阅读说明：本技术 雌酚酮硫酸酯哌嗪的制备方法 (Preparation method of estrone sulfate piperazine ) 是由 李维华 刘真豪 丁永真 吕良飞 祝长斌 于 2019-11-04 设计创作，主要内容包括：本文发明涉及一种高纯度雌-1,3,5(10)-三烯-17-酮-3-硫酸酯哌嗪(1:1)(即雌酚酮硫酸酯哌嗪)的制备方法。该方法反应条件温和,后处理操作简单,杂质容易控制,从而使制备的雌酚酮硫酸酯哌嗪质量可控、稳定性高。主要的步骤是：1)将雌酚酮溶解在有机溶剂中与磺化试剂反应得到雌-1,3,5(10)-三烯-17-酮-3-硫酸酯；2)将哌嗪溶解在有机溶剂中,然后加入到雌-1,3,5(10)-三烯-17-酮-3-硫酸酯的有机溶液中,析出固体,过滤,洗涤,干燥得到高纯度的雌酚酮硫酸酯哌嗪产品。(The present invention relates to a process for the preparation of high purity estra-1, 3,5(10) -trien-17-one-3-sulfate piperazine (1:1), i.e. estrone sulfate piperazine. The method has mild reaction conditions, simple post-treatment operation and easy impurity control, so that the prepared estrone sulfate piperazine has controllable quality and high stability. The method mainly comprises the following steps: 1) dissolving estrone in an organic solvent to react with a sulfonation reagent to obtain estra-1, 3,5(10) -triene-17-ketone-3-sulfate; 2) dissolving piperazine in an organic solvent, adding the solution into an organic solution of estra-1, 3,5(10) -triene-17-ketone-3-sulfate, separating out a solid, filtering, washing and drying to obtain a high-purity estrone sulfate piperazine product.)

1. A process for preparing estra-1, 3,5(10) -triene-17-one-3-sulfate piperazine,

estra-1, 3,5(10) -trien-17-one sulfate and anhydrous piperazine.

2. The process according to claim 1, wherein the estra-1, 3,5(10) -trien-17-one sulfate and the anhydrous piperazine are separately dissolved with an organic solvent; the organic solvent is one or a mixed solvent of any two of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, methanol, ethanol and isopropanol in any proportion; preferably one or any two of tetrahydrofuran, methanol and dichloromethane, and the solvent is mixed at any ratio.

3. The method of claim 1 or 2, wherein the reaction temperature is 20 to 25 ℃.

4. The process according to any one of claims 1 to 3, wherein the estra-1, 3,5(10) -trien-17-one sulfate is prepared by the steps of:

1) reacting estra-1, 3,5(10) -trien-17-one dissolved in an organic base solvent with a sulfonation reagent to obtain a crude product;

2) adding the crude product into an organic solvent, pulping at room temperature, filtering, and washing to obtain the estra-1, 3,5(10) -triene-17-ketone sulfate.

5. The method according to claim 4, wherein the sulfonating agent in step 1) is one of sulfur trioxide pyridine, sulfur trioxide triethylamine, sulfamic acid, preferably sulfur trioxide pyridine or sulfamic acid.

6. The preparation method according to claim 4 or 5, wherein the organic base solvent in step 1) is one of pyridine and triethylamine or a mixed solvent of pyridine and triethylamine in any proportion; triethylamine is preferred.

7. The preparation method according to any one of claims 4 to 6, wherein the organic solvent in step 2) is one of methanol, ethanol, isopropanol or a mixed solvent of any two thereof at any ratio; methanol is preferred.

8. The method according to claims 4 to 7, wherein the reaction temperature in step 1) is 20 to 25 ℃.

9. The method of any one of claims 1 to 8, comprising the steps of:

(1) dissolving estra-1, 3,5(10) -trien-17-one in an organic solvent, adding a sulfonating reagent at the temperature of 20-25 ℃, and heating for reaction;

(2) after the raw materials completely react, concentrating to obtain a crude product, adding an organic solvent, pulping at the temperature of 20-25 ℃, filtering and washing to obtain the estra-1, 3,5(10) -triene-17-ketone sulfate;

(3) dissolving anhydrous piperazine in an organic solvent to obtain a clear solution, dissolving the estra-1, 3,5(10) -trien-17-one sulfate obtained in the step (2) in the same organic solvent, adding the dissolved estra-1, 3,5(10) -trien-17-one sulfate into the anhydrous piperazine organic solvent, and stirring at room temperature to separate out a white solid;

(4) filtering, washing and drying to obtain the product.

Technical Field

The invention relates to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of high-purity estra-1, 3,5(10) -triene-17-ketone-3-sulfate piperazine (estrone sulfate piperazine).

Background

The incidence of osteoporosis in postmenopausal women is 50%, and the main causes of osteoporosis are postmenopausal ovarian hypofunction and bone loss caused by the reduction of estrogen level. Estrogen Replacement Therapy (ERT) is the most traditional, most classical regimen for the prevention and treatment of postmenopausal osteoporosis. However, long-term estrogen use increases the risk of breast and endometrial cancer. The estrone sulfate piperazine is a medicine with high selectivity and small side effect for preventing and treating osteoporosis.

