CN115260276A

CN115260276A - Process for the preparation of steroids 16,17-epoxides

Info

Publication number: CN115260276A
Application number: CN202210950723.2A
Authority: CN
Inventors: 曾春玲; 陈舟; 屈俊; 吴亚克; 刘喜荣
Original assignee: Hunan Keyixin Biomedical Co ltd
Current assignee: Hunan Keyixin Biomedical Co ltd
Priority date: 2022-08-09
Filing date: 2022-08-09
Publication date: 2022-11-01
Anticipated expiration: 2042-08-09
Also published as: CN115260276B

Abstract

The invention provides a preparation method of a steroid 16,17-epoxy compound, which comprises the following steps: mixing the compound A

Carrying out an ethynylation reaction to prepare a first intermediate product; carrying out dehydration reaction on the first intermediate product to prepare a second intermediate product, and then carrying out hydrolysis reaction on the second intermediate product in an acidic environment to prepare a third intermediate product; or the first intermediate product is subjected to Lu Pei rearrangement reaction to prepare a third intermediate product; the third intermediate product is,

And

performing ketal reaction to prepare a fourth intermediate product A; orReacting the third intermediate with

Carrying out an ene etherification reaction to prepare a fourth intermediate product B; performing olefin epoxidation reaction on the fourth intermediate product A or the fourth intermediate product B to prepare a steroid 16,17-epoxy compound; the structure of the steroid 16,17-epoxy is shown as any of:

Description

Process for the preparation of steroids 16,17-epoxides

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a steroid 16,17-epoxy compound.

Background

Melengestrol acetate, chemical name is 17 alpha-acetoxyl group-6-methyl-16-methylene pregna-4,6-diene-3,20-diketone (17 alpha-acetoxy-6-methyl-16-methyl-4,6-prenadiene-3,20-dione), has antitumor and progestogen-like activities, can be widely used as a growth promoting additive for livestock breeding, and can improve the breeding efficiency and accelerate the increase of the weight of livestock. The structural formula of melengestrol acetate is shown below:

in the synthesis and preparation process of melengestrol acetate, the construction of functional groups on a steroid D ring is the most critical. The technical route of British drug houses (Limited) company, the technical route developed by Proteus corporation, and the synthetic preparation process of melengestrol acetate reported by patents and periodicals, wherein epoxy is used as an intermediate, and the route of 16,17-epoxy compound for synthesizing melengestrol acetate is shown as follows:

another technical route developed by the proconcentrate company for melengestrol acetate does not use epoxy as an intermediate, but the implementation conditions are harsh, the individual steps require low temperature, the post-treatment of some steps is complicated, the yield is low, and the individual steps require the use of highly toxic reagents mercuric oxide and dimethyl oxalate, and hazardous reagents butyl lithium, as well as the industrial use of benzene sulfinyl chloride and trimethoxy phosphorus, which are also inconvenient. Therefore, the synthesis of melengestrol acetate by taking the epoxy compound as an intermediate is an extremely important synthesis means, and 16,17-epoxy compound is a key intermediate for preparing melengestrol acetate.

The traditional preparation method of the steroid 16,17-epoxy compound used as the intermediate for synthesizing melengestrol acetate has the following defects: (1) The starting material for synthesizing the steroid 16,17-epoxy compound is not easy to obtain and has higher price, for example, the starting material adopted by the traditional method needs to be synthesized by 10 steps through diosgenin; (2) The conventional preparation method needs to use a diazomethane addition step and a high-temperature (170 ℃) denitrogenation gas process in the introduction of the 16-position methyl group, and the two processes have operation risks and have poisoning and explosion risks.

Disclosure of Invention

Based on the method, the invention provides a preparation method of the steroid 16,17-epoxy compound, which has the advantages of cheap and easily obtained raw materials, high yield and safe and convenient operation.

The invention is realized by the following technical scheme.

A process for preparing a steroid 16,17-epoxy comprising the steps of:

compound A

Performing an alkynylation reaction to prepare a first intermediate product

The first intermediate product is subjected to dehydration reaction to prepare a second intermediate product

Then the second intermediate product is subjected to hydrolysis reaction in an acidic environment to prepare a third intermediate product

Or subjecting the first intermediate product to Lu Pei rearrangement reaction to prepare the third intermediate product;

subjecting the third intermediate product to,

And

ketal reaction to produce a fourth intermediate A

Wherein R is ₁ Each independently selected from C2-3 alkyl, R ₂ Each independently selected from alkyl groups having 1 to 3 carbon atoms; or

