CN101993468A - Synthesis method for improving dienogest - Google Patents
Synthesis method for improving dienogest Download PDFInfo
- Publication number
- CN101993468A CN101993468A CN2009101846613A CN200910184661A CN101993468A CN 101993468 A CN101993468 A CN 101993468A CN 2009101846613 A CN2009101846613 A CN 2009101846613A CN 200910184661 A CN200910184661 A CN 200910184661A CN 101993468 A CN101993468 A CN 101993468A
- Authority
- CN
- China
- Prior art keywords
- formula
- diene
- reaction
- methoxyl group
- female
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention provides a method for improving dienogest. By the method, the dienogest is prepared by performing oxidation, cyanation, hydrolysis and bromination and debromination reactions on 3-methoxy-17-hydroxyl-female-2,5(10)-diene serving as a raw material. The method is easy and convenient to operate, has high yield, and is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of contraceptive bian---the synthetic method of dienogest belongs to chemistry and chemical and medicine industry field.
Background technology
(Dienogest is the contraception new drug of nineteen ninety-five in Germany's listing STS-557) to dienogest, is a kind of mixed type progestogen, and it has the double properties of 19-norepinephrine testosterone derivative and derivatives of progesterone, and has unique pharmacodynamics and pharmacokinetics character concurrently.
The chemistry of dienogest is called 17 alfa-cyanomethyls-17 beta-hydroxy-4,9-estradiene-3-ketone, structural formula
As follows:
Synthetic existing many pieces of bibliographical informations about dienogest:
It is the synthetic dienogest of raw material that U.S. Pat 4248790A discloses with female phenolic ketone-3-methyl ether, and synthetic route is as follows:
In this route, reduction obtains 3-methoxyl group-female steroid-2 to female phenolic ketone-3-methyl ether through Birch, 5 (10)-diene-17-ketone, then in the sulfonium of products therefrom and qdx reagent in DMF and have under the situation that potassium tert.-butoxide exists, reaction generates 3-methoxyl group-13 β-R-gonane-2,5 (10)-diene-17 β-spiral-1 ', 2 '-oxyethane; Obtain 3-methoxyl group-17 alfa-cyanomethyl-13 β-R-gonane-2,5 (10)-diene-17 β-alcohol with the potassium cyanide reaction again; Hydrolysis obtains 17 beta-hydroxyl-17 alphas-cyanogen methyl isophthalic acid 3 β-R-gonane-5 (10) alkene-3-ketone under acidic conditions then; Last products therefrom successively carries out bromination and debromination in pyridine, obtain dienogest.
The route of the disclosed preparation dienogest of PCT patent WO2007066158A is as follows:
In this route, in the presence of pimelinketone, toluene is solvent, 3-methoxyl group-17-hydroxyl-female steroid-2 shown in the formula 1,5 (10)-diene and aluminum isopropylate reaction obtain the 3-methoxyl group-female steroid-2 shown in the formula 2,5 (10)-diene-17-ketone, compound shown in this formula 2 obtains the 3-methoxyl group-17 alfa-cyanomethyl-17 beta-hydroxies-female steroid-2 shown in the formula 3 at 0～-30 ℃ with the reaction of cyanogen lithium methide, 5 (10)-diene, compound and strong organic acid shown in this formula 3 react 17 alfa-cyanomethyls-17 beta-hydroxies-female steroid-5 (10)-alkene-3-ketone shown in the formula that obtains 4 in tetrahydrofuran solution, compound shown in this formula 4 reacts in pyridine with pyridinium tribromide and obtains dienogest by recrystallization.
This method has a lot of advantages really with respect to other synthetic routes of having reported, and the inventor makes that by the improvement to this route this route is simple and direct, mild condition, and operation easily, cost is low, and the yield height is easy to amplify, and adapts to suitability for industrialized production.
Summary of the invention
The purpose of this invention is to provide a kind of synthetic method of improving dienogest.
