CN100590112C - Preparation method of intermediate for preparing eplerenone - Google Patents
Preparation method of intermediate for preparing eplerenone Download PDFInfo
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- CN100590112C CN100590112C CN200710044877A CN200710044877A CN100590112C CN 100590112 C CN100590112 C CN 100590112C CN 200710044877 A CN200710044877 A CN 200710044877A CN 200710044877 A CN200710044877 A CN 200710044877A CN 100590112 C CN100590112 C CN 100590112C
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Abstract
The invention provides a preparation method of the 17 beta- hydroxy-7alpha-carboxyl-3- oxo-17alpha-pregna-4, 9(11)-diene-21-carboxylic acid-gamma-lactone; the starting material of the invention is delta9 (11)- risperidone; with the use of the CuB or CuB2, the starting material reacts with the alkenyl halogenated magnesium; then with the solvent, the mixture of the ozone and oxygen takes part in the reaction; the peracid is added in, then the target product can be collected from the reaction products. The invention can get the product of the higher purity with a higher collection rate and a higher selectivity; the method is simple and safe; the purification is convenient; the invention greatly lowers the production cost. The environmental pollution is little and thus the invention facilitates the implementation of the industrialization.
Description
Technical field
The present invention relates to the method for a kind of preparation eplerenone important intermediate 17 beta-hydroxies-7 α-carboxyl-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone.
Background technology
The English popular name of eplerenone: Eplerenone; English chemistry is by name: 9 (11) α-epoxy-17 β-hydroxy-7 α-carbomethoxy-pregna-4-en-3-one-21-carboxylic acid, γ-lactone (formula 1).
Eplerenone mainly applies to the heart failure after essential hypertension is squeezed myocardial infarction, its main mechanism of action is by combining with aldosterone receptor, aldosterone in the blocking-up renin-angiotensin-aldosterone system (RAAS), thereby the effect that performance brings high blood pressure down.It can be by 17 beta-hydroxies-7 α-carboxyl-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone (formula 2) through over-churning and epoxidation two-step reaction and obtain.
At present, existing technology, as U.S. Pat 6180780, provide the method for a kind of preparation Intermediate of Eplerenone 17 beta-hydroxies-7 α-carboxyl-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone, when its committed step steroidal makes up in the process of 7 α carboxyls, have a large amount of prussic acid gases and discharge from reaction system, prussic acid gas is highly toxic substance, very harmful to environment and human body, so the suitability for industrialized production difficulty, to the equipment requirements height.This method route is loaded down with trivial details simultaneously, and total recovery is low, and problems such as the low difficult purifying of final product yield have also limited its use in suitability for industrialized production.
U.S. Pat 4559332 provides a kind of method, and this method is with Δ
9 (11)-canrenone is a raw material, adopts the reaction of Nagata hydrocyanation to utilize triethyl aluminum and hydrogenation dicyanogen system to obtain diethyl cyaniding aluminium fully and makes up alpha-cyano at 7, and cyan-hydrolysis obtains carboxylic acid subsequently.Wherein triethyl aluminum stores transportation and use existing problems, and prussic acid gas is highly toxic substance air and its sensitivity of water electrode (meeting air and water easy firing).Utilizing this method to obtain is 17 beta-hydroxies-7 α-carboxyl-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone and 17 beta-hydroxies-7 β-carboxyl-3-oxo-17 α-pregnant steroid-4, the miscellany of 9 (11)-diene-21-carboxylic acid-gamma lactone, its ratio is about 4: 1.Must obtain product by column chromatography method, thereby be not suitable for suitability for industrialized production.
Summary of the invention
The purpose of this invention is to provide a kind of a kind of preparation method who is used to prepare Intermediate of Eplerenone for preparing, to overcome the above-mentioned defective that prior art exists.
