CN101318986B - Method for synthesizing eplerenone - Google Patents
Method for synthesizing eplerenone Download PDFInfo
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Abstract
The invention discloses a new method for synthesizing steroid drug eplerenone. A surface cortisol as a byproduct of hydrocortisone is used as a raw material to oxide 17-side chain into ketone; 5, 6-double bond is introduced by 3-one protection; 7-ester group is introduced by cyaniding; 11-hydroxy is eliminated and 9,11-double bond is introduced; 17-ketone group is subjected to epoxidation, condensation and decarboxylation; and finally, the 9,11-double bond is epoxidated to produce the eplerenone. The method has raw materials with cheap prices and available sources, the easy control of processoperation, high yield and low cost and is suitable for industrialized production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to the method for synthesizing steroid antihypertensive drug eplerenone.
Background technology
Eplerenone chemistry 4-alkene-9 α by name, 11 α-epoxy 7 α-methoxycarbonyl base-3-ketone-androstane-21, the 17-carboxylic acid lactone, structural formula is as follows:
Eplerenone is selectivity aldosterone receptor retarding agent (Aldosterone antagonist), has advantages such as strong to the aldosterone receptor selectivity, that antihypertensive effect good, effect is lasting, and can reverse or alleviate aldosterone to cardiovascular many disadvantageous effects.The preparation of eplerenone has the eplerenone sheet by Pfizer/Pharmacia Corp's exploitation at present, trade(brand)name Inspra, these product are lower than spironolactone to the avidity of male sex hormone and PgR, to the not significantly effect of testicular function, ovulation or target organ weight, can reduce the generation of untoward reactions such as gynaecomastia.
The synthetic route of eplerenone mainly is following three routes of US5981744 report at present:
Reaction formula (1)
Reaction formula (2)
Reaction formula (3)
Said synthesis route all is starting raw material with the canrenone, and the commercially available price comparison of canrenone is expensive.And above-mentioned synthetic method all is to introduce earlier 17 lactonic ring, and lactonic ring is under acid and alkaline reaction conditions, and is all unstable, causes reaction yield lower easily, and technological operation is wayward.
Hydrocortisone is important corticosteroid drug, and domestic have many enterprises to produce, and about 40～50 tons of annual production has the by product about 20% in its semisynthetic fermentation reaction process---epicortisol (table hydrocortisone) produces.The method of synthesizing eplerenone provided by the invention is a starting raw material with this epicortisol cheap and easy to get.
Summary of the invention
Technical problem to be solved by this invention is to overcome the method that above-mentioned weak point provides a kind of more rational synthesizing eplerenone.
Technical problem to be solved by this invention can be achieved through the following technical solutions:
A kind of method of synthesizing eplerenone; being to be raw material with the epicortisol, is ketone by oxidation with 17 oxide side chains, and 3 protections introduce 5; 6 pairs of keys; introduce 7-position ester group by cyaniding then, 11 hydroxyls are eliminated, and introduce 9; 11 pairs of keys; 17 ketone groups are through epoxy, condensation, decarboxylation, and last 9,11 double bond epoxidations generate eplerenone.
Concrete reaction formula is as follows:
R in the formula
1, R
3Be C
1-C
5Alkyl; R
2Be acyl group.
In the methods of the invention, R
1, R
3Or/and be preferably ethyl; R
2Be preferably methylsulfonyl.
For said synthesis route, its concrete steps are:
(a) with the epicortisol being raw material, is that ketone obtains formula II compound with 17 oxide side chains;
(b) 3 etherificate protections obtain the formula III compound;
(c) dehydrogenation is introduced 5,6 pairs of keys and is obtained formula IV compound;
(d) cyaniding, acidolysis obtain formula VI compound;
(e) esterification, decyanation obtain formula VII compound;
(f) esterification of 11 hydroxyl methylsulfonic acids obtains formula VIII compound;
(g) 11 methanesulfonates are left away and are introduced 9,11 pairs of keys and obtain formula IX compound;
(h) 17 ketone group epoxidations obtain formula X compound;
(i) carry out the open loop condensation with diethyl malonate and obtain formula XI compound;
(j) decarboxylation obtains formula XII compound;
(k) 9,11 double bond epoxidations obtain eplerenone (I).
