CN111018935A - Synthetic method of ulipristal acetate intermediate - Google Patents
Synthetic method of ulipristal acetate intermediate Download PDFInfo
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- CN111018935A CN111018935A CN201911411491.8A CN201911411491A CN111018935A CN 111018935 A CN111018935 A CN 111018935A CN 201911411491 A CN201911411491 A CN 201911411491A CN 111018935 A CN111018935 A CN 111018935A
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- C07—ORGANIC CHEMISTRY
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- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
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Abstract
A method for synthesizing an ulipristal acetate intermediate, the method comprising the steps of: 1) dissolving the 3-ketal compound (I) in ethyl acetate, adding acetone cyanohydrin, and reacting with triethylamine to obtain 17-cyanohydrin compound (II); 2) protection reaction, adding dichloromethane, imidazole and a silylation reagent into a wet product of 17-cyanohydrin (II), preserving heat at 20-25 ℃ until the raw materials completely react to obtain a protection product (III), 3) methylation reaction, adding an ether solvent into the wet product of the protection product (III), controlling the temperature to be-10-5 ℃, dropwise adding a methyllithium solution, controlling the temperature to be-40-5 ℃ for reaction until the raw materials completely react to obtain a methide (IV-1) solution, 4) adding glycol, triethyl orthoformate and p-toluenesulfonic acid (PTS) into the solution of the ketal reaction methide (IV-1), and preserving heat at 20-25 ℃ for reaction until the raw materials completely react to obtain a bisketal compound (V).
Description
Technical Field
The invention relates to a method for synthesizing a steroid compound.
Background
Ulipristal acetate (also known as ulipristal acetate) is a selective progesterone receptor modulator developed by HRA pharmaceutical, france, to exert an emergency contraceptive effect, mainly by inhibiting ovulation. In 5 months 2009 ulipristal acetate was first approved by the european union for oral administration 120 hours after unprotected sexual intercourse or contraceptive failure, under the trade name elaone; the us FDA approved ulipristal acetate to be marketed in 8 months 2010 as well.
3, 20-bis (ethylenedioxy) -19-norpregna-5, 9-dien-17-ol (bisketal) is the most important intermediate of ulipristal acetate.
Another synthesis is reported in US 5929262. The method takes a 3-ketal (I) as a raw material, reacts with sodium cyanide or potassium cyanide to convert the 3-ketal into a 17-cyanohydrin (II), the hydroxyl group at the 17 position is protected by chloromethyl (dimethyl) chlorosilane, the protected protector (III) generates intramolecular nucleophilic addition reaction under the action of lithium/di-tert-butyl biphenyl, methyl is introduced in this way, then pregnadienol (IV-1) is obtained under the action of acid, and then two carbonyl groups on the pregnadienol are protected by ethylene glycol to obtain a bisketal (V). The biggest problem of the route is to use the highly toxic sodium cyanide or potassium cyanide, and the ultralow temperature reaction is involved in the route, which is also a great problem for industrial production.
The synthetic route is shown as follows
Therefore, on the basis of the existing technical route, the preparation method of the key intermediate bisketal of ulipristal acetate is provided by improving the process, the procedures that highly toxic cyanide is needed and ultralow temperature adjustment is needed are replaced, the total reaction yield is further improved, and the problems to be solved in the prior art are further solved.
Disclosure of Invention
In order to solve the problems, on the basis of a synthesis method reported in US5929262, some improvements are made, acetone cyanohydrin is used for replacing highly toxic sodium cyanide or potassium cyanide, a methyllithium reagent is used for methylation addition after 17-bit hydroxyl group protection, di-tert-butyl biphenyl is avoided, ultralow temperature reaction is not used, and 20-bit ketone group protection is directly carried out after methylation reaction, so that a bisketal compound can be obtained.
The technical scheme provided by the invention is as follows: a synthetic method of ulipristal acetate intermediate is disclosed, wherein the synthetic route is as follows
Characterized in that the synthesis method comprises the following steps
1) Cyano reaction
Dissolving the 3-ketal compound (I) in ethyl acetate, adding acetone cyanohydrin and triethylamine, carrying out heat preservation reaction at 40-65 ℃ until the raw materials completely react, carrying out reduced pressure concentration until no distillate exists, adding ethyl acetate, stirring, cooling, crystallizing, filtering and discharging to obtain the 17-cyanohydrin compound (II).