The method of present method comprises the steps:
(1) with the compound shown in the formula (3) at CuB or CuB
2Exist down, with thiazolinyl magnesium halide reaction 0.1～7h, temperature of reaction is-50～20 ℃ in solvent, the compound shown in the collection type (4) from reaction product then, and yield is 80～99.5%, reaction equation is as follows:
Wherein: X is chlorine, bromine or iodine;
Described thiazolinyl magnesium halide is preferably thiazolinyl magnesium chloride, thiazolinyl magnesium bromide;
Wherein: B is chlorine, bromine, iodine, acetate or Acetyl Acetone;
Preferred CuB is that cuprous halide, cuprous acetate, Acetyl Acetone base are cuprous;
Preferred CuB
2Be copper halide, copper halide, a hydration neutralized verdigris, Glacial acetic acid ketone, Acetyl Acetone copper;
Most preferred is compounds such as cuprous chloride, cuprous bromide, Glacial acetic acid copper, a hydration neutralized verdigris;
Described solvent is tetrahydrofuran (THF), ether, 2-methyl furan, isopropyl ether, 1, more than one of 4-dioxane, glycol dimethyl ether, glycol ether dme, toluene or dimethylbenzene;
The chemical name of the compound shown in the formula (3) is a Δ
9 (11)-print sharp ketone, can adopt Biochim.Biophys.Acta1978, the preparation of 531,308 disclosed methods, the present invention repeats no more;
The thiazolinyl magnesium halide can adopt J.Org.Chem.1957,22,1602; Helv.Chim.Acta.1975,58, the preparation of 1379-1425 disclosed method, bright the repeating no more of we;
The mol ratio of compound is 1～10: 1 shown in thiazolinyl magnesium halide and the formula (3) in reaction;
CuB or CuB
2With the mol ratio of compound shown in the formula (3) be 0.01～1: 1;
(2) with the compound shown in the formula (4), in the presence of solvent, the mixture that feeds ozone and oxygen participates in reaction, and the reaction times is 0.1～24 hour, and temperature of reaction is-78～40 ℃, add peroxy acid, the superoxide that forms behind damage type (3) and the ozonization, the target product-17 beta-hydroxy-7 α-carboxyl shown in the collection type (2)-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone from reaction product then, rate is 80～99%, and reaction equation is as follows:
The weight ratio of said ozone and oxygen mixture is 0.1～99: 1, can conveniently be made by ozone generator;
Said peroxy acid is a Peracetic Acid, benzoyl hydroperoxide, and metachloroperbenzoic acid, weight concentration is that 20～30% hydrogen peroxide or weight concentration are 60～70% hydrogen peroxide;
Described solvent is selected from more than one in methyl alcohol, ethanol, acetonitrile, methylene dichloride, the trimethyl carbinol, sherwood oil, toluene or the dimethylbenzene;
The mol ratio of peroxy acid and compound (4) is 1～5: 1.
The present invention can obtain the higher product of purity with higher yields and highly selective, and employed method is simple, safety.In the first step reaction, use vinyl halogenation magnesium that formula (3) is carried out 1, during the 6-addition reaction, existence at cuprous ion or cupric ion can make reaction preference improve greatly, it is product 17 beta-hydroxies-7 α-vinyl-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone and 17 beta-hydroxies-7 β-vinyl-3-oxo-17 α-pregnant steroid-4, the ratio of 9 (11) diene-21-carboxylic acid-gamma lactone is 9～20: 1, yield significantly improves, the contriver finds that low temperature can effectively suppress the generation of 17 beta-hydroxies-7 β-vinyl-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone simultaneously.Utilize the method for the two keys of ozone oxidation to obtain the superoxide of intermediate state subsequently, this oxide compound is without separating the acquisition target product that directly gets final product high yield with the peroxy acid effect.We's bright institute reported method has been avoided problems such as the product purification difficulty, the yield that are run in this compounds traditional synthesis are low, has been greatly reduced production cost.Avoided simultaneously big, unstable, the problem such as the by product environmental pollution is serious of the reagent toxicity that uses." three wastes " discharging reduces significantly in its production technique.This is that additive method is beyond one's reach.With of the present invention and Intermediate of Eplerenone 17 beta-hydroxies-7 α-carboxyl-3-oxo-17 α-pregnant steroid-4 of preparing of method, 9 (11)-diene-21-carboxylic acid-gamma lactone is because its reaction conditions gentleness, react more complete, can reach more than 99% through its purity after the simple purification.Employed reagent all comparatively is easy to get in entire reaction, while reaction yield height, and the reaction conditions gentleness, solvent can be recycled, thereby is convenient to industrializing implementation.
Embodiment
To help to understand the present invention by following specific implementation method, but not limit content of the present invention.
