping the temperature at 20-25 ℃ after the dropwise adding is finished, reacting completely, standing for layering, concentrating an organic phase to a dichloromethane-free distillate, adding water for elutriation, cooling to 10-15 ℃, centrifuging, washing with water to be neutral, spin-drying, and drying at 65-70 ℃ to obtain a compound II.
The mass ratio of the epiandrosterone to the sodium bicarbonate to the sodium hypochlorite is 1.2-0.3, preferably 1. 2) Etherification reduction hydrolysis reaction
Dissolving a compound II in methanol, controlling the temperature to 20-25 ℃, adding p-toluenesulfonic acid (PTS) to react until completely obtaining a compound III, directly adding a sodium hydroxide aqueous solution to neutralize the reaction system until the pH value is 7-8, slowly adding potassium borohydride (solid) to react at 30-35 ℃ under the condition of heat preservation until completely reacting, then adding a hydrochloric acid solution, controlling the temperature to be 30-35 ℃ to react for 3 hours to obtain a compound IV, after completely reacting, concentrating the methanol under reduced pressure until no distillate exists, adding water to perform elutriation, cooling, filtering, washing, separating and drying to obtain a compound V (androsterone), wherein the mass ratio of the compound II to the methanol is 1: 1, preferably 0.16 to 0.17, wherein the hydrochloric acid solution is prepared from concentrated hydrochloric acid and water according to a mass ratio of 1.
3) Upper debromination reaction
Adding a compound V and hydrochloric acid ethanol into dichloromethane for dissolving, cooling, adding bromine at the temperature of 10-15 ℃, keeping the temperature of 15-20 ℃ for reaction for 2 hours, then heating to 25-30 ℃, keeping the temperature for reaction for 2 hours until the reaction is complete; adding sodium bicarbonate water solution for neutralization, concentrating dichloromethane of an organic layer after layering until the organic layer is dried to obtain a compound VI, directly adding DMF (dimethyl formamide) into a reactor to dissolve the compound VI, adding lithium carbonate and lithium bromide, stirring and heating to 80-85 ℃ for reaction till the reaction is complete, adding water, cooling to 20-25 ℃ for crystallization, filtering, washing to be neutral, separating, and drying at 60-65 ℃ to obtain a compound VII (1-testosterone).
The mass percentage concentration of hydrochloric acid of the hydrochloric acid ethanol is 30-40%, and the mass ratio of the compound V, the hydrochloric acid ethanol and the bromine is 1: 0.08-0.12, 0.5-0.6, wherein the mass ratio of the dichloromethane to the compound V is 12-18: 1. preferably, the mass ratio of the compound V, the hydrochloric acid ethanol and the bromine is 1: 0.1-0.55, wherein the mass ratio of the dichloromethane to the compound V is 15:1, wherein the mass percentage concentration of the hydrochloric acid ethanol is 30%; the mass ratio of DMF to the compound V is 12-15, and the mass ratio of the compound V to lithium carbonate to lithium bromide is 8-10: 8-10, preferably 9: 1.
4) Grignard reaction
Adding a compound VII into tetrahydrofuran, cooling to 0-5 ℃, adding cuprous chloride, slowly adding methyl magnesium chloride at 0-5 ℃, after finishing dripping, keeping the temperature at 5-10 ℃ for reaction till the reaction is complete, slowly adding 5-10% by mass of dilute hydrochloric acid below 20 ℃ for decomposition and neutralizing redundant Grignard reagent, after finishing adding, concentrating until no tetrahydrofuran distillate exists, adding water and cooling to below 20 ℃, performing suction filtration, washing to be neutral, spin-drying, drying at the drying temperature of 60-65 ℃, and drying to obtain a mesterone crude product. The mass ratio of the compound VII, cuprous chloride and methyl magnesium chloride is 1.
5) Refining
Dissolving the mesterone crude product in acetone, adding active carbon, refluxing and decoloring for 30-45 min, filtering to remove the active carbon, concentrating to paste, cooling to-2-5 ℃, leaching after complete crystallization, leaching with glacial acetone (one time) at the temperature lower than 10 ℃, draining, drying a filter cake at the temperature of 60-65 ℃ to obtain the refined mesterone
The mass ratio of the mesterone crude product to the activated carbon to the acetone is 1.08-0.12: 11-14, wherein the mass ratio of the glacial acetone to the mesterone crude product is 0.8-1.2.