For solving goal of the invention, the technical solution used in the present invention is as follows:
A kind of method for preparing dienogest may further comprise the steps:
1) methoxyl group of the 3-shown in the formula 1-17-hydroxyl-female steroid-2,5 (10)-diene and aluminum isopropylate reaction obtain 3-methoxyl group-female steroid-2,5 (10)-diene-17-ketone shown in the formula 2, after reaction finishes, reaction solution is cooled to 70～80 ℃, add water, produce solid, heat filtering is removed solid, filtrate concentrates, add 50% methyl alcohol in 0～10 ℃, separate out solid, get white solid with the dehydrated alcohol recrystallization if needed;
2) the 3-methoxyl group-female steroid-2 shown in the formula 2,5 (10)-diene-17-ketone and acetonitrile and n-Butyl Lithium reaction obtain the 3-methoxyl group-17 alfa-cyanomethyl-17 beta-hydroxies-female steroid-2 shown in the formula 3,5 (10)-diene, this temperature of reaction is-50～-30 ℃, the product that obtains gets white solid with the dehydrated alcohol recrystallization if needed;
3) 3-methoxyl group-17 alfa-cyanomethyl-17 beta-hydroxy-female-2 shown in the formula 3,5 (10)-diene and oxalic acid react 17 alfa-cyanomethyls-17 beta-hydroxy shown in the formula that obtains 4-female-5 (10)-alkene-3-ketone in tetrahydrofuran solution, this temperature of reaction is 17～20 ℃, reaction finishes the mixed extractant solvent reaction solution of back with ethyl acetate and water, it is neutral that organic layer washes with water to pH, concentrate, add re-crystallizing in ethyl acetate and get white solid;
4) 17 alfa-cyanomethyls-17 beta-hydroxies-female steroid-5 (10)-alkene-3-ketone shown in the formula 4 is obtained dienogest by the bromination debromination.
In this route, step 1, after reaction finished, reaction solution was cooled to 70～80 ℃, and this temperature more helps destroying aluminum isopropylate unnecessary in the reaction, and more help the generation of aluminium hydroxide, removing more impurity by heat filtering, be cooled to 0～10 ℃ after concentrating and add 50% methyl alcohol, also is in order to improve the purity of product, experimental results show that strict these two temperature of control, the purity height of the intermediate that obtains.
Step 2, under-50～-30 ℃, the product yield that this reaction obtains reaches more than 90%, and the contriver prepares by method among the patent WO2007066158A, and yield has only 78%, and we have improved more than ten percentage point.
Step 3, by patent WO2007066158 reported method, during the intermediate purity that obtains is far from reporting to be not less than 98% (HPLC) so high, here the inventor is by the patented method operation, find the impurity about 10% to occur, so the inventor repeatedly tests discovery in 17～20 ℃ scope when temperature of reaction during at 25 ℃, through effective aftertreatment, make the purity of this intermediate reach more than 98% (HPLC) finally.
The present invention has following advantage compared to existing technology:
The synthetic route route that the present invention adopts is simple and direct, mild condition, and operation easily, cost is low, and the yield height is easy to amplify, and adapts to suitability for industrialized production.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.
Embodiment 1
The preparation of 3-methoxyl group-female steroid-2,5 (10)-diene-17-ketone:
In the 4L reaction flask, add 3-methoxyl group-17-hydroxyl-female steroid-2,5 (10)-diene (content 85%) 160 grams, aluminum isopropylate 204 grams, 2,6 di tert butyl 4 methyl phenol 1.2 grams add 2200mL toluene and 848mL pimelinketone, oil bath is heated to 110 ℃, back flow reaction 2 hours.Reaction solution is cooled to about 70 ℃-80 ℃, adds water under stirring, and has a large amount of white solids to generate, and stirs the back filtered while hot, uses the toluene wash solid, and filtrate decompression is concentrated into almost can not steam.Concentrated solution cools to 0 ℃-10 ℃ under stirring, and adds 50% methanol solution, has a large amount of solids to separate out, and filters, and dries to such an extent that white solid 122 restrains.Yield 77%.
