阅读说明：本技术 利用LED光源制备9β,10α-去氢***二乙二缩酮的方法 (Method for preparing 9 β,10 α -dehydroprogesterone diethyl ketal by using LED light source ) 是由 潘成学 苏桂发 于成龙 李永怡 杨倩 方淑君 于 2019-11-04 设计创作，主要内容包括：本发明公开了一种利用LED光源制备9β,10α-去氢黄体酮二乙二缩酮的方法,以9α,10β-去氢黄体酮二乙二缩酮为原料,利用具有单一波长的LED光源来进行光化学反应,制备得到地屈孕酮关键中间体9β,10α-去氢黄体酮二乙二缩酮,解决了以汞灯为光源导致光化学反应产物较复杂、工艺不易放大等缺陷,提供一种总产率高、绿色环保、操作简便、容易放大的制备方法。(The invention discloses a method for preparing 9 β,10 α -dehydroprogesterone diethyldiketal by using an LED light source, which takes 9 α,10 β -dehydroprogesterone diethyldiketal as a raw material and utilizes the LED light source with single wavelength to carry out photochemical reaction to prepare the dydrogesterone key intermediate 9 β,10 α -dehydroprogesterone diethyldiketal, overcomes the defects of more complex photochemical reaction product, difficult process amplification and the like caused by using a mercury lamp as the light source, and provides a preparation method with high total yield, environmental protection, simple and convenient operation and easy amplification.)

1. A method for preparing 9 β,10 α -dehydroprogesterone diethylketal by using an LED light source is characterized by comprising the following steps:

s1, performing photochemical ring-opening reaction, namely dissolving 9 α,10 β -dehydroprogesterone diethyl ketal serving as a raw material in a reaction solvent to obtain a raw material solution, adjusting the raw material solution to a reaction temperature in advance, and irradiating the raw material solution by an LED light source with a single wavelength under the protection of nitrogen/inert gas, wherein the wavelength range is 265-300 nanometers, so as to obtain a solution containing a ring-opening reaction intermediate;

and S2, carrying out photochemical ring-closing reaction, namely, under the protection of nitrogen/inert gas, irradiating the solution containing the ring-opening reaction intermediate by an LED light source with a single wavelength, wherein the wavelength range is 305-365 nanometers, and obtaining the solution containing 9 β,10 α -dehydroprogesterone diethyl diketal after the ring-opening reaction intermediate is converted.

2. The method of claim 1, wherein the method comprises using an LED light source to produce 9 β,10 α -dehydroprogesterone diacetin:

and S3, S3, distilling the solution containing 9 β,10 α -dehydroprogesterone diethyldiketal under reduced pressure to recover the solvent, mixing with the purified solvent, cooling, separating out solid, separating solid from liquid, and recovering the solvent from the liquid to obtain 9 β,10 α -dehydroprogesterone diethyldiketal.

3. The method of claim 1, wherein the method comprises using an LED light source to produce 9 β,10 α -dehydroprogesterone diacetin:

the steps S1 and S2 specifically include:

s1, performing photochemical ring-opening reaction, namely dissolving 9 α,10 β -dehydroprogesterone diethyldiketal serving as a raw material in a reaction solvent to obtain a raw material solution, adjusting the temperature of the raw material solution to-35 ℃, protecting the raw material solution by nitrogen/inert gas, flowing the raw material solution through a first photochemical reactor, starting an LED light source with a single wavelength by using the first photochemical reactor, wherein the wavelength range is 265-300 nanometers, and obtaining a solution after the ring-opening reaction;

and S2, performing photochemical ring-closing reaction, namely, under the protection of nitrogen/inert gas, enabling the solution after the ring-opening reaction to flow through a second photochemical reactor, starting an LED light source with single wavelength in the range of 305-365 nanometers by the second photochemical reactor, and obtaining the solution containing 9 β and 10 α -dehydroprogesterone diethyl ketal after the ring-opening reaction intermediate is converted.

4. The method of preparing 9 β,10 α -dehydroprogesterone diacetin using LED light source as claimed in claim 1 or 3 wherein:

in the steps S1 and S2, the reaction temperature is-35 to 35 ℃.

5. The method of claim 4, wherein the method comprises using an LED light source to produce 9 β,10 α -dehydroprogesterone diethylketal:

in steps S1 and S2, the reaction temperature is controlled to not fluctuate more than 5 ℃ throughout the reaction.