The preparation method of mesterone provided by the invention optimizes the existing preparation method of mesterone to produce the following beneficial effects: 1) The safe and universal oxidant sodium hypochlorite is innovatively used to replace the traditional oxidant chromic anhydride, so that the difficult treatment and high-risk characteristics of chromic anhydride heavy metal wastewater are avoided. 2) The three-step reaction continuous discharging-free method of etherification, reduction and acidolysis reduces the bottleneck of instability of desolventizing etherified substances in the intermediate process. And the three steps are combined, so that the yield is higher. 3. In the bromine adding reaction, a stage heating method is adopted, so that the raw materials are promoted to react completely, and the reaction yield is improved. Finally, by optimizing the reactions in each step, about 61g of mesterone finished product can be obtained from every 100g of epiandrosterone raw material, compared with the route that the mesterone is generated by taking the existing epiandrosterone as the raw material and then carrying out oxidation, etherification reduction hydrolysis, debromination and Grignard post-refining, the reaction yield is improved, and the use of heavy metal raw materials such as chromic anhydride and the like is avoided.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
The hydrochloric acid adopted in the embodiment is commercial concentrated hydrochloric acid, and the HCl content is 36 to 38 percent
Example 1
1) Oxidation reaction
Putting 500g of dichloromethane, 100g of epiandrosterone (HPLC purity (98.5%)), 25g of sodium bicarbonate and 100g of water into a reaction bottle, cooling, adding 350g of 10wt% sodium hypochlorite solution at the temperature of 20-25 ℃, controlling the adding time to be 1-1.5 hours, and keeping the temperature for 1 hour at the temperature of 20-25 ℃ after dripping. After heat preservation, the reaction end point is detected by a point plate, after the reaction is finished, the mixture is static and layered, the dichloromethane is concentrated in an organic layer under normal pressure, and the temperature is controlled to be 45-50 ℃ until no dichloromethane effluent liquid exists. Adding water for water precipitation, and cooling to 10-15 ℃. Discharging, centrifuging, washing to neutrality, drying, and drying at 65-70 deg.C to obtain 98g of compound II (HPLC content 98.1%). The quality yield is as follows: 98 percent.
2) Etherification reduction hydrolysis reaction
Adding 980g of methanol and 98g of compound II into a reaction bottle, stirring and dissolving at room temperature, adjusting the temperature to 20-25 ℃, adding 46g of p-toluenesulfonic acid, and keeping the temperature for reaction for 6 hours. After the reaction is finished, a TLC plate is spotted to determine the end point of the reaction, and after the reaction is finished, 10% sodium hydroxide aqueous solution is added to neutralize the reaction solution to pH8, and the neutralization is finished. Slowly adding 16g of potassium borohydride, reacting for 1 hour at the temperature of 30-35 ℃, dotting a plate to ensure complete reaction, pumping hydrochloric acid water (32 g of hydrochloric acid and 68g of water), controlling the temperature to be 30-35 ℃ for reacting for 3 hours, after the reaction is finished, concentrating methanol under reduced pressure until no effluent liquid exists, adding water, cooling, crystallizing, filtering, washing to be neutral, spin-drying, drying at the temperature of 75-80 ℃, and drying to obtain 90.16g of a compound V and an androsaurus (the HPLC content is 98.2%). The mass yield thereof was found to be 92%.
3) Upper debromination reaction
675g of dichloromethane, 45g of compound V and 4.5g of 30% hydrochloric acid ethanol are added into a reaction bottle, stirred and dissolved at room temperature, stirred and cooled to below 5 ℃,25 g of bromine is added at the temperature of 10-15 ℃, the temperature is controlled to be 15-20 ℃ after the addition, the reaction is kept for 2 hours at the internal temperature, and then the temperature is raised to 25-30 ℃ and the reaction is kept for 2 hours. After the reaction, 450g of a 10% aqueous solution of sodium hydrogencarbonate was added to separate the aqueous layer. The organic layer was concentrated dichloromethane to dryness to give compound VI. 570g of DMF, 40g of lithium carbonate and 40g of lithium bromide are added into the compound VI for dissolution, and the mixture is stirred and heated to 80-85 ℃ for reaction for 3 hours. After the reaction is finished, concentrating under reduced pressure at the temperature of 80-85 ℃ until DMF effluent is basically eliminated, adding 600g of water, cooling to 20-25 ℃ for crystallization, carrying out suction filtration, washing to be neutral, spin-drying, and drying at the drying temperature of 60-65 ℃ to obtain 40.5g of compound VII (1-testosterone) (the HPLC content is 95.5 percent). The quality yield is as follows: 90 percent
4) Grignard reaction
Putting 600g of tetrahydrofuran and 40g of a compound VII into a reaction bottle, cooling to 0-5 ℃, adding 1g of cuprous chloride, slowly adding 150g of methyl magnesium chloride at 0-5 ℃, after dripping, keeping the temperature at 5-10 ℃ for reaction for 3 hours, adding a dilute hydrochloric acid aqueous solution (100 g of hydrochloric acid +300g of water) at the temperature below 20 ℃, concentrating tetrahydrofuran until no tetrahydrofuran effluent exists, adding water, cooling to below 20 ℃, performing suction filtration, washing with water to be neutral, spin-drying, drying at the temperature of 60-65 ℃, and drying to obtain 36g of a mesterone crude product. The quality yield is as follows: 90 percent.
