CN114181272A

CN114181272A - Synthesis method of levonorgestrel

Info

Publication number: CN114181272A
Application number: CN202111588340.7A
Authority: CN
Inventors: 谢祚宜; 曾春玲; 靳志忠; 刘喜荣
Original assignee: Hunan Keyixin Biomedical Co ltd
Current assignee: Hunan Keyixin Biomedical Co ltd
Priority date: 2021-12-23
Filing date: 2021-12-23
Publication date: 2022-03-15
Anticipated expiration: 2041-12-23
Also published as: CN114181272B

Abstract

The invention relates to a synthesis method of levonorgestrel, which takes a compound shown in a formula (I) as a raw material, adopts a one-pot method to synthesize levonorgestrel, reduces the operation of separating and purifying intermediates, greatly simplifies the production process, and has high reaction speed and short production period; and the synthesis method does not need acetylene gas, has better safety, higher yield and lower production cost, and is suitable for large-scale industrial production.

Description

Synthesis method of levonorgestrel

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a synthesis method of levonorgestrel.

Background

Levonorgestrel is chemically named as 13-ethyl-17-hydroxy-18, 19-bis-demethyl-17 a-pregn-4-en-20-yn-3-one, and is also named as levonorgestrel in English. Levonorgestrel is a quick-acting, short-term oral contraceptive, mainly acts on hypothalamus and pituitary, can reduce or eliminate the peak level of follicle-stimulating hormone and luteinizing hormone in the middle period of menstruation, and inhibit ovulation; meanwhile, the physical and chemical properties of cervical mucus can be changed, normal development of endometrium is influenced, so that the endometrium is asynchronous with the development of the fertilized egg, implantation is interfered, the fertilized egg is denatured and stops developing, and the purpose of avoiding pregnancy is achieved.

The traditional production process of the levonorgestrel uses an ethoprost as a raw material to react with a saturated acetylene solution of tetrahydrofuran to obtain the levonorgestrel. Wherein, saturated acetylene solution of tetrahydrofuran is obtained by introducing acetylene gas into tetrahydrofuran dissolved with potassium hydroxide to saturation. However, the solubility of acetylene gas in tetrahydrofuran is limited, resulting in large amounts of tetrahydrofuran; the reaction of acetylene gas and potassium hydroxide to generate water can influence the reaction process, and the potassium hydroxide and the acetylene are required to be greatly excessive; and after the acetylene gas is introduced, forming a paste in a tetrahydrofuran solvent of potassium hydroxide, and stirring is difficult, so that the raw materials are difficult to react completely. In addition, acetylene gas is an explosive combustible gas and has a problem of safety in use.

Disclosure of Invention

Based on the method, the synthesis method of the levonorgestrel is simple to operate, good in safety and high in yield.

The technical scheme of the invention for solving the technical problems is as follows.

A synthesis method of levonorgestrel comprises the following steps:

carrying out an alkynylation reaction on a compound shown in a formula (I) and trialkylsilyacetylene in a first organic solvent under the action of an organic metal reagent to obtain a reaction liquid containing a compound shown in a formula (II);

adding a second organic solvent into the reaction liquid containing the compound of the formula (II), then adding water, and removing trialkylsilyl to obtain a compound of a formula (III); the second organic solvent is an alcohol solvent;

carrying out hydrolysis reaction on the compound shown in the formula (III) and acid to obtain the levonorgestrel; the structural formula of the levonorgestrel is shown as a formula (IV);

in some of these embodiments, the organometallic reagent is n-butyllithium or lithium diisopropylamide in the method of synthesizing levonorgestrel.

In some embodiments, in the synthesis method of levonorgestrel, the number of carbon atoms of the alkyl group of the trialkylsilylethylene is 1-5.

In some of these embodiments, the method of synthesizing levonorgestrel comprises selecting at least one of trimethylsilylacetylene, triethylsilylacetylene, triisopropylsilylacetylene, and tri-n-propylsilylacetylene.

In some embodiments, the first organic solvent is selected from at least one of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, and toluene.

In some embodiments, the ratio of the mass of the compound of formula (I) to the volume of the first organic solvent in the method for synthesizing levonorgestrel is 1g (2 mL-20 mL).

In some embodiments, the temperature of the ethynylation reaction is-30 ℃ to 10 ℃ and the time is 0.5h to 6h in the synthesis method of the levonorgestrel.

