CN114736261A - Synthesis method of 8, 11-diene dexamethasone - Google Patents
Synthesis method of 8, 11-diene dexamethasone Download PDFInfo
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- CN114736261A CN114736261A CN202210539601.4A CN202210539601A CN114736261A CN 114736261 A CN114736261 A CN 114736261A CN 202210539601 A CN202210539601 A CN 202210539601A CN 114736261 A CN114736261 A CN 114736261A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a synthesis method of 8, 11-diene dexamethasone, and belongs to the field of drug synthesis. The method takes 17, 21-dexamethasone diester as a raw material, realizes the synthesis of 8, 11-diene dexamethasone for the first time through twice elimination reactions, screens out an optimal synthetic route and reaction conditions through a large number of experiments, obtains a target product with the purity of over 99 percent, can provide reference standards for impurity identification, metabolic mechanism, scientific evaluation of efficiency and the like of dexamethasone, and has practical application value.
Description
Technical Field
The invention belongs to a medicine synthesis technology, and particularly relates to a synthesis method of 8, 11-diene dexamethasone.
Background
Dexamethasone (Dexamethasone) is one of essential drugs of the basic public health system in the basic drug standard list of the world health organization.
The 6 th and 16 th day in 2020, the world health organization shows that the results of preliminary clinical trials in the uk show that dexamethasone can save the lives of severe patients with new coronary pneumonia, and can reduce the death rate by about one third for patients using a ventilator, and by about one fifth for patients who only inhale oxygen.
In 10 months in 2020, the world health organization announces that the latest research result related to the new coronary pneumonia medicine shows that the Reidesciclovir and the like have little effect on preventing the death of the new coronary pneumonia patient or shortening the hospitalization time, and the dexamethasone is still the only effective medicine for the severe patients with the new coronary pneumonia.
Dexamethasone is an artificial corticosteroid used to treat a variety of conditions including rheumatic diseases, certain skin disorders, severe allergies, asthma, chronic obstructive pulmonary disease, laryngitis pseudomembranous, cerebral edema, and possibly in combination with antibiotics in tuberculosis patients.
The production process of dexamethasone determines that some impurities or related compounds are sometimes present in the product. Some of the impurities and related compounds can reduce the curative effect, and some of the impurities and related compounds can even cause harm to human bodies. The European pharmacopoeia, British pharmacopoeia, United states pharmacopoeia, Chinese pharmacopoeia and the like all make provisions for the quality control of dexamethasone.
The European pharmacopoeia clearly notes that 7,9(11) -diene dexamethasone corresponds to the impurity K, and that the isomers of this impurity are 8, 11-diene dexamethasone and 8(14),9(11) -diene dexamethasone, which impurities are believed to be introduced during the production of dexamethasone or to be present by further conversion during storage.
The importance of scientific evaluation of the quality, safety and efficacy of a drug before the drug comes into the market is more fully recognized, wherein the quality of the drug is closely related to the control of impurities contained in the drug. Impurities are often associated with drug safety and in a few cases also with efficacy. Therefore, the separation and identification of impurities are increasingly regarded by medical workers in the process of drug development and research.
The 8, 11-diene dexamethasone is not reported in published data, 17, 21-dexamethasone diester is taken as a raw material, synthesis of 8, 11-diene dexamethasone is realized for the first time through two elimination reactions, an optimal synthetic route and reaction conditions are screened out through a large number of experiments, the purity of a prepared target product can reach more than 99%, a reference standard substance can be provided for impurity identification, metabolic mechanism, scientific efficiency evaluation and the like of dexamethasone, and the method has practical application value.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the prior art, the invention provides a synthesis method of 8, 11-diene dexamethasone, which has the advantages of reasonable process design, strong operability, easy purification of products, high purity and capability of realizing repeated production.
