CN107629102B - Preparation method of nomegestrol acetate - Google Patents
Preparation method of nomegestrol acetate Download PDFInfo
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Abstract
The preparation method of nomegestrol acetate uses nomegestrol acetate as a raw material, firstly, the nomegestrol acetate is dissolved in an organic solvent, and reacts with ethylene glycol under the catalysis of acid in the presence of triethyl orthoformate to obtain a bisketal compound; dissolving the bisketal in an organic solvent, and reacting with hydrogen peroxide under the catalysis of alkali to obtain an epoxy compound: and dissolving the epoxy compound in an organic solvent, performing Grignard addition reaction with methyl magnesium halide, hydrolyzing in a strong acid solution, dehydrating and deprotecting to obtain a methyl compound, finally dissolving the methyl compound in the organic solvent, and performing dehydrogenation reaction with tetrachlorop-benzoquinone to obtain nomegestrol acetate, wherein the HPLC content is 99.0-99.5%, and the total yield of the four-step synthesis reaction is 60-62%. Compared with the traditional method, the method has the advantages of simple and convenient process operation, economy, environmental protection, high total synthesis yield and good product quality, and reduces the cost by 35-40% compared with the traditional method; the solvent used in the process can be recycled, and the method is very beneficial to industrial production.
Description
Technical Field
The invention belongs to a preparation process of steroid hormone medicaments, and particularly relates to a preparation method of a progestational hormone medicament, namely nomegestrol acetate.
Background
Nomegestrol acetate, chemical name: 6-methyl-17 a-acetoxyl-19-nor-pregna-4, 6-diene-3, 20-dione, which is a highly potent progestogenic drug. The 2mg subcutaneous implant is used for female contraception, the effective period is as long as 6 months, and the effective rate is almost 100%. The effect of the traditional Chinese medicine composition for treating endometriosis is about 60 times that of progesterone, and the traditional Chinese medicine composition has good curative effect, low side effect and wide market application prospect. A traditional production method of nomegestrol acetate is disclosed in USP4,544,555, and comprises taking nomegestrol acetate as a raw material, and carrying out five-step reactions such as 3-position olefine etherification, 6-position Vickers reaction formalization, 6-position formaldehyde group reduction, 6-position dehydration methylation, 6-position methine catalytic transposition and the like, wherein the synthetic route is shown in figure 1. The Vickers reaction has high requirement on water content, uses phosphorus oxychloride, is easy to pollute the environment, and is difficult to treat in an environment-friendly way. Particularly, 6-methine catalytic rearrangement has the advantages of large solvent dosage which is 100 times of the feeding amount of the main reaction raw material, low production efficiency, more side reactions and low rearrangement reaction yield, so that the production cost and the market price of the nomegestrol acetate are high.
Disclosure of Invention
The invention aims to solve the problems of low efficiency, more side reactions, low rearrangement reaction yield, high production cost and environmental pollution of the existing nomegestrol acetate production technology, avoid the defects of harsh reaction conditions and the like caused by adopting a Vickers reaction in the traditional production process, and particularly avoid the defects of more impurities, low efficiency, high cost and the like caused by 6-site catalytic transposition reaction. Provides a new preparation method of nomegestrol acetate.
The technical scheme of the invention is as follows: the preparation method of nomegestrol acetate takes nomegestrol acetate as a raw material, firstly synthesizes a bisketal compound, secondly synthesizes an epoxy compound, then synthesizes a methyl compound, and finally synthesizes nomegestrol acetate, namely:
A. synthesizing a bisketal by carrying out acid-catalyzed reaction on norgestrel acetate and ethylene glycol in an organic solvent under the catalysis of triethyl orthoformate to obtain the bisketal: 3, 20-diacetone-norgestrel acetate;
B. the epoxy compound is synthesized by dissolving the bisketal compound in an organic solvent, and reacting 5, 6-bit double bonds in molecules with hydrogen peroxide under the catalysis of alkali to obtain the epoxy compound: 3, 20-diacetone-5 (6) a-epoxy-17 a-acetoxy-19-nor-pregn-3, 20-dione;
C. the methyl compound is synthesized by the following steps that firstly, the epoxy compound and a methyl magnesium halide Grignard reagent are subjected to Grignard reaction in an organic solvent to obtain a Grignard compound, the Grignard compound is directly added with strong acid without being taken out of a pot, dehydration reaction is carried out at the 5-position, and double deprotection reaction is carried out at the 3-position and the 20-position to obtain the methyl compound: 6-methyl-norgestrel acetate;
D. the synthesis of nomegestrol acetate is that 6-position dehydrogenation reaction of methyl compound and tetrachloro-p-benzoquinone in organic solvent to obtain nomegestrol acetate.
