WO2023126014A1 - Estrone synthesis method - Google Patents

Abstract

An estrone synthesis method. The method comprises the following steps: 1) performing aromatization reaction, uniformly mixing estra-4,9-diene-3,17-dione, acetic anhydride, and dichloromethane that serve as raw materials, adding acetyl bromide, then reacting under nitrogen protection, the reaction temperature being 0-50°C, the reaction time being 1-24 h, after the completion of the reaction, adding a lye to regulate the pH to 7-9, layering, and concentrating an organic phase to obtain an esterified product; and 2) performing hydrolysis reaction, adding methanol to disperse the esterified product, adding alkali, continuing the reaction, the reaction temperature being 0-50°C, the reaction time being 1-24 h, after the completion of the reaction, adding acid to neutralize, adding water to dilute, and filtering to obtain estrone.

Description

A kind of synthetic method of estrone technical field

The invention relates to a preparation method of a steroid compound, in particular to a synthesis method of estrone.

Background technique

Estrone is a natural estrogen in humans and animals, which can maintain the secondary physiological characteristics and normal endocrine system of female individuals. Estrone can be extracted from the urine of pregnant women or pregnant horses, but its content is low and the extraction cost is high. The industry usually uses chemical synthesis. At the same time, estrone is a synthetic precursor of various estrogens, such as estradiol, estriol, ethinyl estradiol, etc., and is also an important intermediate in the synthesis of 19-norsteroid drugs. Therefore, the chemical synthesis of estrone has been concerned by steroid academia and industry.

The traditional production route of estrone uses dienes as raw materials, and is synthesized through 7 steps including ketoxime, rearrangement, chlorine purification, cyclization, cyclization hydrolysis, ring opening and bio-fermentation. The production route is long, the source of raw materials is difficult, the synthesis yield is low, and highly toxic substances such as phosphorus oxychloride are used, resulting in a large amount of three wastes, so the total cost of preparing estrone is high.

The synthetic route is as follows:

In 1997, the Templteton group reported the synthesis of estrone by using the retro-aldol reaction, using the ring-opened product as a raw material, and undergoing three-step reactions of esterification, dehydrogenation, and aromatization. However, the yield of each step is not high, and selenium compounds are used in the dehydrogenation reaction, which causes great pollution.

In 2015, Zhang Zhengbin et al. reported the synthesis of estrone by using ADD via ketal reaction in metal lithium and biphenyl. Although the raw materials of this route are easy to obtain and the steps are short, the reaction conditions are harsh and the yield is relatively low. The reaction formula is as follows:

Based on the problems existing in the existing estrone synthesis method, providing a new estrone synthesis method, selecting cheap and easy-to-obtain raw material substrates, and further improving the reaction yield have become urgent problems to be solved in the prior art. question.

Contents of the invention

In order to solve the above-mentioned problems existing in the prior art, the technical solution we provide is:

A synthetic method for estrone, characterized in that: the synthetic method is shown in the following formula

The method comprises the following steps:

1) Aromatization reaction

Mix the 4,9-material, acetic anhydride and methylene chloride as raw materials evenly, add acetyl bromide, and then react under the protection of nitrogen; the reaction temperature is 0-50°C, and the reaction time is 1-24 hours; after the reaction is completed, add alkali Adjust the pH of the liquid to 7-9, separate the layers, and concentrate the organic phase to obtain the esterified product

2) Hydrolysis reaction

Add methanol to disperse the esterified product, add alkali, continue the reaction, the reaction temperature is 0-50°C, and the reaction time is 1-24 hours; after the reaction is completed, add acid to neutralize, add water to dilute, and filter to obtain estrone.

The synthesis method of estrone further includes step 3): adding a recrystallization solvent to the estrone obtained in step 2), heating to reflux for 1-3 hours, cooling to room temperature and continuing to stir for 6 ~ 12h, filter, the filter cake is rinsed with recrystallization solvent, and dried to obtain refined estrone.

The synthetic method of described a kind of estrone, further, in step 1), the weight ratio of described acetic anhydride and 4,9-material is 0.37-2.0, and step 1) described acetyl bromide and 4,9 - The weight ratio of matter is 0.45-2.0.