The technical scheme is as follows: the synthesis method of 8, 11-diene dexamethasone specifically comprises the following steps:
(1) dissolving a compound 1, namely 17, 21-dexamethasone diester in a solvent, and carrying out a first elimination reaction to obtain an intermediate IM-1;
(2) dissolving the intermediate IM-1 obtained in the step (1) in a solvent, and carrying out at most one reaction to obtain an intermediate IM-2;
(3) dissolving the intermediate IM-1 obtained in the step (2) in a solvent, and carrying out a second elimination reaction to obtain an intermediate IM-3;
r1 ═ acetyl, propionyl, n-butyryl, phosphate, or the like;
r2, R3, R4 ═ hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, or a double bond with an adjacent carbon;
r5 ═ hydrogen or a double bond with an adjacent carbon, etc.;
(4) and (4) dissolving the intermediate IM-3 obtained in the step (3) in a solvent, and deprotecting to obtain a compound 2, namely 8, 11-diene dexamethasone.
In the step (1), the solvent is dichloromethane, dichloroethane, toluene, dioxane, tetrahydrofuran, or the like. Preferably, the solvent is dichloroethane.
In the step (1), the elimination reaction reagent is phosphorus pentachloride, phosphorus tribromide, diethylaminosulfur trifluoride, sodium hydroxide, potassium tert-butoxide and the like, and the molar ratio of the used reagent to the compound 1 is 0.5-4: 1. preferably, the elimination reagent used is diethylaminosulfur trifluoride and the molar ratio is 1: 1.5.
in the step (1), the reaction temperature is-78-80 ℃, and the reaction time is 0.5-24 hours. Preferably, the reaction temperature is chosen to be 25 ℃ and the reaction time is 10 hours.
In the step (2), the at most one reaction is carried out for 0 or 1 time. Preferably, the reaction is carried out once.
In the step (2), the solvent is dichloromethane, dichloroethane, dimethyl sulfoxide, toluene, benzene, dioxane, tetrahydrofuran, carbon tetrachloride, acetonitrile, N-dimethylformamide, N-dimethylacetamide, or the like. Preferably, the solvent is dichloromethane or tetrahydrofuran. Particularly preferably, the solvent is tetrahydrofuran.
In the step (2), the reaction reagent is aluminum trichloride, hydrofluoric acid, stannic chloride, phosphorus tribromide, phosphorus pentachloride, carbon tetrabromide, titanium tetrachloride, boron trifluoride diethyl etherate, trimethyl bromosilane, hydrochloric acid, hydrobromic acid and the like, and the molar ratio of the reaction reagent to the intermediate IM-1 is 0.05-3: 1. preferably, the reagent is trimethyl bromosilane, boron trifluoride ethyl ether, hydrofluoric acid and titanium tetrachloride. Particularly preferably, the reagent is titanium tetrachloride and the molar ratio of titanium tetrachloride to intermediate IM-1 is 1.5: 1.
in the step (2), the reaction temperature is-78 ℃ to 150 ℃, and the reaction time is 1-16 hours. Preferably, the reaction temperature is 60 ℃ and the reaction time is 2 hours.
In the step (3), the solvent is dichloromethane, dichloroethane, dimethyl sulfoxide, toluene, benzene, dioxane, tetrahydrofuran, carbon tetrachloride, acetonitrile, N-dimethylformamide, N-dimethylacetamide, water, or the like. Preferably, the solvent is dichloromethane.
In the step (3), the elimination reaction reagent is phosphorus pentachloride, phosphorus tribromide, diethylaminosulfur trifluoride, sodium hydroxide, potassium tert-butoxide, lithium carbonate, sodium carbonate, lithium chloride, lithium bromide, sodium bromide, lithium iodide, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, palladium acetate, palladium tetratriphenylphosphine, palladium chloride and the like, and the molar ratio of the used reagent to the intermediate IM-2 is 0.05-4: 1. preferably, the reagent is phosphorus pentachloride, diethylaminosulfur trifluoride, lithium carbonate, lithium chloride, lithium bromide, sodium bromide and trifluoroacetic acid, particularly preferably, the reagent is phosphorus pentachloride and the molar ratio is 1.2: 1.
in the step (3), the reaction temperature is-78-135 ℃, and the reaction time is 0.5-18 hours. Preferably, the reaction temperature is-60 ℃ and the reaction time is 4 hours.