In some of these embodiments, the method for synthesizing levonorgestrel comprises the step of adding a second organic solvent to the mixture of levonorgestrel and norgestrel.

In some embodiments, the volume ratio of the second organic solvent to the water in the synthesis method of the levonorgestrel is (2-10): 1.

In some embodiments, in the synthesis method of levonorgestrel, the reaction temperature in the step of removing trialkyl silicon group is 10-50 ℃ and the reaction time is 1-5 h.

In some of these embodiments, the method of synthesizing levonorgestrel comprises at least one acid selected from the group consisting of hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid.

In some embodiments, in the synthesis method of levonorgestrel, the temperature of the hydrolysis reaction is 30-70 ℃ and the time is 1-7 h.

Compared with the prior art, the synthesis method of levonorgestrel has the following beneficial effects:

according to the synthesis method of the levonorgestrel, trialkyl silicon-based acetylene is used as an ethynylation reagent and is subjected to ethynylation reaction with the compound of the formula (I) under the action of an organic metal reagent, the obtained reaction liquid containing the compound of the formula (II) is not required to be separated, no extra alkali is required to be added, an alcohol solvent is directly added, the alcohol solvent and the organic metal reagent react to generate a metal alcoholate, the metal alcoholate further generates a metal hydroxide under the action of water, and the problem that the organic metal reagent catches fire when meeting water is effectively avoided; and (3) removing trialkyl silicon base from the compound in the formula (II) under the action of metal hydroxide, and further adding acid for hydrolysis to obtain the levonorgestrel.

The method for synthesizing the levonorgestrel takes the compound shown in the formula (I) as a raw material, adopts a one-pot method to synthesize the levonorgestrel, reduces the operation of separating and purifying intermediates, greatly simplifies the production process, and has high reaction speed and short production period; and the synthesis method does not need acetylene gas, has better safety, higher yield and lower production cost, and is suitable for large-scale industrial production.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.

FIG. 1 is an infrared spectrum of levonorgestrel prepared in example 1;

FIG. 2 is the nuclear magnetic hydrogen spectrum of levonorgestrel prepared in example 1;

FIG. 3 is the nuclear magnetic carbon spectrum of levonorgestrel prepared in example 1.

Detailed Description

The technical solution of the present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. It is to be understood that these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.

The weight of the related components mentioned in the description of the embodiments of the present invention may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, the content of the related components is scaled up or down within the scope disclosed in the description of the embodiments of the present invention as long as it is in accordance with the description of the embodiments of the present invention. Specifically, the weight described in the description of the embodiment of the present invention may be a unit of mass known in the chemical industry field, such as μ g, mg, g, and kg.

One embodiment of the present invention provides a method for synthesizing levonorgestrel, which comprises the following steps S10 to S30.

Step S10: carrying out an alkynylation reaction on a compound shown in a formula (I) and trialkylsilyacetylene in a first organic solvent under the action of an organic metal reagent to obtain a reaction liquid containing a compound shown in a formula (II);

wherein, the chemical name of the compound of the formula (I) is 18-methylestra-2, 5(10) -diene-3-methoxy-17-ketone, and the name is ethyl Wolff; the chemical name of the compound of formula (II) is 13 beta-ethyl-18, 19-didecarbo-17 beta-hydroxypregna-2, 5(10) -diene-3-methoxy-20-trialkylkynyl.

In some examples, in step S10, the organometallic reagent is n-butyl lithium or lithium diisopropylamide. Optionally, the organometallic reagent is n-butyllithium.

In some examples, in step S10, the number of carbon atoms of the alkyl group of the trialkylsilyl acetylene is 1-5. Optionally, the alkyl of the trialkylsilyl acetylene has 1-3 carbon atoms.

In some examples, in step S10, the trialkylsilylethylene is selected from at least one of trimethylsilylacetylene, triethylsilylethyne, triisopropylsilylethyne and tri-n-propylsilylethyne; preferably, the trialkylsilylacetylene is trimethylsilylacetylene.

It will be appreciated that when the trialkylsilylacetylene is trimethylsilylacetylene, the compound of formula (II) is as follows:

in some examples, in step S10, the mass ratio of the trialkylsilylane to the compound of formula (I) is (1-2): 1.