Embodiment 2
The preparation of 3-methoxyl group-17 alfa-cyanomethyl-17 beta-hydroxies-female steroid-2,5 (10)-diene:
Under nitrogen gas stream, the hexane solution that in dry 3000mL reaction flask, adds the 650mL n-Butyl Lithium, add the dilution of 120mL exsiccant tetrahydrofuran (THF), cool to-40 ℃, stir and slowly drip the solution that 80 gram acetonitriles dissolve in 120mL exsiccant tetrahydrofuran (THF) down, have a large amount of white solids to generate, controlled temperature is at-35 ℃.114 gram exsiccant 3-methoxyl group-female steroids-2,5 (10)-diene-17-ketone is dissolved in the 800mL exsiccant tetrahydrofuran (THF), under the nitrogen gas stream protection, is added drop-wise in the reaction solution, add the back and stirred 3 hours for-35 ℃.In reaction solution, add entry, have solid to generate, filter.Filtrate extraction branch vibration layer, organic layer concentrating under reduced pressure stir down and cool to 0 ℃-10 ℃ to about the 400mL, add entry, have a large amount of solids to generate, and be overanxious, dries to such an extent that white solid 118 restrains.Yield 90.5%.
Embodiment 3
The preparation of 3-methoxyl group-17 alfa-cyanomethyl-17 beta-hydroxies-female steroid-2,5 (10)-diene:
Under nitrogen gas stream, the hexane solution that in dry 3000mL reaction flask, adds the 650mL n-Butyl Lithium, add the dilution of 120mL exsiccant tetrahydrofuran (THF), cool to-40 ℃, stir and slowly drip the solution that 80 gram acetonitriles dissolve in 120mL exsiccant tetrahydrofuran (THF) down, have a large amount of white solids to generate, controlled temperature is at-40 ℃.114 gram exsiccant 3-methoxyl group-female steroids-2,5 (10)-diene-17-ketone is dissolved in the 800mL exsiccant tetrahydrofuran (THF), under the nitrogen gas stream protection, is added drop-wise in the reaction solution, add the back and stirred 3 hours for-40 ℃.In reaction solution, add entry, have solid to generate, filter.Filtrate extraction branch vibration layer, organic layer 4 concentrating under reduced pressure stir down and cool to 0 ℃-10 ℃ to about the 400mL, add entry, have a large amount of solids to generate, and be overanxious, dries to such an extent that white solid 118 restrains.Yield 90.5%.
Embodiment 4
The preparation of 3-methoxyl group-17 alfa-cyanomethyl-17 beta-hydroxies-female steroid-2,5 (10)-diene:
Under nitrogen gas stream, the hexane solution that in dry 3000mL reaction flask, adds the 650mL n-Butyl Lithium, add the dilution of 120mL exsiccant tetrahydrofuran (THF), cool to-45 ℃, stir and slowly drip the solution that 80 gram acetonitriles dissolve in 120mL exsiccant tetrahydrofuran (THF) down, have a large amount of white solids to generate, controlled temperature is at-40 ℃.114 gram exsiccant 3-methoxyl group-female steroids-2,5 (10)-diene-17-ketone is dissolved in the 800mL exsiccant tetrahydrofuran (THF), under the nitrogen gas stream protection, is added drop-wise in the reaction solution, add the back and stirred 3 hours for-50 ℃.In reaction solution, add entry, have solid to generate, filter.Filtrate extraction branch vibration layer, organic layer 4 concentrating under reduced pressure stir down and cool to 0 ℃-10 ℃ to about the 400mL, add entry, have a large amount of solids to generate, and be overanxious, dries to such an extent that white solid 120 restrains.Yield 92%.
