CN114315941A

CN114315941A - Synthesis method of tibolone intermediate T6

Info

Publication number: CN114315941A
Application number: CN202111622972.0A
Authority: CN
Inventors: 张峥斌; 李纯; 尹金玉; 张杰锋; 吴静; 吴小芳
Original assignee: Jiangxi Junye Biological Pharmaceutical Co ltd; Zhejiang Xianju Junye Pharmaceutical Co ltd
Current assignee: Jiangxi Junye Biological Pharmaceutical Co ltd; Zhejiang Xianju Junye Pharmaceutical Co ltd
Priority date: 2021-12-28
Filing date: 2021-12-28
Publication date: 2022-04-12
Anticipated expiration: 2041-12-28
Also published as: CN114315941B

Abstract

A synthetic method of tibolone intermediate T6 comprises the following steps: 1) performing ring-opening reaction, dissolving TLW in acetic anhydride, using protonic acid or Lewis acid as a catalyst, performing heating reflux reaction, finishing the reaction, concentrating, dissolving an organic solvent, washing with water, layering, drying, and concentrating to obtain T4B; 2) carrying out reduction reaction, dissolving T4B in methanol, adding sodium borohydride at 0-50 ℃, after the reaction is finished, quenching with dilute hydrochloric acid, concentrating, dissolving in an organic solvent, washing with water, layering, drying, and concentrating to obtain T5B; 3) and (3) esterification, namely dissolving T5B in an organic solvent such as dichloromethane and the like, adding acetic anhydride, adding an organic base or an inorganic base serving as an acid binding agent, and reacting at 0-50 ℃ until the reaction is complete. Adding an alkali solution to quench reaction, concentrating to remove dichloromethane, adding an organic solvent to extract, layering, washing with water, drying to obtain a T6 crude product, putting the T6 crude product into methanol, heating and refluxing, naturally cooling to room temperature, stirring for crystallization, and filtering to obtain a target compound T6.

Description

Synthesis method of tibolone intermediate T6

Technical Field

The invention relates to a preparation method of a steroid compound, in particular to a synthetic method of a tibolone intermediate.

Background

Tibolone is a tissue-selective estrogen activity modulator (STEARs), belonging to the group of artificially synthesized steroid hormones. The traditional Chinese medicine composition is mainly applied to relieving vasomotor state, improving urogenital atrophy symptoms, preventing bone loss, reducing the incidence rate of fracture, improving life-related quality and the like of perimenopausal and postmenopausal women clinically.

The synthetic route of tibolone was first reported in 1967 by p. The method uses dehydroepiandrosterone as a raw material to obtain tibolone through 11 steps, and the total yield is 8.9%.

In 1986, N.P. van Vliet et al reported a second synthetic route to tibolone. The method takes diester T6 as a starting material to synthesize tibolone through 7 steps. The diester T6 is obtained by 7 steps by using a dechlorinated product TLW as a raw material.

In 2004, world patent WO2004031204 reported a third method, which uses nandrolone as a raw material to synthesize tibolone through 8 steps with a yield of 18.04%. In the same year, a fourth method is reported in world patent WO2004078774, and tibolone is synthesized by 8 steps with nandrolone as a starting material, wherein the yield is 21.5%. In 2019, xus tiger et al reported a fifth method, which uses nandrolone precursor acid as raw material to synthesize tibolone through 6 steps. Although the third, fourth and fifth synthesis methods have short steps, the raw material nandrolone or the precursor acid thereof is expensive to remove, and the production cost is high. The method has complicated steps and harsh Birch reduction conditions. Therefore, the second synthesis method is currently widely used in the industry. In this synthesis, T6 is the most central intermediate. In the prior art, T6 can be obtained only by TLW through nearly seven steps of reaction, and how to improve the production efficiency of an intermediate T6 and improve the yield of T6 prepared by taking TLW as a raw material becomes a problem to be solved urgently in the prior art.

