CN115109111B

CN115109111B - Production process of progestogen

Info

Publication number: CN115109111B
Application number: CN202210906447.XA
Authority: CN
Inventors: 崔志刚; 张永赞; 朱士江; 王建; 刘海余; 韩怡; 陈明霞; 刘紫薇; 罗潇; 张磊; 余贵菊; 杨雪; 赵健; 杨孝君; 潘学情
Original assignee: Tianjin Zhongsheng Challenge Biotechnology Co ltd
Current assignee: Tianjin Zhongsheng Challenge Biotechnology Co ltd
Priority date: 2022-07-29
Filing date: 2022-07-29
Publication date: 2023-10-24
Anticipated expiration: 2042-07-29
Also published as: CN115109111A

Abstract

The application provides a production process of progestogen, which takes 3-ketal as a reaction starting point to prepare the allyl progestogen, and the production process adopts one-pot reaction. The production process provided by the application saves the cost and time of raw materials: the process intermediate is not treated and purified, so that the operation time is greatly reduced, and the crystallization process is changed into a method for dissolving and crystallizing, so that impurities can be removed, and the yield time of a finished product can be shortened; the process can be completed in 1-2 days from production to finished product production; the intermediate is not purified due to one-pot reaction, so the overall yield is higher; deprotection with trifluoroacetic acid does not result in isomer impurities of the acidolysis product by addition of catalyst a.

Description

Production process of progestogen

Technical Field

The application relates to the field of compound production, in particular to a production process of progestogen.

Background

Allyl progestogen (Altrenogest), also known as tetraene estrone, is a progestogen. Structurally related to the veterinary drug, the steroid trenbolone, is a synthetic trienic C21 steroid progestogen belonging to the class of 19-nor testosterone. It is an orally active progestogen. Like all steroids, allyl progestogen acts by penetrating its own lipid solubility into target cells and then binding to specific receptors, and acts like the mode of action of natural progesterone ll to inhibit gonadotrophin release, as a drug for livestock estrus in the same period.

CN106810584a discloses a preparation process of allyl progestin, the preparation process of the application is: 3-ketal is used as a raw material, 2-methyltetrahydrofuran is used as a solvent for Grignard reaction, and ethyl acetate and normal hexane are used for crystallizing a crude product; and in the second step, dichloroacetic acid is used as a solvent for deprotection reaction, dichloromethane is used for extraction in post-treatment, DDQ reaction is directly added into the extract, diatomite is used for filtering the reaction solution, and ethyl acetate is crystallized to obtain a pure product. The process has the advantages that: the process has the defects that the ethyl acetate and the n-hexane are recrystallized to waste the solvent, the operation time is longer and more troublesome, the cost of the dichloroacetic acid used in the second step is higher, and the dichloroacetic acid used can generate a larger impurity (namely, 17 alpha-allyl-17 beta-hydroxy-4 (5), 9 (10) -estradien-3-one), the impurity can lead to lower yield of the final product, single impurity is larger, and the process is not suitable for mass production;

201811083005X discloses a preparation process of allyl progestogen, which comprises the following steps: 4, 9-diene-3, 17-diketone is used as a raw material, under the action of diisopropyl An Anji lithium and trimethylchlorosilane, a trimethylchlorosilane-protected intermediate is generated, and the intermediate and an allylmagnesium bromide tetrahydrofuran solution undergo Grignard reaction; step three, deprotection reaction is carried out under the condition of tetrachloro-p-benzoquinone to obtain crude products; finally, recrystallizing with ethyl acetate to obtain a finished product; the process has the advantages that: the first reaction is carried out at 40-50 ℃ below zero, the conditions are harsh, the amplified production is difficult to realize, and the second reaction is carried out by using tetrahydrofuran for Grignard reaction and is difficult to realize;

disclosure of Invention

The application provides a production process of progestogen, which takes 3-ketal as a reaction starting point to prepare the allyl progestogen, and adopts one-pot reaction. The one-pot reaction means that the same solvent is used in each step of reaction contained in the preparation process, and the process intermediate does not need to be subjected to crystallization, purification and other steps.

