阅读说明：本技术 一种甲丙雌二醚的制备方法 (Preparation method of estradiol mesilate ) 是由 何俊杰 陈万能 沈建华 于 2021-06-16 设计创作，主要内容包括：本发明公开了一种甲丙雌二醚的制备方法,该方法采用雌二醇和溴丙烷为原料,在乙酸乙酯溶剂中用正四丁基溴化铵和碳酸钾催化,反应制得中间体雌二醇3-正丙基醚,再采用叔丁醇钾为催化剂,在二甲亚砜溶剂中以硫酸二甲酯与中间体反应制得甲丙雌二醚粗品。本发明采用正四丁基溴化铵作为相转移催化剂,碳酸钾代替乙醇钠,在较温和条件下合成中间体,中间体的收率能达到97.11％,然后在叔丁醇钾催化下合成甲丙雌二醚,使用叔丁醇钾不需要通氮气,安全性高,所得甲丙雌二醚粗品的纯度高达98.5％,收率高达95.99％,该工艺操作简单,无需特殊设备,成本低廉,适合于工业化生产。(The invention discloses a preparation method of estradiol methyl ether, which adopts estradiol and bromopropane as raw materials, uses n-tetrabutylammonium bromide and potassium carbonate to catalyze in ethyl acetate solvent to react to prepare an intermediate estradiol 3-n-propyl ether, and then adopts potassium tert-butoxide as a catalyst to react dimethyl sulfate and the intermediate in dimethyl sulfoxide solvent to prepare a crude product of the estradiol methyl ether. The method adopts n-tetrabutylammonium bromide as a phase transfer catalyst, potassium carbonate replaces sodium ethoxide, an intermediate is synthesized under a mild condition, the yield of the intermediate can reach 97.11%, and then the methyl propyl estradiol ether is synthesized under the catalysis of potassium tert-butoxide, nitrogen is not required to be introduced when the potassium tert-butoxide is used, the safety is high, the purity of the obtained methyl propyl estradiol ether crude product is up to 98.5%, the yield is up to 95.99%, the process is simple to operate, special equipment is not required, the cost is low, and the method is suitable for industrial production.)

1. A preparation method of methylpropaneestradiol is characterized by comprising the following steps of (1) propylation reaction: estradiol and bromopropane are used as raw materials, and are catalyzed by n-tetrabutylammonium bromide and potassium carbonate in an ethyl acetate solvent to react to prepare an intermediate estradiol 3-n-propyl ether; (2) methylation reaction: potassium tert-butoxide is adopted as a catalyst, and dimethyl sulfate and an intermediate react in a dimethyl sulfoxide solvent to prepare a crude product of the estradiol methyl propionate.

2. The preparation method according to claim 1, wherein the mass ratio of the estradiol, the bromopropane, the potassium carbonate, the n-tetrabutylammonium bromide and the ethyl acetate is 1: (0.4-0.5): (0.2-0.3): (0.015-0.03): (5-10).

3. The preparation method according to claim 1, wherein the technical process of the propylation reaction is as follows: 1) adding estradiol, potassium carbonate and n-tetrabutylammonium bromide into ethyl acetate; 2) starting stirring, dropwise adding bromopropane, and heating for reaction; 3) and filtering after the reaction is finished, distilling the filtrate to recover ethyl acetate till the ethyl acetate is dry, recrystallizing the residue, and drying the obtained crystal to obtain the intermediate estradiol 3-n-propyl ether.

4. The method according to claim 3, wherein the heating reaction temperature in step 2) is 50-60 ℃, and the reaction time is preferably 2-4 h.

5. The method according to claim 3, wherein in step 3), the recrystallization process is as follows: cooling the residue to 55-65 deg.C, adding methanol, stirring at 55-65 deg.C until the solid is dissolved, and cooling to 0 + -5 deg.C for 2-3 h.

6. The preparation method according to claim 1, wherein the mass ratio of the intermediate to dimethyl sulfoxide to potassium tert-butoxide to dimethyl sulfate is 1: (1-4): (0.3-0.5): (0.3-0.5).

7. The preparation method according to claim 1, wherein the methylation reaction is carried out as follows: 1) adding potassium tert-butoxide into dimethyl sulfoxide, stirring, adding the intermediate, heating and stirring until the intermediate is dissolved; 2) cooling, dripping dimethyl sulfate, and stirring for reaction; 3) and (3) after the reaction is finished, adding water into the reaction solution, stirring until a solid is separated out, filtering, and drying filter residues to obtain a crude product of the estradiol methyl propionate.