In the step (4), the solvent is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, water and the like. Preferably, the solvent is methanol or water.
In the step (4), the reagent is sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide and the like, and the molar ratio of the reagent to the intermediate IM-3 is 0.1-5: 1. preferably, the reagent is sodium carbonate and the molar ratio is 3: 1.
in the step (4), the reaction temperature is-20 ℃ to 75 ℃, and the reaction time is 1 to 48 hours. Preferably, the reaction temperature is 60 ℃ and the reaction time is 1 hour.
Has the advantages that:
the method realizes the synthesis of 8, 11-diene dexamethasone for the first time, screens out the optimal synthetic route and reaction conditions through a large number of experiments, obtains a target product with the purity of more than 99% through secondary digestion reaction, can provide reference standards for impurity identification, metabolic mechanism, scientific efficiency evaluation and the like of the dexamethasone, and has practical application value.
Drawings
FIG. 1 is an IR spectrum of 8, 11-diendexamethasone prepared in example 1;
FIG. 2 is an NMR spectrum of 8, 11-diendexamethasone prepared in example 1.
FIG. 3 is an HPLC chromatogram of 8, 11-diendexamethasone prepared in example 1.
FIG. 4 is a structural formula of 8, 11-diene dexamethasone and isomers thereof.
Detailed Description
The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the specific material ratios, process conditions and results thereof described in the examples are illustrative only and should not be taken as limiting the invention as detailed in the claims.
Example 1
The synthesis method of 8, 11-diene dexamethasone comprises the following steps:
(1) synthesis of intermediate IM-1a
The reaction process is as follows:
taking 50 g of 17, 21-dexamethasone diacetate (1a) into a round-bottom flask, adding 500 ml of dichloromethane, cooling to 0 ℃, slowly adding 25.39 g of diethylaminosulfur trifluoride, maintaining the temperature, stirring for 2 hours, recovering to 25 ℃, continuing to react for 8 hours, recrystallizing the crude product by dichloromethane and ether after quenching the reaction, and purifying 35.08 g of off-white solid, namely an intermediate IM-1a, [ M + H ]]+The yield was 72.9% as 459.2.
(2) Synthesis of intermediate IM-2a
The reaction process is as follows:
20 g of intermediate IM-1a were dissolved in 800 ml of tetrahydrofuran, 16.55 g of titanium tetrachloride were slowly added in portions at-30 ℃ and gradually returned to room temperature, followed by stirring at 60 ℃ for 2 hours. After the reaction quenching, the crude product is purified by column chromatography to obtain 8.65 g of light yellow solid, namely an intermediate IM-2a, [ M + H ]]+When the yield was 457.2, the yield was 43.4%.
(3) Synthesis of intermediate IM-3a
The reaction process is as follows:
5 g of intermediate IM-2a was dissolved in 120 ml of dichloromethane, 2.73 g of phosphorus pentachloride was added in portions at-60 ℃ and the reaction was then incubated for 4 hours. Subjecting the quenched crude product to silica gel column chromatography, eluting with 75% -40% petroleum ether/ethyl acetate, and recrystallizing with dichloromethane-diethyl ether for purification to obtain 660 mg of white solid, i.e. intermediate IM-3a, [ M + H ]]+The yield was 13.7% as 439.2.