Further, the specific operation steps of the synthesis are as follows:
A. synthesis of bisketal compounds
Dissolving norgestrel acetate in an organic solvent, reacting with ethylene glycol under acid catalysis in the presence of triethyl orthoformate at 20-50 ℃ for 12-16 hours while stirring, confirming the reaction end point by TLC, adding weak base to neutralize to pH 7-7.5 after the reaction is finished, and further carrying out post-treatment to obtain a bisketal: the HPLC content of the 3, 20-diacetone-norgestrel acetate is 97.5-98.5%, and the weight yield is 115-120%;
B. synthesis of epoxy
Dissolving the bisketal in an organic solvent, adding an alkali catalyst, slowly dripping hydrogen peroxide at 10-50 ℃, completing the addition for about 1-1.5 hours, then keeping the temperature at 10-50 ℃, continuing to stir for 10-16 hours, confirming the reaction end point by TLC, adding a proper reducing agent to destroy residual hydrogen peroxide after the reaction is completed, adding an acid to neutralize the system to pH7.5-8.0, and further performing post-treatment to obtain an epoxy compound: 3, 20-diacetone-5 (6) a-epoxy-17 a-acetoxy-19-nor-pregna-3, 20-dione, with HPLC content of 98.0-99.0% and weight yield of 95-100%;
C. synthesis of methyl
Dissolving the epoxy in an organic solvent to prepare a solution for later use; adding organic solvent and magnesium powder into another reaction bottle, stirring, controlling the temperature at 10-50 ℃, dropwise adding or introducing methyl alkyl halide to prepare the Grignard reagent, after the Grignard reagent is prepared, slowly dripping the standby epoxy solution for about 0.5-1.0 hour, after dripping, keeping the temperature at 10-80 ℃ for 8-10 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dripping strong acid solution within 1.0-1.5 hours, reacting for 4-8 hours at 40-100 ℃, TLC confirms the reaction end point, after the reaction is finished, firstly adding alkali liquor to neutralize the pH value of the system to 6-7, then decompressing and concentrating to recover about 90-95% of organic solvent, then adding tap water, stirring and crystallizing for 2-3 hours, filtering, washing with water, and drying to obtain a crude methyl product, wherein the HPLC content is 96.5-98.5%, and the weight yield is 78-82%; and (3) decoloring and recrystallizing the crude product by using alcohol and activated carbon to obtain a methyl substance: the content of HPLC (high performance liquid chromatography) of 6-methyl-norgestrel acetate is more than 99.0 percent, and the reaction weight yield of the step is 68-70 percent;
D. synthesis of nomegestrol acetate
Dissolving the methyl substance into an organic solvent, adding tetrachlorop-benzoquinone under stirring, heating to 60-120 ℃, carrying out reflux reaction for 8-12 hours, confirming the reaction end point by TLC, filtering out hydroquinone after the reaction is finished, washing with liquid alkali until the pH value of an organic layer is 6.8-7.2, then recovering the organic solvent, cooling and carrying out elutriation to obtain a crude nomegestrol acetate product with the HPLC content of 98.0-99.0% and the weight yield of 80-85%; recrystallizing the crude product by using lower alcohol with the carbon number of below 4 to obtain a nomegestrol acetate product with the melting point of 178-183 ℃, the HPLC content of 99.0-99.5 percent and the yield of 75-78 percent; the total yield of the four-step reaction synthesis is 60-62%.
Further, the reaction conditions for synthesizing norgestrel acetate are described as follows:
in the synthesis of the bisketal, the organic solvent is selected from one of dichloromethane, chloroform, toluene, DME, dioxane and THF; the acid catalyst used in the reaction can be one of hydrochloric acid, sulfuric acid and phosphoric acid, or one of acetic acid, p-toluenesulfonic acid and oxalic acid; the weak base used for neutralization is sodium carbonate or pyridine; the reaction temperature is 20-50 ℃; the weight ratio of reactants is, norgestrel acetate: triethyl orthoformate: ethylene glycol: acid = 1: 0.5-1.0: 0.3-0.6: 0.01 to 0.05; the ratio of reactants to solvent is norgestrel acetate: organic solvent =1 g: 2-8 ml;
the organic solvent in the epoxy compound synthesis is selected from one or two of methanol, ethanol, DME, tetrahydrofuran, chloroform and ethyl acetate; the alkali catalyst used in the epoxy reaction is one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; the reaction temperature of the epoxy reaction is 10-50 ℃; the weight ratio of reactants is, bis-ketal: alkali catalyst: hydrogen peroxide = 1: 0.2-0.4: 0.4 to 0.6; the ratio of reactants to solvent is, bis-ketal: organic solvent =1 g: 10-15 ml;
the organic solvent in the methyl compound synthesis is one or two of toluene, chloroform, dichloromethane, diethyl ether, DME, ethyl acetate, tetrahydrofuran and dioxane; the Grignard reagent is one of methyl magnesium chloride, magnesium bromide or magnesium iodide; the acid used in the acid catalyst for the Grignard acidolysis, deprotection acid hydrolysis and dehydration reaction is one of hydrochloric acid, sulfuric acid and phosphoric acid, or one of acetic acid, p-toluenesulfonic acid and oxalic acid; the Grignard reaction temperature is 10-80 ℃, and the hydrolysis and dehydration reaction temperature is 20-80 ℃; the weight ratio of the reactants is that: a Grignard reagent: acid catalyst = 1: 0.25-0.55: 0.5 to 1.5; the ratio of the reactants to the solvent is as follows: organic solvent =1 g: 10-20 ml;
the organic solvent in the nomegestrol acetate synthesis is selected from one of toluene, acetone, dioxane and DME, or one of common esters such as ethyl acetate; the reaction temperature is 40-120 ℃; the weight ratio of reactants is as follows: tetrachloro-p-benzoquinone = 1: 0.4 to 0.6; the ratio of the reactants to the solvent is as follows: organic solvent =1 g: 8-15 ml.