In some examples, in step S10, the first organic solvent is selected from at least one of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, and toluene. Optionally, the first organic solvent is selected from at least one of tetrahydrofuran, methyltetrahydrofuran, dioxane, and ethylene glycol dimethyl ether.

In some examples, in step S10, the first organic solvent is tetrahydrofuran.

In some examples, in step S10, the ratio of the mass of the compound of formula (I) to the volume of the first organic solvent is 1g (2 mL-20 mL). Alternatively, the ratio of the mass of the compound of formula (I) to the volume of the first organic solvent is 1g (2ml to 10 ml). Further, the ratio of the mass of the compound of formula (I) to the volume of the first organic solvent was 1g:5 mL.

In some examples, in step S10, the temperature of the ethynylation reaction is-30 ℃ to 10 ℃ and the time is 0.5h to 6 h.

In some specific examples, the temperature of the ethynylation reaction is-20 ℃ to 0 ℃ in step S10; the time is 2-5 h. Optionally, the temperature of the ethynylation reaction is-15 ℃ to 0 ℃ and the time is 2h to 4 h. Further, the temperature of the ethynylation reaction is-10 ℃ to 0 ℃ and the time is 2 hours.

In some specific examples, in step S10, the compound of formula (i) is added after mixing the trialkylsilylacetylene, the organometallic reagent and the first organic solvent. Further, after mixing an organic metal reagent and a first organic solvent, dropwise adding trialkylsilyl acetylene, reacting for 0.5-2 h under heat preservation to obtain a trialkylsilyl acetylene lithium solution, and then adding the compound shown in the formula (I).

Step S20: adding a second organic solvent into the reaction liquid containing the compound of the formula (II) obtained in the step S10, adding water, and removing trialkylsilyl to obtain a compound of a formula (III); the second organic solvent is an alcohol solvent.

In some examples, in step S20, the second organic solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, ethylene glycol, and ethylene glycol monomethyl ether. Further, the second organic solvent is selected from at least one of methanol and ethanol.

In some examples, in step S20, the ratio of the volume of the second organic solvent to the mass of the compound of formula (I) is (2 mL-30 mL):1 g. Alternatively, the ratio of the volume of the second organic solvent to the mass of the compound of formula (I) is (2 mL-10 mL):1 g. Further, the ratio of the volume of the second organic solvent to the mass of the compound of the formula (I) is (2 mL-8 mL):1 g. Preferably, the ratio of the volume of the second organic solvent to the mass of the compound of formula (I) is 4mL:1 g.

In some examples, in step S20, the volume ratio of the second organic solvent to the water is (2-10): 1. Optionally, the volume ratio of the second organic solvent to the water is (3-6): 1. Preferably, the volume ratio of the second organic solvent to water is 4: 1.

In some examples, in the step of removing trialkylsilyl group in step S20, the reaction temperature is 10 ℃ to 50 ℃ and the reaction time is 1h to 5 h. Furthermore, the reaction temperature is 20-30 ℃ and the reaction time is 2-5 h.

Step S30: carrying out hydrolysis reaction on the compound shown in the formula (III) and acid to obtain levonorgestrel; the structural formula of the levonorgestrel is shown as a formula (IV);

taking trialkyl-silyl acetylene as an alkynylation reagent, carrying out an alkynylation reaction with a compound shown in a formula (I) under the action of an organic metal reagent, directly adding an alcohol solvent into the obtained reaction solution containing the compound shown in the formula (II) without separation and adding extra alkali, reacting the alcohol solvent with the organic metal reagent to generate a metal alcoholate, and further generating a metal hydroxide under the action of water by the metal alcoholate, thereby effectively avoiding the problem that the organic metal reagent catches fire when encountering water; and (3) removing trialkyl silicon base from the compound in the formula (II) under the action of metal hydroxide, and further adding acid for hydrolysis to obtain the levonorgestrel.

It can be understood that when the organic metal reagent is n-butyl lithium, a second organic solvent is added after the ethynylation reaction is finished, the n-butyl lithium reacts with the alcohol solvent to generate lithium alkoxide, the lithium alkoxide generates lithium hydroxide under the action of water, and the trialkyl silicon group of the compound in the formula (II) is removed under the action of the lithium hydroxide without adding extra alkali.

In some examples, in step S30, the acid is selected from at least one of hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid. Optionally, the acid is selected from at least one of hydrochloric acid, hydrobromic acid, and sulfuric acid. Further, the acid is hydrochloric acid.