Said a kind of synthesis method of estrone, further, in step 1), the weight ratio of said acetic anhydride to 4,9-molecule is 0.4-0.5, and said acetyl bromide in step 1) and 4, The weight ratio of 9-item is 0.6-0.7.

According to the synthesis method of estrone, further, in step 1), the volume-to-weight ratio of the dichloromethane to the 4,9-molecule is 1.5-2.

For the synthesis method of estrone, further, in step 1), the reaction temperature is 15°C-30°C, and the reaction time is 5-24h. .

For the synthesis method of estrone, further, in step 1), lye is added to adjust the pH to 7-8, and the lye is preferably a saturated NaHCO ₃ solution.

In the synthesis method of estrone, further, the volume-to-weight ratio of methanol to 4,9-molecule in step 2) is 5-10.

In the synthesis method of estrone, further, step 2), the base is KOH, and the weight ratio of base to 4,9-molecule is 0.20-2.0, more preferably 0.4-0.6.

In the above-mentioned synthesis method of estrone, further, in step 2), the acid is 0.5-2M hydrochloric acid, and after adding the acid for neutralization, the pH of the system is 5-7, more preferably 6-7.

In the synthesis method of estrone, further, in step 2), the volume ratio of water and methanol added is 0.9-2.

The synthetic method of described a kind of estrone, further, described recrystallization solvent is ethanol, methanol, acetone or ethyl acetate; 10-15, the volume ratio of the recrystallization solvent for rinsing to the recrystallization solvent for heating and reflux is 0.08-0.16.

The synthetic method of a kind of estrone provided by the present invention adopts the cheap 4,9-substance that is supplied in large quantities in the market as the raw material, and can obtain estrone through two steps. Compared with the traditional process, it greatly shortens The reaction steps are simplified, the total reaction yield is high, and harsh conditions such as metal lithium and highly toxic and highly polluting reagents such as phosphorus oxychloride are avoided at the same time, which is beneficial to environmental protection and large-scale production.

Detailed ways

The present invention will be further described below in conjunction with specific examples, but the protection scope of the present invention is not limited thereto.

Example 1

Add 4,9-material (20g, HPLC content 98.1%), dichloromethane (30mL), acetic anhydride (8.0g, 0.4w/w) into a 500mL three-necked flask, add dropwise acetyl bromide (12.0g, 0.6w/w ); Stir at room temperature for 5 hours, TLC monitors the disappearance of raw materials; NaHCO ₃ saturated solution adjusts pH to 7-8; after adding, separate liquid, spin dry to paste, add methanol (100mL); 0.42w/w), after stirring for 10 minutes, TLC monitored that the raw materials disappeared; the reaction solution was slowly neutralized with 1M HCl, and the pH was adjusted to 6-7, then water (200mL) was added, filtered, and washed with water (100mL); the white solid was washed with ethanol (250mL) was heated to reflux for 2 hours, cooled to room temperature and continued to stir overnight at room temperature, filtered, and rinsed with ethanol (40mL); the solid was dried at 50°C to obtain 18g of white solid, namely refined estrone, HPLC The content is 99.3%.

Example 2

Add 4,9-material (30g, HPLC content 98.1%), dichloromethane (60mL), acetic anhydride (15.0g, 0.5w/w) into a 500mL three-necked flask, add dropwise acetyl bromide (21.0g, 0.7w/w ); Stir at room temperature for 24 hours, TLC monitors the disappearance of raw materials; NaHCO ₃ saturated solution adjusts pH to 7-8; after adding, separate liquid, spin dry to paste, add methanol (200mL); w/w), after stirring for 10 minutes, TLC monitored the disappearance of the raw materials; the reaction solution was slowly neutralized with 1M HCl, and the pH was adjusted to 6-7, then water (400mL) was added, filtered, and washed with water (100mL); the white solid was washed with ethyl acetate Ester (400mL) was refluxed for 2 hours, cooled to room temperature and stirred overnight at room temperature, filtered, and rinsed with ethyl acetate (40mL); the solid was dried at 50°C to obtain 29g of white solid, namely refined estrol Ketones, HPLC content 99.1%.