8. The preparation method according to claim 7, wherein in the step 1), the heating and stirring temperature is 60-70 ℃, and the heating and stirring time is preferably 1-3 h; preferably, in the step 2), the temperature for reducing the temperature is 25-35 ℃; preferably, in the step 2), the stirring reaction is carried out at 20-30 ℃ for 2-4 h.

9. The preparation method according to claim 1, wherein the refining process is carried out after the crude product of the estradiol mesilate is prepared, and the refining process comprises the following steps: mixing the crude product of the estradiol methyl ether, activated carbon and absolute ethyl alcohol, heating and refluxing, filtering, taking filtrate, cooling, crystallizing and drying to obtain the finished product of the estradiol methyl ether.

10. The preparation method according to claim 9, wherein the mass ratio of the crude product of the mestrane, the activated carbon and the absolute ethyl alcohol is 1: (0.04-0.06): (1-4).

Technical Field

The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of methylpropaneestradiol.

Background

At present, the preparation method of the alpah estradiol ether mainly uses estradiol as an initial raw material, and utilizes a Willamson synthesis method, because the method uses metallic sodium to react with ethanol to prepare sodium ethoxide, the metallic sodium is difficult to control in the actual production, the process conditions are harsh, the price is higher, the manufacturing cost is increased, the method is not beneficial to batch production, and sodium hydride is used as an alkaline catalyst in the methylation reaction, so the sodium hydride has high risk, is easy to generate hydrogen, and is not beneficial to industrial production.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides a preparation method of the alpacal-estradiol, which is suitable for industrial production, can be widely applied to clinic, relieves the pain of patients and improves the medical level.

According to one aspect of the present invention, there is provided a process for the preparation of methylpropaneestradiol ether comprising (1) a propylation reaction: estradiol and bromopropane are used as raw materials, and are catalyzed by n-tetrabutylammonium bromide and potassium carbonate in an ethyl acetate solvent to react to prepare an intermediate estradiol 3-n-propyl ether; (2) methylation reaction: potassium tert-butoxide is adopted as a catalyst, and dimethyl sulfate and an intermediate react in a dimethyl sulfoxide solvent to prepare a crude product of the estradiol methyl propionate.

In some embodiments of the invention, the weight ratio of estradiol, bromopropane, potassium carbonate, n-tetrabutylammonium bromide and ethyl acetate is 1: (0.4-0.5): (0.2-0.3): (0.015-0.03): (5-10).

In some embodiments of the invention, the process of the propylation reaction is as follows: 1) adding estradiol, potassium carbonate and n-tetrabutylammonium bromide into ethyl acetate; 2) starting stirring, dropwise adding bromopropane, and heating for reaction; 3) and filtering after the reaction is finished, distilling the filtrate to recover ethyl acetate till the ethyl acetate is dry, recrystallizing the residue, and drying the obtained crystal to obtain the intermediate estradiol 3-n-propyl ether.

In some embodiments of the invention, in step 2) of the propylation reaction, the bromopropane is added dropwise over 1 h; in the step 2), the heating reaction temperature is 50-60 ℃, and the reaction time is 2-4 h; in the step 3), the drying temperature is 40-50 ℃, and the drying time is 3-5 h.

In some embodiments of the invention, in step 3) of the propylation reaction, the distillation is an atmospheric distillation at 70-80 ℃.

In some embodiments of the invention, in step 3) of the propylation reaction, the recrystallization process is as follows: cooling the residue to 55-65 deg.C, adding methanol, stirring at 55-65 deg.C until the solid is dissolved, and cooling to 0 + -5 deg.C for 2-3 h.

In some embodiments of the invention, the intermediate, dimethyl sulfoxide, potassium tert-butoxide and dimethyl sulfate are in a mass ratio of 1: (1-4): (0.3-0.5): (0.3-0.5).

In some embodiments of the invention, the methylation reaction is conducted as follows: 1) adding potassium tert-butoxide into dimethyl sulfoxide, stirring, adding the intermediate, heating and stirring until the intermediate is dissolved; 2) cooling, dripping dimethyl sulfate, and stirring for reaction; 3) and (3) after the reaction is finished, adding water into the reaction solution, stirring until a solid is separated out, filtering, and drying filter residues to obtain a crude product of the estradiol methyl propionate. The inorganic salt generated in the reaction can be dissolved in the process of adding water for crystallization.

In some embodiments of the present invention, in step 1) of the methylation reaction, the temperature of the heating and stirring is 60-70 ℃, and the time of the heating and stirring is preferably 1-3 h; preferably, in the step 2), the temperature for reducing the temperature is 25-35 ℃, and the dimethyl sulfate is dropwise added within 1 hour; preferably, in the step 2), the stirring reaction is carried out at 20-30 ℃ for 2-4 h.

In some embodiments of the present invention, in step 3) of the methylation reaction, the drying temperature is 35 to 45 ℃ and the drying time is 3 to 5 hours.

