LU102541B1 - Preparation Method for Progesterone - Google Patents

Abstract

The invention discloses a preparation method for progesterone. The preparation method comprises the following steps: reacting in a solvent by taking (20S)-20- hydroxymethylpregna-4-ene-3-keone as a raw material and an acidic ion liquid catalyst as a catalyst; after the reaction is ended, separating the catalyst to obtain reaction liquid which is sequentially subjected to normal-pressure compression, separation-out of solids by adding water and filtration so as to obtain a progesterone crude product; and re-crystallizing the progesterone crude product to obtain a progesterone fine product. The acidic controllable ion liquid catalyst is adopted for catalytic preparation, and has characteristics of strong designability, small green pollution and the like; moreover, the catalyst and a product are automatically layered after reaction while the acidic controllable ion liquid catalyst is taken as the catalyst, and acidic controllability and regeneration of the catalyst can be realized through simple treatment after the catalyst is recycled.

Description

* LU102541

DESCRIPTION Preparation Method for Progesterone

TECHNICAL FIELD The invention relates to the technical field of progesterone preparation, In particular to a preparation method for progesterone by taking acidic controllable ion liquid as a catalyst.

BACKGROUND Progesterone, also known as progestin, progestone and gestogen, is natural progestogen secreted by ovarian corpus luteum, and is a most important progestogen in pregnane series. As an essential substance for keeping pregnancy, progesterone can promote development and maturation of uterus and mammary gland, and has a structure of pregnane-4-ene-3, 20-keone. Studies have found that progesterone is not only used to the field of procreation health, but also to treat obstetrical and gynecological diseases, chronic ascites, sleep apnea syndrome, chronic respiratory failure, ureteral calculi and the like. As a key intermediate of steroid drugs such as cortical hormone and androgen, progesterone has annular domestic and international market demand of 500 tons or more, which is difficult to meet as a result of raw material price rise and the like, and has multiple production methods while prepared by taking natural plants as raw materials. Preparation for the progesterone by a chemical synthesis method gradually attracts close attention of manufacturers at home and abroad.

At present, there are many reports associated with synthesis of progesterone, and development of a progesterone preparation process is restrained by problems such as a complex process, great difficulty, severe pollution, poor safety and high cost. Therefore, development of a clean production process for progesterone is of great significance in improving progesterone production, improving a production environment, relieving burden of a patient and meeting domestic and foreign demands.

SUMMARY The invention provides a preparation method for progesterone, which is prepared by an acidic controllable ion liquid catalyst with characteristics of strong designability, small green pollution and the like; moreover, the catalyst and a product are automatically layered after reaction while the acidic controllable ion liquid catalyst is taken as the catalyst, and acidic controllability and regeneration of the catalyst can be realized through simple treatment after the catalyst is recycled for many times, and thus, the preparation method has a very good application prospect.

A preparation method for progesterone comprises the following steps: reacting in a solvent by taking (20S)-20-hydroxymethylpregna-4-ene-3-keone as a raw material and an acidic ion liquid catalyst as a catalyst; after the reaction is ended, separating the catalyst to obtain reaction liquid which is sequentially subjected to normal-pressure compression, separation-out of solids by adding water and filtration so as to obtain a progesterone crude product; and re-crystallizing the progesterone crude product to obtain a progesterone fine product.

A synthesis route diagram is as shown in formula (i):

HC SL LC CH, LH, CH Oxidative CH décarbonyl” ‘ ation 0 0 (205)-20-hydroxymethylpr Progesterone egna-4-ene-3-keone (1) Several optional methods are provided below, but they are not intended as additional limitations on the above-mentioned overall plan, are only further supplements or optimizations. On the premise of no technical or logical contradictions, each optional mode can be carried out separately for the above-mentioned overall plan, can also be a combination of multiple optional ways. Optionally, dosage of the catalyst is 4%-8% of the mass of (20S)-20-hydroxymethylpregna-4-ene-3-keone. Further, dosage of the catalyst is 6%-8% of the mass of (20S)-20-hydroxymethylpregna-4-ene-3-keone. Optionally, the reaction temperature is 30-50 C. Optionally, the reaction time lasts for 4-8 hours. Optionally, the solvent is one of methanol, n-butyl alcohol and DMF.

Optionally, the separated catalyst is washed by ethyl acetate, dried in vacuum and directly used for next-time reaction after reaction is ended.

