CN111675745A - Preparation method of ethinylestradiol - Google Patents
Preparation method of ethinylestradiol Download PDFInfo
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- CN111675745A CN111675745A CN202010509728.2A CN202010509728A CN111675745A CN 111675745 A CN111675745 A CN 111675745A CN 202010509728 A CN202010509728 A CN 202010509728A CN 111675745 A CN111675745 A CN 111675745A
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- ethinylestradiol
- reaction
- organic solvent
- estrone
- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a preparation method of ethinylestradiol, and belongs to the technical field of preparation and processing of medicines. According to the method, estrone is used as an initial raw material, and one-step ethynylation reaction is carried out to prepare the ethinylestradiol disclosed by the invention. The method can effectively shorten the reaction process by improving the defects of the traditional process, has mild reaction conditions, avoids using lithium reagents and Grignard reagents with larger potential safety hazards, has high overall conversion rate and simple and convenient operation, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of preparation of medicines, and particularly relates to a preparation method of ethinylestradiol.
Background
Ethinylestradiol, which is known as Ethinylestradiol in English and 3-hydroxy-19-nor-17 alpha-pregna-1, 3,5(10) -triene-20-alkyne-17-ol in chemical name, is an oral effective potent estrogen, supplements the insufficiency of estrogen, treats female gonad dysfunction, amenorrhea, climacteric syndrome and the like, can inhibit ovulation by being used together with progestational hormones, can be used as a contraceptive, and can also treat amenorrhea and infertility of gonad dysfunction and infertility of multi-follicular ovary caused by the insufficiency of gonadotropin secretion.
The preparation method of ethinyl estradiol in national raw material medicine process compilation comprises the steps of performing azeotropic dehydration on potassium hydroxide, isobutanol and toluene, reacting with acetylene to prepare potassium ethinyl, and finally reacting with estrone to obtain the ethinyl estradiol, wherein the reaction route is as follows:
the method for preparing potassium acetylene by utilizing toluene azeotropic dehydration has low production efficiency and high energy consumption, and is not beneficial to industrial production.
The traditional preparation method of the ethinyl estradiol also introduces an ethynyl group by using a Grignard reagent or a lithium reagent, firstly uses the acetylene to prepare the Grignard reagent or the lithium reagent, and then reacts with the estrone to obtain the ethinyl estradiol. The reaction route is as follows:
disclosure of Invention
In order to solve the problems, the invention provides a preparation method of ethinyl estradiol, which has a simple reaction process and mild conditions.
The purpose of the invention is realized by the following modes: a preparation method of ethinyl estradiol comprises the following synthetic route:
the method is a one-step ethynylation reaction method, and comprises the following specific steps: dissolving estrone in an organic solvent A, adding an organic base, introducing acetylene at the temperature of-20-30 ℃, stirring for reaction, adding an acid solution for neutralization after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product by using an organic solvent B, and drying to obtain the ethinylestradiol.
Further, the organic solvent A is at least one of acetone, butanone, tetrahydrofuran, methyl-tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, sulfolane, toluene and xylene, and the volume consumption of the organic solvent A is 5-30 times that of the substrate estrone;
further, the organic base is one of potassium tert-butoxide, potassium isobutoxide, potassium isopropoxide, potassium ethoxide, sodium ethoxide or sodium methoxide, and the weight consumption of the organic base is 1-5 times of that of the substrate estrone;
further, the acid solution is one of aqueous solutions of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid, and the mass concentration of the acid solution is 5-35%.
Further, the organic solvent B is one of methanol, ethanol and acetone.
Compared with the prior art, the invention has the beneficial effects that:
1. the method has simple and convenient operation and mild reaction conditions, is completely carried out at low temperature or room temperature, and is suitable for industrial production.
2. The total mass yield of the method is higher than 90%, and the product purity is higher than 99.0%.
3. Low requirement on a reaction device, low operation cost, suitability for industrial production and better market prospect.
4. In the traditional process, water is generated by using potassium hydroxide for the ethynylation reaction, which is not beneficial to the reaction, but the method of the invention uses alkali metal alcoholate to replace alkali metal hydroxide for the ethynylation reaction, which can not generate water for hindering the reaction and greatly improves the reaction efficiency.
Detailed Description
The invention is further illustrated with reference to the following examples, which are not intended to limit the invention.
The specific experimental procedures or conditions are not shown in the examples, and the procedures can be performed according to the conventional experimental methods described in the publications in the field, and the reagents or equipment used are not indicated by manufacturers, and are all conventional products which can be obtained commercially.