In the above-mentioned steps of the inventive method, wherein committed step is step h, i, j, specifically describes as follows to step h, i, j below:
Step h: with formula IX compound and bromo trimethylammonium thioether reactant, introduce epoxy group(ing) at its 17, the compound that obtains formula X specifically is in the mixed solvent of DMSO and THF, add organic alkali and be heated to 50～70 ℃ and stir after 30 minutes, be cooled to-10～0 ℃, add formula IX compound after adding fast bromo trimethylammonium thioether, insulation reaction after 1～5 hour elutriation, filtration, oven dry promptly get formula X compound.
The mol ratio of formula IX compound and bromination trimethylammonium thioether, organic alkali is 1: 1～3: 1～2, preferred 1: 1.6～1.8: 1.5～1.6.Preferred-5～0 ℃ of temperature of reaction, preferred 1～2 hour of insulation reaction time.
The preferred potassium tert.-butoxide of said organic alkali.
Step I: formula X compound and diester malonate are carried out the open loop condensation, obtaining formula XI compound specifically is in the ethanolic soln of sodium ethylate, add diester malonate earlier, add formula X compound after forming carbanion, back flow reaction was reduced to room temperature after 2～6 hours, and elutriation, filtration, room temperature oven dry promptly get formula XI compound.
The mol ratio of formula X compound and diester malonate, sodium ethylate is 1: 2～4: 2～3, preferred 1: 3～3.5: 2.5～3.Preferred 75～80 ℃ of back flow reaction temperature, preferred 3～4 hours of reflux time.
The preferred diethyl malonate of said diester malonate.
Step j: formula XI compound is carried out decarboxylic reaction, and to obtain formula XII compound specifically be that formula XI compound is dissolved among the DMF, adds entry, about 3～6 hours postcooling to 70 of reflux ℃, washes, filters, is drying to obtain formula XII compound.
Preferred 95～100 ℃ of temperature of reaction, preferred 3～4 hours of reaction times.
Method raw material sources of the present invention cheaply are easy to get, and technological operation is easy to control, the yield height, and cost is low, has bigger suitability for industrialized production to be worth.
Embodiment
The present invention is further detailed explanation below in conjunction with embodiment.
Embodiment 1
4-alkene-11 Alpha-hydroxy-3,17-diketone-androstane (II)
Under the argon shield 10.0g epicortisol is added in the 400ml ethyl acetate, add 40.0g Manganse Dioxide, reflux 3 hours.Filtered while hot.Filter cake added 60ml ethyl acetate and stirring and refluxing 30 minutes after washing with the 30ml ethyl acetate again.Repeat once.Dried with being evaporated to after the filtrate merging that obtains, obtain faint yellow crude product 6.4 grams.Crude product adds 10ml methanol eddy half an hour, freezing crystallization.Filter, dry 5.0g product (II).
Embodiment 2
3-oxyethyl group-3,5 (6)-diene--11 Alpha-hydroxies-17-ketone-androstane (III)
Under the argon shield, 10.0g formula II compound is dissolved in the 350ml dioxane, adds 34ml triethyl orthoformate, 0.6g tosic acid and 10ml dehydrated alcohol then successively.Reaction is warming up to 40 ℃, insulation reaction 1.5 hours.TLC (hexanaphthene: ethyl acetate=3: 1) track to and react completely, add the saturated NaHCO of 140ml fast
3The solution termination reaction, reaction solution adds the 300ml methylene dichloride and stirs standing demix to going in the 1L water.The water of telling is extracted to no product with methylene dichloride (50 * 3).Merge organic layer, organic layer is washed till neutrality with saturated NaCl, anhydrous Na
2SO
4Dry.Filter, filtrate is concentrated into dried yellow solid.Crude product with recrystallizing methanol refining etherate 9.0g.