Optionally, the acidic ion liquid based catalyst is prepared by the following method: filtering, washing and drying in vacuum after reaction is ended to obtain an ion liquid intermediate by taking 1,3- propane sultone and organic amine as raw materials; drying, washing and drying in vacuum after reaction is ended to obtain sulfonated organic amine hydrogen sulphate or sulfonated organic amine hydrochloride by taking the ionic liquid intermediate and acid as raw materials, where the acid is concentrated sulfuric acid or concentrated hydrochloric acid; and drying, and drying in vacuum after reaction is ended to obtain a sulfonated organic amine metal salt, namely an acidic ion liquid based catalyst by taking sulfonated organic amine hydrogen sulphate and metal oxides as raw materials or sulfonated organic amine hydrochloride and metal chlorides as raw materials.

Optionally, the organic amine is hexamethylene tetramine, N, N-carboxyl diimidazole, pyridine, triethylamine, N-methylimidazole, tributylamine, piperidine, quinoline, pyrazine or indole; the metal oxides are CuO, Cu20 or ZnO: and the metal chlorides are FeCI3, AICI3, CuCl2, Cu2CI2 or ZnCI2.

When the organic amine is selected from hexamethylene tetramine, N, N-carboxyl diimidazole, pyridine, triethylamine, N-methylimidazole,

tributylamine, piperidine, quinoline, pyrazine or indole, the acid is optionally concentrated sulfuric acid, and the metal oxide which is CuO is optionally adopted, the prepared acidic iron liquid catalyst is separately as follows: tetrapropyl sulfonic acid group hexamethyl tetraamine copper sulphate, 1-methyl-3-(propyl-3-sulfonic acid group) pyridine copper sulphate, dipropanesulfonic acid group N, N-carbonyl copper imidazole sulphate, 1-methyl-3(propyl-3-sulfonic acid group) copper triethylamine sulphate, 1-methyl-3-(propyl-3-sulfonic acid group) copper tributylamine sulphate, 1-methyl-3-(propyl-3-sulfonic acid group) imidazole copper sulphate, 1-methyl-3-(propyl-3-sulfonic acid group) pyridine copper sulphate, 1-methyl-3(propyl-3-suifonic acid group) copper quinoline sulphate, dipropanesulfonic acid group pyridine copper sulphate, and 1-methyl-3-(propyl-3-sulfonic acid group) indole copper sulphate.

Optionally, the organic amine is hexamethylene tetramine, N, N-carboxyl diimidazole or pyrazine; the acid is concentrated sulfuric acid; the metal oxides are CuO; and the metal chlorides are CuCl2.

Optionally, the organic amine is hexamethylene tetramine; the acid is concentrated sulfuric acid, and the metal oxides are CuO. The prepared acid ionic liquid catalyst is tetrapropyl sulfonic acid group hexamethyl tetraamine copper suiphate.

Optionally, the 1,3-propane sultone and the organic amine are in a molar ratio of (1-4) to 1; the ion liquid intermediate and acid are in a molar ratio of 1 to (1-4); the sulfonated organic amine hydrogen sulphate and the metal oxides are in a motar ratio of 1 to (1-4); and the sulfonated organic amine hydrochloride and the metal oxides are in molar ratio of 1 to (1-4).

Further optionally, the organic amine is hexamethylene tetramine; the acid is concentrated sulfuric acid, and the metal oxides are CuQ; and the sulfonated organic amine hydrogen sulphate and the metal oxides are in a molar ratio of 1 to (2-3).

Further optionally, the organic amine is hexamethylene tetramine; the acid is concentrated sulfuric acid, and the metal oxides are CuO; and the sulfonated organic amine hydrogen sulphate and the metal oxides are in a molar ratio of 1 to 2.

Optionally, the ion liquid intermediate is prepared by water-bath stirring, where a reaction temperature is 40-80 C, and reaction time lasts for 1-3 hours.

Optionally, the sulfonated organic amine hydrogen sulphate or the sulfonated organic amine hydrochloride is prepared by oil-bath stirring, where a reaction temperature is 70-100 C, and reaction time lasts for 2-4 hours.

Optionally, the sulfonated organic amine metal sait is prepared by water-bath stirring until a system is clear, where a reaction temperature is 30-50 TC.

Optionally, the organic amine or the concentrated sulfuric acid needs to slowly drop within 30 minutes.

’ LU102541 Compared with the prior art, the invention has one of the following beneficial effects: Firstly, the acidic controllable ion liquid catalyst is prepared by taking organic amine and metal salt as raw materials, so that the problems such as a complex conventional catalyst process, great difficulty, severe pollution, poor safety and high cost are solved; meanwhile, the catalyst is strong in designability and small in green pollution; moreover, the catalyst and the product are automatically layered after reaction while the acidic controllable ion liquid catalyst is taken as the catalyst, and acidic controllability and regeneration of the catalyst can be realized through simple treatment after the catalyst is recycled for many times.