2) Protection reaction
Adding dichloromethane, imidazole and a silanization reagent into the wet 17-cyanohydrin (II) obtained in the step 1), keeping the temperature at 20-25 ℃ until the raw materials react completely, filtering, washing with water, concentrating under normal pressure until no distillate exists, adding petroleum ether, stirring, cooling, filtering and discharging to obtain a protective substance (III), wherein the silanization reagent is selected from one of chloromethyl dimethylchlorosilane, trimethylchlorosilane and tert-butyldimethylchlorosilane,
3) methylation reaction
Adding an ether solvent into the wet product of the protective substance (III), controlling the temperature to be minus 10-5 ℃, dropwise adding a methyllithium solution, controlling the temperature to be minus 40-5 ℃, reacting until the raw materials completely react, and adding water for quenching. Concentrating under reduced pressure until no distillate exists, adding dichloromethane for dissolution, washing with dilute acid water, standing for layering, adding anhydrous sodium sulfate into the organic phase for dehydration, and filtering to obtain a methylated compound (IV-1) solution, wherein the ether solvent is selected from one of diethoxymethane, tetrahydrofuran, diethyl ether and dimethyltetrahydrofuran;
4) ketal reaction
Adding ethylene glycol, triethyl orthoformate and p-toluenesulfonic acid (PTS) into a methylated compound (IV-1) solution, carrying out heat preservation reaction at 20-25 ℃ until the raw materials are completely reacted, adding an alkaline aqueous solution to quench, washing with water, standing for layering, collecting an organic phase, concentrating under normal pressure until no distillate exists, adding ethanol, stirring, cooling, filtering, discharging, and drying to obtain a bisketal compound (V), wherein the alkaline aqueous solution is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine solution.
The synthesis method of the ulipristal acetate intermediate is further characterized in that in the step 1), in the cyano reaction, the reaction temperature is 50-55 ℃, and the mass ratio of the 3-ketal (I) serving as the substrate to other raw materials in the cyano reaction is 3-ketal (I): ethyl acetate to dissolve 3-ketal (I): acetone cyanohydrin: triethylamine is 1:1 to 10:0.15 to 2:0.1 to 0.5. .
The synthetic method of the ulipristal acetate intermediate is further characterized in that the silylation reagent in the protection reaction in the step 2) is chloromethyl dimethylchlorosilane, and the mass ratio of the raw material of the protection reaction to the initially added 3-ketal (I) is dichloromethane: imidazole: chloromethyl dimethylchlorosilane: 3-ketal (I) of 5 to 30:0.3 to 1: 1.
the synthetic method of the ulipristal acetate intermediate is further characterized in that in the methylation reaction in the step 3), the reaction temperature is-10-5 ℃, the ether solvent is diethoxymethane, the acid added by dilute acid water washing is acetic acid, hydrochloric acid or sulfuric acid, the concentration is 15-70%, the concentration of a methyllithium solution is 1.0-2.5M, and the mass ratio of other raw materials of the methylation reaction to the initially-added 3-ketal (I) is diethoxymethane: methyl lithium solution: 3-ketal (I) is 2-10: 1.5-5.0: 1.
further, the alkaline aqueous solution of the ketal reaction is triethylamine solution, and the mass ratio of other raw materials of the ketal reaction to the initially input 3-ketal (I) is ethylene glycol: triethyl orthoformate: PTS: 3-ketal (I) is 0.2 to 1: 0.5-2: 0.1-0.4: 1.
the synthetic method of the ulipristal acetate intermediate further has the working pressure of 10-40 KPa during reduced pressure concentration.