The optimized conditions for synthesizing nomegestrol acetate are as follows:
the organic solvent in the synthesis of the bisketal compound is dichloromethane or toluene; the acid catalyst used in the reaction is p-toluenesulfonic acid; the weak base used for neutralization is pyridine; the reaction temperature is 25-30 ℃; the weight ratio of reactants is, norgestrel acetate: triethyl orthoformate: ethylene glycol: acid = 1: 0.8: 0.5: 0.02; the ratio of reactants to solvent is norgestrel acetate: organic solvent =1 g: 6 ml;
the organic solvent in the epoxy compound synthesis is methanol; the alkali catalyst used in the epoxy reaction is sodium hydroxide; the reaction temperature of the epoxy reaction is 20-25 ℃; the weight ratio of reactants, bis-ketal: alkali catalyst: hydrogen peroxide = 1: 0.30: 0.45 of; the ratio of reactants to solvent is: bis-ketal compounds: organic solvent =1 g: 12 ml;
the organic solvent in the methyl compound synthesis is tetrahydrofuran; the Grignard reagent is methyl magnesium bromide; the acid used in the acid catalyst for the Grignard acidolysis, deprotection acid hydrolysis and dehydration reaction is hydrochloric acid or sulfuric acid; the Grignard reaction temperature is 50-55 ℃, and the hydrolysis and dehydration reaction temperature is 60-65 ℃; the weight ratio of the reactants is that: a Grignard reagent: acid catalyst = 1: 0.40: 1.0; the ratio of the reactants to the solvent is epoxy: organic solvent =1 g: 15 ml;
the organic solvent in the synthesis of the nomegestrol acetate is dioxane; the reaction temperature is 90-95 ℃; the weight ratio of reactants, methyl: tetrachloro-p-benzoquinone = 1: 0.5; the ratio of the reactants to the solvent is as follows: organic solvent =1 g: 10 ml.
The invention has the beneficial effects that: compared with the traditional synthesis method of nomegestrol acetate, the synthesis method has the advantages of short synthesis route, simple and convenient process operation, economic and environment-friendly production, high total synthesis yield, good product quality, low production cost and the like, avoids the defects of harsh reaction conditions, difficult environment-friendly treatment and the like required by adopting a Vickers reaction in the traditional process, and particularly avoids the defects of more impurities, low efficiency, high cost and the like caused by 6-position catalytic transposition reaction; the production cost is reduced by 35-40% compared with the traditional production method; the solvent used in the process can be recycled, is economical and environment-friendly, and is very beneficial to industrial production.
Drawings
FIG. 1 is a schematic diagram of a conventional synthesis process for nomegestrol acetate;
FIG. 2 is a schematic diagram of the synthesis process of nomegestrol acetate according to the invention.
Detailed Description
To illustrate the gist and spirit of the present invention in more detail, three examples are described below:
example one
A. Preparation of bisketals
Adding 100g norgestrel acetate, 600ml dichloromethane, 50g ethylene glycol, 80ml triethyl orthoformate and 2g p-toluenesulfonic acid into a 1000ml three-necked bottle, keeping the temperature to be kept at 25-30 ℃, stirring and reacting for 12-16 hours, detecting the reaction end point by TLC, adding 3ml pyridine after the reaction is finished, stirring for 20-25 minutes to neutralize the acid, then carrying out reduced pressure concentration, recovering 90-95% dichloromethane, then adding 600ml tap water, stirring and crystallizing for 3-4 hours at 10-15 ℃, centrifuging, washing with water to obtain a crude bisketal product, directly adding the crude bisketal product into 800ml50% alcohol without drying, firstly refluxing for 1-1.5 hours, then distilling out about 400ml alcohol under normal pressure, then cooling the system to-5-0 ℃, stirring and crystallizing for 2-3 hours, carrying out suction filtration, washing with a small amount of ethanol, drying a filter cake below 70 ℃ to obtain 118.6g bisketal, HPLC content 99.2%, weight yield 118.6%. Combining the washing liquid and the filtrate, and recovering the solvent and the crude product to be respectively used in the next refining process;
B. preparation of epoxy
Adding 100g of the self-made etherate and 1200ml of methanol into a 2000ml three-necked bottle, adding 100g of 30% caustic soda solution under stirring, controlling the temperature to be 20-25 ℃, slowly dripping 150g of 30% hydrogen peroxide, finishing the addition within 0.5-1.0 hour, continuing to perform heat preservation stirring reaction for 12-16 hours after finishing the dripping, detecting the reaction end point by TLC (thin layer chromatography), adding 30g of sodium hydrosulfite after the reaction is finished, stirring for reaction for 0,5-1.0 hour to destroy redundant hydrogen peroxide, slowly dripping 2N hydrochloric acid to pH6.5-7.0, concentrating under reduced pressure to recover 90-95% of methanol after finishing the dripping, then adding 500ml of tap water, stirring for crystallization for 2-3 hours, filtering, washing with water, and drying to obtain a crude epoxy product; and adding the crude epoxy product into 600ml of alcohol, heating to dissolve the crude epoxy product, adding 5g of activated carbon, refluxing and decoloring for 1-1.5 hours, filtering while the solution is hot, soaking and washing a filter cake with about 80ml of alcohol, combining filtrate and washing solution, concentrating at normal pressure until about 85% alcohol is recovered, cooling the system to 0-5 ℃, stirring and crystallizing for 2-3 hours, filtering, washing the filter cake with 10ml of 50% ethanol solution, drying at the temperature of below 70 ℃ to obtain 98.8g of epoxy, wherein the HPLC content is 99.2%, the weight yield is 98.8%, combining the filtrate and the washing solution, and recovering alcohol and epoxy mother solution which are respectively used in the next refining process.
