CN114315941B

CN114315941B - Synthesis method of tibolone intermediate T6

Info

Publication number: CN114315941B
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: 2023-05-02
Anticipated expiration: 2041-12-28
Also published as: CN114315941A

Abstract

A synthesis method of tibolone intermediate T6 comprises the following steps: 1) Ring-opening reaction, namely dissolving TLW in acetic anhydride, taking protonic acid or Lewis acid as a catalyst, heating and refluxing for reaction, concentrating after the reaction is finished, dissolving in an organic solvent, washing with water, layering, drying and concentrating to obtain T4B; 2) Dissolving T4B in methanol, adding sodium borohydride at 0-50 ℃, quenching by dilute hydrochloric acid after the reaction is finished, concentrating, dissolving by an organic solvent, washing by water, layering, drying and concentrating to obtain T5B; 3) And (3) performing esterification reaction, namely dissolving T5B in an organic solvent such as dichloromethane, adding acetic anhydride, adding an organic base or an inorganic base serving as an acid binding agent, and performing reaction at 0-50 ℃ until the reaction is completed. Adding an alkali solution for quenching reaction, concentrating to remove dichloromethane, adding an organic solvent for extraction, layering, washing with water, drying to obtain a crude product of T6, placing the crude product of T6 in methanol, heating and refluxing, naturally cooling to room temperature, stirring for crystallization, and filtering to obtain the 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 synthesis method of a tibolone intermediate.

Background

Tibolone is a regulator of tissue selective estrogenic activity (steps), which is an artificially synthesized steroid hormone. The preparation is mainly applied to the aspects of relieving vasomotor state, improving urogenital atrophy symptom, preventing bone loss, reducing the incidence of fracture, improving life-related quality and the like of perimenopausal and postmenopausal women clinically.

In 1967, P. Wieland et al reported for the first time a synthetic route to tibolone. The route takes dehydroepiandrosterone as a raw material, and tibolone is obtained in 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 tibolone is synthesized by 7 steps by taking diester T6 as a starting material. And the diester T6 is obtained by taking dechlorinated matter TLW as a raw material and performing 7 steps.

In 2004, world patent WO2004031204 reports a third method of synthesizing tibolone from nandrolone as a starting material in 8 steps with a yield of 18.04%. In the same year, world patent WO2004078774 reports a fourth method, which uses also nandrolone as starting material, to synthesize tibolone in 8 steps, with a yield of 21.5%. In 2019, xu Saihu et al reported a fifth method of synthesizing tibolone in 6 steps using the norbornyl precursor acid as a starting material. Although the third, fourth and fifth synthetic methods have short steps, the raw material of nandrolone or its precursor acid is expensive and has high production cost. The method has complicated step and harsh Birch reduction conditions. Thus, a second synthetic method is currently common in the industry. In this synthetic method, T6 is the most core intermediate. In the prior art, T6 can be obtained by using TLW to perform seven steps of reaction, and how to improve the production efficiency of an intermediate T6 and the yield of the T6 prepared by using TLW as a raw material becomes a problem to be solved in the prior art.

Disclosure of Invention

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

a synthesis method of tibolone intermediate T6 is characterized by comprising the following steps: the synthesis method is shown as the following formula

The method comprises the following steps:

1) Ring opening reaction

TLW is dissolved in acetic anhydride, protonic acid or Lewis acid is used as a catalyst, the heating reflux reaction is finished, the reaction is concentrated, the organic solvent is dissolved, the organic solvent is washed with water, the layers are separated, dried and concentrated to obtain T4B.

As a preferred embodiment, the volumetric weight ratio of acetic anhydride to TLW of step 1) is 1-20, more preferably 5-10. Further preferably 10.

As a preferable 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 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 sulfuric acid, and the weight ratio of sulfuric acid to TLW is preferably 0.04.

2) Reduction reaction

Dissolving T4B in methanol to 0-50 ^o Adding sodium borohydride under the condition of C, quenching by dilute hydrochloric acid after the reaction is finished, concentrating, dissolving by an organic solvent, washing by water, layering, drying and concentrating to obtain the 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 base or inorganic base as acid binding agent, and adding 0-50 ^o The reaction was completed under C. Adding an alkali solution for quenching reaction, concentrating to remove dichloromethane, adding an organic solvent for extraction, layering, washing with water, drying to obtain a crude intermediate T6, placing the crude intermediate T6 in methanol, naturally cooling to room temperature, stirring for crystallization, and filtering to obtain a target compound T6;

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

As a preferred embodiment, step 3) 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; 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 triethylamine to T5B is preferably 0.5. The volume weight ratio of the methanol to the T5B is 5-6.