Reacting the third intermediate product with

By etherification to produce a fourth intermediate

Subjecting said fourth intermediate a or said fourth intermediate B to an olefin epoxidation reaction to produce said steroid 16,17-epoxide; the steroid 16,17-epoxy compound has the structure represented by any of the following formulas (1) and (2):

in one embodiment, the ethynylation reaction conditions include:

mixing the compound A, acetylene, inorganic base and a first organic solvent, and carrying out an ethynylation reaction at the temperature of-20 ℃ for 1-3 h; or

Reacting said compound A with

By carrying out vinyl ethersAnd (3) carrying out an ethynylation reaction, mixing a product obtained by the alkene etherification reaction with trimethylsilyl ethynyl lithium, carrying out an ethynylation reaction at a temperature of between-78 and-20 ℃, and mixing the product obtained by the ethynylation reaction with alkali and acid in sequence.

In one embodiment, the first organic solvent is selected from one or more of tetrahydrofuran and ethanol.

In one embodiment, the conditions of the dehydration reaction include:

mixing the first intermediate product, phosphorus oxychloride and a second organic solvent, and performing dehydration reaction at the temperature of 60-70 ℃ for 1-10 h; or

Mixing the first intermediate product, copper sulfate and a third organic solvent, and performing dehydration reaction at the temperature of 110-130 ℃ for 4-6 h; or

And mixing the first intermediate product with a fourth organic solvent, cooling to-35 to-15 ℃, mixing with N-chlorosuccinimide and a pyridine solution of sulfur dioxide, and performing dehydration reaction.

In one embodiment, the second organic solvent is pyridine;

the third organic solvent is selected from one or more of toluene and xylene;

the fourth organic solvent is pyridine.

In one embodiment, the conditions of the hydrolysis reaction include:

mixing the second intermediate product with organic acid, and carrying out hydrolysis reaction at the temperature of 70-80 ℃ for 0.5-3 h; the organic acid is selected from one or two of formic acid and acetic acid; or

And mixing the second intermediate product, hydrochloric acid and ethyl acetate, and carrying out hydrolysis reaction at the temperature of 75-85 ℃ for 0.5-1.5 h.

In one embodiment, the conditions for the Lu Pei rearrangement reaction include:

mixing the first intermediate product with acid, and carrying out Lu Pei rearrangement reaction at the temperature of 80-100 ℃ for 0.5-1.5 h.

In one embodiment, the conditions for the ketal reaction include:

the ketal reaction is carried out in a fifth organic solvent; the fifth organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, dioxane and ethanol.

In one embodiment, the conditions of the alkyletheration reaction include:

the ene etherification reaction is carried out in a sixth organic solvent; the sixth organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, dioxane and ethanol.

In one embodiment, the olefin epoxidation reaction conditions include:

mixing hydrogen peroxide, inorganic base and a seventh organic solvent with the fourth intermediate product A or the fourth intermediate product B, and carrying out olefin epoxidation reaction at the temperature of 25-40 ℃ for 24-72 h; the seventh organic solvent is selected from one or more of methanol, ethanol and dichloromethane.

Compared with the prior art, the preparation method of the steroid 16,17-epoxy compound has the following beneficial effects:

the 4-AD methyl substance (androst-4-ene-16-methyl-3,17-diketone) is used as an initiator, and the steroid 16,17-epoxy compound is prepared through four-step or five-step reaction, and the initiator compound can be prepared from 4-AD (androst-4-ene-3,17-diketone) which is a cheap raw material through two steps according to the prior art, and can also be obtained conveniently through the market, and is cheap and easily available. Moreover, the preparation method of the invention has the advantages of high product yield, less by-products, direct reaction without purification from the second step to the fourth step, simple operation, no need of using highly toxic and dangerous reagents in the whole preparation process, convenient solvent and reagent recovery, and suitability for industrial production.

Drawings

FIG. 1 is a synthetic route for the steroid 16,17-epoxy provided by the present invention;

FIG. 2 is a nuclear magnetic spectrum of a first intermediate provided by the present invention;

FIG. 3 is a nuclear magnetic spectrum of a first intermediate provided by the present invention;

FIG. 4 is a nuclear magnetic spectrum of a second intermediate provided by the present invention;

FIG. 5 is a nuclear magnetic spectrum of a third intermediate provided by the present invention;

FIG. 6 is a nuclear magnetic spectrum of a by-product of a third intermediate production process provided by the present invention;

FIG. 7 is a nuclear magnetic spectrum of a fourth intermediate product B provided by the present invention;

FIG. 8 is a nuclear magnetic spectrum of steroid 16,17-epoxy provided by the present invention.

Detailed Description

To facilitate an understanding of the invention, the invention will now be described more fully hereinafter with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, 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 herein in the description of the invention 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.