Disclosure of Invention

In order to solve the above problems in the prior art, the technical scheme provided by the inventor is as follows:

a synthetic method of tibolone intermediate T6 is characterized in that: the synthesis method is shown as the following formula

The method is provided with the following steps:

1) ring opening reaction

Dissolving TLW in acetic anhydride, using protonic acid or Lewis acid as a catalyst, heating and refluxing for reaction, finishing the reaction, concentrating, dissolving in an organic solvent, washing with water, layering, drying, and concentrating to obtain T4B.

As a preferred technical scheme, the volume weight ratio of the acetic anhydride to the TLW in the step 1) is 1-20, and more preferably 5-10. More preferably 10.

As a preferred technical scheme, the protonic acid is sulfuric acid, hydrochloric acid, hydrogen chloride gas, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, preferably sulfuric acid; the Lewis acid is selected from boron tribromide, titanium tetrachloride or ferric trichloride, preferably the weight ratio of protonic acid or Lewis acid to TLW is 0.01-10.0, preferably 0.01-0.5; the catalyst is preferably sulphuric acid, the weight ratio of sulphuric acid to TLW preferably being 0.04.

2) Reduction reaction

Dissolving T4B in methanol, 0-50^oAnd adding sodium borohydride at the position of C, finishing the reaction, quenching with dilute hydrochloric acid, concentrating, dissolving with an organic solvent, washing with water, layering, drying and concentrating to obtain T5B.

As a preferable technical scheme, the weight ratio of the sodium borohydride to the T5B is 0.10-0.12, more preferably 0.11, and the reaction temperature is preferably 0-10 ℃.

3) Esterification reaction

Dissolving T5B in organic solvent such as dichloromethane, adding acetic anhydride, adding organic or inorganic base as acid-binding agent, and adding 0-50% of^oAnd C, reacting to be complete. Adding alkali solution to quench the reaction, concentrating to remove dichloromethane, addingExtracting with organic solvent, layering, washing with water, drying to obtain crude intermediate T6, placing crude intermediate T6 in methanol, naturally cooling to room temperature, stirring for crystallization, and filtering to obtain target compound T6;

as a preferred technical solution, in step 3): the weight ratio of the acetic anhydride to the T5B is 1-20, more preferably 1-3, further preferably 1, and the reaction temperature is preferably 15-30 ℃.

As a preferred technical scheme, the organic base in the step 3) is selected from triethylamine, pyridine or imidazole; the inorganic base is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; the weight ratio of the acid-binding agent to T5B is 0.1-10, more preferably 0.5-2; the acid-binding agent is preferably triethylamine, and the weight ratio of the triethylamine to T5B is preferably 0.5. The volume weight ratio of the methanol to the T5B is 5-6.

According to the tibolone intermediate T6 synthesis method provided by the invention, tibolone intermediate TLW which is available in large quantities and cheap in market is used as a raw material, and tibolone important intermediate T6 is obtained through 3 steps.

Detailed Description

The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

Example 1

TLW (50.0 g, HPLC content. gtoreq.98%) was dissolved in a solution of acetic anhydride (500 mL), and concentrated sulfuric acid (2.0 g) was added thereto, followed by stirring at room temperature for 6 hours. TLC detection reaction is complete, reaction is stopped, concentration is carried out to be pasty, ethyl acetate (500 mL) and water (200 mL) are added, layers are separated, water layer is extracted by ethyl acetate (200 mL), layers are separated, organic phases are combined, saturated brine is washed (200 mL), layers are separated, drying and concentration are carried out, and yellow solid T4B, 57.0 g is obtained.

Example 2

T4B (57.0 g) was dissolved in methanol (570 mL) solution and sodium borohydride (6.3 g), 0, was added^oC, reacting for 1 hour, detecting by TLC to complete reaction, and adjusting the pH to be neutral by using dilute hydrochloric acidConcentrated to a paste, added with ethyl acetate (570 mL) and water (280 mL), separated into layers, extracted with ethyl acetate (280 mL) and separated into layers, the organic phases combined, washed with saturated brine (280 mL), separated into layers, dried and concentrated to give T5B as a yellow solid, 57.0 g.