Example 3

Add 4,9-material (100g, HPLC content 98.1%), dichloromethane (200mL), acetic anhydride (45.0g, 0.45w/w) into a 500mL three-necked flask, add dropwise acetyl bromide (60.0g, 0.6w/w ); Stir at room temperature for 20 hours, TLC monitors the disappearance of raw materials; NaHCO ₃ saturated solution adjusts pH to 7-8; after adding, separate liquid, spin dry to paste, add methanol (1000mL); w/w), after stirring for 10 minutes, TLC monitored the disappearance of the raw materials; the reaction solution was slowly neutralized with 1M HCl, and the pH was adjusted to 6-7, then water (900mL) was added, filtered, and washed with water (300mL); the white solid was washed with ethyl acetate Ester (1000mL) was refluxed for 2 hours, cooled to room temperature and stirred overnight at room temperature, filtered and rinsed with ethyl acetate (80mL); the solid was dried at 50°C to obtain 95g of white solid, namely refined estrol Ketone HPLC content 99.1%.

Claims (8)

A synthetic method for estrone, characterized in that: the synthetic method is shown in the following formula

The method comprises the following steps: 1) Aromatization reaction Mix the 4,9-material, acetic anhydride and methylene chloride as raw materials evenly, add acetyl bromide, and then react under the protection of nitrogen; the reaction temperature is 0-50°C, and the reaction time is 1-24 hours; after the reaction is completed, add alkali Adjust the pH of the liquid to 7-9, separate layers, and concentrate the organic phase to obtain the esterified product; 2) Hydrolysis reaction Add methanol to disperse the esterified product, add alkali, continue the reaction, the reaction temperature is 0-50°C, and the reaction time is 1-24 hours; after the reaction is completed, add acid to neutralize, add water to dilute, and filter to obtain estrone. The synthetic method of a kind of estrone as claimed in claim 1, is characterized in that, also comprises step 3): adding recrystallization solvent to refining estrone obtained in step 2), heating to reflux for 1～3h, cooling to Continue to stir at room temperature for 6-12 hours, filter, rinse the filter cake with recrystallization solvent, and dry to obtain refined estrone. A kind of synthetic method of estrone as claimed in claim 1, is characterized in that, in step 1), the weight ratio of described acetic anhydride and 4,9-material is 0.37-2.0, and described acetyl bromide and 4, The weight ratio of the 9-material is 0.45-2.0. a kind of synthetic method of estrone as claimed in claim 3 is characterized in that: in step 1), the weight ratio of described acetic anhydride and 4,9-material is 0.4-0.5, and described acetyl bromide and The weight ratio of the 4,9-substance is 0.6-0.7, the volume-to-weight ratio of the dichloromethane to the 4,9-substance is 1.5-2, the reaction temperature is 15°C-30°C, the reaction time is 5-24h, adding The pH of the lye is adjusted to 7-8, and the lye is a saturated NaHCO ₃ solution. The synthetic method of a kind of estrone as claimed in claim 1, is characterized in that, in step 2), the volume weight ratio of described methanol and 4,9-material is 5～10, and described alkali is KOH, The weight ratio of the base to the 4,9-form is 0.20-2.0, the acid is 0.5-2M hydrochloric acid, and the pH of the system is 5-7 after adding the acid for neutralization; The synthetic method of a kind of estrone as claimed in claim 5 is characterized in that, in step 2), the weight ratio of alkali and 4,9-molecule is 0.4～0.6, after adding acid to neutralize, the pH of the system for 6-7. A kind of synthetic method of estrone as claimed in claim 1, is characterized in that: step 2), the volume ratio of the added water and methanol is 0.9～2. a kind of synthetic method of estrone as claimed in claim 1 is characterized in that: described recrystallization solvent is ethanol, methyl alcohol, acetone or ethyl acetate; The volume-to-weight ratio of the product is 10-15, and the volume ratio of the recrystallization solvent for rinsing to the recrystallization solvent for heating and reflux is 0.08-0.16.