(4) Synthesis of compound 2, 8, 11-diene dexamethasone
The reaction process is as follows:
dissolving 500 mg of intermediate IM-3a in 10 ml of methanol, adding 363 mg of sodium carbonate and 1 ml of water, replacing the system with nitrogen for 3 times, reacting at 60 ℃ for 1 hour, subjecting the crude product after the reaction treatment to silica gel column chromatography, eluting with 90-30% petroleum ether/ethyl acetate, and recrystallizing with methanol-acetonitrile to obtain 310 mg of white solid, namely compound 2, 8, 11-diene dexamethasone, [ M + H ], (M + H)]+355.2, yield 76.7%, liquid phase purity 99.5666%, IR as shown in FIG. 1,1H-NMR and HPLC are shown in FIG. 2 and 3, respectively.
Example 2
The synthesis method of 8, 11-diene dexamethasone comprises the following steps:
(1) synthesis of intermediate IM-1b
The reaction process is as follows:
taking 40 g of 17, 21-dexamethasone dipropionate (1b) to a round-bottom flask, adding 600 ml of tetrahydrofuran, cooling to-50 ℃, and adding 18.9 in batches8 grams of phosphorus pentachloride, then stirred at 0 degrees Celsius for 6 hours. After quenching the reaction with sodium carbonate solution, the crude product was purified by recrystallization from dichloromethane and diethyl ether to 24.05 g of a white solid, intermediate IM-1b, [ M + H ]]+The yield was 62.4% as 486.2.
(2) Synthesis of intermediate IM-2b
The reaction process is as follows:
9.75 g of intermediate IM-1b was dissolved in 97.5 ml of methylene chloride, and 7.67 g of trimethylbromosilane and 2.5 ml of boron trifluoride diethyl etherate were added thereto and reacted at 40 ℃ for 16 hours. Concentrating the reaction solution, slurrying and purifying the crude product by using a mixed solution of diethyl ether/n-hexane (1: 3) to obtain 9.20 g of a crude product, namely an intermediate IM-2b crude product, [ M + H ]]+547.2, 549.2, was used directly in the next reaction.
(3) Synthesis of intermediate IM-3b
The reaction process is as follows:
9.20 g of the crude intermediate IM-2b was dissolved in 120 ml of DMAc, and 2.19 g of lithium bromide and 1.86 g of lithium carbonate were added thereto and reacted at 100 ℃ for 3 hours. Washing the reaction with saturated saline water and ethyl acetate, subjecting the crude product to silica gel column chromatography, eluting with 80% -40% petroleum ether/ethyl acetate, and recrystallizing with ethyl acetate-n-hexane to obtain 1.12 g white solid, i.e., [ M + H ] intermediate IM-3b]+When the yield was 466.2, the yield was 14.3%.
(4) Synthesis of compound 2, 8, 11-diene dexamethasone
The reaction process is as follows:
500 mg of intermediate IM-3b are dissolved inAdding 116 mg of sodium methoxide into 10 ml of methanol, replacing the system with nitrogen for 3 times, reacting for 3 hours at 45 ℃, after reaction treatment, performing silica gel column chromatography on a crude product, and eluting by using 90-30% petroleum ether/ethyl acetate to obtain 120 mg of white solid, namely a compound 2, 8, 11-diene dexamethasone, [ M + H ] dexamethasone]+355.2, IR and1H-NMR was the same as in example 1. The yield is 31.6 percent, and the purity of the liquid phase is 99.1240 percent.
Example 3
The synthesis method of 8, 11-diene dexamethasone comprises the following steps:
(1) synthesis of intermediate IM-1b
The reaction process is as follows:
40 g of 17, 21-dexamethasone dipropionate (1b) is put into a round-bottom flask, 600 ml of tetrahydrofuran is added, after cooling to-50 ℃, 18.98 g of phosphorus pentachloride is added in portions, and then stirring is carried out for 6 hours at 0 ℃. After quenching the reaction with sodium carbonate solution, the crude product was purified by recrystallization from dichloromethane and diethyl ether to obtain 24.05 g of a white solid, i.e. intermediate IM-1b, in 62.4% yield, as in example 2.