Embodiment 1
The preparation of 17 beta-hydroxies-7 α-vinyl-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone:
Be full of in the 250mL there-necked flask that nitrogen is equipped with magnetic stirring apparatus, thermometer, constant pressure funnel at an exsiccant and add anhydrous tetrahydro furan 100mL successively, (Fw:99.01,0.01g 10mmol), cool the temperature to-20 ℃ to cuprous chloride.With the tetrahydrofuran solution of thiazolinyl magnesium chloride (2M 50mL) slowly drops in the system, dropwises in about 5 minutes. after dropwising, system continues to stir 2 minutes at-20 ℃, subsequently with Δ
9 (11)-(Fw:338.19,3.38g 10mmol) are dissolved in the 15mL anhydrous tetrahydro furan, are transferred to constant pressure funnel to print sharp ketone.System temperature is reduced to-50 ℃, with Δ
9 (11)The sharp ketone tetrahydrofuran solution of-periodical slowly drops to system, and temperature of reaction is controlled at-50 ℃, dropwises in about 1 hour.Continued under this temperature stirring reaction after dropwising 6 hours.
Subsequently, 1M hydrochloric acid 50mL is slowly dropped to mixture in the reaction system.After dropwising, in the system mixture after filtration, separatory uses the ether extraction water, merges organic phase.Organic phase washes with water after three times, uses dried over sodium sulfate.Subsequent filtration is removed inorganic salt, and filtrate gets thickness weak yellow liquid 3.31g through underpressure distillation, yield: 90%, do not need purifying, and can be directly in next step use.
Embodiment 2
The preparation of 17 beta-hydroxies-7 α-vinyl-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone:
Be full of in the 250mL there-necked flask that nitrogen is equipped with magnetic stirring apparatus, thermometer, constant pressure funnel at an exsiccant and add anhydrous diethyl ether 100mL successively, Glacial acetic acid copper (Fw:181.63,0.018g, 10mmol), with temperature maintenance at 20 ℃.(after dropwising, system continues to stir 5 minutes at 20 ℃, subsequently with Δ for 2M, 60mL) disposable adding in the system with the tetrahydrofuran solution of thiazolinyl magnesium chloride
9 (11)-(Fw:338.19,3.38g 10mmol) are dissolved in the 15mL anhydrous diethyl ether, are transferred to constant pressure funnel to print sharp ketone.System temperature is reduced to 0 ℃, with Δ
9 (11)The sharp ketone diethyl ether solution of-periodical slowly drops to system, and temperature of reaction is controlled at 0 ℃, dropwises in about 5 minutes.Continued under this temperature stirring reaction after dropwising 5 minutes.
Subsequently, 1M hydrochloric acid 50mL is slowly dropped to mixture in the reaction system.After dropwising, in the system mixture after filtration, separatory uses the ether extraction water, merges organic phase.Organic phase washes with water after three times, uses dried over sodium sulfate.Subsequent filtration is removed inorganic salt, filtrate through underpressure distillation concentrate thickness weak yellow liquid 3.37g, yield 92%.This liquid does not need purifying, can be directly in next step use.
Embodiment 3
The preparation of 17 beta-hydroxies-7 α-carboxyl-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone:
17 beta-hydroxies-7 α-vinyl-3-oxo-17 α-pregnant steroid-4 with embodiment 1 preparation, 9 (11)-diene-21-carboxylic acid-gamma lactone (Fw:366.49,10g, 27.3mmol), be dissolved in the 100mL methylene dichloride, subsequently system temperature is reduced to-78 ℃, in the slowly feeding system of mixed gas with ozone and oxygen, temperature of reaction remains on-78 ℃.After the system of passing to becomes blueness, stop the feeding of ozone.Subsequently system temperature is risen to-10 ℃, (Fw:76.05,3.11g 41.0mmol) are diluted in the 10mL methylene dichloride, slowly drop to subsequently in the system, and temperature remains on-3 ℃, dropwise in about 30 minutes with Peracetic Acid.System is warming up to room temperature after dropwising, and continues subsequently to stir 20 hours.Subsequently saturated aqueous sodium thiosulfate is added dropwise to system to starch potassium iodide paper and does not show blue.Mixture is transferred to separating funnel, and separatory is used the dichloromethane extraction water, merges organic phase, and organic phase washes with water three times, dried over sodium sulfate.The drying after-filtration that finishes is removed inorganic salt, filtrate through underpressure distillation remove desolvate faint yellow solid, get white product 9.2g through butanone-sherwood oil recrystallization, yield 86%.HPLC content is greater than 99%.