Referring to fig. 1, the present invention provides a method for preparing steroid 16,17-epoxy compound, comprising the steps of:

mixing the compound A

Carrying out an alkynylation reaction to prepare a first intermediate product

Or the first intermediate product is subjected to Lu Pei rearrangement reaction to prepare a third intermediate product;

the third intermediate product is,

And

ketal reaction to produce a fourth intermediate A

The third intermediate product is reacted with

By etherification to produce a fourth intermediate

Performing olefin epoxidation reaction on the fourth intermediate product A or the fourth intermediate product B to prepare a steroid 16,17-epoxy compound; the structure of steroid 16,17-epoxy compound is shown in either of the following formulas (1) and (2):

it is understood that in the invention, the starting material compound A is 4-AD methyl (androst-4-ene-16-methyl-3,17-diketone), and can be prepared by two steps by using cheap 4-AD (androst-4-ene-3,17-diketone) as a raw material, and the yield is high and can also be obtained by market.

In one particular example of the use of the invention,

selected from trimethyl orthoformate, triethyl orthoformate or tripropyl orthoformate.

In one particular example of the use of the invention,

selected from ethylene glycol or propylene glycol.

In one particular example, the conditions of the ethynylation reaction include:

mixing the compound A, acetylene, inorganic base and a first organic solvent, and carrying out an ethynylation reaction at the temperature of-20 ℃ for 1-3 h.

In a specific example, the first organic solvent is selected from one or more of tetrahydrofuran and ethanol. More specifically, the first organic solvent is a mixed solvent of tetrahydrofuran and ethanol.

In a specific example, the inorganic base is selected from one or more of potassium hydroxide and potassium tert-butoxide.

In one specific example, the weight ratio of compound a to inorganic base is 1:2.

More specifically, the conditions of the ethynylation reaction include: at the temperature of minus 20 ℃ to 20 ℃, acetylene gas is introduced into an organic solvent containing inorganic base, then the solution of the compound A is dripped, after 1 to 3 hours of reaction, the pH value is adjusted to acidity by acid, water is added for elutriation after partial organic solvent is removed by concentration, the compound 5 is obtained by recrystallization by methanol after suction filtration and drying, and the yield is 80 to 85 percent. When the starting compound a is 16 α methyl-4-AD, the first intermediate obtained is a mixture containing the diastereoisomer of the methyl group at position 16, most of the 16 α methyl group undergoing configuration inversion, while the ethynyl group is all in the α configuration. The mixture ratio is temperature dependent, with a ratio of 16 α to 16 β of about 1:4 at 0 ℃.

In one particular example, the conditions of the ethynylation reaction include:

reacting a compound A with

Carrying out an ene etherification reaction, mixing a product obtained by the ene etherification reaction with trimethylsilyl ethynyl lithium, carrying out an ethynylation reaction at a temperature of-78-20 ℃, and mixing the product obtained by the ethynylation reaction with alkali and acid in sequence.

Preferably, the base is a carbonate. More specifically, the carbonate is potassium carbonate.

In one particular example, the acid is hydrochloric acid.

In one particular example, the alkyletheration reaction is carried out in an organic solvent with an acid.

More specifically, the organic solvent is selected from one or more of ethanol, tetrahydrofuran and dichloromethane. Preferably, the organic solvent is ethanol.

More specifically, the acid is selected from one or more of p-toluenesulfonic acid, sulfuric acid and hydrogen chloride. Preferably, the acid is p-toluenesulfonic acid.

More specifically, the conditions of the ethynylation reaction include: reacting a raw material compound A with ortho-formic acid triester in an organic solvent under the catalysis of acid to obtain an alkene etherification product protected by a 3-carbonyl group, reacting the obtained alkene etherification product with trimethylsilyl ethynyl lithium at a temperature of between-78 and-20 ℃, removing a TMS group on an alkynyl group by using potassium carbonate, and finally removing the 3-protecting group in methanol by using hydrochloric acid to obtain a first intermediate product, wherein the first intermediate product obtained by the method is a product basically maintained in a 16-methyl configuration.

In one specific example, the conditions of the dehydration reaction include:

mixing the first intermediate product, phosphorus oxychloride and a second organic solvent, and carrying out dehydration reaction at the temperature of 60-70 ℃ for 1-10 h.

In a specific example, the second organic solvent is pyridine.

In a specific example, the feeding ratio of the phosphorus oxychloride to the first intermediate product is 1 to 3 times by weight. Preferably, the feeding ratio of the phosphorus oxychloride to the first intermediate product is 2 times by weight.