6. The method of claim 2, wherein the method comprises using an LED light source to produce 9 β,10 α -dehydroprogesterone diacetin:

the solvent comprises: a mixed solvent of ethanol and acetonitrile, a mixed solvent of methanol and tetrahydrofuran, a mixed solvent of acetone and tetrahydrofuran, a mixed solvent of acetonitrile and tetrahydrofuran, and methanol or isopropanol.

7. The method of claim 6, wherein the method comprises using an LED light source to produce 9 β,10 α -dehydroprogesterone diethylketal:

when the solvent is a mixed solvent of ethanol and acetonitrile, the volume ratio of the ethanol to the acetonitrile is 3: 1;

when the solvent is a mixed solvent of methanol and acetonitrile, the volume ratio of the methanol to the acetonitrile is 4: 1;

when the solvent is a mixed solvent of methanol and tetrahydrofuran, the volume ratio of the methanol to the tetrahydrofuran is 4: 1;

when the solvent is a mixed solvent of acetone and tetrahydrofuran, the volume ratio of the acetone to the tetrahydrofuran is 3: 1;

when the solvent is a mixed solvent of acetonitrile and tetrahydrofuran, the volume ratio of the acetonitrile to the tetrahydrofuran is 4: 1.

8. The method of claim 2, wherein the method comprises using an LED light source to produce 9 β,10 α -dehydroprogesterone diacetin:

in step S3, the mixing with the purification solvent is performed by heating and refluxing for 5-10 min.

9. The method of claim 2, wherein the method comprises using an LED light source to produce 9 β,10 α -dehydroprogesterone diacetin:

in step S3, the cooling temperature is-5 to 5 ℃.

10. The method of claim 1, wherein the method comprises using an LED light source to produce 9 β,10 α -dehydroprogesterone diacetin:

in step S1, the reaction solvent is methanol, ethanol, isopropanol, glyme, tetrahydrofuran, methyltetrahydrofuran, or cyclohexane.

Technical Field

The invention relates to the technical field of photochemical synthesis, in particular to a method for preparing 9 β,10 α -dehydroprogesterone diethylketal by using an LED light source.

Background

Dydrogesterone (Dydrogesterone) is widely used for fetus protection, abortion prevention and treatment of various diseases caused by endogenous progesterone deficiency, is sold in the world in 1961 in more than 150 countries, but only Abbott (Abbott) in the United states can produce 9 β,10 α -dehydroprogesterone diethyl diketal 1 and 9 β,10 α -pregna-4, 6-diene-3, 20-dione diethyl diketal at present in the world for technical reasons, is a key intermediate for synthesizing Dydrogesterone, and the structural formula of the Dydrogesterone is shown as follows.

At present, no mature technology for industrially preparing 9 β,10 α -dehydroprogesterone diethylketal exists in China, so that the dydrogesterone cannot be successfully simulated.

The currently disclosed method for synthesizing 9 β,10 α -dehydroprogesterone diethyldiketal is basically obtained by using a mercury lamp as a light source and reacting 9 α,10 β -dehydroprogesterone diethyldiketal 2 as a raw material in a kettle type, bubble type or micro-flow type reactor, wherein the structural formula of the 9 α,10 β -dehydroprogesterone diethyldiketal 2 is shown as follows:

as the light source components of the mercury lamp are complex, the reaction product is complex, and the process is not easy to be amplified, so that the industrial preparation is not easy to realize.

For example, European patent No. EP0558119, Chinese patents No. ZL201410085871.8 and No. ZL 201010621400.6, and India patent No. IN 201811020593 all disclose methods for preparing 9 β and 10 α -dehydroprogesterone diethyldiketal from 9 α and 10 β -dehydroprogesterone diethyldiketal by using a reactor using medium and high pressure mercury lamps as light sources, and the reaction formulas are as follows.

These methods have the disadvantages of complicated reaction product, difficult process amplification, etc.

Because the global market of the dydrogesterone is large, the annual domestic sales amount exceeds 8 hundred million RMB, only the Yapek company in the United states produces and sells the dydrogesterone, and the technology is kept secret all the time, develops a novel preparation process of the key intermediate 1, which is easy to amplify, and has very important economic and social values.