Embodiment 4
The preparation of 17 beta-hydroxies-7 α-carboxyl-3-oxo-17 α-pregnant steroid-4,9 (11)-diene-21-carboxylic acid-gamma lactone:
17 beta-hydroxies-7 α-vinyl-3-oxo-17 α-pregnant steroid-4 with embodiment 2 preparations, 9 (11)-diene-21-carboxylic acid-gamma lactone (Fw:366.49,10g, 27.3mmol), be dissolved in 120mL methyl alcohol, system temperature maintained 20 ℃ subsequently, with the mixed gas of ozone and oxygen (50: 1, weight ratio) in the slowly feeding system, temperature of reaction remains on 20 ℃.After the system of passing to becomes blueness, stop the feeding of ozone.System temperature is risen to 40 ℃ subsequently, with metachloroperbenzoic acid (Fw:172.57,85%, 7.76g 38.2mmol) is diluted in the 10mL methyl alcohol, slowly drops to subsequently in the system, temperature remains on 40 ℃, dropwises in about 5 minutes.System is warming up to room temperature after dropwising, and continues subsequently to stir 5 minutes.Subsequently saturated aqueous sodium thiosulfate is added dropwise to system to starch potassium iodide paper and does not show blue.The mixture concentrating under reduced pressure is removed most of solvent, in residuum, add 150mL distilled water.Subsequently with the dichloromethane extraction water to there not being product, merge organic phase, organic phase washes with water three times, dried over sodium sulfate.The drying after-filtration that finishes is removed inorganic salt, filtrate through underpressure distillation remove desolvate faint yellow solid, get white product 8.5g through butanone-sherwood oil recrystallization, yield 81%.HPLC content is greater than 99%.
Claims (10)
1. a preparation method who is used to prepare Intermediate of Eplerenone is characterized in that, comprises the steps:
With the compound shown in the formula (3) at CuB or CuB
2Exist down, in solvent with the reaction of thiazolinyl magnesium halide, the compound shown in the collection type (4) from reaction product then, reaction equation is as follows:
Wherein: X is chlorine, bromine or iodine;
B is chlorine, bromine, iodine, acetate or Acetyl Acetone;
(2) with the compound shown in the formula (4), in the presence of solvent, the mixture that feeds ozone and oxygen participates in reaction, add peroxy acid then, target product-17 beta-hydroxy-7 α-the carboxyl shown in the collection type (2)-3-oxo-17 α-pregnant steroid-4 from reaction product then, 9 (11)-diene-21-carboxylic acid-gamma lactone, reaction equation is as follows:
2. method according to claim 1 is characterized in that, said thiazolinyl magnesium halide is thiazolinyl magnesium chloride, thiazolinyl magnesium bromide.
3. method according to claim 1 is characterized in that, CuB is that cuprous halide, cuprous acetate or Acetyl Acetone base are cuprous; CuB
2Be copper halide, a hydration neutralized verdigris, Glacial acetic acid ketone or Acetyl Acetone copper.
4. method according to claim 3 is characterized in that, CuB or CuB
2Be cuprous chloride, cuprous bromide, Glacial acetic acid copper or a hydration neutralized verdigris.
5. method according to claim 1 is characterized in that, the mol ratio of compound is 1～10: 1 shown in thiazolinyl magnesium halide and the formula (3); CuB or CuB
2With the mol ratio of compound shown in the formula (3) be 0.01～1: 1.
6. method according to claim 1 is characterized in that, the weight ratio of said ozone and oxygen mixture is 0.1～99: 1.
7. method according to claim 1 is characterized in that, said peroxy acid is a Peracetic Acid, benzoyl hydroperoxide, and metachloroperbenzoic acid, weight concentration is that 20～30% hydrogen peroxide, weight concentration are 60～70% hydrogen peroxide.
8. method according to claim 1 is characterized in that, the mol ratio of peroxy acid and compound (4) is 1～5: 1.
9. method according to claim 1, it is characterized in that, the described solvent of step (1) is tetrahydrofuran (THF), ether, 2-methyl furan, isopropyl ether, 1, more than one of 4-dioxane, glycol dimethyl ether, glycol ether dme, toluene or dimethylbenzene, the described solvent of step (2) is selected from more than one in methyl alcohol, ethanol, acetonitrile, methylene dichloride, the trimethyl carbinol, sherwood oil, toluene or the dimethylbenzene.
10. method according to claim 1 is characterized in that, step (1) reaction times 0.1～7h, and temperature of reaction is-50～20 ℃; Step (2) reaction times is 0.1～24 hour, and temperature of reaction is-78～40 ℃.
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Denomination of invention: A preparation method for preparing the intermediate of epridone Effective date of registration: 20230103 Granted publication date: 20100217 Pledgee: Shaoyang small and medium-sized enterprise financing guarantee Co.,Ltd. Pledgor: HUNAN YUXIN PHARMACEUTICAL CO.,LTD. Registration number: Y2023980030141 |
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