C. Preparation of methyl
Adding 100g of the self-made epoxy and 800ml of THF into a 1000ml three-necked bottle, stirring and heating to 40-45 ℃ to completely dissolve the epoxy, and slowly cooling for later use; adding 700ml of THF and 10g of magnesium metal powder into another 2000ml reaction bottle, replacing air, starting to slowly introduce methyl bromide at 30-35 ℃ until magnesium metal completely reacts, stopping introducing methyl bromide, continuously keeping the temperature and stirring for reaction for 1-1.5 hours, continuously heating to 50-55 ℃, starting to dropwise add the standby epoxy solution, finishing dropwise addition within 1.0-1.5 hours, continuously keeping the temperature and reacting at 50-55 ℃ for 8-10 hours after finishing dropwise addition, detecting the reaction end point by TLC, slowly dropwise adding 300ml of 30% hydrochloric acid after finishing reaction, finishing dropwise addition within 1.5-2.0 hours, continuously keeping the temperature and stirring for reaction at 60-65 ℃ for 6-8 hours after finishing dropwise addition, detecting the reaction end point by TLC, concentrating first after reaction, recovering 90-95% of THF under reduced pressure, adding 800ml of tap water, cooling to 10-15 ℃, stirring for crystallization for 3-4 hours, filtering, washing and drying to obtain a crude methyl product, combining the filtrate with a washing liquid, concentrating under reduced pressure to recover residual solvent, and discharging into a wastewater treatment tank; then, the crude product is decolored and recrystallized by alcohol and active carbon according to a conventional method to obtain 69.5g of methyl substance, the HPLC content is 99.2 percent, and the weight yield is 69.5 percent.
D. Preparation of nomegestrol acetate
Adding 100g of the self-made methyl and 1000ml of dioxane into a 2000ml three-necked bottle, adding 50g of tetrachlorop-benzoquinone under stirring, slowly heating to 90-95 ℃, keeping the temperature, stirring, reacting for 8-12 hours, confirming the reaction end point by TLC, filtering out hydroquinone after the reaction is finished, washing twice by 400ml of 30% liquid alkali until the pH value of an organic layer is 6.8-7.2, then carrying out reduced pressure concentration, recovering 90-85% of dioxane, adding 600ml of tap water, cooling to 10-15 ℃, stirring, crystallizing for 2-3 hours, filtering, washing by water to be neutral, drying a filter cake below 70 ℃, and obtaining 84.2g of a nomegestrol crude product with the HPLC content of 98.8% and the weight yield of 84.2%; combining the filtrate and the washing liquid, recovering the residual solvent and discharging into a wastewater treatment tank; the crude product is decolored and recrystallized by alcohol and activated carbon according to a conventional method to obtain 77.8g of nomegestrol acetate, the melting point is 178-183 ℃, the HPLC content is 99.5 percent, and the yield is 77.8 percent.