Preferably, the solvent of each step of the one-pot reaction is 2-methyltetrahydrofuran.

Preferably, any one of the above-mentioned processes comprises the steps of:

step 1: dissolving 3-ketal in anhydrous 2-methyltetrahydrofuran, heating, stirring and dissolving, cooling to room temperature, then reacting, slowly adding the solution into the prepared 2-methyltetrahydrofuran Grignard reagent solution, and stirring at room temperature until the raw materials react completely after the addition is completed; pouring the reaction solution into an ammonium chloride solution, stirring and separating the solution;

the concentration of the 2-methyltetrahydrofuran Grignard reagent solution is preferably 0.5-5mol/L. The grignard reagent of the application is a grignard reagent conventionally used in the prior art, can be obtained by a commercial purchase way, and can also be prepared by itself, wherein the preparation method is a conventional method in the prior art, and the method for preparing the grignard reagent in the prior art is suitable for the application (such as CN 106810584A).

Further, the present application preferably provides a grignard reagent prepared by the following method:

preparation of grignard reagent solution: 70ml of 2-methyltetrahydrofuran is weighed and put into a 250ml reaction bottle, and stirred; 60g of magnesium flakes and 0.5g of iodine are added and stirred; 36.0g of bromopropene and 23ml of 2-methyltetrahydrophthalic acid were weighed and mixed; placing about 5% of 2-methyltetrahydrofuran solution of bromopropene into a funnel, slowly adding the solution into the funnel, observing, and dropwise adding the rest bromopropene solution at the temperature of 30-50 ℃ after initiating reaction; after the addition, the mixture was stirred at the maintained temperature for 1 hour, and the mixture was filtered to obtain a Grignard solution.

Step 2: slowly adding an organic acid and a catalyst A into the organic phase obtained in the step 1, and stirring at a constant temperature until the raw materials are completely reacted; adjusting the PH value to be between 6 and 8 by using a sodium carbonate solution, separating liquid, separating to obtain an organic layer, drying and filtering the organic layer by using anhydrous sodium sulfate to obtain filtrate;

step 3: adding DDQ into the filtrate obtained in the step 2, and stirring until the raw materials react completely after adding; adding sodium carbonate solution, stirring, standing for layering, adding water into the organic layer respectively for twice, stirring, standing for separating liquid, adding anhydrous sodium sulfate into the organic layer for drying and filtering, and concentrating the filtrate until the filtrate is dried to obtain a crude product; adding acetone into the crude product, stirring for dissolving, slowly pouring into water, precipitating solid, and filtering to obtain allyl progestogen;

step 4: and (3) adding acetone into the crude product obtained in the step (3) for dissolution, adding water for separating out solids, and filtering and drying to obtain the finished product of the allyl progestogen.

In any of the above, it is preferable that in step 1, the ratio of 3-ketal to anhydrous 2-methyltetrahydrofuran is such that 20g of 3-ketal is dissolved in 50 to 500mL of anhydrous 2-methyltetrahydrofuran, and preferably 20g of 3-ketal is dissolved in 50mL, 100mL, 150mL, 200mL, 250mL, 300mL, 350mL, 400mL, 450mL or 500mL of anhydrous 2-methyltetrahydrofuran.

In step 1, the temperature is preferably not higher than 50 ℃ during the heating and stirring dissolution, the preferred dissolution temperature is controlled to be 40-50 ℃, and the preferred dissolution temperature is controlled to be 40, 45 and 50 ℃.

In step 1, the reaction is preferably carried out under room temperature conditions by heating, stirring, dissolving, and then reducing the temperature to room temperature to start the reaction.

Preferably, in step 1, the ammonium chloride solution is 10-50% ammonium chloride solution, and the concentration of the ammonium chloride solution is preferably 10%, 20%, 30%, 40%, 50%.