In a specific example, the second organic solvent is fed in a 5-8 times volume ratio to the first intermediate product. Preferably, the charge ratio of the second organic solvent to the first intermediate product is 6 times by volume.

In one specific example, the heating temperature is from 60 ℃ to reflux, preferably 70 ℃; the reaction time is 1-10h, preferably 6h at 70 ℃.

In one specific example, the second intermediate product is prepared by quenching the mixture after the dehydration reaction in dilute hydrochloric acid, extracting the quenched mixture with ethyl acetate, concentrating the extract to dryness, and then pulping the concentrated extract with ethanol.

In one specific example, the conditions of the dehydration reaction include:

mixing the first intermediate product, copper sulfate and a third organic solvent, and carrying out dehydration reaction at the temperature of 110-130 ℃ for 4-6 h.

In a specific example, the third organic solvent is selected from one or more of toluene and xylene. Preferably, the third organic solvent is xylene.

In a specific example, the heating temperature is 120 ℃ to reflux, preferably reflux, and the reaction time is preferably 5h at reflux.

In a specific example, the amount of copper sulfate is 0.1 times to 5 times by weight, preferably 3 times by weight of the first intermediate product.

Although the usage amount of copper sulfate is small in the traditional dehydration reaction, a water separator is needed to remove generated water, the industrial mass production is not facilitated, and more importantly, more raw materials are left. The invention has better dehydration effect by using excessive copper sulfate, and the copper sulfate can be filtered and recycled. After the reaction, the copper sulfate is filtered and removed, and the organic solvent is dried in a rotary manner to obtain yellow to brown solid. The reaction by-product is mainly a Rupe rearrangement product, namely a third intermediate product of a next step, and the product synthesized by the method can be directly used in the next step without purification.

In one specific example, the conditions of the dehydration reaction include:

mixing the first intermediate product with a fourth organic solvent, cooling to-35 to-15 ℃, mixing with N-chlorosuccinimide and a pyridine solution of sulfur dioxide, and performing dehydration reaction.

The reaction temperature control and the dropping speed are important because the 18-methyl rearrangement reaction is liable to occur.

In a specific example, the fourth organic solvent is pyridine.

In a specific example, the fourth organic solvent is added in an amount of 4 to 10 times by volume, preferably 5 times by volume, of the first intermediate product.

In a specific example, the N-chlorosuccinimide is added in an amount of 0.8 to 1 times by weight, preferably 0.84 times by weight, based on the first intermediate product.

In one particular example, the pyridine solution of sulfur dioxide has a mass concentration of 30%. More specifically, the amount of the pyridine solution of sulfur dioxide added was 2 times the volume of the first intermediate product.

More specifically, the conditions of the dehydration reaction include: and dissolving the first intermediate product in pyridine, cooling, adding NCS, dropwise adding a sulfur dioxide pyridine solution, detecting reaction by TLC, and quenching the reaction by hydrochloric acid after the reaction is finished.

In one particular example, the conditions of the hydrolysis reaction include:

mixing the second intermediate product with organic acid, and carrying out hydrolysis reaction at the temperature of 70-80 ℃ for 0.5-3 h; the organic acid is selected from one or two of formic acid and acetic acid.

In a specific example, at least one of sulfuric acid and hydrochloric acid is further added to the hydrolysis reaction. Both sulfuric acid and hydrochloric acid catalyze the accelerated reaction.

In a specific example, the reaction temperature is 70 ℃ to reflux, preferably 80 ℃ in the presence of strong acid catalysis, preferably reflux in the absence of strong acid catalysis, and the reaction time is 0.5 to 3 hours, preferably 1 hour.

In one specific example, after the reaction is complete, the reaction solvent is spun dry and after water precipitation a brown oil is obtained which is purified as a yellow solid. The third intermediate product synthesized by the method can be directly used in the next step without purification after the reaction solvent is dried by spinning.

In one particular example, the conditions of the hydrolysis reaction include:

mixing the second intermediate product, hydrochloric acid and ethyl acetate, and carrying out hydrolysis reaction at the temperature of 75-85 ℃ for 0.5-1.5 h.

More specifically, the second intermediate product was mixed with a hydrochloric acid-ethyl acetate system and subjected to hydrolysis reaction at a temperature of 80 ℃ for 1 hour.

In one specific example, hydrochloric acid and ethyl acetate are both added in amounts of 10 volumes relative to the second intermediate product.

In one specific example, the conditions for the Lu Pei rearrangement reaction include:

mixing the first intermediate product with acid, and carrying out Lu Pei rearrangement reaction at 80-100 ℃ for 0.5-1.5 h.