(2) Directly carrying out an elimination reaction and a deprotection reaction on the intermediate IM-1b to obtain a compound 2, 8, 11-diene dexamethasone, wherein the reaction process comprises the following steps:
5 g of intermediate IM-1b was taken and put into a 500 ml closed tube, 100 ml of dimethyl sulfoxide and 2.30 g of potassium tert-butoxide were added, the system was bubbled with nitrogen for 30 minutes, reacted at 130 ℃ for 4 hours, then cooled to room temperature, added with 10 ml of water, and reacted at room temperature for 2 hours. Subjecting the crude product to silica gel column chromatography, eluting with 90% -30% petroleum ether/ethyl acetate, and purifying by preparative chromatography using C18 (50X 300mm,10 μm), flow rate (40 ml/min), and flow rateMobile phase methanol/water 5/95(0-10 min), 5/95-25/75(10-20 min), 25/75-65/35(20-40 min) to give 280 mg of a white solid, compound 2, 8, 11-diendexamethasone, IR and1H-NMR was the same as in example 1. The yield is 7.7%, and the purity of the liquid phase is 98.8420%.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, it is possible to make various modifications, decorations, or adjustment reaction sequences without departing from the principle of the present invention, and these should also be regarded as the protection scope of the present invention.
Claims (17)
1. A method for synthesizing 8, 11-diene dexamethasone is characterized by comprising the following steps:
(1) dissolving a compound 1, namely 17, 21-dexamethasone diester in a solvent, and carrying out a first elimination reaction to obtain an intermediate IM-1;
(2) dissolving the intermediate IM-1 obtained in the step (1) in a solvent, and carrying out at most one reaction to obtain an intermediate IM-2;
(3) dissolving the intermediate IM-2 obtained in the step (2) in a solvent, and carrying out a second elimination reaction to obtain an intermediate IM-3;
wherein:
r1 ═ acetyl, propionyl, n-butyryl, or phosphate;
r2, R3, R4 are hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl or form a double bond with the adjacent carbon;
r5 is hydrogen or forms a double bond with an ortho carbon;
(4) and (4) dissolving the intermediate IM-3 obtained in the step (3) in a solvent, and deprotecting to obtain a compound 2, namely 8, 11-diene dexamethasone.
2. The method for synthesizing 8, 11-diene dexamethasone as claimed in claim 1, wherein in step (1), intermediate IM-1 has a structure corresponding to that defined in claim 1 for R1, R2, R3, R4 and R5, and at least one double bond is present between R2, R3, R4 and R5.
3. The method for synthesizing 8, 11-diene dexamethasone as claimed in claim 1, wherein in step (1), the solvent is dichloromethane, dichloroethane, toluene, dioxane or tetrahydrofuran.
4. The method for synthesizing 8, 11-diene dexamethasone according to claim 1, wherein in step (1), the reagent for elimination reaction is phosphorus pentachloride, phosphorus tribromide, diethylaminosulfur trifluoride, sodium hydroxide, potassium tert-butoxide; and the molar ratio of the used reagent to the compound 1 is 0.5-4: 1.
5. the method for synthesizing 8, 11-diene dexamethasone as claimed in claim 1, wherein the reaction temperature in step (1) is-78-80 ℃ and the reaction time is 0.5-24 hours.
6. The method for synthesizing 8, 11-diene dexamethasone as claimed in claim 1, wherein in step (2), the corresponding structure of intermediate IM-2 is in accordance with the definition range of R1, R2, R3, R4 and R5 in claim 1.
7. The method for synthesizing 8, 11-diene dexamethasone according to claim 1, wherein in step (2) the at most one reaction is 0 or 1 reaction, when 0 reactions are carried out, the intermediate IM-1 and IM-2 are of the same structure.
8. The method for synthesizing 8, 11-diene dexamethasone according to claim 1, wherein in step (2), the solvent is dichloromethane, dichloroethane, dimethyl sulfoxide, toluene, benzene, dioxane, tetrahydrofuran, carbon tetrachloride, acetonitrile, N-dimethylformamide or N, N-dimethylacetamide when the reaction is performed once.