Preferably, any one of the above-mentioned organic acids is at least one of trifluoroacetic acid, lactic acid or malic acid, and the catalyst a is sulfamic acid. The mass ratio of the organic acid to the sulfamic acid is as follows: 40:0.5-5.

In step 2, the reaction temperature of the organic acid and sulfamic acid is preferably 40-50 ℃, preferably 40, 45, 50 ℃.

Preferably, any one of the above organic acids is trifluoroacetic acid, the addition mass ratio of the trifluoroacetic acid to the sulfamic acid is 40:0.5-5, 20ml of the trifluoroacetic acid, and 0.5g of 2% sulfamic acid. Sulfamic acid is a solid strong acid, which catalyzes the reaction and increases the strength of the acid.

In step 3, preferably, 15 to 18g of DDQ is slowly added to the filtrate, preferably 15, 16, 17, 18g of DDQ is added.

In a preferred embodiment of the application, the production process is:

dissolving 20g of 3-ketal in 100ml of anhydrous 2-methyltetrahydrofuran, stirring and dissolving at 40-50 ℃, cooling to room temperature, then starting the reaction, slowly adding the solution into the prepared 2-methyltetrahydrofuran grignard reagent solution, stirring for 2 hours at room temperature after the addition is finished, and monitoring the reaction of the raw materials by TLC (thin layer chromatography). Pouring the reaction solution into 30% ammonium chloride solution, stirring for 0.5 hours, and separating the solution;

then 20ml of trifluoroacetic acid, 0.5g of 2% catalyst A, was slowly added to the organic phase, stirred at 40-50℃for 4 hours, and TLC monitored until the starting material was completely reacted. The ph=7 was adjusted with sodium carbonate solution, the aqueous layer was separated and discarded, and the obtained organic layer was dried over 50g of anhydrous sodium sulfate for 15 minutes and filtered.

To the filtrate was slowly added 16g of DDQ, and after the addition, stirring was performed at room temperature for 1 hour, and TLC detected complete reaction of the starting materials. Adding 100ml of 10% sodium carbonate solution, stirring for 10 min, standing for layering, adding 100ml of water into an organic layer respectively for washing twice, stirring for 10 min, standing for separating liquid, adding 20g of anhydrous sodium sulfate into the organic layer for drying for 15 min, filtering, and concentrating the filtrate to dryness to obtain a crude product; 100ml of acetone is added into the crude product, the mixture is stirred and dissolved, the mixture is slowly poured into 200ml of water, a large amount of solid is separated out, and the mixture is filtered to obtain 16.5g of light yellow allylpregna crude product with molar yield (calculated by 3-ketal): 83.6%.

The crude product is added with 40ml of acetone for dissolution, then 20ml of water is added to precipitate solid, light yellow solid is filtered and dried to obtain 13g of finished product, and the molar yield (calculated as 3-ketal): 78.7%.

The production process provided by the application adopts 2-methyltetrahydrofuran as a solvent, and the optimized intermediate is directly obtained into a crude product by a one-pot method without analysis and purification, and then the crude product is crystallized by acetone and water to obtain a finished product. The single impurity is small, the yield is high, the cost is saved, and the method is suitable for large-scale production of the process.

2-methyltetrahydrofuran is a relatively good reagent developed in recent years, can be used as a green solvent to replace tetrahydrofuran and diethyl ether to be used as a Grignard reaction solvent, is widely used for synthesizing spices, new materials and the like, and is also used as a main raw material for synthesizing medicines chloroquine phosphate and primaquine phosphate; but for reasons of high price, less reagents are used;

based on the property of 2-methyltetrahydrofuran, according to the characteristic of the experiment, in the Grignard reaction, the reagent tetrahydrofuran used as the Grignard reaction does not cause the Grignard reaction, but the danger of using diethyl ether is high, so that the Grignard reaction is carried out by adopting 2-methyltetrahydrofuran, the effect is good, and meanwhile, whether the reagent can also carry out hydrolysis reaction and oxidation reaction or not is studied; in the process provided by the application, the 2-methyltetrahydrofuran is only a solvent and does not participate in the reaction.