It will be appreciated that in the present invention, the acid added in the Lu Pei rearrangement reaction serves a catalytic function.

More specifically, the conditions for the Lu Pei rearrangement reaction include:

mixing the first intermediate product with formic acid, and carrying out Lu Pei rearrangement reaction at the temperature of 80-100 ℃ for 0.5-1.5 h.

More specifically, lu Pei the rearrangement reaction is accomplished in formic acid as solvent at 100 ℃ for 1 hour, or in formic acid as solvent with sulfuric acid as catalyst at 80 ℃ for 1 hour.

In one specific example, a third intermediate product is prepared by column chromatography after the completion of the Lu Pei rearrangement reaction.

In one particular example, the conditions of the ketal reaction include:

In one specific example, the ketal reaction described above also adds an acid. More specifically, the acid is one or more of sulfuric acid, p-toluenesulfonic acid, hydrochloric acid and phosphoric acid. Preferably, the ketal reaction is carried out in a dichloromethane-p-toluenesulfonic acid, dichloromethane-phosphoric acid or ethanol-phosphoric acid system. More preferably, the ketal reaction is carried out in a methylene chloride-p-toluenesulfonic acid system.

In one specific example, the reaction is terminated by adding triethylamine after the ketal reaction is completed, the solvent is dried by spinning, and methanol is added for pulping to prepare a fourth intermediate product A.

In one particular example, the conditions of the ene etherification reaction include:

In a specific example, an acid is also added to the above-described alkyletheration reaction. More specifically, the acid is one or more of sulfuric acid, p-toluenesulfonic acid, hydrochloric acid and phosphoric acid. Preferably, the ene etherification reaction is carried out in a dichloromethane-p-toluenesulfonic acid, dichloromethane-phosphoric acid or ethanol-phosphoric acid system. More preferably, the ene etherification reaction is carried out in a dichloromethane-p-toluene sulfonic acid system.

In one particular example of the use of the invention,

is added in an amount of 0.6 to 2 times the volume of the third intermediate product, preferably 1 time the volume. More specifically, triethyl orthoformate is added in an amount of 0.6 to 2 times by volume, preferably 1 time by volume, of the third intermediate product.

In one specific example, after the etherification reaction is finished, triethylamine is added to stop the reaction, the solvent is dried by spinning, and methanol is added to carry out pulping to prepare a fourth intermediate product B.

In one particular example, the olefin epoxidation reaction conditions include:

hydrogen peroxide, inorganic base, seventh organic solvent and the fourth intermediate product A or the fourth intermediate product B are mixed, and olefin epoxidation reaction is carried out at the temperature of 25-40 ℃ for 24-72 h.

In a specific example, the seventh organic solvent is selected from one or more of methanol, ethanol, and dichloromethane.

In one particular example, the inorganic base is aqueous sodium hydroxide.

In one specific example, the steroid 16,17-epoxy is prepared by condensation after the olefin epoxidation reaction is completed, mixing with water, and elutriation.

The process for the preparation of the steroid 16,17-epoxy compound of the present invention is described in further detail below with reference to specific examples. The starting materials used in the following examples are all commercially available products unless otherwise specified. The reaction charge ratio in the present invention is usually expressed in terms of a weight-to-volume ratio of the weight of the reaction raw material to the weight or volume of the reaction reagent, unless otherwise specified.

Example 1

This example provides a method for preparing a first intermediate product, which includes:

weighing 24g of potassium hydroxide powder, adding 120ml of tetrahydrofuran and 13ml of anhydrous ethanol, introducing acetylene gas for 1h under stirring in an ice bath, dropwise adding 12g of 40ml of tetrahydrofuran solution of an initiator compound A, completing dropwise addition after about half an hour, continuously introducing the acetylene gas, reacting for 2h, detecting by TLC to complete basic reaction, dropwise adding 10% hydrochloric acid until the pH value is 1-2, continuously stirring for 10 min, and then concentrating under reduced pressure to remove most of organic solvents. 150ml of water was added and filtered to obtain a yellow solid. Adding the crude product into 24ml methanol, pulping for 3h, filtering to obtain light yellow to white solid, drying to obtain 10.7g product with 82% yield, the product is a mixture of 16 alpha and 16 beta methyl, and the nuclear magnetic spectrum is shown in figure 2.