Secondly, progesterone is prepared by adopting the acidic controllable ion liquid catalyst which loads the catalyst and a catalyst promoter, so that the problems such as a complex process, great difficulty, severe pollution, poor safety and high cost due to use of various catalysts and catalyst promoters in a progesterone oxidative decarbonylation process are solved, and thus, the method is more suitable for industrial production.

DESCRIPTION OF THE INVENTION Although specific embodiments of the invention have been described in detail in combination with data below, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. It is to be noted that experimental methods used in the embodiments below, unless otherwise noted, are conventional methods; and materials and reagents used in the embodiments, unless otherwise noted, can be commercially available.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments of the invention belong. The terms used herein are for the purpose of describing specific embodiments only and are not intended to limit the invention.

The invention solves the problems such as a complex process, great difficulty, severe pollution, poor safety and high cost due to use of various catalysts and catalyst promoters in a progesterone oxidative decarbonylation process. The used catalyst has characteristics of strong designability, small green pollution and the like; moreover, the catalyst and a product are automatically layered after reaction, and acidic controllability and regeneration of the catalyst can be realized through simple treatment after the catalyst is recycled for many times.

In an embodiment, a preparation method for an acidic controllable liquid ion catalyst disclosed specifically included the following steps: (1) 1,3-propane sultone and organic amine were taken as raw materials and ethyl acetate was taken as a solvent, where the 1,3-propane sultone and the organic amine were in a molar ratio of (1-4) to 1; the organic amine was dropwise added under a water-bath stirring condition, where a reaction temperature was 40-80 °C and stirring time lasted for 1-3 hours; and an ion liquid intermediate could be obtained through filtering, washing and vacuum

? LU102541 drying after reaction was ended, where the organic amine was selected from hexamethylene tetramine, N, N-carboxyl diimidazole, pyridine, triethylamine, N-methylimidazole, tributylamine, piperidine, quinoline, pyrazine or indole.

(2) the ion liquid intermediate prepared in the step (1), concreated sulfuric acid or concentrated hydrochloric acid were taken as raw materials and water was taken as a solvent, where the ion liquid intermediate and the concreated sulfuric acid or concentrated hydrochloric acid were in a molar ratio of 1 to (1-4); concreated sulfuric acid or concentrated hydrochloric acid was slowly dropped under an oil-bath condition, where a reaction temperature was 70-100 © and stirring time lasted for 2-4 hours; and sulfonated organic amine hydrogen sulphate or sulfonated organic amine hydrochloride was obtained through drying, washing and vacuum drying after reaction was ended.

And (3) the sulfonated organic amine hydrogen sulphate prepared in the step (2) and metal oxides were taken as raw materials or sulfonated organic amine hydrochloride prepared in the step (2) and metal chlorides were taken as raw materials, and deionized water was taken as a solvent to perform mechanical stirring reaction until a reaction system was clear, where the reaction temperature was 30-40 C; and sulfonated organic amine metal salt, namely the acidic controllable ion liquid based catalyst, was obtained by water evaporating and vacuum drying after reaction was ended. The metal oxides or the metal chlorides in the step were selected from CuO, Cu20 or ZnO, FeCI3, AICI3, CuCl2, Cu2CI2 or ZnCI2.

À preparation method for the acidic controllable ion liquid catalyst was described through specific examples: Example 1 In this example, by taking tetrapropyl sulfonic acid group hexamethyt tetraamine copper sulphate ([TshxH][ (2Cu2+)S042-]4 for short) as an example, a preparation method for the catalyst was as follows: (1) 0.4 mol of 1,3-propane sultone and 1000 mL of ethyl acetate were weighted and added into a 250mL three-neck flask, 0.1 mol of hexamethylene tetraamine was dropwise added for stirring reaction for 2 hours at 70 °C; and the ion liquid intermediate, namely tetrapropyl sulfonic acid group hexamethy! tetraamine copper tetrasulphate ([TshxH][ (ÆCu2+)SO42-]4 for short) could be obtained by filtering, washing and vacuum drying after reaction was ended.

(2) at the room temperature, a precursor, 0.1 mol of Tshx (prepared in step (1)) was dissolved into 60 mL of water, and 0.4 mol of concentrated sulfuric acid was dropwise added for constant-temperature reaction for 3 hours at 90°C; and yellow viscous liquid, namely tetrapropyl sulfonic acid group hexamethyl tetraamine hydrogen tetrasulphate ([TshxH][HSO4]4 for short) was obtained by drying, washing and vacuum drying after reaction was ended.