Example 3

T5B (57.0 g) was dissolved in a dichloromethane (300 mL) solution, acetic anhydride (57.0 g) was added, triethylamine (28.5 g) was added, and the mixture was stirred at room temperature for 12 hours. TLC detection reaction is complete, sodium bicarbonate solution is added to quench the reaction, filtration is carried out, filtrate is dried to be pasty, ethyl acetate (570 mL) and water (280 mL) are added for separation, water layer is extracted by ethyl acetate (280 mL), organic phases are combined, saturated brine is washed (280 mL), separation is carried out, drying and concentration are carried out, and yellow solid T6 crude product, 62.0 g, is obtained. The crude T6 product was taken up in methanol (310 mL), heated to reflux, allowed to cool to room temperature, stirred for crystallization, and filtered to give T6 as a white solid, 55.8g, 99% HPLC purity.

Claims

1. A synthetic method of tibolone intermediate T6 is characterized in that: the synthesis method is shown as the following formula

The method is provided with the following steps:

1) ring opening reaction

Dissolving TLW in acetic anhydride, using protonic acid or Lewis acid as a catalyst, heating and refluxing for reaction, after the reaction is finished, concentrating, dissolving an organic solvent, washing with water, layering, drying, and concentrating to obtain T4B;

2) reduction reaction

Dissolving T4B in methanol, 0-50^oAdding sodium borohydride at the position of C, finishing the reaction, quenching with dilute hydrochloric acid, concentrating, dissolving with an organic solvent, washing with water, layering, drying and concentrating to obtain T5B;

3) esterification reaction

Dissolving T5B in organic solvent such as dichloromethane, adding acetic acidAdding organic or inorganic base 0-50 wt% as acid-binding agent into anhydride^oC, reacting to be complete; adding an alkali solution to quench reaction, concentrating to remove dichloromethane, adding an organic solvent to extract, layering, washing with water, drying to obtain a T6 crude product, placing the T6 crude product in methanol, heating and refluxing, naturally cooling to room temperature, stirring for crystallization, and filtering to obtain a target compound T6.

2. The method for synthesizing tibolone intermediate T6 according to claim 1, wherein the volume weight ratio of acetic anhydride to TLW in step 1) is 1-20, the protonic acid is sulfuric acid, hydrochloric acid, hydrogen chloride gas, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, the Lewis acid is boron tribromide, titanium tetrachloride or ferric trichloride, and the weight ratio of protonic acid or Lewis acid to TLW is 0.01-10.0.

3. The method for synthesizing tibolone intermediate T6 according to claim 2, wherein the volume weight ratio of acetic anhydride to TLW in step 1) is 5-10, and the weight ratio of protonic acid or Lewis acid to TLW is 0.01-0.5.

4. The synthesis method of tibolone intermediate T6 as claimed in claim 2, wherein the volume weight ratio of acetic anhydride to TLW in step 1) is 10, the catalyst is sulfuric acid, and the weight ratio of sulfuric acid to TLW is 0.04.

5. The method for synthesizing tibolone intermediate T6 according to claim 1, wherein the weight ratio of sodium borohydride to T5B in step 2) is 0.10-0.12, and the reaction temperature is preferably 0-10 ℃.

6. The method for synthesizing tibolone intermediate T6 according to claim 1, wherein the weight ratio of acetic anhydride to T5B in step 3) is 1-20, the organic base is selected from triethylamine, pyridine or imidazole; the inorganic base is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, and the weight ratio of the acid-binding agent to T5B is 0.1-10; the reaction temperature is preferably 15-30 ℃; the volume weight ratio of the methanol to the T5B is 5-6.

7. The method for synthesizing tibolone intermediate T6 as claimed in claim 6, wherein the weight ratio of acetic anhydride to T5B in step 3) is 1-3; the weight ratio of the acid-binding agent to T5B is 0.5-2.

8. The method for synthesizing tibolone intermediate T6 as claimed in claim 6, wherein the weight ratio of acetic anhydride to T5B in step 3) is 1; the acid-binding agent is triethylamine, and the weight ratio of the triethylamine to the T5B is 0.5.