Compared with the prior art, the synthetic method of the ulipristal acetate intermediate provided by the invention has the advantages that the operation is simpler, the toxicity is lower, the ultralow temperature reaction is avoided, the energy is saved, one-step reaction is reduced, the total mass yield reaches 82-88%, the molar yield is improved to 64.06% -68.75%, the cost of raw and auxiliary materials is greatly reduced, and meanwhile, after the reaction of the intermediate step is finished, the product can be directly put into the next reaction in a wet product or solution state without being dried, the operation is simple and convenient, the drying link is reduced, and the labor and energy costs are saved.
Detailed Description
Example 1 Synthesis of Ulipristal acetate intermediate, the synthetic route is as follows
Comprises the following steps
1) And (3) cyano reaction:
adding 100kg of 3-ketal (I) into 150kg of ethyl acetate, 50kg of acetone cyanohydrin and 10kg of triethylamine, keeping the temperature at 50-55 ℃ for reaction for 12 hours, analyzing the raw materials by TLC to react completely, concentrating under reduced pressure until no effluent liquid exists in a sight glass, adding 100kg of ethyl acetate, stirring, cooling to 0-5 ℃, centrifuging, and discharging to obtain a wet product of the 17-cyanohydrin (II).
2) Protection reaction
Adding 1000kg of dichloromethane, 40kg of imidazole and 40kg of chloromethyl dimethylchlorosilane into the wet 17-cyanohydrin (II) obtained in the step 1), stirring and reacting for 6 hours, filtering, washing the filtrate with 200kg of water, concentrating under normal pressure until no effluent exists from a sight glass, adding 100kg of petroleum ether, stirring and cooling to 0-5 ℃, centrifuging, and discharging to obtain the wet protective agent (III).
3) Methylation reaction
Adding 300kg of diethoxymethane into the wet product of the protective substance (III), stirring and cooling to-5 ℃, dropwise adding 200kg of methyllithium solution (1.5M, diethoxymethane) to react for 4 hours, analyzing the complete reaction of raw materials by TLC, slowly adding 100kg of water, concentrating under reduced pressure until no effluent liquid exists on a viewing mirror, adding 1000kg of dichloromethane to dissolve, adding 50kg of 18.5% hydrochloric acid solution to wash and separate layers, adding anhydrous sodium sulfate into an organic phase to dehydrate and stir for 1 hour, and filtering to obtain a methylated substance (IV-1) solution.
4. Ketal reaction
Adding 20kg of ethylene glycol, 70kg of triethyl orthoformate and 15kg of PTS into the methylated compound (IV-1) solution, stirring and reacting for 2 hours, adding 15kg of triethylamine and 200kg of water, washing and layering, concentrating under normal pressure until no effluent exists from a sight glass, adding 100kg of ethanol, stirring and cooling to 0-5 ℃, centrifuging, discharging, and drying to obtain 85kg of bisketal. HPLC is more than or equal to 99.0 percent, and single impurity is less than or equal to 0.5 percent.
Claims (5)
1. A synthetic method of ulipristal acetate intermediate is disclosed, wherein the synthetic route is as follows
Characterized in that the synthesis method comprises the following steps
1) Cyano reaction
Dissolving the 3-ketal compound (I) in ethyl acetate, adding acetone cyanohydrin and triethylamine, carrying out heat preservation reaction at 40-65 ℃ until the raw materials completely react, carrying out reduced pressure concentration until no distillate exists, adding ethyl acetate, stirring, cooling, filtering and discharging to obtain a 17-cyanohydrin compound (II);
2) protection reaction
Adding dichloromethane, imidazole and a silanization reagent into the wet 17-cyanohydrin (II) obtained in the step 1), keeping the temperature at 20-25 ℃ until the raw materials react completely, filtering, washing, concentrating under normal pressure until no distillate exists, adding petroleum ether, stirring, cooling, filtering and discharging to obtain a protective substance (III), wherein the silanization reagent is selected from one of chloromethyl dimethylchlorosilane, trimethylchlorosilane and tert-butyldimethylchlorosilane;
3) methylation reaction
Adding an ether solvent into the wet product of the protective substance (III), controlling the temperature to be minus 10-5 ℃, dropwise adding a methyllithium solution, controlling the temperature to be minus 40-5 ℃, reacting until the raw materials completely react, and adding water for quenching. Concentrating under reduced pressure until no distillate exists, adding dichloromethane for dissolution, washing with dilute acid water, standing for layering, adding anhydrous sodium sulfate into the organic phase for dehydration, and filtering to obtain a methylated compound (IV-1) solution, wherein the ether solvent is selected from one of diethoxymethane, tetrahydrofuran, diethyl ether and dimethyltetrahydrofuran;
4) ketal reaction
Adding ethylene glycol, triethyl orthoformate and p-toluenesulfonic acid (PTS) into a methylated compound (IV-1) solution, carrying out heat preservation reaction at 20-25 ℃ until the raw materials are completely reacted, adding an alkaline aqueous solution to quench, washing with water, standing for layering, collecting an organic phase, concentrating under normal pressure until no distillate exists, adding ethanol, stirring, cooling, filtering, discharging, and drying to obtain a bisketal compound (V), wherein the alkaline aqueous solution is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate or triethylamine solution.
