CN116003501A

CN116003501A - Natural product Estrone derivative and synthesis method thereof

Info

Publication number: CN116003501A
Application number: CN202211389406.4A
Authority: CN
Inventors: 计巧珍; 宋纪双; 顾先涛; 张更; 吴妍; 曹菊林
Original assignee: Electric Power Research Institute of State Grid Anhui Electric Power Co Ltd; Anhui Xinli Electric Technology Consulting Co Ltd
Current assignee: Electric Power Research Institute of State Grid Anhui Electric Power Co Ltd; Anhui Xinli Electric Technology Consulting Co Ltd
Priority date: 2022-11-08
Filing date: 2022-11-08
Publication date: 2023-04-25

Abstract

The invention discloses a natural product Estrone derivative and a synthesis method thereof, wherein the structure of the natural product Estrone derivative is shown as follows:

compared with Estrone, the solubility of the novel Estrone derivative in a solvent is obviously improved, the Estrone derivative is favorable for intestinal absorption and storage in fat, and the Estrone derivative can be slowly released through the action of in-vivo enzyme, so that the long-acting effect is achieved. Therefore, the method has potential value of becoming long-acting oral estrogen, and the raw materials for reaction are easy to obtain and easy to realize industrial production.

Description

Natural product Estrone derivative and synthesis method thereof

Technical Field

The invention belongs to the field of organic chemical synthesis, and in particular relates to a natural product Estrone derivative and a synthesis method thereof.

Background

(8R, 9S,13S, 14S) -3-hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17 Hcyclintea alpha-phenothrin-17-one (estrone) is a natural steroid, a sex hormone, originally extracted from pregnant mares urine by Doisy and Butenandt. The estrogen and its derivative have their own physiological activities, so they can be widely used for treating various gynecological diseases, and can be used as an important component of contraceptive. The main purpose of the structural modification using estrone as a substrate is not to improve pharmacological activity, but to enable oral administration or to make the activity of the drug long-acting, so as to prolong half-life. Such as mestranol, the introduction of alkyl ethers in nieiestrol increases its solubility in human fat globules. So that the medicine becomes a long-acting oral estrogen. Thus, estrone derivatives which are engineered to give alkyl ethers are likely to have potential pharmaceutical value.

Disclosure of Invention

The invention aims to provide a natural product Estrone derivative and a synthesis method thereof. Compared with Estrone, the Estrone derivative obtained by the invention has obviously improved solubility in a solvent, is favorable for intestinal absorption and storage in fat, can be slowly released through the action of in-vivo enzyme, thus achieving long-acting effect, has potential value of becoming long-acting oral estrogen, and the raw materials for reaction are easy to obtain and easy to realize industrial production.

The structure of the natural product Estrone derivative is shown as follows:

the synthesis method of the natural product Estrone derivative comprises the following steps:

step 1: wolff-Kishner-Huang Ming Dragon reduction reaction: mixing estrone, hydrazine hydrate, DME and n-butanol, heating to 200 ℃ for reflux reaction, adding KOH, and distilling under reduced pressure to remove the n-butanol; cooling to room temperature after the reaction is finished, filtering, washing with water, and separating and purifying by column chromatography to obtain an intermediate 2;

step 2: placing the intermediate 2 obtained in the step 1, potassium carbonate and allyl bromide into acetone for reaction at 60 ℃, and obtaining an intermediate 3 through extraction, drying and column chromatography separation and purification after the reaction is finished;

step 3: and (3) placing the intermediate 3 obtained in the step (2) in N, N-diethyl aniline, heating to 250 ℃, and obtaining intermediates 4a and 4b through [3,3] rearrangement, extraction, drying, column chromatography separation and purification. 4a and 4b are difficult to separate, and the synthetic route shows that the ratio of the two to 2:1 (molar ratio) is known from the nuclear magnetic resonance result, but in the subsequent reaction of step 4, the reaction is actually carried out by the intermediate 4a, 4b is not reacted, and separation can be obtained.

Step 4: adding the intermediate 4a, the intermediate 4b, the potassium carbonate and the methyl iodide obtained in the step 3 into acetone, reacting at 60 ℃, and obtaining an intermediate 5 through extraction, drying, column chromatography separation and purification after the reaction is finished;

step 5: hydroboration oxidation: adding the intermediate 5 obtained in the step 4 into borane-tetrahydrofuran solution at 0 ℃ for reaction for 1H, and then adding NaOH solution and H ₂ O ₂ The solution reacts at room temperature, and the target product (I) is obtained through extraction, drying, column chromatography separation and purification.