When 2-methyltetrahydrofuran is used for deprotection reaction, hydrochloric acid, sulfuric acid or acetic acid and the like are used for hydrolysis reaction in the conventional reaction, but the conventional reaction has the defects of unsatisfactory effect, incomplete reaction, larger impurity, and possible reasons for preliminary analysis are that the hydrochloric acid, the sulfuric acid is inorganic acid, all hydrogen ions are ionized, the reaction is more severe, the impurity is higher, and the reaction is incomplete if the dosage is insufficient; acetic acid is probably the reason of weak acid, the reaction can not be completed all the time, and impurities can be gradually increased along with the extension of time; based on the consideration, an organic strong acid trifluoroacetic acid is selected, but the expected effect is not achieved by simply using the trifluoroacetic acid from the aspect of the reaction effect, and a catalyst A is added on the basis, so that the whole reaction is smoother, less impurities are generated and the time is short after the optimization;

in the DDQ oxidation reaction process, common solvents are dichloromethane, chloroform and the like, according to the property of the 2-methyltetrahydrofuran, the 2-methyltetrahydrofuran is adopted as the solvent, the room-temperature reaction effect is good, and the reaction can be completed within one hour after the addition;

after the process is optimized, 2-methyltetrahydrofuran can be used as a solvent in each step of reaction, so that the cost and time are saved. The application optimizes the one-pot reaction, and the optimized process can directly carry out the next reaction without intermediate step purification to obtain the final product; not only the yield is greatly improved, but also the time is greatly saved, and the method is a process which can be fully used for mass production.

The technical scheme of the application has the beneficial effects that:

1. the cost of raw materials is saved: the 2-methyltetrahydrofuran can be recycled;

2. time is saved: the process intermediate is not treated and purified, so that the operation time is greatly reduced, and the crystallization process is changed into a method for dissolving and crystallizing, so that impurities can be removed, and the yield time of a finished product can be shortened; the process can be completed in 1-2 days from production to finished product production; (other processes typically require 5-7 days for drying operations due to extraction, concentration, and presence);

3. the yield is improved; the intermediate is not purified due to one-pot reaction, so the overall yield is higher;

4. reduction operation: because of one-pot reaction, many post-treatment operations are omitted;

5. less impurity, deprotection with trifluoroacetic acid, and addition of catalyst A does not produce isomer impurity of acidolysis product (i.e. 17α -allyl-17β -hydroxy-4 (5), 9 (10) -estradien-3-one)

Abbreviations involved in the present application:

3-ketal: cyclo-3- (1, 2-ethyleneacetal) -estra-5 (10), 9 (11) -diene-3, 17-dione

DDQ:2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone

Detailed Description

The present application will be more clearly and fully described by the following examples, which are intended to be illustrative of only some, but not all, of the examples. The examples are presented to aid in understanding the application and should not be construed to limit the scope of the application in any way.

Example 1

Dissolving 20g of 3-ketal in 100ml of anhydrous 2-methyltetrahydrofuran, stirring and dissolving at 40-50 ℃, cooling to room temperature, slowly adding into the prepared 2-methyltetrahydrofuran grignard reagent solution, stirring at room temperature for 2 hours after adding, and monitoring the reaction of the raw materials by TLC until the reaction is complete. Pouring the reaction solution into 30% ammonium chloride solution, stirring for 0.5 hours, and separating the solution;

then 20ml of trifluoroacetic acid, 0.5g of 2% catalyst A, was slowly added to the organic phase, stirred at 40-50℃for 4 hours, and TLC monitored until the starting material was completely reacted. The ph=7 was adjusted with sodium carbonate solution, the aqueous layer was separated, and the organic layer was dried over 50g of anhydrous sodium sulfate for 15 minutes and filtered. The catalyst A is sulfamic acid. Experiments prove that the sulfamic acid is not added, and the impurity is increased by 3 to 10 percent. The addition of sulfamic acid effectively inhibits the isomer impurity (i.e., 17α -allyl-17β -hydroxy-4 (5), 9 (10) -estradien-3-one) that produces acidolysis products during the reaction.