According to the synthesis method of the tibolone intermediate T6, the tibolone important intermediate T6 is obtained through 3 steps by using a large amount of tibolone intermediate TLW which is supplied in the market and is low in cost as a raw material, compared with the traditional process, the reaction steps are greatly shortened, the total reaction yield is improved, the use of dangerous metal reagents is avoided, and the method is beneficial to environmental protection and large-scale production.

Detailed Description

The invention will be further illustrated with reference to specific examples, but the scope of the invention is not limited thereto.

Example 1

TLW (50.0 g, HPLC content. Gtoreq.98%) was dissolved in acetic anhydride (500. 500 mL), concentrated sulfuric acid (2.0 g) was added, and stirred at room temperature for 6 hours. TLC checked completion of the reaction, stopped the reaction, concentrated to paste, ethyl acetate (500 mL) and water (200 mL), layered, aqueous layer extracted with ethyl acetate (200 mL), layered, combined organic phases, saturated brine (200 mL), layered, dried, concentrated to give yellow solid T4B,57.0 g.

Example 2

Dissolving T4B (57.0 g) in methanol (570 mL) solution, adding sodium borohydride (6.3 g), 0 ^o The reaction was completed by TLC under C for 1 hour, diluted hydrochloric acid was adjusted to neutral, concentrated to paste, ethyl acetate (570 mL) and water (280 mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (280 mL), the organic phases were combined, saturated brine (280 mL) was separated, dried, and concentrated to give yellow solid T5B,57.0 g.

Example 3

T5B (57.0 g) was dissolved in methylene chloride (300 mL), 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 was used to examine completion of the reaction, the reaction was quenched by addition of sodium bicarbonate solution, filtered, the filtrate was dried to a paste by spin-drying, ethyl acetate (570 mL) and water (280 mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (280 mL), the layers were separated, the organic phases were combined, saturated brine (280 mL) and separated, dried and concentrated to give crude yellow solid T6, 62.0 g. The crude T6 product is placed in methanol (310, mL), heated to reflux, naturally cooled to room temperature, stirred for crystallization and filtration to obtain white solid T6, 55.8g and HPLC purity of 99%.

Claims

1. A synthesis method of tibolone intermediate T6 is characterized by comprising the following steps: the synthesis method is shown as the following formula

The method comprises the following steps:

1) Ring opening reaction

TLW is dissolved in acetic anhydride, sulfuric acid is used as a catalyst, heating reflux reaction is carried out, reaction is finished, concentration is carried out, organic solvent is dissolved, water washing, layering, drying and concentration are carried out, and T4B is obtained;

2) Reduction reaction

Dissolving T4B in methanol, adding sodium borohydride at 0-50deg.C, quenching with dilute hydrochloric acid, concentrating, dissolving in organic solvent, washing with water, layering, drying, and concentrating to obtain T5B;

3) Esterification reaction

Dissolving T5B in dichloromethane, adding acetic anhydride, adding organic base or inorganic base as acid binding agent, reacting at 0-50deg.C until the reaction is completed, adding alkali solution for quenching reaction, concentrating to remove dichloromethane, adding organic solvent for extraction, layering, washing with water, drying to obtain T6 crude product, heating and refluxing the T6 crude product in methanol, naturally cooling to room temperature, stirring for crystallization, and filtering to obtain target compound T6.

2. A process for the synthesis of tibolone intermediate T6 according to claim 1, wherein the volumetric weight ratio of acetic anhydride to TLW in step 1) is 1-20ml/g and the weight ratio of sulfuric acid to TLW is 0.01-10.0.

3. A process for the synthesis of tibolone intermediate T6 according to claim 2, wherein the volumetric weight ratio of acetic anhydride to TLW in step 1) is 5-10ml/g and the weight ratio of sulfuric acid to TLW is 0.01-0.5.

4. A process for the synthesis of tibolone intermediate T6 according to claim 2, wherein the volumetric weight ratio of acetic anhydride to TLW in step 1) is 10ml/g and the weight ratio of sulfuric acid to TLW is 0.04.

5. A process for the synthesis of tibolone intermediate T6 according to claim 1, wherein in step 3) the weight ratio of acetic anhydride to T5B 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 the 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 ml/g.

6. The process for the synthesis of tibolone intermediate T6 as claimed in claim 5, wherein in step 3) the weight ratio of acetic anhydride to T5B is 1-3; the weight ratio of the acid binding agent to the T5B is 0.5-2.

7. The process for the synthesis of tibolone intermediate T6 as claimed in claim 5, 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.