5) Refining
Putting 465g of acetone, 36g of mesterone crude product and 3.6g of active carbon into a reaction bottle, heating to 60-65 ℃, carrying out reflux decoloration for 30-45 minutes, filtering and concentrating to be pasty, freezing and cooling to-2-5 ℃, crystallizing to be complete, carrying out suction filtration, leaching with glacial acetone, carrying out suction drying, carrying out drying at 60-65 ℃, and drying to obtain 30.6g of refined mesterone (the content of HPLC is 99.0%). The mass yield is 85%.
Claims (7)
1. A preparation method of mesterone takes epiandrosterone as a raw material, and prepares mesterone through oxidation reaction, etherification reduction hydrolysis reaction, upper debromination reaction, grignard reaction and refining: the reaction formula is as follows
The method is characterized by comprising the following specific steps:
1) Oxidation reaction
Dissolving a compound I in dichloromethane, adding a sodium bicarbonate aqueous solution, cooling to 20-25 ℃, dropwise adding a sodium hypochlorite solution, controlling the adding time to be 1-1.5 h, keeping the temperature at 20-25 ℃ after dropwise adding until the reaction is complete, standing for layering, concentrating an organic phase until no dichloromethane distillate exists, adding water for elutriation, cooling to 10-15 ℃, centrifuging, washing to be neutral, spin-drying, and drying at 65-70 ℃ to obtain a compound II;
2) Etherification reduction hydrolysis reaction
Dissolving a compound II in methanol, controlling the temperature to be 20-25 ℃, adding p-toluenesulfonic acid to react until the p-toluenesulfonic acid is completely reacted to obtain a compound III, directly adding a sodium hydroxide aqueous solution to neutralize the pH value to be 7-8 in a reaction system, slowly adding solid potassium borohydride to react at the temperature of 30-35 ℃ under the condition of heat preservation until the reaction is completely performed, then adding a hydrochloric acid solution to react for 3 hours at the temperature of 30-35 ℃ to obtain a compound IV, concentrating the methanol under reduced pressure until no distillate exists after the reaction is completely performed, adding water to perform elutriation, cooling, filtering, washing with water, separating and drying to obtain a compound V;
3) Upper debromination reaction
Adding a compound V and hydrochloric acid ethanol into dichloromethane for dissolving, cooling, adding bromine at the temperature of 10-15 ℃, preserving heat at the temperature of 15-20 ℃ for 2 hours, and then heating to the temperature of 25-30 ℃ for preserving heat for 2 hours until the reaction is complete; adding a sodium bicarbonate aqueous solution for neutralization, concentrating dichloromethane of an organic layer after layering until the dichloromethane is dried to obtain a compound VI, directly adding DMF (dimethyl formamide) into a reactor to dissolve the compound VI, adding lithium carbonate and lithium bromide, stirring and heating to 80-85 ℃ for reaction till the reaction is complete, adding water, cooling to 20-25 ℃ for crystallization, filtering, washing to be neutral, separating, and drying at 60-65 ℃ to obtain a compound VII;
4) Grignard reaction
Adding a compound VII into tetrahydrofuran, cooling to 0-5 ℃, adding cuprous chloride, slowly adding methyl magnesium chloride at 0-5 ℃, after finishing dripping, keeping the temperature at 5-10 ℃ for reaction till the reaction is complete, slowly adding 5-10% by mass of dilute hydrochloric acid below 20 ℃ for decomposition and neutralizing redundant Grignard reagent, after finishing adding, concentrating until no tetrahydrofuran distillate exists, adding water and cooling to below 20 ℃, performing suction filtration, washing to be neutral, spin-drying, drying at the drying temperature of 60-65 ℃, and drying to obtain a mesterone crude product;
5) Refining
Dissolving the mesterone crude product in acetone, adding active carbon, refluxing and decoloring for 30-45 min, filtering to remove the active carbon, concentrating to paste, cooling to-2-5 ℃, leaching after complete crystallization, leaching with glacial acetone at the temperature lower than 10 ℃, draining, and drying a filter cake at the temperature of 60-65 ℃ to obtain the refined mesterone.