Embodiment 3
4,6-diene-11 Alpha-hydroxy-3,17-diketone-androstane (IV)
10.0g formula III compound dissolution in 70ml acetone, is stirred, be warming up to 30-35 ℃.Solid all dissolves the back and adds 25ml water, separates out solid, is cooled to 25-30 ℃, and logical argon shield reaction system adds the 8.0g tetrachlorobenzoquinone under the lucifuge, and insulation reaction finished in about 1.5 hours.Reaction finishes the back impouring with in the NaOH solution of 210ml 10%, stirs 0.5 hour.Filter.Filter cake washs with methylene dichloride 50ml.Merging filtrate is with dichloromethane extraction (50ml * 4).Dichloromethane layer is successively used saturated Na
2S
2O
3The aqueous solution and washing.Anhydrous Na
2SO
4Dry.Filter.Filtrate is concentrated into dried yellow crude product.Crude product is refining with isopropyl ether, obtains formula IV compound 8.0g.
Embodiment 4
5 beta-cyanos-11 Alpha-hydroxy 3,17,20-triketone-androstane-4 α, 7 α, 20-cyclopentanone (VI)
10.0g formula IV compound is joined among the 20ml DMF, after the stirring and dissolving, add the 3.0g lithium chloride and continue and stirred 20 minutes.Add 7ml acetone cyanohydrin and 3ml25% tetramethylammonium hydroxide aqueous solution, system is warming up to 85 ℃, be incubated and add other 2ml25% tetramethylammonium hydroxide aqueous solution after one hour, continued insulation reaction 2 hours, (hexanaphthene: acetone=1: 1) detection raw material point and intermediate point primitive reaction are complete for TLC, be added dropwise to 100ml 2N hydrochloric acid, have a large amount of yellow solids to separate out after the adding.Be warming up to backflow, reacted 3 hours, TLC detects intermediate, and (enamine, V) primitive reaction is complete.Be cooled to 70 ℃, and feed the prussic acid gas of argon gas to take wherein, tail gas absorbs with the chlorine bleach liquor.Mixture was chilled to 0 ℃ and insulated and stirred 30 minutes.Filter, filter cake is washed till neutrality with frozen water.60 ℃ of vacuum-dryings got yellow solid in 12 hours.The gained crude product is refining with ethyl acetate, obtains formula VI compound 9.4g.
Embodiment 54-alkene-7 α-methoxycarbonyl base-11 Alpha-hydroxy 3,17-diketone-androstane (VII)
10.0g formula V compound is added in the 400ml absolute methanol solution of 3.0g potassium methylate, mixture is warming up to backflow.Add other 2.0g potassium methylate after 3 hours, continued insulation reaction 7 hours, TLC follows the tracks of reaction (TLC: hexanaphthene: ethyl acetate=1: 2).After reaction finished, system was reduced to room temperature, is added dropwise to 100ml2N hydrochloric acid in 30 minutes, and room temperature continues to stir 30 minutes.System is warming up to 60 ℃ again, pressure reducing and steaming methyl alcohol.Add 100ml water, (3 * 100ml) extract product from aqueous phase, organic phase is washed to neutrality with saturated common salt with methylene dichloride.Anhydrous Na
2SO
4Dry.Filter, filtrate decompression concentrate yellow solid (VII).Weight yield about 85%.
*Precaution: adding has hypertoxic prussic acid gas to produce in the sour process, absorb with the chlorine bleach liquor.