Example two
A. Preparation of bisketals
Adding 100g of norgestrel acetate, 600ml of toluene, 50g of ethylene glycol, 80ml of triethyl orthoformate and 2g of 98% sulfuric acid into a 1000ml three-necked bottle, keeping the temperature, stirring and reacting at 25-30 ℃ for 12-16 hours, detecting the reaction end point by TLC (thin layer chromatography), adding 3ml of pyridine after the reaction is finished, stirring for 20-25 minutes to neutralize the acid, then carrying out reduced pressure concentration, recovering 90-95% of toluene, then adding 600ml of tap water, stirring and crystallizing at 10-15 ℃ for 3-4 hours, centrifuging, washing with water, and obtaining a crude bisketal. The crude product is directly added into 800ml of 50% alcohol without drying, firstly reflows for 1-1.5 hours, then about 400ml of alcohol is evaporated under normal pressure, then the system is cooled to-5-0 ℃, stirred and crystallized for 2-3 hours, filtered, washed by a small amount of ethanol, and a filter cake is dried below 70 ℃ to obtain 116.8g of bisketal, the HPLC content is 99.5%, and the weight yield is 116.8%. Combining the washing liquid and the filtrate, and recovering the solvent and the crude product to be respectively used in the next refining process;
preparation of the B epoxy
Adding 100g of the self-made etherate and 1200ml of ethanol into a 2000ml three-neck flask, adding 100g of 30% caustic soda solution under stirring, controlling the temperature to be 20-25 ℃, slowly dripping 150g of 30% hydrogen peroxide, finishing the addition within about 0.5-1.0 hour, continuing to perform heat preservation and stirring reaction for 12-16 hours after finishing the dripping, detecting the reaction end point by TLC (thin layer chromatography), adding 30g of sodium bisulfite after the reaction is finished, stirring and reacting for 0.5-1.0 hour to destroy redundant hydrogen peroxide, slowly dripping 2N hydrochloric acid to pH6.5-7.0, concentrating under reduced pressure and recovering 90-95% methanol after finishing the dripping, then adding 500ml of tap water, stirring and crystallizing for 2-3 hours, filtering, washing with water, and drying to obtain a crude epoxy product; and adding the crude epoxy product into 600ml of alcohol, heating to dissolve the crude epoxy product, adding 5g of activated carbon, refluxing and decoloring for 1-1.5 hours, filtering while the solution is hot, soaking and washing a filter cake with about 80ml of alcohol, combining filtrate and washing solution, concentrating at normal pressure until about 85% alcohol is recovered, cooling the system to 0-5 ℃, stirring and crystallizing for 2-3 hours, filtering, washing the filter cake with 10ml of 50% ethanol solution, drying at the temperature of below 70 ℃ to obtain 97.6g of epoxy, wherein the HPLC content is 99.4%, the weight yield is 97.6%, combining the filtrate and the washing solution, and recovering alcohol and epoxy mother solution which are respectively used in the next refining process.
Preparation of C methyl
Adding 100g of the self-made epoxy and 800ml of toluene into a 1000ml three-neck bottle, stirring and heating to 40-45 ℃ to completely dissolve the epoxy, and slowly cooling for later use; adding 700ml of THF and 10g of magnesium metal powder into another 2000ml reaction bottle, replacing air, starting to slowly introduce methyl chloride at 30-35 ℃ until magnesium metal completely reacts, stopping introducing methyl chloride, continuously keeping the temperature and stirring for reaction for 1-1.5 hours, heating to 50-55 ℃, starting to dropwise add the standby epoxy solution, finishing dropwise adding after 1.0-1.5 hours, continuously keeping the temperature and reacting at 50-55 ℃ for 8-10 hours after finishing dropwise adding, detecting the reaction end point by TLC, slowly dropwise adding 200ml of 50% sulfuric acid after finishing the reaction, finishing dropwise adding after 1.5-2.0 hours, continuously keeping the temperature and stirring for reaction at 60-65 ℃ for 6-8 hours after finishing dropwise adding, detecting the reaction end point by TLC, concentrating firstly after finishing the reaction, recovering 90-95% of decompressed THF and toluene, adding 800ml of tap water, cooling to 10-15 ℃, stirring for crystallization for 3-4 hours, filtering, washing and drying to obtain a crude methyl product, combining the filtrate with a washing liquid, concentrating under reduced pressure to recover residual solvent, and discharging into a wastewater treatment tank; then, the crude product is decolored and recrystallized by alcohol and active carbon according to a conventional method to obtain 68.9g of methyl substance, the HPLC content is 99.5 percent, and the weight yield is 68.9 percent.
Preparation of D nomegestrol acetate
Adding 100g of the self-made methyl and 1000ml of ethyl acetate into a 2000ml three-necked bottle, adding 50g of tetrachlorop-benzoquinone under stirring, slowly heating to 75-80 ℃, keeping the temperature and stirring for reaction for 8-12 hours, confirming the reaction end point by TLC, filtering out hydroquinone after the reaction is finished, washing the hydroquinone twice by 400ml of 30% liquid alkali till the pH value of an organic layer is 6.8-7.2, then carrying out reduced pressure concentration, recovering 90-85% of ethyl acetate, then adding 600ml of tap water, cooling to 10-15 ℃, stirring for crystallization for 2-3 hours, filtering, washing by water to be neutral, drying a filter cake at the temperature of below 70 ℃ to obtain 82.6g of a nomegestrol crude product with the HPLC content of 98.5% and the weight yield of 82.6%; combining the filtrate and the washing liquid, recovering the residual solvent and discharging into a wastewater treatment tank; the crude product is decolored and recrystallized by alcohol and active carbon according to a conventional method to obtain 76.9g of nomegestrol acetate, the melting point is 178-182 ℃, the HPLC content is 99.4 percent, and the yield is 76.9 percent.