Embodiment 5
17 alfa-cyanomethyls-17 beta-hydroxy-female-5 (10)-alkene-3-ketone preparation:
Get 3-methoxyl group-17 alfa-cyanomethyl-17 beta-hydroxy-female-2,5 (10)-diene 60 grams and join in the 1000mL reaction flask, add 400mL tetrahydrofuran (THF) stirring and dissolving, add 230mL water, cool to 5 ℃-10 ℃, add solid oxalic acid 46.6 grams under stirring.There are a large amount of pasty solids to separate out, are warmed up to 19 ℃ and stirred 1 hour, the reaction solution clarification.Add 80mL water and 560mL ethyl acetate, extraction, organic layer washes PH with water for neutral, dense the doing of reduce pressure, re-crystallizing in ethyl acetate is filtered, and dries to such an extent that 47.8 restrain white solids.Yield 83%.Purity 99.0% (HPLC).
Embodiment 6
17 alfa-cyanomethyls-17 beta-hydroxy-female-5 (10)-alkene-3-ketone preparation:
Get 3-methoxyl group-17 alfa-cyanomethyl-17 beta-hydroxy-female-2,5 (10)-diene 60 grams and join in the 1000mL reaction flask, add 400mL tetrahydrofuran (THF) stirring and dissolving, add 230mL water, cool to 5 ℃-10 ℃, add solid oxalic acid 46.6 grams under stirring.There are a large amount of pasty solids to separate out, are warmed up to 17 ℃ and stirred 1 hour, the reaction solution clarification.Add 80mL water and 560mL ethyl acetate, extraction, organic layer washes PH with water for neutral, dense the doing of reduce pressure, re-crystallizing in ethyl acetate is filtered, and dries to such an extent that 46.1 restrain white solids.Yield 80%.Purity 98.9% (HPLC).
Embodiment 7
The preparation of dienogest:
Getting 17 alfa-cyanomethyls-17 beta-hydroxy-female-5 (10)-alkene-3-ketone 43.2 grams joins in the 1000mL single port reaction flask, add 480mL pyridine stirring and dissolving, lower the temperature 10 ℃-15 ℃, add hydrogen bromide pyridine perbromide 46 grams under stirring in batches, have a large amount of solids to generate.Be warming up to 48 ℃, stirring reaction 1 hour gets reddish-brown liquid, and a large amount of solids are arranged.Reaction solution in the beaker of going into 5000mL, is stirred 10% the dilution heat of sulfuric acid that adds 1500mL down, and surveys pH value is 4-5, and solid is earlier molten to have a large amount of khaki color solids to separate out after clearly, the solid suction filtration.Wash solid with 500ml, infrared lamp is yellow solid 40 grams of oven dry down.Yield 92%.
Claims (1)
1. a method for preparing dienogest may further comprise the steps:
1) methoxyl group of the 3-shown in the formula 1-17-hydroxyl-female steroid-2,5 (10)-diene and aluminum isopropylate reaction obtain 3-methoxyl group-female steroid-2,5 (10)-diene-17-ketone shown in the formula 2, after it is characterized in that reacting end, reaction solution is cooled to 70～80 ℃, add water, produce solid, heat filtering is removed solid, filtrate concentrates, add 50% methyl alcohol in 0～10 ℃, separate out solid, get white solid with the dehydrated alcohol recrystallization if needed.
2) the 3-methoxyl group-female steroid-2 shown in the formula 2,5 (10)-diene-17-ketone and acetonitrile and n-Butyl Lithium reaction obtain the 3-methoxyl group-17 alfa-cyanomethyl-17 beta-hydroxies-female steroid-2 shown in the formula 3,5 (10)-diene, it is characterized in that temperature of reaction is-50～-30 ℃, the product that obtains gets white solid with the dehydrated alcohol recrystallization if needed.
3) 3-methoxyl group-17 alfa-cyanomethyl-17 beta-hydroxy-female-2 shown in the formula 3,5 (10)-diene and oxalic acid react 17 alfa-cyanomethyls-17 beta-hydroxy shown in the formula that obtains 4-female-5 (10)-alkene-3-ketone in tetrahydrofuran solution, it is characterized in that temperature of reaction is 17～20 ℃, reaction finishes the mixed extractant solvent reaction solution of back with ethyl acetate and water, it is neutral that organic layer washes with water to pH, concentrate, add re-crystallizing in ethyl acetate and get white solid.