The preparation method of estrone sulfate piperazine is only reported, and the reported preparation method (Steroids 7(1966), 577-587, Steroids 12(1968), 49-60) generally comprises the steps of reacting estrone with some sulfonation reagents (sulfur trioxide pyridine, sulfur trioxide triethylamine, sulfur trioxide piperazine and sulfamic acid) in an organic solvent to obtain estrone sulfate, preparing sodium salt and ammonium salt, and then forming amine salt with piperazine to obtain estrone sulfate piperazine. The reaction steps are complicated, the temperature and the pH value need to be carefully controlled during the reaction, the total yield is low, and impurities are difficult to control. Therefore, the development of a preparation method of estrone sulfate piperazine, which has the advantages of high reaction yield, mild reaction conditions, simple post-treatment operation and easy impurity control, is urgently needed.

Disclosure of Invention

The invention provides a preparation method of estra-1, 3,5(10) -triene-17-ketone-3-sulfate piperazine (1:1), which has the advantages of mild reaction conditions, simple post-treatment operation treatment and easy impurity control, and the obtained estra-1, 3,5(10) -triene-17-ketone-3-sulfate piperazine (estrone sulfate piperazine) has controllable quality and high stability.

The invention relates to a method for preparing estra-1, 3,5(10) -trien-17-one-3-sulfate piperazine, which is obtained by reacting estra-1, 3,5(10) -trien-17-one sulfate with anhydrous piperazine.

Preferably, the estra-1, 3,5(10) -trien-17-one sulfate and the anhydrous piperazine are respectively dissolved by using an organic solvent; the organic solvent is one of dichloromethane, tetrahydrofuran, ethyl acetate, isopropyl acetate, methanol, ethanol and isopropanol or a mixed solvent of any two of the dichloromethane, the tetrahydrofuran, the ethyl acetate, the isopropyl acetate, the methanol, the ethanol and the isopropanol in any proportion; preferably one of tetrahydrofuran, methanol and dichloromethane or a mixed solvent of any two solvents thereof in any proportion. Preferably, the reaction temperature may be 20 to 25 ℃.

The preparation method of the estra-1, 3,5(10) -triene-17-ketone-3-sulfate piperazine directly uses estra-1, 3,5(10) -triene-17-ketone sulfate to react with piperazine, and omits the purification process of sodium salt or ammonium salt in the prior art.

In another aspect, the invention relates to a process for the preparation of estra-1, 3,5(10) -trien-17-one-3-sulfate piperazine, said estra-1, 3,5(10) -trien-17-one sulfate being prepared by the steps of:

1) reacting estra-1, 3,5(10) -trien-17-one dissolved in an organic base solvent with a sulfonation reagent to obtain a crude product;

2) adding the crude product into an organic solvent, pulping at room temperature, filtering, and washing to obtain the estra-1, 3,5(10) -triene-17-ketone sulfate.

Preferably, the sulfonating reagent in step 1) is one of sulfur trioxide pyridine, sulfur trioxide triethylamine, sulfamic acid, preferably sulfur trioxide pyridine or sulfamic acid.

Preferably, the organic base solvent in the step 1) is one of pyridine and triethylamine or a mixed solvent of pyridine and triethylamine in any proportion; triethylamine is preferred.

Preferably, the organic solvent in step 2) is one of methanol, ethanol and isopropanol or a mixed solvent of any two of the methanol, the ethanol and the isopropanol in any proportion; methanol is preferred.

Preferably, said reaction temperature in step 1) is 20-25 ℃.

The invention relates to a preparation method of estra-1, 3,5(10) -triene-17-ketone-3-sulfate piperazine, which specifically comprises the following steps:

(1) dissolving estra-1, 3,5(10) -trien-17-one in an organic solvent, adding a sulfonating reagent at the temperature of 20-25 ℃, and heating for reaction;

(2) after the raw materials completely react, concentrating to obtain a crude product, adding an organic solvent, pulping at the temperature of 20-25 ℃, filtering and washing to obtain the estra-1, 3,5(10) -triene-17-ketone sulfate;

(3) dissolving anhydrous piperazine in an organic solvent to obtain a clear solution, dissolving the estra-1, 3,5(10) -trien-17-one sulfate obtained in the step (2) in the same organic solvent, adding the dissolved estra-1, 3,5(10) -trien-17-one sulfate into the anhydrous piperazine organic solvent, and stirring at room temperature to separate out a white solid;

(4) filtering, washing and drying to obtain the product.

The method provided by the invention adopts the methods in documents Steroids 7(1966)577-587 and Steroids 12(1968)49-60, takes estrone as a raw material to react with sulfonation reagents such as pyridine trioxide, triethylamine trioxide and sulfamic acid in an organic alkali solvent, the inventor carries out system research on the sulfonation reagents, the reaction temperature and the reaction time, the process of the documents is improved in a targeted manner, and finally, the estrone sulfate piperazine is directly obtained without sodium salt or ammonium salt purification. Meanwhile, the salt forming process is optimized, the impurity of estrone and other related impurities are very stably controlled, and the obtained estrone sulfate piperazine with the purification of not less than 99.9 percent is obtained.

The invention has the advantages that:

the synthesized estrone sulfate (P-1) is directly salified with piperazine, so that the purification process of intermediate sodium salt or ammonium salt is omitted, the process is simplified, and the industrial production is facilitated;

obviously reduces the content of the estrone impurities and the total impurities in the raw material and improves the product purity.

Detailed Description

The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. Without departing from the inventive concept, a person skilled in the art may make modifications to the manufacturing method and the apparatus used within the scope of the claims, and such modifications should also be considered as within the scope of the invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

In the examples below, unless otherwise indicated, the test procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown in the figure can be obtained by a commercially available mode.