In some examples, in step S30, the mass ratio of acid to compound of formula (I) is (1-10): 1. Optionally, the mass ratio of acid to compound of formula (I) is (1-3): 1. Further, the mass ratio of acid to compound of formula (I) is 2: 1.

In some examples, in step S30, the temperature of the hydrolysis reaction is 30 ℃ to 70 ℃ for 1h to 7 h. Optionally, the temperature of the hydrolysis reaction is 50-70 ℃, and the time is 1-3 h. Furthermore, the temperature of the hydrolysis reaction is 50-60 ℃ and the time is 2-3 h.

In some examples, after the hydrolysis reaction in step S30 is finished, step S40 is further included.

Step S40: adding alkali into the reaction system after the hydrolysis reaction for neutralization.

In some examples, the base is an inorganic base in step S40; further, the inorganic base is at least one selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide.

In some specific examples, the base is added as an aqueous solution in step S40.

In some specific examples, in step S40, the alkali concentration is 2% to 20% by mass.

And adding alkali into a reaction system after the hydrolysis reaction for neutralization, concentrating, adding water for water precipitation, and filtering to obtain a crude levonorgestrel product.

In some of these examples, refinement of levonorgestrel includes the steps of:

and mixing the crude levonorgestrel product with a third organic solvent, and crystallizing to obtain a refined levonorgestrel product.

It can be understood that when the crude levonorgestrel and the third organic solvent are mixed, the crude levonorgestrel is dissolved in the third organic solvent, can be dissolved by heating, and then is cooled and crystallized.

In some of these examples, the third organic solvent is selected from at least one of dichloromethane, methanol, ethanol, ethyl acetate, isopropyl acetate, acetone, butanone, and tetrahydrofuran.

In some specific examples thereof, the third organic solvent is selected from at least one of dichloromethane, methanol, ethanol, ethyl acetate, acetone, and tetrahydrofuran.

It is understood that the devitrification may be performed a plurality of times.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Hereinafter, the synthesis method of levonorgestrel according to the present invention is exemplified, and it is understood that the synthesis method of levonorgestrel according to the present invention is not limited to the following examples.

Example 1

Adding 500mL of THF (tetrahydrofuran) into 450mL of n-butyllithium (2.5M) solution for dilution, cooling to-10 ℃, dropwise adding 105g of trimethylsilyl acetylene, and keeping the temperature at-10-0 ℃ for reaction for 0.5 hour after dropwise adding. Adding 100g of ethyl Wolff substance, and reacting for 2 hours at the temperature of-10-0 ℃. After adding 400mL of methanol, 100mL of water is added, and the temperature is raised to 20-30 ℃ for reaction for 2 hours. Adding 200g of concentrated hydrochloric acid, heating to 50-60 ℃ and reacting for 2 hours. Adding potassium carbonate solution for neutralization, concentrating to a small amount, adding 500mL of water for water precipitation, and filtering to obtain a crude levonorgestrel product. Adding acetone into the crude levonorgestrel product, heating to dissolve, cooling, crystallizing, filtering, and refining with acetone for 1 time to obtain 93.6g white solid with HPLC purity of 99.2%. The infrared spectrum of the white solid is shown in figure 1 after detection; the nuclear magnetic hydrogen spectrum of the white solid is shown in FIG. 2; the nuclear magnetic carbon spectrum of the white solid is shown in FIG. 3; i.e. the white solid is levonorgestrel.

Example 2

600mL of n-butyllithium (2.5M) solution is diluted by adding 600mL of ethylene glycol dimethyl ether, cooled to-20 ℃, added with 155g of trimethylsilyl acetylene dropwise, and kept at the temperature of-15-0 ℃ for reaction for 0.5 hour after the dropwise addition is finished. Adding 100g of ethyl Woods, and reacting for 3 hours at the temperature of minus 15-0 ℃. After adding 400mL of methanol, 100mL of water is added, and the temperature is raised to 20-30 ℃ for reaction for 2 hours. Adding 250g of hydrobromic acid, heating to 60-70 ℃ and reacting for 1 hour. Adding potassium hydroxide solution for neutralization, concentrating to a small amount, adding 500mL of water for water precipitation, and filtering to obtain a crude product. Adding tetrahydrofuran into the crude product, heating to dissolve, and steaming to a small amount to obtain a white solid. Refining with acetone for 1 time to obtain levonorgestrel 86.3g with HPLC purity of 99.4%.