EXAMPLE 1 preparation of ethinylestradiol
Dissolving 50g of estrone in 250ml of tetrahydrofuran, adding 50g of potassium tert-butoxide, controlling the temperature to be 5 ℃, introducing acetylene, stirring for reaction, neutralizing with a 5% hydrochloric acid aqueous solution after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product with ethanol, and drying to obtain 46g of ethinyl estradiol, wherein the mass yield of the obtained product is 92%, the melting point of the product is 182.0-183.5 ℃, and the HPLC content is 99.5%.
EXAMPLE 2 preparation of ethinylestradiol
Dissolving 50g of estrone in 100ml of dimethyl sulfoxide and 800ml of toluene, adding 70g of potassium isobutyl alcohol, controlling the temperature to be 30 ℃, introducing acetylene, stirring for reaction, neutralizing with a 10% sulfuric acid aqueous solution after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product with methanol, and drying to obtain 47g of ethinyl estradiol, wherein the mass yield of the obtained product is 94%, the melting point of the product is 182.5-183.9 ℃, and the HPLC content is 99.6%.
EXAMPLE 3 preparation of ethinylestradiol
Dissolving 50g of estrone in 1500ml of acetone, adding 250g of sodium ethoxide, controlling the temperature to be minus 20 ℃, introducing acetylene, stirring for reaction, neutralizing with 35% acetic acid aqueous solution after the reaction is finished, concentrating, adding water for water precipitation, filtering to obtain a crude product, refining the crude product with acetone, and drying to obtain 45.5g of ethinylestradiol, wherein the mass yield of the obtained product is 91%, the melting point of the product is 182.1-183.2 ℃, and the HPLC content is 99.5%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (2)
1. The preparation method of the ethinylestradiol is characterized by comprising the following synthetic route:
the method is a one-step ethynylation reaction method, and comprises the following specific steps: dissolving estrone in an organic solvent A, adding an organic base, introducing acetylene at the temperature of-20-30 ℃, stirring for reaction, adding an acid solution for neutralization after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product by using an organic solvent B, and drying to obtain the ethinylestradiol.
2. The method for preparing ethinylestradiol according to claim 1, wherein the organic solvent A is at least one selected from acetone, butanone, tetrahydrofuran, methyl-tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, sulfolane, toluene and xylene, and the volume of the organic solvent A is 5-30 times that of the substrate estrone; the organic base is one of potassium tert-butoxide, potassium isobutoxide, potassium isopropoxide, potassium ethoxide, sodium ethoxide or sodium methoxide, and the weight consumption of the organic base is 1-5 times of that of the estrone substrate; wherein the acid solution is one of aqueous solutions of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and formic acid, and the mass concentration of the acid solution is 5-35%; the organic solvent B is one of methanol, ethanol and acetone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010509728.2A CN111675745A (en) | 2020-06-05 | 2020-06-05 | Preparation method of ethinylestradiol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010509728.2A CN111675745A (en) | 2020-06-05 | 2020-06-05 | Preparation method of ethinylestradiol |
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| Publication Number | Publication Date |
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| CN111675745A true CN111675745A (en) | 2020-09-18 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN202010509728.2A Pending CN111675745A (en) | 2020-06-05 | 2020-06-05 | Preparation method of ethinylestradiol |
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| Country | Link |
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| CN (1) | CN111675745A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS588094A (en) * | 1981-07-08 | 1983-01-18 | Mitsubishi Chem Ind Ltd | Preparation of ethynylestradiol |
| CN102134265A (en) * | 2009-12-29 | 2011-07-27 | 黄云生 | Method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone |
-
2020
- 2020-06-05 CN CN202010509728.2A patent/CN111675745A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS588094A (en) * | 1981-07-08 | 1983-01-18 | Mitsubishi Chem Ind Ltd | Preparation of ethynylestradiol |
| CN102134265A (en) * | 2009-12-29 | 2011-07-27 | 黄云生 | Method for synthesizing 6-methyl-17alpha-acetoxyl-19-norpregnane-4,6-diene-3,20-diketone |
Non-Patent Citations (1)
| Title |
|---|
| HE-LIN LU ET AL.: "An Improved Synthesis of Nomegestrol Acetate", 《ORG. PROCESS RES. DEV.》 * |
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Application publication date: 20200918 |
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| RJ01 | Rejection of invention patent application after publication |