The characterization results were as follows: ¹ H NMR(400MHz,CDCl ₃ )δ5.78(s,1H,4-H)，2.63+2.56(s,0.2H+0.8H,21-H)，1.20(s,3H,19-H)，1.17+1.09(d,0.6H+2.4H,22-H)，0.94+0.87(s,0.6H+2.4H,18-H)； ¹³ C NMR(CDCl ₃ )δ199.58，171.18，123.86，88.98，84.06，83.81，79.37，77.17，73.49，53.51，53.43，48.52，48.35，47.52，47.47，44.63，41.26，38.64，36.05，35.68，34.36，34.00，33.95，32.80，32.70，31.88，31.74，31.42，20.69，20.60，17.48，17.45，17.43，17.13，13.47，13.02。

example 2

This example provides a method for preparing a first intermediate product, specifically as follows:

dissolving 4.41g of trimethylethynylsilane in 20ml of tetrahydrofuran, cooling to-30 ℃, dropwise adding 18ml of butyllithium (2.5 mol/L) under the protection of nitrogen, continuously reacting for 1h after completing dropwise adding, dropwise adding 30ml of tetrahydrofuran solution of 8.2g of etherate of a compound A (obtained by carrying out catalytic reaction on the compound A and triethyl orthoformate in an ethanol solvent for 5h by using p-toluenesulfonic acid), and continuously reacting for 2h after completing dropwise adding. After the reaction, adding a mixed solution of 1.73g of potassium carbonate, 12.5g of water and 30ml of methanol, heating to 25 ℃, continuing the reaction for 2 hours, dropwise adding hydrochloric acid to adjust the pH value to 2-3, stirring overnight at room temperature, concentrating most of the solvent under reduced pressure, adding 40ml of water for precipitation, separating out yellow solid, performing suction filtration, washing with 40ml of water, pulping the obtained yellow solid with 19ml of isopropyl ether, performing suction filtration to obtain pale yellow to white solid, drying and weighing 7.10g, and obtaining the yield of 87%. The NMR of the product is shown in FIG. 3 and is 16 alpha methyl configuration.

The characterization results were as follows: ¹ H NMR(400MHz,CDCl ₃ )δ5.73(s,1H),2.63(s,1H),2.49–2.21(m,5H),2.03(ddd,1H),1.86–1.59(m,6H),1.59–1.37(m,4H),1.26–1.20(m,1H),1.19(s,3H),1.17(d,3H),1.08–0.95(m,2H),0.94(s,3H). ¹³ C NMR(CDCl ₃ )δ199.63，171.30，123.85，84.05，83.82，77.16，53.51，48.34，47.53，41.25，38.65，36.04，35.64，33.94，32.79，32.70，31.88，31.42，20.59，17.42，17.13，13.02。MS m/z：[M+H ⁺ ]＝327.2。

example 3

This example provides a method for preparing a second intermediate product, specifically as follows:

5g of the first intermediate synthesized in example 1 were dissolved in 50ml of xylene, 15g of copper sulfate was added, and the mixture was heated under reflux for 5 hours under nitrogen, and the reaction was checked by TLC until it was substantially complete. After suction filtration, the filter cake is washed by dimethylbenzene, the filtrate is combined and then is dried in a rotary manner to obtain yellow solid, and the product is directly put into the next step without purification. The second intermediate product can be obtained by column chromatography or recrystallization. The NMR spectrum of the product is shown in FIG. 4.

The characterization results were as follows: ¹ H NMR(400MHz,CDCl ₃ )δ5.72(s,1H),3.17(s,1H),2.50–2.22(m,5H),2.13–1.96(m,3H),1.85(s,5H),1.79–1.58(m,4H),1.50(ddd，1H)1.42–1.30(m,2H),1.20(s,3H),1.05(m,3H),0.87(s,3H)； ¹³ C NMR(CDCl ₃ )δ199.43，170.98，148.48，129.26，123.99，82.44，79.00，55.07，54.32，47.94，38.79，36.80，35.54，34.63，34.22，33.94，32.77，31.82，20.77，17.22，16.60，16.04。MS m/z：[M+H ⁺ ]＝309.2。

example 4

5g of the first intermediate synthesized in example 1 were dissolved in 50ml of xylene, 15g of copper sulfate was added, and the mixture was heated under reflux for 5 hours under nitrogen, and the reaction was checked by TLC until it was substantially complete. After suction filtration, the filter cake is washed by dimethylbenzene, the filtrates are combined and then spin-dried to obtain a yellow solid, and the product is directly put into the next step without purification. The second intermediate product can be obtained by column chromatography or recrystallization.

example 5

under the protection of nitrogen, 10g of the first intermediate product synthesized in example 1 and 50ml of pyridine are added, stirred to obtain a clear solution system, cooled to-20 ℃, added with 8.4g of NCS at the temperature of-15 ℃ to-20 ℃ and cooled to-35 ℃. Measuring 30% SO ₂ Pyridine solution 20ml, dilution with pyridine 40ml, SO diluted ₂ Dripping pyridine solution into a reaction system, heating the system violently, controlling the internal temperature to be-25 to-40 ℃, finishing dripping within about 1 hour, keeping the temperature at-25 to-35 ℃ for reaction for 20-30min after finishing dripping, and detecting by TLC (thin-layer chromatography) until the reaction is complete. After the reaction is finished, pouring the system into a hydrochloric acid aqueous solution precooled to below 5 ℃ to separate out a large amount of white solid, stirring for 1 hour at the temperature of 0-5 ℃, filtering, washing, drying by pressure and drying to obtain white8.2g of a colored solid, yield 86.8%.