2. The method for preparing mesterone as claimed in claim 1, wherein in the step 1), the mass ratio of the epiandrosterone, the sodium bicarbonate and the sodium hypochlorite is 1.2-0.3.
3. The method for preparing mesterone according to claim 1, wherein the mass ratio of the compound II to the methanol in the step 2) is 1: the hydrochloric acid solution is prepared from concentrated hydrochloric acid and water according to the mass ratio of 1.
4. The method for preparing mesterone according to claim 1, wherein in the step 3), the concentration of hydrochloric acid of the ethanol hydrochloride is 30-40% by mass, and the mass ratio of the compound V, the ethanol hydrochloride and the bromine is 1: 0.08-0.12, wherein the mass ratio of the dichloromethane to the compound V is 12-18: 1, the mass ratio of DMF to compound V is 12-15: 8-10, wherein the mass ratio of the added water to the DMF is (1-1.5): 1.
5. the method for preparing mesterone according to claim 1, wherein in the step 4), the mass ratio of the compound VII, cuprous chloride and methyl magnesium chloride is 1.
6. The method for preparing mesterone according to claim 1, wherein in the step 5), the mass ratio of the mesterone crude product, the activated carbon and the acetone is 1: 11-14, wherein the mass ratio of the glacial acetone to the mesterone crude product is 0.8-1.2.
7. A method of preparing mesterone as claimed in any one of claims 1 to 6, wherein:
step 1), the mass ratio of epiandrosterone, sodium bicarbonate and sodium hypochlorite is 1.25;
in the step 2), the mass ratio of potassium borohydride to the compound II is 0.16-0.17;
in the step 3), the mass ratio of the compound V, lithium carbonate and lithium bromide is preferably 9: 0.1: 0.55-0.6, wherein the mass ratio of the dichloromethane to the compound V is 15:1, the mass percentage concentration of the hydrochloric acid ethanol is 30%;
in the step 4), the mass ratio of the compound VII, the cuprous chloride and the methyl magnesium chloride is 1.
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| FR1382468A (en) * | 1964-01-28 | 1964-12-18 | Spofa Vereinigte Pharma Werke | Process for the preparation of 1-methyl-substituted 3-keto-androstane compounds, and products according to those obtained by the present or similar process |
| GB1049448A (en) * | 1963-12-04 | 1966-11-30 | Spofa Vereinigte Pharma Werke | A method of preparing 1-methyl substituted 3-ketoandrostane compounds |
| WO1994022878A1 (en) * | 1993-03-30 | 1994-10-13 | Schering Aktiengesellschaft | Alkylating agent and 1,4-addition process of an alkyl group onto an alpha, beta-unsaturated ketone compound |
| WO2008145318A2 (en) * | 2007-05-31 | 2008-12-04 | Bayer Schering Pharma Ag | USE OF α, β-UNSATURATED CARBONYL COMPOUNDS AS QUENCHING REAGENTS FOR BIRCH REDUCTION |
| CN110563788A (en) * | 2019-09-24 | 2019-12-13 | 华中药业股份有限公司 | preparation method of 5 alpha-androstane-3, 17-dione |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20080300428A1 (en) * | 2007-05-31 | 2008-12-04 | Ingo Ortmann | USE OF alpha,beta -UNSATURATED CARBONYL COMPOUNDS AS QUENCH REAGENTS FOR THE BIRCH REDUCTION |
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| GB1049448A (en) * | 1963-12-04 | 1966-11-30 | Spofa Vereinigte Pharma Werke | A method of preparing 1-methyl substituted 3-ketoandrostane compounds |
| FR1382468A (en) * | 1964-01-28 | 1964-12-18 | Spofa Vereinigte Pharma Werke | Process for the preparation of 1-methyl-substituted 3-keto-androstane compounds, and products according to those obtained by the present or similar process |
| WO1994022878A1 (en) * | 1993-03-30 | 1994-10-13 | Schering Aktiengesellschaft | Alkylating agent and 1,4-addition process of an alkyl group onto an alpha, beta-unsaturated ketone compound |
| WO2008145318A2 (en) * | 2007-05-31 | 2008-12-04 | Bayer Schering Pharma Ag | USE OF α, β-UNSATURATED CARBONYL COMPOUNDS AS QUENCHING REAGENTS FOR BIRCH REDUCTION |
| CN110563788A (en) * | 2019-09-24 | 2019-12-13 | 华中药业股份有限公司 | preparation method of 5 alpha-androstane-3, 17-dione |
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