Example 3

450mL of n-butyllithium (2.5M) solution is diluted by adding 500mL of dioxane, cooled to-20 ℃, 110g of trimethylsilyl acetylene is added dropwise, and the reaction is carried out for 1 hour at the temperature of-20 to-10 ℃ after the dropwise addition is finished. Adding 100g of ethyl Woods, and reacting for 3 hours at the temperature of minus 10-0 ℃. Adding 400mL of ethanol, adding 100mL of water, and heating to 20-30 ℃ for reaction for 2 hours. Adding 200g of 30% dilute sulfuric acid, and heating to 50-60 ℃ for reaction for 2 hours. Adding sodium hydroxide solution for neutralization, concentrating to a small amount, adding 500mL of water for elutriation, and filtering to obtain a crude product. The crude product was refined 2 times with ethyl acetate to obtain 91.6g of levonorgestrel with HPLC purity of 99.1%.

Example 4

450mL of n-butyllithium (2.5M) solution is diluted by adding 500mL of dioxane, cooled to-30 ℃, 110g of trimethylsilyl acetylene is dripped, and the temperature is kept between-10 and 0 ℃ for reaction for 0.5 hour after dripping. Adding 100g of ethyl W-type substance, and reacting for 4 hours at the temperature of minus 20 to minus 10 ℃. Adding 400mL of ethylene glycol, adding 100mL of water, and heating to 20-30 ℃ for reaction for 2 hours. Adding 180g of concentrated hydrochloric acid, and heating to 60-70 ℃ for reaction for 1 hour. Adding sodium carbonate solution for neutralization, concentrating to a small amount, adding 500mL of water for elutriation, and filtering to obtain a crude product. The crude product is refined by ethyl acetate for 1 time and acetone for 1 time to obtain 85.6g of levonorgestrel with HPLC purity of 98.7%.

Example 5

450mL of n-butyllithium (2.5M) solution is diluted by adding 500mL of THF, cooled to-20 ℃, 105g of trimethylsilyl acetylene is dripped in, and the temperature is kept at-10-0 ℃ for reaction for 0.5 hour after dripping. Adding 100g of ethyl Woods, and reacting for 2 hours at the temperature of minus 10-0 ℃. Adding 400mL of methanol, adding 100mL of water, and heating to 20-30 ℃ for reaction for 2 hours. Adding 200g of concentrated hydrochloric acid, and heating to 60-70 ℃ for reaction for 2 hours. Adding sodium hydroxide solution for neutralization, concentrating to a small amount, adding 500mL of water for elutriation, and filtering to obtain a crude product. The crude product is refined by dichloromethane for 1 time and acetone for 1 time to obtain 88.7g of levonorgestrel with HPLC purity of 99.0%.

Example 6

450mL of n-butyllithium (2.5M) solution is added with THF500mL for dilution, cooled to-15 ℃, added with 110g of trimethylsilyl acetylene dropwise, and kept at-15-0 ℃ for reaction for 0.5 hour after the dropwise addition. Adding 100g of ethyl Woods, and reacting for 3 hours at the temperature of minus 15-0 ℃. Adding 400mL of isopropanol, adding 100mL of water, and heating to 20-30 ℃ for reaction for 2 hours. Adding 200g of concentrated hydrochloric acid, and heating to 60-70 ℃ for reaction for 2 hours. Adding potassium hydroxide solution for neutralization, concentrating to a small amount, adding 500mL of water for water precipitation, and filtering to obtain a crude product. The crude product is refined 1 time by acetone and 1 time by ethyl acetate to obtain 89.4g of levonorgestrel with HPLC purity of 98.9%.

Example 7

Adding THF (500 mL) into 400mL of n-butyllithium (2.5M) solution for dilution, cooling to-15 ℃, dropwise adding 100g of trimethylsilyl acetylene, and keeping the temperature at-15-0 ℃ for reaction for 0.5 hour after dropwise adding. Adding 100g of ethyl Woods, and reacting for 3 hours at the temperature of minus 15-0 ℃. Adding 400mL of ethanol, adding 100mL of water, and heating to 20-30 ℃ for reaction for 2 hours. Adding 180g of concentrated hydrochloric acid, and heating to 50-60 ℃ for reaction for 3 hours. Adding potassium hydroxide solution for neutralization, concentrating to a small amount, adding 500mL of water for water precipitation, and filtering to obtain a crude product. Refining the crude product with methanol for 1 time and refining with ethyl acetate for 1 time to obtain 92.6g of levonorgestrel with HPLC purity of 98.9%.