In some embodiments of the present invention, the crude product of the estradiol mesilate is further refined, and the refining process comprises the following steps: mixing the crude product of the estradiol methyl ether, activated carbon and absolute ethyl alcohol, heating and refluxing, filtering, taking filtrate, cooling, crystallizing and drying to obtain the finished product of the estradiol methyl ether.

In some embodiments of the present invention, the mass ratio of the crude methallyl estradiol ether, the activated carbon and the absolute ethyl alcohol is 1: (0.04-0.06): (1-4).

In some embodiments of the present invention, in the refining process, the heating reflux temperature is 70-80 ℃ and the reflux time is 1-2 h.

In some embodiments of the invention, in the refining process, the temperature of the filtrate is reduced to 0 ± 5 ℃ for crystallization for 1-3 h.

In some embodiments of the present invention, the temperature of the drying is 35-45 ℃ and the time of the drying is 3-5h in the refining process.

According to a preferred embodiment of the present invention, at least the following advantages are provided:

1. the method adopts n-tetrabutylammonium bromide as a phase transfer catalyst, potassium carbonate replaces sodium ethoxide, an intermediate is synthesized under a mild condition, the yield of the intermediate can reach 97.11%, and then the methyl propyl estradiol ether is synthesized under the catalysis of potassium tert-butoxide, nitrogen is not required to be introduced when the potassium tert-butoxide is used, the safety is high, the purity of the obtained methyl propyl estradiol ether crude product is up to 98.5%, the yield is up to 95.99%, the process is simple to operate, special equipment is not required, the cost is low, and the method is suitable for industrial production.

2. The potassium carbonate is used as an acid-binding agent and a catalyst, so that impurities generated by excessive side reactions are avoided, the potassium carbonate is cheap and easy to purchase, the cost is reduced, the post-treatment is simple, and the reaction solution is obtained by direct filtration.

3. The bromopropane is used as a propylation reagent, the reaction is more direct, excessive raw materials can be directly removed by post-treatment, and the reaction temperature balance is not too violent.

Detailed Description

The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.

Example 1

In this example, a specific process for preparing mesylether is as follows:

(1) and (3) performing a propylation reaction: adding 600g of ethyl acetate into a 1000ml dry flask at normal temperature, sequentially adding 100g of estradiol, 25.4g of potassium carbonate and 2g of n-tetrabutylammonium bromide from a feeding port, starting stirring, dropwise adding 45.2g of bromopropane, after dropwise adding within 1h, slowly heating to 55 ℃, keeping the temperature at normal pressure, stirring and reacting for 3h under heat preservation, after the reaction is finished, carrying out suction filtration on a reaction solution, keeping the temperature of a filtrate at 75 ℃ under normal pressure, distilling and recovering ethyl acetate to dryness, after the ethyl acetate is recovered, cooling the residue to 60 ℃, adding 400g of methanol, keeping the temperature at 60 ℃ and stirring to dissolve the solid, cooling to 0 +/-5 ℃, keeping for 2h, carrying out suction filtration, recovering a methanol solution to a recovery barrel, transferring to a filter cake oven, drying for 4h at 45 ℃, and obtaining 107.1g of the intermediate estradiol 3-n-propyl ether with the purity of 99.68%;

the yield of the intermediate is calculated according to the following formula:

conversion factor:

(2) methylation reaction: adding 35.6g of potassium tert-butoxide and 200g of dimethyl sulfoxide into a dry 1L reaction bottle at normal temperature, stirring, adding 100g of an intermediate, slowly heating to 65 ℃, keeping the temperature and stirring for 2h to fully dissolve and uniformly mix the intermediate, automatically and slowly dropwise adding 40g of dimethyl sulfate from a dropping funnel at 30 ℃, keeping the temperature at 30 ℃, finishing dropwise adding, then stirring and reacting for 3h at normal pressure and normal temperature (25 ℃), adding 400g of purified water into the reaction solution after the reaction is finished, stirring for 1.5h, separating out a solid, performing suction filtration, discarding a mother solution, transferring a filter cake into an oven, drying for 4h at 40 ℃ to obtain 105g of a crude product of the estradiol mesilate, wherein the purity of the crude product of the estradiol mesilate is 98.5%;

the yield of the crude product is calculated according to the following formula:

conversion factor:

(3) refining: adding 100g of a procalcitonin crude product, 5g of activated carbon and 200g of absolute ethyl alcohol into a dry 1L reaction bottle at normal temperature, stirring, slowly heating to 75 ℃, keeping the temperature and refluxing for 1h, performing suction filtration, transferring filtrate into the dry reaction bottle, cooling to 0 +/-5 ℃, crystallizing for 2h, performing suction filtration, transferring a filter cake into an oven, drying for 4h at 40 ℃ to obtain 90.3g of a procalcitonin finished product, wherein the purity of the procalcitonin finished product is 99.94%.

