CN111647035A

CN111647035A - Preparation method of levonorgestrel

Info

Publication number: CN111647035A
Application number: CN202010540656.8A
Authority: CN
Inventors: 邵振平; 王荣; 王炳乾; 王洪福; 黄橙橙; 雷灵芝; 王友富
Original assignee: ZHEJIANG SHENZHOU PHARMACEUTICAL CO Ltd
Current assignee: ZHEJIANG SHENZHOU PHARMACEUTICAL CO Ltd
Priority date: 2020-06-15
Filing date: 2020-06-15
Publication date: 2020-09-11

Abstract

The invention discloses a preparation method of levonorgestrel, belonging to the technical field of preparation and processing of medicines. The levonorgestrel is prepared by taking 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone as a starting material through the steps of ethynylation and hydrolysis. The preparation method of the levonorgestrel has the advantages of improving the defects of the traditional process, along with mild reaction conditions, high overall conversion rate, simple and convenient operation, suitability for industrial production and wide market prospect.

Description

Preparation method of levonorgestrel

Technical Field

The invention relates to the technical field of preparation of medicines, and particularly relates to a preparation method of levonorgestrel.

Background

The chemical name of the levonorgestrel is D (-) -17 alpha-ethynyl-17 beta-hydroxy-18-methylestra-4-en-3-one, and the levonorgestrel is an oral contraceptive with wider application. Levonorgestrel can inhibit ovulation and prevent pregnant ovum implantation, and simultaneously increases cervical mucus concentration and prevents sperm progression, thus being one of the most widely applied emergency contraceptives at home and abroad at present. Levonorgestrel can also be used for treating menoxenia, dysfunctional uterine bleeding and endometriosis.

The existing synthesis methods of levonorgestrel mainly comprise two methods:

the method is characterized in that DL-18-methyl-4-estrene-3, 17-diketone is used as a starting material, acetylene is introduced to react in the presence of potassium hydroxide, and the synthetic route of the 18-methylnorethindrone is as follows:

the method is characterized in that 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone is used as a starting material, potassium hydroxide is reacted with acetylene to prepare potassium acetylide, the potassium acetylide is subjected to ethynylation reaction with the starting material, and hydrolysis is carried out to obtain 18-methylnorethindrone, wherein the synthetic route is as follows:

in the two synthetic routes, water is generated in the reaction process, which is not beneficial to the proceeding of the ethynylation reaction, and the total conversion rate is not high, so that the method is not suitable for industrial production.

Disclosure of Invention

In order to solve the problems, the invention provides a preparation method of levonorgestrel, which has the advantages of simple reaction process, mild conditions and high conversion rate.

The purpose of the invention is realized by the following modes: a preparation method of levonorgestrel comprises the following steps:

the method specifically comprises the following steps:

1) alkynylation reaction: dissolving 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone (1) in an organic solvent A, adding an organic base A, controlling the temperature to be minus 20-30 ℃, introducing acetylene, stirring for reaction, adding an acid solution A for neutralization after the reaction is finished, concentrating, adding water for elutriation, and filtering to obtain an intermediate 2;

2) and (3) hydrolysis reaction: dissolving the intermediate (2) obtained in the step 1) in an organic solvent B, adding an acid solution B, reacting at-10-50 ℃, adding an alkali B for neutralization after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product with an organic solvent C, and drying to obtain the levonorgestrel.

Further, in the step 1), the organic solvent A is at least one of acetone, butanone, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, toluene, xylene or sulfolane, and the volume amount of the organic solvent A is 5-30 times that of the substrate 18-methylestra-2, 5(10) -diene-3-methoxy-17-one (1); wherein the organic base A 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 A is 1-5 times of that of 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone (1) serving as a substrate; wherein the acid solution A is one of aqueous solutions of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or formic acid, and the mass concentration of the acid solution A is 5-30%.

Further, the organic solvent B in the step 2) is one of acetone, butanone, tetrahydrofuran or methyl tetrahydrofuran, and the volume consumption of the organic solvent B is 5-30 times that of the substrate intermediate (2); wherein the acid solution B is a hydrochloric acid or sulfuric acid aqueous solution, the mass concentration of the acid solution B is 5-30%, and the dosage of the acid solution B is 0.5-5 times of that of the substrate intermediate (2); the alkali B is one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium sulfite, sodium hydroxide and potassium hydroxide aqueous solutions, and the mass concentration of the alkali B is 5-30%.

Further, the organic solvent C is one of methanol, ethanol and acetone.

Compared with the prior art, the invention has the beneficial effects that:

1. the reaction raw materials of the invention are cheap and easy to obtain.

2. The method has the advantages of short reaction route, low operation cost and simple and convenient operation, and is suitable for industrial production.