Example 8

450mL of n-butyllithium (2.5M) solution is added with THF500mL for dilution, cooled to-15 ℃, added with 110g of trimethylsilyl acetylene dropwise, and kept at-15-0 ℃ for reaction for 0.5 hour after the dropwise addition. Adding 100g of ethyl Woods, and reacting for 3 hours at the temperature of minus 15-0 ℃. Adding 400mL of n-propanol, then adding 100mL of water, and heating to 20-30 ℃ for reaction for 2 hours. Adding 200g of concentrated hydrochloric acid, and heating to 60-70 ℃ for reaction for 2 hours. Adding sodium hydroxide solution for neutralization, concentrating to a small amount, adding 500mL of water for elutriation, and filtering to obtain a crude product. The crude product is refined by tetrahydrofuran for 1 time and refined by methanol for 1 time to obtain 87.5g of levonorgestrel with the HPLC purity of 99.1 percent.

Example 9

Adding THF (500 mL) into 400mL of n-butyllithium (2.5M) solution for dilution, cooling to-20 ℃, dropwise adding 100g of trimethylsilyl acetylene, and keeping the temperature at-15-0 ℃ for reaction for 0.5 hour after dropwise adding. Adding 100g of ethyl Woods, and reacting for 3 hours at the temperature of minus 10-0 ℃. Adding 400mL of methanol, adding 100mL of water, and heating to 20-30 ℃ for reaction for 2 hours. 170g of concentrated hydrochloric acid is added, and the temperature is raised to 60-70 ℃ for reaction for 2 hours. Adding sodium hydroxide solution for neutralization, concentrating to a small amount, adding 500mL of water for elutriation, and filtering to obtain a crude product. The crude product is refined 1 time by dichloromethane and 1 time by ethanol to obtain 86.9g of levonorgestrel with the HPLC purity of 99.5 percent.

Example 10

Adding 500mL of THF (tetrahydrofuran) into 450mL of n-butyllithium (2.5M) solution for dilution, cooling to-20 ℃, dropwise adding 110g of trimethylsilyl acetylene, and keeping the temperature at-15-0 ℃ for reacting for 0.5 hour after dropwise addition. Adding 100g of ethyl Woods, and reacting for 3 hours at the temperature of minus 10-0 ℃. Adding 400mL of ethanol, adding 100mL of water, and heating to 20-30 ℃ for reaction for 2 hours. Adding 200g of concentrated hydrochloric acid, and heating to 50-60 ℃ for reaction for 3 hours. Adding potassium carbonate solution for neutralization, concentrating to a small amount, adding 500mL of water for water precipitation, and filtering to obtain a crude product. Refining the crude product with methanol for 1 time and refining the crude product with dichloromethane for 1 time to obtain 89.4g of levonorgestrel with the HPLC purity of 99.3 percent.

Comparative example 1

Adding 500mL of THF (tetrahydrofuran) into 450mL of n-butyllithium (2.5M) solution for dilution, cooling to-10 ℃, dropwise adding 105g of trimethylsilyl acetylene, and keeping the temperature at-10-0 ℃ for reaction for 0.5 hour after dropwise adding. Adding 100g of ethyl Wolff substance, and reacting for 2 hours at the temperature of-10-0 ℃. After adding 400mL of acetone, adding 100mL of water, and heating to 20-30 ℃ for reaction for 2 hours. Adding 200mL of hydrochloric acid, and heating to 50-60 ℃ for reaction for 2 hours. Adding potassium carbonate solution for neutralization, concentrating to a small amount, adding 500mL of water for water precipitation, and filtering to obtain a crude levonorgestrel product. Adding acetone into the crude levonorgestrel product, heating to dissolve, cooling, crystallizing, filtering to obtain a white solid, and refining with acetone for 1 time to obtain levonorgestrel 85.3g with HPLC purity of 95.6%.