To the filtrate was slowly added 16g of DDQ, and after addition, stirring was performed for 1 hour, and TLC detected complete reaction of the starting material. Adding 100ml of 10% sodium carbonate solution, stirring for 10 min, standing for layering, adding 100ml of water into an organic layer respectively for washing twice, stirring for 10 min, standing for separating liquid, adding 20g of anhydrous sodium sulfate into the organic layer for drying for 15 min, filtering, and concentrating the filtrate to dryness to obtain a crude product; 100ml of acetone is added into the crude product, the mixture is stirred and dissolved, the mixture is slowly poured into 200ml of water, a large amount of solid is separated out, and the mixture is filtered to obtain 16.5g of light yellow allylpregna crude product with molar yield (calculated by 3-ketal): 83.6%.

Example 1 comparative effect with CN106810584A (in molar yield)

Manufacturer' s	Grignard step	Crude product	Refining	Total yield of	Time period
						The scheme is provided	-------	83.6％	78.7％	65.9％	For 1-2 days
CN106810584A	73.5％	57％	70％	29.3％	For 5-7 days

Example 2

Example 2 is similar to example 1 except that trifluoroacetic acid is replaced with lactic acid, the amount of lactic acid added in the reaction process is 25g, and the molar yield (calculated as 3-ketal) is: 55.1%. The addition of sulfamic acid effectively inhibits the isomer impurity (i.e., 17α -allyl-17β -hydroxy-4 (5), 9 (10) -estradien-3-one) that produces acidolysis products during the reaction.

Example 3

Example 3 is similar to example 1 except that trifluoroacetic acid is replaced with malic acid, the amount of malic acid added in the reaction process is 25g, and the molar yield (calculated as 3-ketal) is: 53.0%. The addition of sulfamic acid effectively inhibits the isomer impurity (i.e., 17α -allyl-17β -hydroxy-4 (5), 9 (10) -estradien-3-one) that produces acidolysis products during the reaction.

Claims

1. The production process of progestogen, which takes 3-ketal as a reaction starting point to prepare the allyl progestogen, is characterized in that the production process adopts one-pot reaction and comprises the following steps:

step 1: dissolving 3-ketal in anhydrous 2-methyltetrahydrofuran, heating, stirring and dissolving, cooling to room temperature, starting to react, slowly adding the 3-ketal into the prepared 2-methyltetrahydrofuran Grignard reagent solution, and stirring at room temperature until the raw materials react completely after the addition; pouring the reaction solution into an ammonium chloride solution, stirring and separating the solution;

step 2: slowly adding an organic acid and a catalyst A into the organic phase obtained in the step 1, and stirring at a constant temperature until the raw materials are completely reacted; adjusting the pH value to be between 6 and 8 by using a sodium carbonate solution, separating the solution, separating an organic layer, drying and filtering the organic layer by using anhydrous sodium sulfate to obtain a filtrate, wherein the catalyst A is sulfamic acid, and the organic acid is at least one of trifluoroacetic acid, lactic acid or malic acid;

2. The process according to claim 1, wherein in step 1, the 3-ketal is added to anhydrous 2-methyltetrahydrofuran in a ratio of 20g of 3-ketal to 50-500ml of anhydrous 2-methyltetrahydrofuran.

3. The process according to claim 1, wherein in step 1, the ammonium chloride solution is a 10-50% ammonium chloride solution.

4. A production process according to claim 3, wherein in step 2, the reaction temperature of the organic acid and sulfamic acid is 40-50 ℃.

5. The process according to claim 3, wherein in step 2, the organic acid is trifluoroacetic acid, and the ratio of trifluoroacetic acid to sulfamic acid is 20ml of trifluoroacetic acid and 0.5g of 2% sulfamic acid.

6. The process according to claim 1, wherein in step 3, 15-18g of DDQ is slowly added to the filtrate.