Embodiment 6
4-alkene-7 α-methoxycarbonyl base-11 α-mesyloxy-3,17-diketone-androstane (VIII)
20.0g formula VI compound is joined in the 200ml methylene dichloride, and solid all dissolves the back system and is chilled to 0 ℃.-5 ℃ add the 16ml methylsulfonyl chloride down, when dropping to-5 ℃, system temperature drips the mixed solution of triethylamine and 75ml methylene dichloride, controlled temperature is not higher than 0 ℃, added in about 1 hour, add still maintenance and reacted 3～5 hours down for-5 ℃, TLC (cyclohexane: till ethyl acetate=1:3) the detection raw material reaction finishes.Reaction is finished, and 0 ℃ drips frozen water 50ml, and transfer to neutrality with 0.5N NaOH down.Layering, water layer are with 3 * 50ml dichloromethane extraction, and the combined dichloromethane layer washs with 2 * 50ml saturated brine.Anhydrous Na
2SO
4Dry.Filter, filtrate decompression concentrate weak yellow foam shape thing 26.8g.Add the 75ml methylene dichloride in crude product, stirring is Dropwise 35 0ml ether down, is controlled to drip off more than 2 hours, separates out the off-white color solid.Filter, 40 ℃ of vacuum-dryings get formula VIII compound 21.6g.Weight yield 108%.
Embodiment 7
4,9 (11)-diene-7 α-methoxycarbonyl base-3,17-diketone-androstane (IX)
Add sodium acetate 2.2g in the exsiccant there-necked flask, ice bath is added dropwise to trifluoroacetic acid 23ml to-10 ℃.In the 20 ℃ of trifluoroacetic anhydride of property adding next time 5ml, add and heat up 30 ℃ insulated and stirred 1 hour again.Be cooled to 10 ℃, add formula VII compound 5.0g in three batches, the every batch of interval 10 minutes slowly is warming up to 30 ℃ of reactions 15 hours after adding material.After reaction finished, reaction solution was evaporated to trifluoroacetic acid and has steamed (liquid does not have till the bubble in the bottle).Concentrate the ethyl acetate that adds 100ml in the heavy-gravity oily matter that obtains and stir evenly (some salt does not dissolve, and can add the little water dissolving), in separating funnel,, use saturated NaHCO again with the washing (removing most of methylsulfonic acid) of 2 * 25ml
3Solution is washed till neutrality, and the 25ml saturated salt is washed once.The water layer of all washings merges, and with 3 * 25ml ethyl acetate extraction (extraction liquid is neutral), merges all organic phases, anhydrous Na
2SO
4Dry.Filter.Add 0.5g gac room temperature in the filtrate and stir 2 hours (removing the red in the reaction).Filter, filtrate decompression is concentrated into dried the yellow foam (IX) of 4.0g.
Embodiment 8
4,9 (11)-diene-7 α-methoxycarbonyl base-3-ketone-androstane-17 (20)-epoxy (formula X)
DMSO30ml, THF20ml, potassium tert.-butoxide 5.0g are heated to 60 ℃ of reactions 0.5 hour, are cooled to-5 ℃, drop into bromination trimethylammonium thioether 8.0g fast, stirred 30 minutes, add 10.0g formula IX compound, 0 ℃ of reaction 1 hour at 0 ℃.After reaction finished, the frozen water elutriation filtered, and oven dry gets formula X compound 9.0g.
Embodiment 9
4,9 (11)-diene-7 α-methoxycarbonyl base-3-ketone-androstane-17 (20)-epoxy (formula X)
DMSO30ml, THF20ml, potassium tert.-butoxide 6.0g are heated to 50 ℃ of reactions 1 hour, are cooled to-10 ℃, drop into bromination trimethylammonium thioether 10.0g fast, stirred 30 minutes, add 10.0g formula IX compound, 0 ℃ of reaction 3 hours at-5 ℃.After reaction finished, the frozen water elutriation filtered, and oven dry gets formula X compound 7.3g.
Embodiment 10
4,9 (11)-diene-7 α-methoxycarbonyl base-3-ketone-androstane-17 (20)-epoxy (formula X)
DMSO30ml, THF20ml, potassium tert.-butoxide 6.0g are heated to 70 ℃ of reactions 0.5 hour, are cooled to-5 ℃, drop into bromination trimethylammonium thioether 9.0g fast, stirred 30 minutes, add 10.0g formula IX compound, 0 ℃ of reaction 2 hours at 0 ℃.After reaction finished, the frozen water elutriation filtered, and oven dry gets formula X compound 8.1g.