EXAMPLE III
A. Preparation of bisketals
Adding 100g norgestrel acetate, 600ml dichloromethane, 50g ethylene glycol, 80ml triethyl orthoformate and 10g hydrochloric acid ethanol solution into a 1000ml three-necked bottle, keeping the temperature at 25-30 ℃, stirring and reacting for 12-16 hours, detecting the reaction end point by TLC, adding 3ml pyridine after the reaction is finished, stirring for 20-25 minutes to neutralize the acid, then carrying out reduced pressure concentration, recovering 90-95% dichloromethane, then adding 600ml tap water, stirring and crystallizing for 3-4 hours at 10-15 ℃, centrifuging, washing with water, and obtaining the crude bisketal. The crude product is directly added into 800ml of 50% alcohol without drying, firstly reflows for 1-1.5 hours, then about 400ml of alcohol is evaporated under normal pressure, then the system is cooled to-5-0 ℃, stirred and crystallized for 2-3 hours, filtered, washed by a small amount of ethanol, and the filter cake is dried below 70 ℃ to obtain 116.2g of the bisketal, the HPLC content is 99.6%, and the weight yield is 116.2%. The washing liquid and the filtrate are combined, and the recovered solvent and the crude product are respectively used in the next refining process.
Preparation of the B epoxy
Adding 100g of the self-made etherate and 1200ml of DME into a 2000ml three-necked bottle, adding 100g of 30% sodium carbonate solution under stirring, controlling the temperature to be 20-25 ℃, slowly dripping 150g of 30% hydrogen peroxide, finishing the addition within 0.5-1.0 hour, continuing to perform heat preservation stirring reaction for 12-16 hours after finishing the dripping, detecting the reaction end point by TLC (thin layer chromatography), firstly adding 30g of sodium thiosulfate after the reaction is finished, stirring and reacting for 0.5-1.0 hour to destroy redundant hydrogen peroxide, then slowly dripping 2N sulfuric acid to pH6.5-7.0, concentrating under reduced pressure and recovering 90-95% of DME after finishing the dripping, then adding 500ml of tap water, stirring and crystallizing for 2-3 hours, filtering, washing with water, and drying to obtain a crude epoxy product; and adding the crude epoxy product into 600ml of alcohol, heating to dissolve the crude epoxy product, adding 5g of activated carbon, refluxing and decoloring for 1-1.5 hours, filtering while the solution is hot, soaking and washing a filter cake with about 80ml of alcohol, combining filtrate and washing solution, concentrating at normal pressure until about 85% alcohol is recovered, cooling the system to 0-5 ℃, stirring and crystallizing for 2-3 hours, filtering, washing the filter cake with 10ml of 50% ethanol solution, drying at the temperature of below 70 ℃ to obtain 96.5g of epoxy, wherein the HPLC content is 99.4%, the weight yield is 96.5%, combining the filtrate and the washing solution, and recovering alcohol and epoxy mother solution which are respectively used in the next refining process.
Preparation of C methyl
Adding 100g of the self-made epoxy and 800ml of chloroform into a 1000ml three-necked bottle, stirring and heating to 40-45 ℃ to completely dissolve the epoxy, and slowly cooling for later use; adding 700ml of diethyl ether and 10g of metal magnesium powder into another 2000ml reaction bottle, replacing air, then beginning to slowly drip methyl iodide at 35-40 ℃ until metal magnesium completely reacts, stopping adding methyl iodide, continuing to keep warm and stir for reaction for 1-1.5 hours, continuing to heat to 50-55 ℃, beginning to drip the standby epoxy solution, finishing dripping within 1.0-1.5 hours, continuing to keep warm and react at 50-55 ℃ for 8-10 hours after finishing dripping, detecting the reaction end point by TLC, after finishing the reaction, slowly dripping 300ml of 30% hydrochloric acid, finishing dripping within 1.5-2.0 hours, continuing to keep warm and stir for reaction at 60-65 ℃ for 6-8 hours after finishing dripping, detecting the reaction end point by TLC, concentrating firstly after finishing the reaction, recovering 90-95% decompressed diethyl ether and chloroform, adding 800ml of tap water, cooling to 10-15 ℃, stirring for crystallization for 3-4 hours, filtering, washing and drying to obtain a crude methyl product, combining the filtrate and a washing solution, concentrating under reduced pressure, recovering the residual solvent and then discharging into a wastewater treatment tank; then, the crude product is decolored and recrystallized by alcohol and active carbon according to a conventional method to obtain 68.7g of methyl substance, the HPLC content is 99.3 percent, and the weight yield is 68.7 percent.
Preparation of D nomegestrol acetate
Adding 100g of the self-made methyl and 1000ml of toluene into a 2000ml three-necked bottle, adding 50g of tetrachlorop-benzoquinone under stirring, slowly heating to 105-110 ℃, keeping the temperature and stirring for reaction for 8-12 hours, confirming the reaction end point by TLC, filtering out hydroquinone after the reaction is finished, washing the organic layer twice by 400ml of 30% liquid alkali until the pH value of the organic layer is 6.8-7.2, then carrying out reduced pressure concentration, recovering 90-85% of dioxane, adding 600ml of tap water, cooling to 10-15 ℃, stirring for crystallization for 2-3 hours, filtering, washing the filter cake to be neutral, drying the filter cake below 70 ℃ to obtain 82.8g of crude nomegestrol acetate, wherein the HPLC content is 98.6%, and the weight yield is 82.8%; combining the filtrate and the washing liquid, recovering the residual solvent and discharging into a wastewater treatment tank; the crude product is decolored and recrystallized by alcohol and active carbon according to a conventional method to obtain 76.2g of nomegestrol acetate, the melting point is 179-183 ℃, the HPLC content is 99.5 percent, and the yield is 76.2 percent.