4) 17 alfa-cyanomethyls-17 beta-hydroxies-female steroid-5 (10)-alkene-3-ketone shown in the formula 4 is obtained dienogest by the bromination debromination.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101846613A CN101993468A (en) | 2009-08-27 | 2009-08-27 | Synthesis method for improving dienogest |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101846613A CN101993468A (en) | 2009-08-27 | 2009-08-27 | Synthesis method for improving dienogest |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101993468A true CN101993468A (en) | 2011-03-30 |
Family
ID=43784278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101846613A Pending CN101993468A (en) | 2009-08-27 | 2009-08-27 | Synthesis method for improving dienogest |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101993468A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105829335A (en) * | 2013-12-16 | 2016-08-03 | 吉瑞工厂 | A process for the production of of 19-norpregn-4-en-3,20-dione-17.alpha.-ol (gestonorone) and intermediates therefor |
| CN110357937A (en) * | 2018-03-26 | 2019-10-22 | 华润紫竹药业有限公司 | A kind of Dienogest compound |
-
2009
- 2009-08-27 CN CN2009101846613A patent/CN101993468A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105829335A (en) * | 2013-12-16 | 2016-08-03 | 吉瑞工厂 | A process for the production of of 19-norpregn-4-en-3,20-dione-17.alpha.-ol (gestonorone) and intermediates therefor |
| CN105829335B (en) * | 2013-12-16 | 2018-05-29 | 吉瑞工厂 | The Preparation Method And Their Intermediate of -17 α -ol (gestonorone) of 19- norpregna -4- alkene -3,20- diketone |
| CN110357937A (en) * | 2018-03-26 | 2019-10-22 | 华润紫竹药业有限公司 | A kind of Dienogest compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106589037A (en) | Method for preparing progesterone and derivatives thereof | |
| CN103724261A (en) | Novel industrial production method for hydroxychloroquine sulfate | |
| CN105198863A (en) | Method for preparing high-purity losartan | |
| CN114874277A (en) | Synthesis method of cholesterol | |
| CN116496159A (en) | Preparation method of ethyl 6,8-dichloro octoate | |
| CN115368272A (en) | Preparation method of 4-cyano-2-methoxybenzaldehyde | |
| CN107286043A (en) | The preparation method of 2- methoxyl group -5- acetylaminoanilines | |
| CN107602651A (en) | A kind of preparation method of dehydroepiandros-sterone intermediate and dehydroepiandros-sterone | |
| CN107245089A (en) | A kind of preparation method of shellfish cholic acid difficult to understand | |
| CN104086619B (en) | The preparation method of danazol | |
| CN101993468A (en) | Synthesis method for improving dienogest | |
| CN111848517B (en) | Preparation method of edaravone | |
| CN103665084A (en) | Method for preparing abiraterone acetate | |
| CN105175317B (en) | A kind of method for preparing picosulfate sodium | |
| CN113336764B (en) | Bipyridine ligand with axial chirality and synthetic method thereof | |
| CN106749098B (en) | A kind of preparation method preparing dioxopromethazine hydrochloride using oxygen as oxidant | |
| CN103965020A (en) | Method for preparing 5-iodine-2-bromobenzylalcohol | |
| CN104402728A (en) | Preparation method for 5-chlorine-2-hydroxyl-3-nitroacetophenone | |
| CN111057121B (en) | Recycling method and application of levonorgestrel mother liquor | |
| CN102827230A (en) | Preparation method of hydrocortisone acetate | |
| CN106866378B (en) | Synthetic process of phloroglucinol | |
| CN108129536A (en) | A kind of preparation method of Dexamethasone Intermediate | |
| US20120165532A1 (en) | One-Step Synthesis Method of 2,9-Dimethyl-4,7-Diphenyl-1,10- Phenanthroline | |
| CN109232222A (en) | A kind of preparation method of (E)-octyl- 4- alkene -1,8- diacid | |
| CN102977040A (en) | Method for synthesizing 2-quinoxalinyl dimethylacetal and 2-quinoxalinyl formaldehyde |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110330 |