Example 6

This example provides a preparation method of a third intermediate product, which includes:

50ml of 98% formic acid was added to the second intermediate product synthesized in example 3, a drop of sulfuric acid was added dropwise, the mixture was heated in an oil bath at 80 ℃ for 1h, TLC was performed to detect completion of the reaction, formic acid was spin-dried to obtain a black to brown oil, water was added to precipitate a brown viscous solid, 50ml of dichloro was added to dissolve it, sodium carbonate was added to neutralize and remove residual sulfuric acid and formic acid, the solution was separated and dried, the solvent was concentrated to obtain a brown viscous solid, and the reaction was directly carried out to the next step without purification. And the pure product of the third intermediate product can be obtained by column chromatography or recrystallization.

The characterization results were as follows: ¹ H NMR(400MHz,CDCl ₃ )δ5.71(s,1H),2.48–2.31(m,3H),2.29(m,1H),2.26(s,3H),2.21(ddd,1H),2.14(m,2H),2.01(s,3H),1.98(m,1H),1.83(m,1H),1.76–1.55(m,3H),1.49(m,1H),1.30(m,3H),1.19(s,3H),1.14-1.01(m,1H),0.98(s,3H). ¹³ C NMR(CDCl ₃ )δ199.44，198.89，170.93，151.74，148.23，123.98，54.07，54.03，48.27，39.65，38.70，35.52，34.96，33.93，33.71，32.72，31.80，31.42，20.82，17.98，17.20，16.12。MS m/z：[M+H ⁺ ]＝327.2。

example 7

3g of the first intermediate product from example 1 are dissolved in 30ml of formic acid, a drop of sulfuric acid is added, the mixture is heated in an oil bath at 80 ℃ for 1h, the reaction is checked by TLC and is completed, the formic acid is dried by spinning to give a black to brown oil, and the mixture is chromatographed to give 1.44g of a yellow solid third intermediate product with a yield of 48%. The nuclear magnetic spectrum of the product is shown in figure 5, and the nuclear magnetic spectrum of the by-product of column chromatography is shown in figure 6.

Example 8

This example provides a preparation method of a fourth intermediate product B, which includes:

compound 3 obtained in example 6 was dissolved in 50ml of methylene chloride, and 5ml of triethyl orthoformate was added, and 0.05g of p-toluenesulfonic acid was further added thereto, and the reaction was terminated by adding 1ml of triethylamine after stirring at room temperature for 3 hours. Concentrating under reduced pressure to remove solvent, adding 25ml methanol, stirring and pulping to obtain solid, performing suction filtration to obtain brown solid, adding the obtained brown solid into 10ml isopropyl ether, pulping for 1h, and performing suction filtration to obtain 2.21g of yellow solid. The overall yield for the three steps of example 3, example 6 and example 8 was 41%. The NMR spectrum of the product is shown in FIG. 7.

The characterization results were as follows: ¹ H NMR(400MHz,CDCl ₃ )δ5.21(q,1H)，5.12(d，1H)，3.78(m，2H)，2.28(s,3H)，2.03(s,3H)，1.30(t,3H)，1.01(s,6H)； ¹³ C NMR(CDCl ₃ )δ199.28，154.64，152.08，148.49，141.50，117.43，98.98，62.18，55.09，48.64，48.36，39.74，35.35，35.20，33.70，31.48，31.39，30.08，25.50，20.93，18.91，17.97，16.18，14.67。MS m/z：[M+H ⁺ ]＝355.3。

example 9

This example provides a method for preparing steroid 16,17-epoxy compound, which comprises the following steps:

2.92g of the fourth intermediate product B prepared in example 8 were weighed, added with 45ml of ethanol and 15ml of dichloromethane, added with 9.6ml of sodium hydroxide solution (10%), placed in a water bath at 30 ℃, added with 15ml of 30% hydrogen peroxide, and stirred for reaction for 72h until the reaction was substantially complete. Most of the reaction solution is removed by concentration under reduced pressure, 15ml of water is added, water is separated out, and yellow solid 2.81g is obtained by suction filtration, and the yield is 92%. The NMR spectrum of the product is shown in FIG. 8.