2. The method for synthesizing ulipristal acetate intermediate as claimed in claim 1, wherein in the step 1) of cyano reaction, the reaction temperature is 50 ℃ to 55 ℃, and the mass ratio of the 3-ketal (I) as the substrate to the other raw materials in the cyano reaction is 3-ketal (I): ethyl acetate: acetone cyanohydrin: triethylamine is 1:1 to 10:0.15 to 2:0.1 to 0.5.
3. The method for synthesizing ulipristal acetate intermediate as claimed in claim 1, wherein the silylation reagent in the protection reaction in step 2) is chloromethyldimethylchlorosilane, and the mass ratio of the raw material of the protection reaction to the initially charged 3-ketal (I) is dichloromethane: imidazole: chloromethyl dimethylchlorosilane: 3-ketal (I) is 5-30: 0.3-1: 1.
4. the method for synthesizing ulipristal acetate intermediate according to claim 1, wherein in the methylation reaction of step 3), the reaction temperature is-10 ℃ to 5 ℃, the concentration of the methyllithium solution is 1.0 to 2.5M, the ether solvent is diethoxymethane, the acid added by dilute acid washing is selected from acetic acid, hydrochloric acid or sulfuric acid solution, the concentration is 15% to 70%, and the mass ratio of other raw materials of the methylation reaction to the initially added 3-ketal (I) is diethoxymethane: methyl lithium solution: 3-ketal (I) is 2-10: 1.5-5.0: 1.
5. the method according to claim 1, wherein the aqueous alkaline solution of the ketal reaction is triethylamine solution, and the mass ratio of the other raw materials of the ketal reaction to the initially charged 3-ketal (I) is ethylene glycol: triethyl orthoformate: PTS: 3-ketal (I) is 0.2 to 1: 0.5-2: 0.1-0.4: 1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516345A (en) * | 2011-11-01 | 2012-06-27 | 上海优拓医药科技有限公司 | Preparation method of ulipristal acetate and key intermediate thereof |
| CN104558089A (en) * | 2013-10-25 | 2015-04-29 | 上海医药工业研究院 | Preparation method of 3-(ethylendioxy)-17beta-cyano-17alpha-hydroxy-estra-5(10),9(11)-diene |
| CN106866768A (en) * | 2017-04-25 | 2017-06-20 | 广西万德药业有限公司 | A kind of synthetic method of Nomegestrol intermediate |
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- 2019-12-31 CN CN201911411491.8A patent/CN111018935A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516345A (en) * | 2011-11-01 | 2012-06-27 | 上海优拓医药科技有限公司 | Preparation method of ulipristal acetate and key intermediate thereof |
| CN104558089A (en) * | 2013-10-25 | 2015-04-29 | 上海医药工业研究院 | Preparation method of 3-(ethylendioxy)-17beta-cyano-17alpha-hydroxy-estra-5(10),9(11)-diene |
| CN106866768A (en) * | 2017-04-25 | 2017-06-20 | 广西万德药业有限公司 | A kind of synthetic method of Nomegestrol intermediate |
Non-Patent Citations (1)
| Title |
|---|
| XU CHENG ET AL.: "A new and efficient method for the synthesis of Ulipristal acetate", 《STEROIDS》 * |
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Application publication date: 20200417 |