Comparative example 1

The comparative example prepares an intermediate, estradiol 3-n-propyl ether, and differs from example 1 in that the phase transfer catalyst is n-tetrabutylammonium hydrogen sulfate, and the specific process is as follows:

adding 600g of ethyl acetate into a 1000ml dry flask at normal temperature, sequentially adding 100g of estradiol, 25.4g of potassium carbonate and 2g of n-tetrabutylammonium hydrogen sulfate from a feeding port, starting stirring, dropwise adding 45.2g of bromopropane, slowly heating to 55 ℃, keeping the temperature of the mixture at normal pressure and stirring for 3 hours after dropwise adding is completed within 1 hour, after the reaction is completed, carrying out suction filtration on the reaction liquid, keeping the temperature of the filtrate at 75 ℃ under normal pressure and distilling to recover the ethyl acetate to dryness, cooling the residue to 60 ℃, adding 400g of methanol, keeping the temperature at 60 ℃ and stirring to dissolve the solid, cooling to 0 +/-5 ℃ and keeping the temperature for 2 hours, carrying out suction filtration, recovering the methanol solution to a recovery barrel, transferring to a filter cake oven, drying for 4 hours at 45 ℃ to obtain 102g of estradiol 3-n-propyl ether, wherein the yield of the intermediate is 92.5% and the purity is 92.5%.

Comparative example 2

The comparative example is used for preparing an intermediate estradiol 3-n-propyl ether, and is different from the example 1 in that an acid binding agent and a catalyst are sodium hydroxide, and the specific process is as follows:

adding 600g of ethyl acetate into a 1000ml dry flask at normal temperature, sequentially adding 100g of estradiol, 7.4g of sodium hydroxide and 2g of n-tetrabutylammonium bromide from a feeding port, starting stirring, dropwise adding 45.2g of bromopropane, slowly heating to 55 ℃, keeping the temperature of the mixture at normal pressure and stirring for 3 hours under the condition of keeping the temperature at the normal pressure, after the reaction is finished, carrying out suction filtration on the reaction liquid, keeping the temperature of the filtrate at 75 ℃, distilling to recover the ethyl acetate to dryness under the normal pressure, cooling the residue to 60 ℃, adding 400g of methanol, keeping the temperature at 60 ℃ and stirring to dissolve the solid, cooling to 0 +/-5 ℃, keeping the temperature for 2 hours, carrying out suction filtration, recovering the methanol solution to a recovery barrel, transferring to a filter cake oven, drying for 4 hours at 45 ℃ to obtain 98g of estradiol 3-n-propyl ether, wherein the yield of the intermediate is 88.9%, the purity is 95.8%, and the side reaction impurities are 3.5%.

Comparative example 3

The comparative example is used for preparing an intermediate estradiol 3-n-propyl ether, and is different from the example 1 in that a propylation reagent adopts chloropropane, and the specific process is as follows:

adding 600g of ethyl acetate into a 1000ml dry flask at normal temperature, sequentially adding 100g of estradiol, 25.4g of potassium carbonate and 2g of n-tetrabutylammonium bromide from a feeding port, starting stirring, dropwise adding 28.85g of chloropropane, after dropwise adding within 1h, slowly heating to 55 ℃, keeping the temperature of the mixture at normal pressure and stirring for 3h, after the reaction is finished, carrying out suction filtration on a reaction solution, keeping the temperature of a filtrate at 75 ℃ under normal pressure for distilling and recovering the ethyl acetate to be dry, after the ethyl acetate is completely recovered, cooling the residue to 60 ℃, adding 400g of methanol, keeping the temperature at 60 ℃ for stirring to dissolve the solid, cooling to 0 +/-5 ℃, keeping the temperature for 2h, carrying out suction filtration, recovering a methanol solution to a recovery barrel, transferring a filter cake to an oven, drying for 4h at 45 ℃ to obtain 103g of estradiol 3-n-propyl ether as an intermediate, wherein the yield of the intermediate is 93.4%, and the purity is 98.1%.

It can be seen from comparative examples 1-3 that when other species are used for the phase transfer catalyst, acid-binding agent, catalyst and propylation reagent, the yield and purity of the product are inferior to those of example 1, indicating that the reagents used in the present invention and the process steps of the present invention combine to achieve higher yields and purities.

The embodiments of the present invention have been described in detail, but the present invention is not limited to the embodiments, and various changes can be made without departing from the gist of the present invention within the knowledge of those skilled in the art. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.