Disclosure of Invention

The invention aims to provide a method for preparing 9 β,10 α -dehydroprogesterone diethylketal by using an LED light source with single wavelength to perform photochemical reaction aiming at the defects of more complex photochemical reaction products, difficult process amplification and the like caused by using a mercury lamp as a light source in the photochemical reaction for preparing the dydrogesterone key intermediate by using 9 α,10 β -dehydroprogesterone diethylketal as a raw material through the photochemical reaction, and the method has the advantages of high total yield, environmental friendliness, simplicity and convenience in operation and easiness in amplification.

In order to achieve the purpose, the technical scheme of the invention is as follows:

a method for preparing 9 β,10 α -dehydroprogesterone diethylketal by using an LED light source, comprising the following steps:

s1, performing photochemical ring-opening reaction, namely dissolving 9 α,10 β -dehydroprogesterone diethyl ketal serving as a raw material in a reaction solvent to obtain a raw material solution, adjusting the raw material solution to a reaction temperature in advance, and irradiating the raw material solution by an LED light source with a single wavelength under the protection of nitrogen/inert gas, wherein the wavelength range is 265-300 nanometers, so as to obtain a solution containing a ring-opening reaction intermediate;

and S2, carrying out photochemical ring-closing reaction, namely, under the protection of nitrogen/inert gas, irradiating the solution containing the ring-opening reaction intermediate by an LED light source with a single wavelength, wherein the wavelength range is 305-365 nanometers, and obtaining the solution containing 9 β,10 α -dehydroprogesterone diethyl diketal after the ring-opening reaction intermediate is converted.

And further comprising the step S3 of S3, distilling the solution containing 9 β,10 α -dehydroprogesterone diethyldiketal under reduced pressure to recover the solvent, mixing with the purified solvent, cooling, separating out solids, separating the solids from the liquid, and taking the liquid to recover the solvent to obtain the 9 β,10 α -dehydroprogesterone diethyldiketal.

Preferably, the steps S1 and S2 specifically include:

s1, performing photochemical ring-opening reaction, namely dissolving 9 α,10 β -dehydroprogesterone diethyldiketal serving as a raw material in a reaction solvent to obtain a raw material solution, adjusting the temperature of the raw material solution to-35 ℃, protecting the raw material solution by nitrogen/inert gas, flowing the raw material solution through a first photochemical reactor, starting an LED light source with a single wavelength by using the first photochemical reactor, wherein the wavelength range is 265-300 nanometers, and obtaining a solution after the ring-opening reaction;

and S2, performing photochemical ring-closing reaction, namely, under the protection of nitrogen/inert gas, enabling the solution after the ring-opening reaction to flow through a second photochemical reactor, starting an LED light source with single wavelength in the range of 305-365 nanometers by the second photochemical reactor, and obtaining the solution containing 9 β and 10 α -dehydroprogesterone diethyl ketal after the ring-opening reaction intermediate is converted.

Preferably, in the steps S1 and S2, the reaction temperature is-35 to 35 ℃. More preferably, the reaction temperature is controlled to not fluctuate by more than 5 ℃ in steps S1 and S2.

Preferably, the solvent comprises: mixed solvent of ethanol and acetonitrile, mixed solvent of methanol and tetrahydrofuran, mixed solvent of acetone and tetrahydrofuran, mixed solvent of acetonitrile and tetrahydrofuran, and pure methanol or isopropanol.

Preferably, when the solvent is a mixed solvent of ethanol and acetonitrile, the volume ratio of the ethanol to the acetonitrile is 3: 1;

when the solvent is a mixed solvent of methanol and acetonitrile, the volume ratio of the methanol to the acetonitrile is 4: 1;

when the solvent is a mixed solvent of methanol and tetrahydrofuran, the volume ratio of the methanol to the tetrahydrofuran is 4: 1;

when the solvent is a mixed solvent of acetone and tetrahydrofuran, the volume ratio of the acetone to the tetrahydrofuran is 3: 1;

when the solvent is a mixed solvent of acetonitrile and tetrahydrofuran, the volume ratio of the acetonitrile to the tetrahydrofuran is 4: 1.

Preferably, in step S3, the solvent is mixed by heating and refluxing for 5-10 min.

Preferably, in step S3, the cooling temperature is-5 to 5 ℃.

Preferably, in step S1, the reaction solvent is methanol, ethanol, isopropanol, glyme, tetrahydrofuran, methyltetrahydrofuran, or cyclohexane.