Embodiment 11
4,9 (11)-diene-7 α-methoxycarbonyl base-3-ketone-androstane-21,17-carboxylic acid lactone-21-ethyl formate (formula XI)
Sodium ethylate 5.1g is dissolved in the 100ml dehydrated alcohol.Be heated to 30 ℃, add diethyl malonate 13.6ml.Be warming up to 35 ℃, continue to stir 10 minutes, drop into 10.0g formula X compound, reflux 3 hours, reaction is cooled to room temperature after finishing.Elutriation.Filter, room temperature dry formula XI compound 11.0g (can not heating, drying).
Embodiment 12
4,9 (11)-diene-7 α-methoxycarbonyl base-3-ketone-androstane-21,17-carboxylic acid lactone-21-ethyl formate (formula XI)
Sodium ethylate 6.0g is dissolved in the 100ml dehydrated alcohol.Add diethyl malonate 15.0ml under the room temperature.Be warming up to 40 ℃, continue to stir 10 minutes, drop into 10.0g formula X compound, be heated to 65 ℃, insulation reaction 6 hours, reaction is cooled to room temperature after finishing.Elutriation.Filter, room temperature dry formula XI compound 9.2g (can not heating, drying).
Embodiment 13
4,9 (11)-diene-7 α-methoxycarbonyl base-3-ketone-androstane-21,17-carboxylic acid lactone-21-ethyl formate (formula XI)
Sodium ethylate 6.0g is dissolved in the 100ml dehydrated alcohol.Add diethyl malonate 14.0ml under the room temperature.Be warming up to 35 ℃, continue to stir 15 minutes, drop into 10.0g formula X compound, reflux 3 hours, reaction is cooled to room temperature after finishing.Elutriation.Filter, room temperature dry formula XI compound 10.3g (can not heating, drying).
Embodiment 14
4,9 (11)-diene-7 α-methoxycarbonyl base-3-ketone-androstane-21,17-carboxylic acid lactone (formula XII)
10.0g formula XI compound dissolution in the DMF of 60ml, is added the water of 10ml, reflux 3 hours.Reaction is cooled to 70 ℃ after finishing.Filter, filter cake is washed with a small amount of.Drying gets formula XII compound 8.0g.
Embodiment 15
4,9 (11)-diene-7 α-methoxycarbonyl base-3-ketone-androstane-21,17-carboxylic acid lactone (formula XII)
10.0g formula XI compound dissolution in the DMF of 60ml, is added the water of 10ml, reflux 5 hours.Reaction is cooled to 70 ℃ after finishing.Filter, filter cake is washed with a small amount of.Drying gets formula XII compound 7.8g.
Embodiment 16
4-alkene-9 α, 11 α-epoxy-7 α-methoxycarbonyl base-3-ketone-androstane-21,17-carboxylic acid lactone (formula I)
10.0g formula XII compound is joined in the 100ml methylene dichloride, stir and make the solid dissolving.Be cooled to 15 ℃, add metachloroperbenzoic acid 11.0g in batches, add 23-25 ℃ of reaction of back temperature control.Reacted 2 hours, TLC follows the tracks of reaction (TLC: ethyl acetate: hexanaphthene=2: 1).After reaction finishes, add the saturated sodium bicarbonate termination reaction.Static layering is told organic phase, and water is used dichloromethane extraction (3 * 50ml) again.Merge organic layer, (2 * 50ml) washings, washings is used the back extraction of 50ml methylene dichloride once again with saturated aqueous common salt.Merge organic layer, anhydrous Na
2SO
4Dry.Filter, concentrating under reduced pressure gets 10.0g crude product (formula I), and HPLC purity is greater than 95%.
Above said content only is the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.