The characterization results were as follows: ¹ H NMR(400MHz,CDCl ₃ )δ5.10(s,1H)，5.03(s，1H)，3.70(m，2H)，2.14(s,3H,21-H)，1.37(s,3H,22-H)，1.22(t,3H,24-H)，0.98(s,3H,19-H)，0.91(s,3H,18-H)； ¹³ C NMR(CDCl ₃ )δ206.15，154.57，141.22，117.35，98.91，77.33，68.31，62.17，48.47，46.33，44.40，35.36，33.69，33.31，31.73，31.49，29.84，29.82，25.45，20.55，18.92，16.73，15.43，14.65。MS m/z：[M+H ⁺ ]＝371.3。

example 10

This example provides a preparation method of a fourth intermediate product a, which includes:

1.63g triethyl orthoformate and 0.66g ethylene glycol were weighed, 50ml dichloromethane and then 0.05g p-toluenesulfonic acid were added, stirred at room temperature for 1 hour, then 2.51g Compound 3 was added, and after 0.5 hour of reaction, 1ml triethylamine was added to terminate the reaction. Extracting the organic phase twice with water, separating, drying, filtering, vacuum concentrating to remove solvent, and passing through column to obtain fourth intermediate product A.

Example 11

2.92g of the fourth intermediate product A prepared in example 10 was weighed, added with 45ml of ethanol and 15ml of dichloromethane, added with 9.6ml of sodium hydroxide solution (10%), placed in a water bath at 40 ℃, added with 15ml of 30% hydrogen peroxide, and stirred to react for 40 hours until the basic reaction was completed. Most of reaction liquid is removed by decompression concentration, 15ml of water is added, water is separated out, and yellow solid 2.75g is obtained by suction filtration, and the yield is 90%.

The characterization results were as follows: ¹ H NMR(400MHz,CDCl ₃ )δ5.72(s,1H),2.51–2.25(m,4H),2.21(s,3H),2.06–1.93(m,1H),1.88–1.74(m,2H),1.73–1.58(m,4H),1.58–1.46(m,2H),1.45(s,3H),1.36(t,1H),1.29–1.21(m,1H),1.19(s,3H),1.14-1.08/1.05-0.93(m,2H),1.07(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ205.96,199.27,170.48,124.05,76.95,68.20,53.83,45.46,44.32,38.63,35.58,33.88,33.43,33.21,32.67,31.63,31.48,29.78,20.34,17.21,16.66,15.40.MS m/z：[M+H ⁺ ]＝343.28。

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, which is convenient for specific and detailed understanding of the technical solutions of the present invention, but the present invention should not be construed as being limited to the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the 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 present invention should be subject to the content of the appended claims, and the description and the drawings can be used for explaining the content of the claims.

Claims

1. A process for preparing a steroid 16,17-epoxy compound comprising the steps of:

the compound

Carrying out an alkynylation reaction to prepare a first intermediate product

subjecting the third intermediate product to,

And

ketal reaction to produce a fourth intermediate

Reacting the third intermediate product with

By etherification to produce a fourth intermediate

2. a process for the preparation of a steroid 16,17-epoxy compound as claimed in claim 1, wherein the ethynylation conditions comprise:

Reacting said compound A with

3. The process for preparing steroid 16,17-epoxy compound as claimed in claim 2, wherein the first organic solvent is selected from one or more of tetrahydrofuran and ethanol.

4. A process for the preparation of a steroid 16,17-epoxy compound as claimed in claim 1, wherein the conditions of the dehydration reaction include:

5. The process for preparing a steroid 16,17-epoxy compound as claimed in claim 4, wherein the second organic solvent is pyridine;

the third organic solvent is selected from one or more of toluene and xylene;

the fourth organic solvent is pyridine.

6. A process for the preparation of a steroid 16,17-epoxy compound as claimed in claim 1 wherein the conditions of the hydrolysis reaction comprise:

7. The process for the preparation of steroidal 16,17-epoxy compounds as claimed in any one of claims 1 to 6, wherein the conditions of Lu Pei rearrangement reaction include:

8. The method of preparing steroid 16,17-epoxy compound according to any of claims 1 to 6, wherein the ketal reaction conditions comprise:

9. A process for the preparation of a steroid 16,17-epoxy compound as claimed in any of claims 1 to 6 wherein the conditions of the alkenoation reaction include:

10. A process for the preparation of a steroid 16,17-epoxy compound as claimed in any of claims 1 to 6, wherein the olefin epoxidation reaction conditions comprise: