CN117683072A - A kind of synthesis technology of 6-methyl Grignard hydrolyzate - Google Patents
A kind of synthesis technology of 6-methyl Grignard hydrolyzate Download PDFInfo
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- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
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Abstract
本发明属于化学合成技术领域，具体涉及一种6‑甲基格氏水解物的合成工艺。所述6‑甲基格氏水解物的合成工艺，包括以17α‑羟基孕甾‑4‑烯‑3,11,20‑三酮为起始原料，依次经过缩酮反应、还原反应、环氧反应、格氏反应、水解反应和消除反应，17α‑羟基孕甾‑4‑烯‑3,11,20‑三酮与乙二醇在催化剂和脱水剂存在下进行反应得到6‑甲基缩酮物，与还原剂反应得到6‑甲基还原物，6‑甲基还原物氯仿溶液与过氧酸在连续流反应器中停留反应得到6‑甲基环氧化物，与格氏试剂反应得到格氏反应液，水解反应后与硫酸溶液保温反应，最后进行消除反应得到6‑甲基格氏水解物。反应收率较高，能耗低，方法安全。The invention belongs to the technical field of chemical synthesis, and specifically relates to a synthesis process of 6-methyl Grignard hydrolyzate. The synthesis process of the 6-methyl Grignard hydrolyzate includes using 17α-hydroxypregnant-4-ene-3,11,20-trione as the starting material, and sequentially undergoes a ketal reaction, a reduction reaction, and an epoxy reaction. reaction, Grignard reaction, hydrolysis reaction and elimination reaction, 17α-hydroxypregnant-4-ene-3,11,20-trione reacts with ethylene glycol in the presence of a catalyst and a dehydrating agent to obtain 6-methyl ketal The substance reacts with the reducing agent to obtain the 6-methyl reduced product. The chloroform solution of the 6-methyl reduced product reacts with the peroxyacid in the continuous flow reactor to obtain 6-methyl epoxide, which reacts with the Grignard reagent to obtain the Grignard reagent. reaction solution, after the hydrolysis reaction, it is incubated with a sulfuric acid solution, and finally undergoes an elimination reaction to obtain 6-methyl Grignard hydrolyzate. The reaction yield is high, energy consumption is low, and the method is safe.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis process of a 6-methyl Grignard hydrolysate.
Background
The corticoids have the functions of anti-inflammatory, antitoxic, antiallergic, antishock, immunity inhibition and antipyretic, are mostly used for inhibiting inflammatory reaction, reducing tissue injury, stabilizing intracellular organelles, and the batch hormone can relieve acute symptoms, and clinically common dexamethasone, prednisone, methylprednisolone, hydrocortisone, methylprednisolone and the like. Wherein the molecular formula of the methylprednisolone is C 22 H 30 O 5 Is white or almost whiteThe colored crystalline powder has strong anti-inflammatory effect and is used for emergency treatment of critical diseases, and the structural formula of the colored crystalline powder is shown as formula (1):
the 6-methyl Grignard hydrolysate is used as a key intermediate for synthesizing the corticosteroid drug methylprednisolone, and the structural formula is shown as formula (2):
disclosure of Invention
The invention aims to provide a synthesis process of a 6-methyl Grignard hydrolysate, which takes 17 alpha-hydroxy pregna-4-ene-3, 11, 20-trione as a starting material to sequentially perform ketal reaction, reduction reaction, epoxy reaction, grignard reaction, hydrolysis reaction and elimination reaction, and has higher yield.
The synthesis process of the 6-methyl Grignard hydrolysate in the technical scheme of the invention comprises the steps of taking 17 alpha-hydroxy pregna-4-ene-3, 11, 20-trione as a starting raw material, and sequentially carrying out ketal reaction, reduction reaction, epoxy reaction, grignard reaction, hydrolysis reaction and elimination reaction.
Further, the ketal reaction is that 17 alpha-hydroxy pregn-4-ene-3, 11, 20-trione and ethylene glycol are reacted in the presence of a catalyst and a dehydrating agent to obtain 6-methyl ketal.
The ketal reaction of ethylene glycol and 17 alpha-hydroxy pregn-4-ene-3, 11, 20-trione can produce water, and the water produced by the reaction can be destroyed by the dehydrating agent, so that the reaction is promoted to right, and the reaction yield is improved.
Further, the dehydrating agent is one or more of trimethyl orthoformate, triethyl orthoformate, acetyl chloride and carbodiimide.
Further, the mass ratio of 17 alpha-hydroxy pregn-4-ene-3, 11, 20-trione to glycol is 1.0:2.5-3.5; and/or the mass of the catalyst is 3.0-8.0% of the mass of 17 alpha-hydroxy pregna-4-ene-3, 11, 20-trione.
Further, the catalyst is a strong protonic acid, and one or more of p-toluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid are listed.
Further, the mass of the dehydrating agent is 1.2 to 2.0 times of that of 17 alpha-hydroxy pregna-4-ene-3, 11, 20-trione.
Further, the ketal reaction temperature is 30-35 ℃ and the time is 10-12 h.
Preferably, the ketal reaction is to stir 17 alpha-hydroxy pregna-4-ene-3, 11, 20-trione, glycol and dehydrating agent uniformly, then to heat to 20-30 ℃ and add catalyst, to cool to 25-30 ℃ after reaction, to adjust pH of the reaction solution to 7-8, and to obtain 6-methyl ketal after centrifugation.
Further, the reduction reaction is that 6-methyl ketal reacts with a reducing agent for 24-48 hours at 55-70 ℃, and the 6-methyl reducing substance is obtained after vacuum decompression concentration, pH adjustment, water separation, centrifugation and drying.
Further, the mass of the reducing agent is 0.3 to 0.8 times of the mass of the 6-methyl ketal.
Further, the reducing agent is one or more of sodium borohydride, potassium borohydride and lithium aluminum hydride.
Preferably, the reduction reaction is to uniformly mix 6-methyl ketal, sodium hydroxide, tetrahydrofuran and water, slowly add a reducing agent for reaction, adjust the pH to 6-7 after vacuum decompression concentration, add water for water precipitation for 0.5-1.0 h, and dry after centrifugation to obtain the 6-methyl reducing substance.
Further, 12-15L of tetrahydrofuran is added into each kg of 6-methyl ketal, and the volume ratio of tetrahydrofuran to water is 40-120:1.
Further, the mass of the sodium hydroxide is 0.5 to 1.0% of the mass of the 6-methyl ketal.
Further, the epoxy reaction is that 6-methyl reducing substance chloroform solution and peroxy acid stay in a continuous flow reactor for reaction for 10-15 min at 10-40 ℃, and the 6-methyl epoxide is obtained after pH is regulated, reduced pressure concentration, filtration and drying.
Further, the peroxyacid is obtained by standing hydrogen peroxide, phthalic anhydride and ethyl acetate in a continuous flow reactor at 30-40 ℃ for 5-10 min, separating reaction liquid after the reaction, washing, layering, drying and filtering.
Further, the mass of phthalic anhydride, ethyl acetate and hydrogen peroxide is 0.5 to 1.0 times, 3.0 to 4.0 times and 3.0 to 4.0 times of the mass of the 6-methyl reducing substance respectively.
Further, the chloroform mass in the 6-methyl reducing substance chloroform solution is 4 to 8 times of the 6-methyl reducing substance mass.
Further, the chloroform solution of the 6-methyl reducing substance is obtained by reacting and mixing the 6-methyl reducing substance and chloroform at the temperature of 10-15 ℃ for 25-35 min.
Preferably, the epoxy reaction is to add a chloroform solution of a 6-methyl reducing substance and peroxy acid into a continuous flow reactor, react for 10-15 min at 10-40 ℃ with heat preservation, cool the feed liquid to 0-5 ℃, adjust the pH of the reaction liquid to 7-8, decompress and concentrate, filter and dry at 60-80 ℃ to obtain the 6-methyl epoxide.
Further, the Grignard reaction is that 6-methyl epoxide reacts with Grignard reagent for 4-5 hours at 60-70 ℃ to obtain Grignard reaction liquid.
Further, 8-12L of Grignard reagent is added per kg of 6-methyl epoxide. Preferably, the Grignard reagent is methyl magnesium chloride tetrahydrofuran solution with the concentration of 0.5-1.0 mol/L.
Preferably, the Grignard reaction is to add tetrahydrofuran into 6-methyl epoxide, slowly add Grignard reagent at 40-50 ℃ in nitrogen atmosphere with the vacuum degree of 0.02-0.04 MPa, and reflux at 60-70 ℃ for 4-5 h to obtain Grignard reaction liquid.
Further, 1.0 to 1.5L of tetrahydrofuran is added per kg of 6-methyl epoxide.
Further, in the hydrolysis reaction, the Grignard reaction solution is added into glacial acetic acid solution at the temperature of 30-50 ℃ in nitrogen atmosphere, and the upper organic layer is separated after standing to obtain the hydrolysis reaction solution.
Further, the volume ratio of glacial acetic acid to water in the glacial acetic acid solution is 1.0:5.0-6.0.
Preferably, the hydrolysis reaction is to cool the glacial acetic acid solution to-5 to 5 ℃, then slowly add the Grignard reaction solution in nitrogen atmosphere after heating to 30 to 50 ℃, then add cyclohexane, stand for 1 to 3 hours, and separate the upper organic layer.
Further, the volume of cyclohexane is 3-4 times of the volume of glacial acetic acid.
Further, the elimination reaction is to react sulfuric acid solution with hydrolysis reaction liquid at 20-30 ℃ for 1-2 hours, then slowly dropwise add NaOH solution, heat reflux for 50-70 minutes, reduce the temperature and adjust the pH, decompress and concentrate, water out, centrifuge and dry to obtain 6-methyl Grignard hydrolysate.
Further, the concentration of the sulfuric acid solution is 0.5-1.0 kg/L, and the dosage is 90-120L.
Further, the concentration of the NaOH solution is 0.2-0.4 kg/L, and the dosage is 300-400L.
Further, the heating reflux temperature is 50-60 ℃.
Further, the temperature reduction and pH adjustment are carried out by reducing the temperature to 40-50 ℃ and adjusting the pH to 6-8.
Preferably, the reagent used for adjusting the pH in the synthesis process of the 6-methyl Grignard hydrolysate is one or more of hydrochloric acid, sulfuric acid, acetic acid, sodium hydroxide and triethylamine.
The synthesis process of the 6-methyl Grignard hydrolysate comprises the following reaction processes:
compared with the prior art, the technical scheme of the invention has the following beneficial effects:
(1) 17 alpha-hydroxy pregna-4-ene-3, 11, 20-trione is used as a starting material, and 6-methyl Grignard hydrolysate is obtained in higher yield through ketal reaction, reduction reaction, epoxy reaction, grignard reaction, hydrolysis reaction and elimination reaction in sequence;
(2) The dehydrating agent is added during ketal reaction to destroy water generated by the reaction, promote the reaction to the right and improve the reaction yield;
(3) The epoxy reaction adopts a micro-channel continuous flow method, so that the experimental risk can be effectively reduced, the safety is improved, the production cost is saved, and the production efficiency is improved;
(4) The temperature of each reaction is not high, the energy consumption is low, and the method is safe.
Detailed Description
The technical scheme of the present invention will be further described by the following specific examples, and it should be understood that the specific examples described herein are only for aiding in understanding the present invention, and are not intended to be limiting. Unless otherwise indicated, all materials used in the examples of the present invention are those commonly used in the art, and all methods used in the examples are those commonly used in the art.
Example 1
The synthesis process of the 6-methyl Grignard hydrolysate comprises the following steps:
(1) Ketal reaction: uniformly stirring 300kg of 17 alpha-hydroxy pregn-4-ene-3, 11, 20-trione, 900kg of ethylene glycol and 450kg of triethyl orthoformate in a reaction kettle, heating to 25 ℃, adding 15kg of trifluoromethanesulfonic acid, reacting at 30 ℃ for 12 hours, cooling to 25 ℃, adding triethylamine to adjust the pH of the reaction solution to 7, and centrifuging to obtain 6-methyl ketal with the mass yield of 100%;
(2) Reduction reaction: uniformly mixing 6-methyl ketal, 2kg of sodium hydroxide, 3600L of tetrahydrofuran and 60L of water in a reaction kettle, slowly adding 150kg of lithium aluminum hydride, reacting at 60 ℃ for 36h, concentrating under vacuum, adding acetic acid to adjust pH to 7, adding water for water precipitation for 1.0h, centrifuging and drying to obtain a 6-methyl reducing substance, wherein the yield is 98%;
(3) The epoxy reaction uses a microchannel continuous flow process: regulating the flow rate of a horizontal flow pump and the frequency of a peristaltic pump, pumping 1000kg of 30% hydrogen peroxide and phthalic anhydride-ethyl acetate solution (225 kg of phthalic anhydride is dissolved in 1080kg of ethyl acetate) into a continuous flow reactor, standing at 35 ℃ for reaction for 6min, separating reaction liquid by using a separation device, adding ammonium sulfate solution for washing twice, standing for layering, adding anhydrous magnesium sulfate for drying, and filtering to obtain peroxy acid; adding a 6-methyl reducing substance-chloroform solution (6-methyl reducing substance is dissolved in 1500kg chloroform) and peroxyacid into a continuous flow reactor, standing for reacting for 12min at 30 ℃, cooling the feed liquid to 0 ℃, adding triethylamine to adjust the pH of the reaction liquid to 7, washing the mother liquid with water, standing for layering, concentrating an organic layer under reduced pressure, concentrating with acetone again, leaching a filter cake and a previous filter cake with methanol and water in sequence, and drying at 80 ℃ to obtain 6-methyl epoxide, wherein the yield is 85%;
(4) Grignard reaction: adding 6-methyl epoxide into a reaction kettle, adding 200L tetrahydrofuran, replacing with nitrogen for three times, opening a grignard reagent overhead tank valve, slowly adding 1500L grignard reagent at 45 ℃ in a nitrogen atmosphere with the vacuum degree of 0.03MPa, and refluxing at 65 ℃ for 5 hours to obtain a grignard reaction solution;
(5) Hydrolysis reaction: 200L of glacial acetic acid and 1200L of water are added into a reaction kettle, the temperature is reduced to 0 ℃, nitrogen is used for three times of replacement, grignard reaction liquid is slowly added at 40 ℃, 600L of cyclohexane is added for extraction, standing is carried out for 2h, and an upper organic layer is separated to obtain hydrolysis reaction liquid;
(6) Elimination reaction: adding 90L of sulfuric acid solution with the concentration of 0.7kg/L into the hydrolysis reaction solution through a high-level tank, carrying out heat preservation reaction for 1.5h at 25 ℃, slowly dropwise adding 300L of NaOH solution with the concentration of 0.25kg/L, heating and refluxing at 50 ℃ for 60min, cooling to 45 ℃, adding glacial acetic acid to adjust the pH to 6, concentrating under reduced pressure, carrying out water separation, centrifuging and drying to obtain 6-methyl Grignard hydrolysate, wherein the yield is 65%.
Example 2
This example differs from example 1 only in the ketal reaction of step (1): 300kg of 17 alpha-hydroxy pregn-4-ene-3, 11, 20-trione, 850kg of ethylene glycol and 500kg of trimethyl orthoformate are uniformly stirred in a reaction kettle, 18kg of p-toluenesulfonic acid is added when the temperature is raised to 30 ℃, the temperature is reduced to 25 ℃ after the reaction is carried out for 12 hours at 35 ℃, triethylamine is added to adjust the pH of the reaction solution to 8, and the 6-methyl ketal is obtained after centrifugation, wherein the yield is 99%.
Example 3
This example differs from example 1 only in the reduction reaction of step (2): uniformly mixing 6-methyl ketal, 2.5kg of sodium hydroxide, 3800L of tetrahydrofuran and 65L of water in a reaction kettle, slowly adding 160kg of sodium borohydride, reacting at 65 ℃ for 36h, concentrating under reduced pressure in vacuum, adding acetic acid to adjust pH to 6, adding water for salting out for 1.0h, centrifuging and drying to obtain a 6-methyl reduced product with the yield of 96%.
Example 4
This example differs from example 1 only in the step (3) epoxy reaction microchannel continuous flow process: regulating the flow rate of a horizontal flow pump and the frequency of a peristaltic pump, pumping 1050kg of 30% hydrogen peroxide and phthalic anhydride-ethyl acetate solution (250 kg of phthalic anhydride is dissolved in 1100kg of ethyl acetate) into a continuous flow reactor, standing at 32 ℃ for reaction for 10min, separating reaction liquid by using a separation device, adding ammonium sulfate solution for washing twice, standing for layering, adding anhydrous magnesium sulfate for drying, and filtering to obtain peroxy acid; adding a 6-methyl reducing substance-chloroform solution (6-methyl reducing substance is dissolved in 1550kg chloroform) and peroxyacid into a continuous flow reactor, standing and reacting for 14min at 25 ℃ to cool the feed liquid to 2 ℃, adding triethylamine to adjust the pH of the reaction liquid to 8, standing and layering, concentrating an organic layer under reduced pressure, concentrating with acetone again, filtering, eluting a filter cake and a previous filter cake with methanol and water in sequence, and drying at 70 ℃ to obtain 6-methyl epoxide, wherein the yield is 84%.
Example 5
This example differs from example 1 only in the step (4) grignard reaction: adding 6-methyl epoxide into a reaction kettle, adding 220L tetrahydrofuran, replacing with nitrogen for three times, opening a grignard reagent overhead tank valve, slowly adding 1600L grignard reagent at 40 ℃ in a nitrogen atmosphere with the vacuum degree of 0.03MPa, and refluxing at 62 ℃ for 5 hours to obtain grignard reaction liquid; the final 6-methyl Grignard hydrolysate yield was 64%.
Example 6
This example differs from example 1 only in the hydrolysis reaction of step (5): adding 250L of glacial acetic acid and 1200L of water into a reaction kettle, cooling to-2 ℃, replacing with nitrogen for three times, slowly adding a Grignard reaction solution at 45 ℃, adding 800L of cyclohexane for extraction, standing for 1.5h, and separating an upper organic layer to obtain a hydrolysis reaction solution; the final 6-methyl Grignard hydrolysate yield was 64%.
Example 7
This example differs from example 1 only in the step (6) elimination reaction: 100L of sulfuric acid solution with the concentration of 0.7kg/L is added into hydrolysis reaction liquid through a high-level tank, the reaction is carried out for 1.5 hours at the temperature of 28 ℃, 320L of NaOH solution with the concentration of 0.25kg/L is slowly dripped, the heating reflux is carried out for 60 minutes at the temperature of 60 ℃, the temperature is reduced to 40 ℃, glacial acetic acid is added to adjust the pH value to 7, and the 6-methyl Grignard hydrolysate is obtained through decompression concentration, water separation, centrifugation and drying, wherein the yield is 65%.
Example 8
This example differs from example 1 only in the ketal reaction of step (1): 300kg of 17 alpha-hydroxy pregn-4-ene-3, 11, 20-trione, 900kg of ethylene glycol and 315kg of triethyl orthoformate are stirred uniformly in a reaction kettle, 15kg of trifluoromethanesulfonic acid is added when the temperature is raised to 25 ℃, the temperature is reduced to 25 ℃ after the reaction is carried out for 12 hours, triethylamine is added to adjust the pH of the reaction solution to 7, and the 6-methyl ketal is obtained after centrifugation, wherein the yield is 90%.
Example 9
This example differs from example 1 only in the ketal reaction of step (1): 300kg of 17 alpha-hydroxy pregn-4-ene-3, 11, 20-trione, 900kg of ethylene glycol and 600kg of triethyl orthoformate are stirred uniformly in a reaction kettle, 15kg of trifluoromethanesulfonic acid is added when the temperature is raised to 25 ℃, the temperature is reduced to 25 ℃ after the reaction is carried out for 12 hours, triethylamine is added to adjust the pH of the reaction solution to 7, and the 6-methyl ketal is obtained after centrifugation, wherein the yield is 85%.
Comparative example 1
The difference between the comparative example and the example 1 is that 225kg of phthalic anhydride is added into a reaction kettle in the epoxy reaction of the step (3), 1080kg of ethyl acetate and 1000kg of hydrogen peroxide are added, the mixture is stirred and reacted for 20 hours at 35 ℃, the upper organic layer is peroxy acid after standing, 6-methyl reducing substance and 1500kg of chloroform are stirred and reacted for 24 hours at 15 ℃ in the reaction kettle, peroxy acid is slowly added dropwise, the reaction is carried out for 12 hours at 20 ℃, triethylamine is used for adjusting the pH value of the reaction liquid to 7, and the mixture is centrifuged and dried to obtain 6-methyl epoxide, wherein the yield is 78%.
Examples 1 to 7 use 17 alpha-hydroxy pregn-4-ene-3, 11, 20-trione as a starting material, and sequentially undergo ketal reaction, reduction reaction, epoxy reaction, grignard reaction, hydrolysis reaction and elimination reaction to obtain 6-methyl Grignard hydrolysate with higher yield, example 8 uses less triethyl orthoformate, reaction yield is reduced, example 9 uses more triethyl orthoformate, more dissolved materials affect reaction efficiency and product yield, and comparative example 1 adopts a conventional reaction kettle reaction, which has long reaction time and low product yield.
Finally, it should be noted that the specific embodiments described herein are merely illustrative of the spirit of the invention and are not limiting of the invention's embodiments. Those skilled in the art to which the invention pertains may make various modifications or additions to the described embodiments or may be substituted in a similar manner, without and without all of the embodiments herein being fully understood. While these obvious variations and modifications, which come within the spirit of the invention, are within the scope of the invention, they are to be construed as being without departing from the spirit of the invention.
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| CN108912192A (en) * | 2018-07-25 | 2018-11-30 | 岳阳环宇药业有限公司 | A kind of methylprednisolone production technology and process units |
| CN121378372A (en) * | 2025-11-21 | 2026-01-23 | 山东斯瑞药业有限公司 | A method for preparing 11β,17α-dihydroxy-6α-methylpregn-4-ene-3,20-dione |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| GB934706A (en) * | 1959-03-27 | 1963-08-21 | Roussel Uclaf | Improvements in or relating to the production of steroid compounds |
| CN102911233A (en) * | 2012-11-14 | 2013-02-06 | 宝鸡康乐生物科技有限公司 | Synthesis method of medroxyprogesterone acetate |
| CN106699830A (en) * | 2016-11-20 | 2017-05-24 | 中国石油大学(华东) | 16-beta methylpregnene steroid hormone intermediate and preparation method of 16-beta methylpregnene steroid hormone intermediate |
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