Claims (16)
1. the method for a synthesizing eplerenone is characterized in that, comprises the steps:
(a) with the epicortisol being raw material, is that ketone obtains formula II compound with 17 oxide side chains;
(b) 3 etherificate protections obtain formula III compound;
(c) dehydrogenation is introduced 5,6 pairs of keys and is obtained formula IV compound;
(d) cyaniding, acidolysis obtain formula VI compound;
(e) esterification, decyanation obtain formula VII compound;
(f) esterification of 11 hydroxyl methylsulfonic acids obtains formula VIII compound;
(g) 11 methanesulfonates are left away and are introduced 9,11 pairs of keys and obtain formula IX compound;
(h) 17 ketone group epoxidations obtain formula X compound;
(i) carry out the open loop condensation with diethyl malonate and obtain formula XI compound;
(j) decarboxylation obtains formula XII compound;
(k) 9,11 double bond epoxidations obtain eplerenone (I);
Concrete reaction formula is as follows:
R in the formula
1Be C
1-C
5Alkyl, R
2Be methylsulfonyl, R
3Be ethyl.
2. method according to claim 1 is characterized in that R
1Be ethyl.
3. method according to claim 1 and 2, it is characterized in that, it is in the mixed solvent of DMSO and THF that 17 ketone group epoxidations of described step (h) obtain formula X compound, add organic alkali and be heated to 50～70 ℃ and stir after 30 minutes, be cooled to-10～0 ℃, add formula IX compound after adding fast bromination trimethylammonium thioether, insulation reaction after 1～5 hour elutriation, filtration, oven dry promptly get formula X compound.
4. method according to claim 3 is characterized in that, the mol ratio of formula IX compound and bromination trimethylammonium thioether, organic alkali is 1: 1～3: 1～2.
5. method according to claim 3 is characterized in that, the mol ratio of formula IX compound and bromination trimethylammonium thioether, organic alkali is 1: 1.6～1.8: 1.5～1.6.
6. method according to claim 3 is characterized in that, the insulation reaction temperature is-5～0 ℃.
7. method according to claim 3 is characterized in that, the insulation reaction time is 1～2 hour.
8. method according to claim 3 is characterized in that, said organic alkali is a potassium tert.-butoxide.
9. method according to claim 1 and 2, it is characterized in that, described step (i) is carried out the open loop condensation with formula X compound and diethyl malonate, obtaining formula XI compound specifically is in the ethanolic soln of sodium ethylate, add diethyl malonate earlier, add formula X compound after forming carbanion, back flow reaction was reduced to room temperature after 2～6 hours, and elutriation, filtration, room temperature oven dry promptly get formula XI compound.
10. method according to claim 9 is characterized in that, the mol ratio of formula X compound and diethyl malonate, sodium ethylate is 1: 2～4: 2～3.
11. method according to claim 9 is characterized in that, the mol ratio of formula X compound and diethyl malonate, sodium ethylate is 1: 3～3.5: 2.5～3.
12. method according to claim 9 is characterized in that, the back flow reaction temperature is 75～80 ℃.
13. method according to claim 9 is characterized in that, reflux time is 3～4 hours.
14. method according to claim 1 and 2, it is characterized in that, described step (j) is carried out decarboxylic reaction with formula XI compound, and to obtain formula XII compound specifically be that formula XI compound is dissolved among the DMF, add entry, about 3～6 hours postcooling to 70 of reflux ℃, wash, filter, be drying to obtain formula XII compound.
15. method according to claim 14 is characterized in that, the back flow reaction temperature is 95～100 ℃.
16. method according to claim 14 is characterized in that, reflux time is 3～4 hours.
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| CN101863951B (en) * | 2009-04-15 | 2012-06-06 | 浙江省天台县奥锐特药业有限公司 | Method for preparing eplerenone |
| CN102276684B (en) * | 2010-06-08 | 2013-04-10 | 中国科学院上海药物研究所 | Preparation method of eplerenone and intermediate thereof |
| CN103145785B (en) * | 2013-03-19 | 2016-03-02 | 浙江仙居仙乐药业有限公司 | A kind of synthetic method of cyproterone acetate dehydrogen substance |
| CN108047299B (en) * | 2017-12-29 | 2021-11-09 | 广西万德药业有限公司 | Preparation method of important intermediate of canrenone |
| CN115433252A (en) * | 2022-08-24 | 2022-12-06 | 浙江亚瑟医药有限公司 | Preparation method of delta 9 (11) -canrenone |
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