9. The method for synthesizing 8, 11-diene dexamethasone according to claim 1, wherein in step (2), when the first reaction is performed, the reaction reagent is aluminum trichloride, hydrofluoric acid, stannic chloride, phosphorus tribromide, phosphorus pentachloride, carbon tetrabromide, titanium tetrachloride, boron trifluoride diethyl etherate, trimethyl bromosilane, hydrochloric acid, hydrobromic acid, or the like, and the molar ratio of the reaction reagent to the intermediate IM-1 is 0.05-3: 1.
10. the method for synthesizing 8, 11-diene dexamethasone as claimed in claim 1, wherein in step (2), the reaction temperature is-78 ℃ to 150 ℃ and the reaction time is 1 to 16 hours.
11. The method for synthesizing 8, 11-diene dexamethasone according to claim 1, wherein in step (3), the corresponding structure of intermediate IM-3 conforms to the definition range of R1, R2, R3, R4 and R5 in claim 1, and there are at most two double bonds between R2, R3, R4 and R5.
12. The method for synthesizing 8, 11-diene dexamethasone according to claim 1, wherein in step (3), the solvent is dichloromethane, dichloroethane, dimethyl sulfoxide, toluene, benzene, dioxane, tetrahydrofuran, carbon tetrachloride, acetonitrile, N-dimethylformamide, N-dimethylacetamide, or water.
13. The method for synthesizing 8, 11-diene dexamethasone as claimed in claim 1, wherein in step (3), the reagent for elimination reaction is phosphorus pentachloride, phosphorus tribromide, diethylaminosulfur trifluoride, sodium hydroxide, potassium tert-butoxide, lithium carbonate, sodium carbonate, lithium chloride, lithium bromide, sodium bromide, lithium iodide, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, p-toluenesulfonic acid, palladium acetate, palladium tetrakistriphenylphosphine, palladium chloride; the molar ratio of the used reagent to the intermediate IM-2 is 0.05-4: 1.
14. the method for synthesizing 8, 11-diene dexamethasone as claimed in claim 1, wherein in step (3), the reaction temperature is-78 ℃ to 135 ℃ and the reaction time is 0.5 to 18 hours.
15. The method for synthesizing 8, 11-diene dexamethasone as claimed in claim 1, wherein in step (4), the solvent is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or water.
16. The method for synthesizing 8, 11-diene dexamethasone as claimed in claim 1, wherein in step (4), the reagent in the deprotection reaction is sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide; the molar ratio of the reagent to the intermediate IM-3 is 0.1-5: 1.
17. the method for synthesizing 8, 11-diene dexamethasone as claimed in claim 1, wherein in step (4), the reaction temperature is-20 ℃ to 75 ℃ and the reaction time is 1 to 48 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080287404A1 (en) * | 2005-12-05 | 2008-11-20 | Lajosne Dancsi | High Purity 17Alpha-Cyanomethyl-17Beta-Hydroxy-Estra-4,9-Diene-3- One and Process For the Syntheses Thereof |
| CN101397320A (en) * | 2007-09-29 | 2009-04-01 | 天津天药药业股份有限公司 | Method for preparing dexamethasone and series products thereof |
| CN102603843A (en) * | 2012-02-20 | 2012-07-25 | 湖南诺凯生物医药有限公司 | Preparation method of dexamethasone intermediate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080287404A1 (en) * | 2005-12-05 | 2008-11-20 | Lajosne Dancsi | High Purity 17Alpha-Cyanomethyl-17Beta-Hydroxy-Estra-4,9-Diene-3- One and Process For the Syntheses Thereof |
| CN101397320A (en) * | 2007-09-29 | 2009-04-01 | 天津天药药业股份有限公司 | Method for preparing dexamethasone and series products thereof |
| CN102603843A (en) * | 2012-02-20 | 2012-07-25 | 湖南诺凯生物医药有限公司 | Preparation method of dexamethasone intermediate |
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