3. The method is carried out at low temperature or slightly higher than room temperature, the overall reaction is mild, the total mass yield is higher than 85%, and the product purity is higher than 99.0%.

4. In the traditional process, water is generated when potassium hydroxide is used for carrying out the alkynylation reaction, and the reaction is not carried out.

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 a method for the preparation of levonorgestrel, comprising the steps of:

1) alkynylation reaction: dissolving 18 g of methyl estra-2, 5(10) -diene-3-methoxy-17-ketone (1) in 750ml of tetrahydrofuran, adding 50g of potassium tert-butoxide, introducing acetylene at the controlled temperature of 5 ℃, stirring for reaction, adding a 5% hydrochloric acid aqueous solution for neutralization to neutrality after the reaction is finished, concentrating, adding water for elutriation, and filtering to obtain 52g of an intermediate 2;

2) and (3) hydrolysis reaction: dissolving 52g of the intermediate (2) obtained in the step 1) in 1500ml of acetone, adding 250ml of 5% hydrochloric acid aqueous solution, reacting at 0 ℃, adding 10% sodium carbonate aqueous solution to neutralize to be neutral 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 43g of levonorgestrel, wherein the total mass yield of the product is 86% and the HPLC content is 99.3%.

Example 2 a method for preparing levonorgestrel, comprising the steps of:

1) alkynylation reaction: dissolving 18 g of methyl estra-2, 5(10) -diene-3-methoxy-17-ketone (1) in 250ml of dimethyl sulfoxide, adding 100g of potassium isopropoxide, controlling the temperature and introducing acetylene at 30 ℃, stirring for reaction, adding 10% sulfuric acid water solution A to neutralize to be neutral after the reaction is finished, concentrating, adding water for elutriation, and filtering to obtain 53g of intermediate 2;

2) and (3) hydrolysis reaction: dissolving 53g of the intermediate (2) obtained in the step 1) in 250ml of tetrahydrofuran, adding 27ml of 30% hydrochloric acid aqueous solution, reacting at-10 ℃, adding 5% sodium hydroxide aqueous solution to neutralize to be neutral 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 43.5g of levonorgestrel, wherein the total mass yield of the product is 87%, and the HPLC content is 99.2%.

Example 3 a method of preparing levonorgestrel, comprising the steps of:

1) alkynylation reaction: dissolving 18 g of methyl estra-2, 5(10) -diene-3-methoxy-17-ketone (1) in 1500ml of toluene, adding 250g of sodium ethoxide, controlling the temperature to be minus 20 ℃, introducing acetylene, stirring for reaction, adding 30% acetic acid aqueous solution for neutralization to be neutral after the reaction is finished, concentrating, adding water for water precipitation, and filtering to obtain 51g of an intermediate 2;

2) and (3) hydrolysis reaction: dissolving 51g of the intermediate (2) obtained in the step 1) in 750ml of butanone, adding 70ml of 10% sulfuric acid aqueous solution, reacting at 50 ℃, adding 30% sodium sulfite aqueous solution to neutralize to be neutral after the reaction is finished, concentrating, adding water for elutriation, filtering to obtain a crude product, refining the crude product with acetone, and drying to obtain 43g of levonorgestrel, wherein the total mass yield of the product is 86% and the HPLC content is 99.4%.

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

1. A preparation method of levonorgestrel is characterized by comprising the following preparation route:

the method specifically comprises the following steps:

2. The method for preparing levonorgestrel according to claim 1, wherein the organic solvent A in step 1) is at least one selected from acetone, butanone, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, toluene, xylene and sulfolane, and the volume of the organic solvent A is 5-30 times that of the 18-methylestra-2, 5(10) -diene-3-methoxy-17-one (1) serving as a substrate; wherein the organic base A 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 A is 1-5 times of that of 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone (1) serving as a substrate; wherein the acid solution A is one of aqueous solutions of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or formic acid, and the mass concentration of the acid solution A is 5-30%.

3. The method for preparing levonorgestrel according to claim 1, wherein the organic solvent B in the step 2) is one of acetone, butanone, tetrahydrofuran or methyltetrahydrofuran, and the volume of the organic solvent B is 5-30 times that of the substrate intermediate (2); wherein the acid solution B is a hydrochloric acid or sulfuric acid aqueous solution, the mass concentration of the acid solution B is 5-30%, and the dosage of the acid solution B is 0.5-5 times of that of the substrate intermediate (2); wherein the alkali B is one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium sulfite, sodium hydroxide and potassium hydroxide aqueous solutions, and the mass concentration of the alkali B is 5-30%; the organic solvent C is one of methanol, ethanol and acetone.