Nuclear magnetic resonance structural characterization data of starting material 9 α,10 β -dehydroprogesterone diethyldiketal and product 9 β,10 α -dehydroprogesterone diethyldiketal 1:

9 α,10 β -dehydroprogesterone diethyldiketal:¹H NMR (400 MHz, CDCl₃) 5.55~5.57(m, 1H),5.37~5.39(m, 1H), 3.86~4.00(m, 8H), 2.58(dd, J= 15.0, 1.5Hz, 1H), 2.27(dd, J=15.0, 2.8Hz, 1H), 2.05~ 2.17(m, 2H), 1.71~1.89(m, 9H), 1.59~1.62(m, 2H), 1.42~1.48(m, 1H), 1.30(s, 3H), 1.25(dd, J= 12.8, 4.4 Hz, 1H), 0.96(s, 3H), 0.72(s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 140.72, 139.19, 120.15, 116.76, 112.10,108.90, 65.15, 64.58, 64.45, 63.47, 57.88, 54.52, 46.10, 42.46, 40.35, 38.98,37.55, 37.03, 31.48, 24.64, 23.18, 22.75, 21.10, 16.30, 13.09.

9 β,10 α -dehydroprogesterone diethyldiketal 1:¹H NMR (400 MHz, CDCl3) 5.61(dd, J=5.2,2.4Hz, 1H), 5.43~5.44(m, 1H), 3.84~4.01(m, 8H), 2.48~2.56(m, 2H), 2.26~2.29(m, 2H), 2.02~2.10(m, 2H), 1.71~1.84(m, 6H), 1.40~1.60(m, 5H),1.30(s, 3H),0.76(s, 3H), 0.70(s, 3H). 13C NMR (101 MHz, CDCl3) δ 140.55, 140.31, 120.64,115.90, 111.83, 109.31, 65.51, 64.68, 64.44, 63.37, 59.46, 49.83, 45.70,41.35, 40.46, 37.30, 36.76, 36.60, 31.41, 24.54, 23.30, 22.17, 19.72, 19.22,13.63.

by adopting the method for preparing 9 β,10 α -dehydroprogesterone diethyl ketal by using the LED light source, the conversion rate of the ring-opening reaction can exceed 90% in the photochemical ring-opening reaction, about 20-75% of raw materials are converted into target products in the further photochemical ring-closing reaction, the total yield is high, the operation is simple and convenient, the control points are few, the amplified production is easy to carry out, the introduced solvent is few, the energy consumption in the preparation process is low, and the method is green and environment-friendly.

Furthermore, the solution containing 9 β,10 α -dehydroprogesterone diethyldiketal after the reaction is heated, refluxed and separated to obtain a crude product of the target product, the yield of the crude product is 18-72%, the content of impurities is low, and the method has the prospect of industrial production and has very important economic and social values.

Drawings

FIG. 1 shows the preparation of 9 α,10 β -dehydroprogesterone diethyldiketal as a starting material¹H-NMR spectrum.

FIG. 2 shows the preparation of 9 α,10 β -dehydroprogesterone diethyldiketal as a starting material¹³C-NMR spectrum.

FIG. 3 is a drawing of the product 9 β,10 α -dehydroprogesterone diethyldiketal¹H-NMR spectrum.

FIG. 4 is a drawing of the product 9 β,10 α -dehydroprogesterone diethyldiketal¹³C-NMR spectrum.

Detailed Description

The present invention is further illustrated by the following specific examples, but the scope of the present invention is not limited to the following examples.

The reaction apparatus employed in this example includes a feed tank, a first photochemical reactor, a second photochemical reactor, and a receiving tank. The reaction apparatus is provided with a flow meter to control the flow rate during the reaction, and the position of the flow meter can be set properly, and this embodiment is exemplified by being disposed between the feed tank and the first photochemical reactor. The solution flow can be adjusted by utilizing the height difference between the feeding tank and the receiving tank, the inner diameter or the relative angle of the communicating pipeline of the feeding tank and the receiving tank, and can also be adjusted by a flowmeter valve. And the feeding tank, the first photochemical reactor and the second photochemical reactor are matched with a condensing system. The light sources of the first photochemical reactor and the second photochemical reactor are both single-wavelength LED light sources generated by a photoelectric technology.