Claims (4)
1. The preparation method of nomegestrol acetate takes nomegestrol acetate as a raw material, and is characterized in that a bisketal compound is synthesized firstly, an epoxide compound is synthesized secondly, then a methyl compound is synthesized, and finally nomegestrol acetate is synthesized, namely:
A. synthesizing a bisketal compound, namely reacting norgestrel acetate with ethylene glycol in an organic solvent under the catalysis of triethyl orthoformate to obtain the bisketal compound: 3, 20-diacetone-norgestrel acetate;
B. the epoxy compound is synthesized by dissolving the bisketal compound in an organic solvent, and reacting 5, 6-bit double bonds in molecules with hydrogen peroxide under the catalysis of alkali to obtain the epoxy compound: 3, 20-diacetone-5 (6) a-epoxy-17 a-acetoxy-19-nor-pregn-3, 20-dione;
C. the methyl compound is synthesized by the following steps that firstly, the epoxy compound and a methyl magnesium halide Grignard reagent are subjected to Grignard reaction in an organic solvent to obtain a Grignard compound, one of hydrochloric acid, sulfuric acid and phosphoric acid is directly added to the Grignard compound without being taken out of a pot, dehydration reaction is carried out at the 5-position, and double deprotection reaction is carried out at the 3-position and the 20-position to obtain the methyl compound: 6-methyl-norgestrel acetate;
D. the synthesis of nomegestrol acetate is that 6-position dehydrogenation reaction of methyl compound and tetrachloro-p-benzoquinone in organic solvent to obtain nomegestrol acetate.
2. The method for preparing nomegestrol acetate according to claim 1, which comprises the following steps:
A. synthesis of bisketal compounds
Dissolving norgestrel acetate in an organic solvent, reacting with ethylene glycol under acid catalysis in the presence of triethyl orthoformate at 20-50 ℃ for 12-16 hours while stirring, confirming the reaction end point by TLC, adding weak base to neutralize to pH 7-7.5 after the reaction is finished, and further carrying out post-treatment to obtain a bisketal: the HPLC content of the 3, 20-diacetone-norgestrel acetate is 97.5-98.5%, and the weight yield is 115-120%;
B. synthesis of epoxy
Dissolving the bisketal in an organic solvent, adding an alkali catalyst, slowly dripping hydrogen peroxide at 10-50 ℃, finishing the addition for 1-1.5 hours, keeping the temperature at 10-50 ℃, continuously stirring and reacting for 10-16 hours, confirming the reaction end point by TLC (thin layer chromatography), adding a reducing agent to destroy residual hydrogen peroxide after the reaction is finished, adding an acid to neutralize the system to pH7.5-8.0, and further performing post-treatment to obtain the epoxy compound: 3, 20-diacetone-5 (6) a-epoxy-17 a-acetoxy-19-nor-pregna-3, 20-dione, with HPLC content of 98.0-99.0% and weight yield of 95-100%;
C. synthesis of methyl
Dissolving the epoxy in an organic solvent to prepare a solution for later use; adding organic solvent and magnesium powder into another reaction bottle, stirring, controlling the temperature at 10-50 ℃, dropwise adding or introducing methyl alkyl halide to prepare the Grignard reagent, after the Grignard reagent is prepared, slowly dripping the standby epoxy solution for 0.5-1.0 hour, keeping the temperature at 10-80 ℃ after dripping for 8-10 hours, confirming the reaction end point by TLC, after the reaction is finished, slowly dripping one of hydrochloric acid, sulfuric acid and phosphoric acid within 1.0-1.5 hours, reacting for 4-8 hours at 40-100 ℃, TLC confirms the reaction end point, after the reaction is finished, alkali liquor is added to neutralize the pH value of the system to 6-7, then the organic solvent is recovered by decompression and concentration to about 90-95%, then adding tap water, stirring and crystallizing for 2-3 hours, filtering, washing with water, and drying to obtain a crude methyl product, wherein the HPLC content is 96.5-98.5%, and the weight yield is 78-82%; and (3) decoloring and recrystallizing the crude product by using alcohol and activated carbon to obtain a methyl substance: the content of HPLC (high performance liquid chromatography) of 6-methyl-norgestrel acetate is more than 99.0 percent, and the reaction weight yield of the step is 68-70 percent;
D. synthesis of nomegestrol acetate
Dissolving the methyl substance into an organic solvent, adding tetrachlorop-benzoquinone under stirring, heating to 60-120 ℃, carrying out reflux reaction for 8-12 hours, confirming the reaction end point by TLC, filtering out hydroquinone after the reaction is finished, washing with liquid alkali until the pH value of an organic layer is 6.8-7.2, then recovering the organic solvent, cooling and carrying out elutriation to obtain a crude nomegestrol acetate product with the HPLC content of 98.0-99.0% and the weight yield of 80-85%; recrystallizing the crude product by using lower alcohol with the carbon number of below 4 to obtain a nomegestrol acetate product with the melting point of 178-183 ℃, the HPLC content of 99.0-99.5 percent and the yield of 75-78 percent; the total yield of the four-step reaction synthesis is 60-62%.
3. The method for preparing nomegestrol acetate according to claim 1 or 2, wherein the nomegestrol acetate is synthesized under the following reaction conditions:
A. in the synthesis of the bisketal compound, the organic solvent is selected from one of dichloromethane, chloroform, toluene, ethylene glycol dimethyl ether, dioxane and tetrahydrofuran; the acid catalyst used in the reaction is selected from one of hydrochloric acid, sulfuric acid and phosphoric acid, or one of acetic acid and p-toluenesulfonic acid; the weak base used for neutralization is sodium carbonate or pyridine; the reaction temperature is 20-50 ℃; the weight ratio of reactants is, norgestrel acetate: triethyl orthoformate: ethylene glycol: acid 1: 0.5-1.0: 0.3-0.6: 0.01 to 0.05; the ratio of reactants to solvent is norgestrel acetate: organic solvent ═ 1 g: 2-8 ml;
B. the organic solvent in the epoxy compound synthesis is selected from one or two of methanol, ethanol, ethylene glycol dimethyl ether, tetrahydrofuran, chloroform and ethyl acetate; the alkali catalyst used in the epoxy reaction is one of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; the reaction temperature is 10-50 ℃; the weight ratio of reactants is, bis-ketal: alkali catalyst: hydrogen peroxide 1: 0.2-0.4: 0.4 to 0.6; the ratio of reactants to solvent is, bis-ketal: organic solvent ═ 1 g: 10-15 ml;
C. the organic solvent in the methyl compound synthesis is one or two of toluene, chloroform, dichloromethane, diethyl ether, ethylene glycol dimethyl ether, ethyl acetate, tetrahydrofuran and dioxane; the Grignard reagent is one of methyl magnesium chloride, magnesium bromide or magnesium iodide; the acid used in the acid catalyst for the Grignard acidolysis, deprotection acid hydrolysis and dehydration reaction is one of hydrochloric acid, sulfuric acid and phosphoric acid, or one of acetic acid and p-toluenesulfonic acid; the Grignard reaction temperature is 10-80 ℃, and the hydrolysis and dehydration reaction temperature is 20-80 ℃; the weight ratio of the reactants is that: a Grignard reagent: acid catalyst ═ 1: 0.25-0.55: 0.5 to 1.5; the ratio of the reactants to the solvent is as follows: organic solvent ═ 1 g: 10-20 ml;
D. the organic solvent in the synthesis of nomegestrol acetate is one of toluene, acetone, dioxane, ethylene glycol dimethyl ether and ethyl acetate; the reaction temperature is 40-120 ℃; the weight ratio of reactants is as follows: tetrachloro-p-benzoquinone ═ 1: 0.4 to 0.6; the ratio of the reactants to the solvent is as follows: organic solvent ═ 1 g: 8-15 ml.
4. A process for the preparation of nomegestrol acetate as claimed in claim 1 or 2, wherein the conditions for the synthesis of nomegestrol acetate are optimized as follows:
A. the organic solvent in the synthesis of the bisketal compound is dichloromethane or toluene; the acid catalyst used in the reaction is p-toluenesulfonic acid; the weak base used for neutralization is pyridine; the reaction temperature is 25-30 ℃; the weight ratio of reactants is, norgestrel acetate: triethyl orthoformate: ethylene glycol: acid 1: 0.8: 0.5: 0.02; the ratio of reactants to solvent is norgestrel acetate: organic solvent ═ 1 g: 6 ml;
B. the organic solvent in the epoxy synthesis is methanol; the alkali catalyst is sodium hydroxide; the reaction temperature is 20-25 ℃; the weight ratio of reactants, bis-ketal: alkali catalyst: hydrogen peroxide 1: 0.30: 0.45 of; the ratio of reactants to solvent is: bis-ketal compounds: organic solvent ═ 1 g: 12 ml;
C. the organic solvent in the methyl synthesis is tetrahydrofuran; the Grignard reagent is methyl magnesium bromide; the acid used in the acid catalyst for the Grignard acidolysis, deprotection acid hydrolysis and dehydration reaction is hydrochloric acid or sulfuric acid; the Grignard reaction temperature is 50-55 ℃, and the hydrolysis and dehydration reaction temperature is 60-65 ℃; the weight ratio of the reactants is that: a Grignard reagent: acid catalyst ═ 1: 0.40: 1.0; the ratio of the reactants to the solvent is epoxy: organic solvent ═ 1 g: 15 ml;
D. the organic solvent in the synthesis of nomegestrol acetate is dioxane; the reaction temperature is 90-95 ℃; the weight ratio of reactants, methyl: tetrachloro-p-benzoquinone ═ 1: 0.5; the ratio of the reactants to the solvent is as follows: organic solvent ═ 1 g: 10 ml.
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