The reaction scheme is as follows:

in the step 1, the mass-volume ratio of the estrone, the hydrazine hydrate, the potassium hydroxide, the DME and the n-butanol is 5g:3g:3.2g:40mL:14mL.

In the step 1, the early reaction temperature is 200 ℃, after the reaction is carried out for 1h, the temperature is reduced to 50 ℃ and the reaction is continued for 4h.

In step 2, the mass-to-volume ratio of intermediate 2, allyl bromide, potassium carbonate and acetone is 3.3g:3.6g:5.4g:60mL.

In the step 2, the reaction temperature is 60 ℃ and the reaction time is 12 hours.

In step 3, the mass-to-volume ratio of intermediate 3 to N, N-diethylaniline was 0.888g:10mL.

In the step 3, the reaction temperature is 250 ℃ and the reaction time is 8 hours.

In the step 4, the mass volume ratio of the intermediate 4 to methyl iodide to potassium carbonate to acetone is 5g:5g:7g:10mL. The proportions here are based on the total mass of intermediate 4a and intermediate 4b.

In the step 4, the reaction temperature is 60 ℃ and the reaction time is 12 hours.

In step 5, intermediate 5, borane-THF, tetrahydrofuran mass to volume ratio of 0.31g:2g:10mL of sodium hydroxide solution and hydrogen peroxide solution in a volume ratio of 1:1 (concentration of sodium hydroxide solution is 2M, concentration of hydrogen peroxide solution is 30%).

In the step 5, in the earlier stage ice water bath, the reaction time is 1h, the later stage reaction temperature is raised to room temperature, and the reaction time is 1h.

The beneficial effects of the invention are as follows:

the preparation route has fewer process steps, easily available raw materials and suitability for industrial production.

Compared with Estrone, the novel Estrone derivative obtained by the invention is added into 0.5ml of solvent respectively by the same mass (10 mg) of the novel Estrone derivative and Estrone through a solubility test, the solubility of the novel Estrone derivative in the solvent is obviously improved by naked eyes, and the novel Estrone derivative is more beneficial to intestinal absorption and storage in fat, as shown in figure 2.

Drawings

FIG. 1 is nuclear magnetic data of a target product of the present invention.

FIG. 2 is a graph showing the solubility of the target product of the present invention and Estrone, wherein the left graph A shows the dissolution of the added solvent, and the right graph B shows the state of the compound after the solvent is volatilized.

Detailed Description

The invention will be further described in detail with reference to the following examples for the purpose of making the objects and advantages of the invention more apparent, it being understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

The embodiment of the invention provides a synthetic method of Estrone derivatives, which comprises the following synthetic route:

1. estrone (10 mmol,2.71 g), 6ml n-butanol, 1.5ml hydrazine hydrate and 25ml diethylene glycol were placed in a 100m two-neck schlenk flask, the reaction mixture was heated to 200℃until the solution became a clear liquid, and heating was continued for 1 hour; cooling to 50deg.C, adding KOH (30 mmol,1.68 g), then distilling off n-butanol under reduced pressure, keeping the reaction at 50deg.C for 4 hours, and cooling to room temperature; adding ice-water mixture into the reaction solution, adding 6M hydrochloric acid, stirring to obtain white solid, filtering, washing with water, and adding water to obtain CHCl ₃ Separating and purifying by column chromatography as an eluent to obtain an intermediate 2;

2. placing intermediate 2 (13 mmol), potassium carbonate (52 mmol) and acetone 60ml obtained in the step 1 into a 200ml reaction bottle under nitrogen atmosphere, adding allyl bromide (30 mmol) at 0 ℃, heating to 60 ℃, reacting for 12h, and monitoring complete conversion of raw materials by TLC; 50ml of water was added to the reaction solution, the mixture was separated, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and column chromatography was performed to obtain intermediate 3 (PE: etoac=20:1, V/V);

3. adding the intermediate 3 (3 mmol) obtained in the step 2 into 10ml of N, N-diethyl aniline under nitrogen atmosphere, heating to 250 ℃ for reflux reaction for 8h, adding 3M hydrochloric acid for washing, extracting with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, removing a solvent, and separating and purifying by column chromatography (PE: etOAc=3:1, V/V) to obtain an intermediate 4 (intermediate 4a and intermediate 4 b);