Comparative example 2

880mL of n-butyllithium (2.5M) solution is diluted by adding 500mL of tetrahydrofuran, cooled to-15 ℃, 200g of trimethylsilyl acetylene is dripped in, and the temperature is kept at-15-0 ℃ for reaction for 1 hour after dripping. Adding 100g of ethyl W-type substance, and reacting for 4 hours at the temperature of minus 20 to minus 10 ℃. Adding 400mL of acetonitrile, adding 100mL of water, and heating to 20-30 ℃ for reaction for 2 hours. Adding 300mL of trifluoroacetic acid, and heating to 60-70 ℃ for reacting for 2 hours. Adding lithium hydroxide solution for neutralization, concentrating to a small amount, adding 500mL of water for elutriation, and filtering to obtain a crude product. The crude product was purified 2 times with acetone to yield 84.6g of levonorgestrel with an HPLC purity of 94.1%.

Comparative example 3

880mL of n-butyllithium (2.5M) solution is diluted by adding 500mL of tetrahydrofuran, cooled to-15 ℃, introduced with 60g of acetylene gas, and reacted for 2 hours at-15-0 ℃. Adding 100g of ethyl W-type substance, and reacting for 4 hours at the temperature of minus 20 to minus 10 ℃. Adding 300mL of trifluoroacetic acid, and heating to 60-70 ℃ for reacting for 2 hours. Adding lithium hydroxide solution for neutralization, concentrating to a small amount, adding 500mL of water for elutriation, and filtering to obtain a crude product. The crude product was purified 2 times with acetone to give 76.6g of levonorgestrel with HPLC purity of 94.7%.

Comparative example 4

Adding 300g of potassium hydroxide, adding 2500mL of tetrahydrofuran and 150mL of acetone, cooling to-10 ℃, introducing 60g of acetylene gas, and reacting for 2 hours at the temperature of-15-0 ℃. Adding 100g of ethyl W-type substance, and reacting for 4 hours at the temperature of minus 20 to minus 10 ℃. Adding 700mL of hydrochloric acid, and heating to 60-70 ℃ for reaction for 1 hour. Adding sodium hydroxide solution for neutralization, concentrating to a small amount, adding 500mL of water for elutriation, and filtering to obtain a crude product. The crude product was refined 2 times with acetone to give 74.4g of levonorgestrel with HPLC purity of 92.2%.

The kinds of the first organic solvent, the second organic solvent and the acid used in each example and comparative example, and the yield and purity conditions are shown in table 1.

TABLE 1

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the appended claims. Therefore, the protection scope of the patent of the invention is subject to the content of the appended claims, and the description can be used for explaining the content of the claims.

Claims

1. A synthesis method of levonorgestrel is characterized by comprising the following steps:

2. the method of synthesizing levonorgestrel according to claim 1, wherein the organometallic reagent is n-butyllithium or lithium diisopropylamide.

3. The method of synthesizing levonorgestrel according to claim 1, wherein the number of carbon atoms in the alkyl group of trialkylsilylethylene is 1 to 5.

4. The method of synthesizing levonorgestrel according to claim 3, wherein the trialkylsilylethylene is selected from at least one of trimethylsilylacetylene, triethylsilylethyne, triisopropylsilylethyne and tri-n-propylsilylethyne.

5. The method for synthesizing levonorgestrel according to any one of claims 1 to 4, wherein the first organic solvent is at least one selected from the group consisting of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether and toluene; and/or

The ratio of the mass of the compound of the formula (I) to the volume of the first organic solvent is 1g (2 mL-20 mL).

6. The method for synthesizing levonorgestrel according to any one of claims 1 to 4, wherein the temperature of the ethynylation reaction is-30 ℃ to 10 ℃ and the time is 0.5h to 6 h.

7. The method for synthesizing levonorgestrel according to any one of claims 1 to 4, wherein the second organic solvent is at least one selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, ethylene glycol and ethylene glycol monomethyl ether; and/or

The volume ratio of the second organic solvent to the water is (2-10): 1.

8. The method for synthesizing levonorgestrel according to any one of claims 1 to 4, wherein the step of removing trialkylsilyl groups is performed at a reaction temperature of 10 ℃ to 50 ℃ for 1h to 5 h.

9. A method of synthesizing levonorgestrel according to any one of claims 1 to 4, wherein the acid is at least one selected from the group consisting of hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid.

10. The method for synthesizing levonorgestrel according to any one of claims 1 to 4, wherein the hydrolysis reaction is carried out at 30 to 70 ℃ for 1 to 7 hours.