4. placing the intermediate 4 (1.69 mmol), potassium carbonate (3.38 mmol) and acetone 10ml obtained in the step 3 into a 100ml reaction bottle under nitrogen atmosphere, adding methyl iodide (3.38 mmol) at 0 ℃, heating to 60 ℃, reacting overnight, and monitoring complete conversion of the raw materials by TLC; 10ml of water was added to the reaction solution, the mixture was separated, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed, and column chromatography was performed to obtain intermediate 5 (PE: etoac=10:1, V/V);

5. dissolving the intermediate 5 (1.69 mmol) obtained in the step 4 in 10ml of tetrahydrofuran solution under nitrogen atmosphere, dropwise adding 1M borane-tetrahydrofuran solution (3.38 mmol) at 0 ℃, and monitoring complete conversion of the raw materials by TLC; 2ml of 2M NaOH and 2ml of H were added to the reaction solution ₂ O ₂ The solution (30% strength) was reacted at room temperature for 1 hour, water was added, the mixture was separated, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed, and purified by column chromatography (PE: etoac=1:1, V/V) to give the objective product I.

The Estrone derivative product was tested as follows.

(I) (II) was a white solid, and the overall yield of the mixture was 22%.

¹ H NMR(400MHz,Chloroform-d)δ7.20(d,J＝8.6Hz,1H),6.76(d,J＝8.6Hz,1H),3.83(s,3H),3.60-3.57(m,2H),2.94-2.91(m,1H),2.72-2.78(m,3H),2.42-2.39(m,1H),2.33-2.27(m,3H),2.16-2.12(m,2H),2.05-2.01(m,1H),1.93-1.89(m,1H),1.78-1.75(m,2H),1.69-1.63(m,1H),1.49-1.45(m,4H),1.28-1.25(m,3H),0.94(s,3H).

Claims

1. A natural product Estrone derivative, characterized by the following structure:

2. a method of synthesizing the natural product Estrone derivative of claim 1, comprising the steps of:

step 2: placing the intermediate 2, potassium carbonate and allyl bromide obtained in the step 1 into acetone, and obtaining an intermediate 3 through extraction, drying, column chromatography separation and purification after the reaction is finished;

step 3: placing the intermediate 3 obtained in the step 2 into N, N-diethyl aniline, carrying out [3,3] rearrangement reaction, extracting, drying, and separating and purifying by column chromatography to obtain intermediates 4a and 4b;

step 4: adding the intermediate 4a, the intermediate 4b, the potassium carbonate and the methyl iodide obtained in the step 3 into acetone, and obtaining an intermediate 5 through extraction, drying, column chromatography separation and purification after the reaction is finished;

step 5: hydroboration oxidation: adding the intermediate 5 obtained in the step 4 into borane-tetrahydrofuran solution at 0 ℃ for reaction for 1H, and then adding NaOH solution and H ₂ O ₂ The solution reacts at room temperature, and the target product (I) is obtained through extraction, drying, column chromatography separation and purification;

the reaction scheme is as follows:

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3. the synthesis method according to claim 1, wherein:

in the step 1, the mass ratio of the estrone, the hydrazine hydrate and the potassium hydroxide is 5g:3g:3.2g.

4. The synthesis method according to claim 1, wherein:

5. The synthesis method according to claim 1, wherein:

in the step 2, the mass ratio of the intermediate 2, the allyl bromide and the potassium carbonate is 3.3g:3.6g:5.4g; the reaction temperature was 60℃and the reaction time was 12 hours.

6. The synthesis method according to claim 1, wherein:

in step 3, the mass-to-volume ratio of intermediate 3 to N, N-diethylaniline was 0.888g:10mL; the reaction temperature was 250℃and the reaction time was 8 hours.

7. The synthesis method according to claim 1, wherein:

in the step 4, the mass ratio of the intermediate 4 to methyl iodide to potassium carbonate is 5g:5g:7g; the reaction temperature was 60℃and the reaction time was 12 hours.

8. The synthesis method according to claim 1, wherein:

in step 5, the mass ratio of intermediate 5 to borane was 0.31g:2g; the volume ratio of the sodium hydroxide solution to the hydrogen peroxide solution is 1:1, a step of; in the early stage of ice-water bath, the reaction time is 1h, the later stage of reaction temperature is raised to room temperature, and the reaction time is 1h.