And (3) 0.1 mol of [TshxH][HSO4]4 and 0.2 mol of copper oxide were added into deionized water, and stirred and reacted at 35 °C until the reaction system is clear and free of obvious solids; and Brensted-Lewis acidic functional ion liquid, tetrapropyl sulfonic acid group tetrasulphate [TshxH][ (*2Cu2+)S042-]4 was obtained by water evaporating and vacuum drying after reaction was ended.

The organic amine in the step (1) was replaced to prepare different catalyst: 1-methyi-3-(propyl-3-sulfonic acid group) pyridine copper suiphate, dipropanesulfonic acid group N, N-carbonyl copper imidazole sulphate, 1-methyl-3(propyl-3-sulfonic acid group) copper triethylamine sulphate, 1-methyl-3-(propyl-3-suffonic acid group) copper tributylamine sulphate, 1-methyl-3-(propyl-3-sulfonic acid group) imidazole copper sulphate, 1-methyl-3-(propyl-3-sulfonic acid group) pyridine copper sulphate, 1-methyl-3(propyl-3-sulfonic acid group) copper quinoline sulphate, dipropanesulfonic acid group pyridine copper sulphate, 1-methyl-3-(propyl-3-sulfonic acid group) indole copper sulphate, Based on different catalysts prepared by the method in the Example 1, a preparation method for an acidic controllable liquid ion catalyst disclosed specifically included the following steps in another embodiment: (1) Raw material (20S)-20-hydroxymethylpregna-4-ene-3-keone was mixed with a solvent, and different acidic controllable ion liquid based catalysts prepared in the Example 1 were taken as a catalyst for reaction in a three-neck flask with air.

(2) Cooling was performed after reaction was ended, the acidic controllable ion liquid based catalyst was separated from the reaction system,

and was directly used for next-time reaction after ether washing and vacuum drying.

And (3) reaction liquid was distilled under the normal pressure, was added with water to separate out solids, and was filtered to obtain a progesterone crude product which was re-crystallized to obtain a progesterone fine product.

It should be noted that the solvent was one of methanol, n-butyl alcohol and DMF, dosage of the catalyst was 4%-8% of mass of (208)-20-hydroxymethylpregna-4-ene-3-keone, the reaction temperature was 30-50 °C, and the reaction time lasted for 4-8 hours.

An embodiment of the present invention was explained in detail using the examples: Example 2 To verify catalysis effects of different catalysts, 20g of raw material (20S)-20-hydroxymethylpregna-4-ene-3-keone, 100 mL of the solvent N, N-dimethylformamide (DMF) and 1.2g of the catalyst were sequentially added into the threes-neck flask with air, and were quickly stirred for 6 hours at 40 TC.

While the reaction was ended, the catalyst and the reaction system were layered, and the catalyst was repeatedly used after being washed with ethyl acetate and dried in air; the upper organic layer was taken and distilled under normal pressure to remove fractions at a temperature lower than 200 'C, was added with water to separate solids after being cooled, and was filtered to obtain a progesterone crude product which was recrystallized to obtain a progesterone fine product.

Different catalysts prepared in the Example 1 were selected, and operating examples were performed in accordance with a method of preparing progesterone by catalysis through the acidic controllable ion liquid catalyst disclosed in the example, so that finally obtained aldehyde oxidative decarbonylation results were as shown in Table 1.

Table 1 Aldehyde oxidative decarbonylation results of different organic amine catalysts Catalyst Species Aldehyde Oxidative Decarbonylation Yield _ _ (%) Tetrapropyl sulfonic acid group hexamethyl 86.1 tetraamine copper sulphate Dipropanesulfonic acid group N, N-carbonyl copper 81.3 imidazole sulphate 1-methyl-3-(propyl-3-sulfonic acid group) imidazole 76.1 copper sulphate 1-methyl-3-(propyl-3-sulfonic acid group) pyridine 72.5 copper sulphate 1-methyl-3{propyl-3-sulfonic acid group) copper 64.8 triethylamine sulphate 1-methyl-3-(propyl-3-sulfonic acid group) copper 67.4 tributylamine sulphate 1-methyl-3-(propyl-3-sulfonic acid group) pyridine 73.7 copper sulphate _ ] 1-methyi-3(propyl-3-sulfonic acid group) copper 77.9 quinoline sulphate ) Dipropanesulfonic acid group pyridine copper 82.3 sulphate 1-methyl-3-(propyl-3-sulfonic acid group) indole 67.7 copper sulphate

According to the results of Table 1, aldehyde oxidative decarbonylation yields of different catalysts prepared in Example 1 are mostly 70% or higher, where aldehyde oxidative decarbonylation yields of tetrapropyl sulfonic acid group hexamethyl tetraamine copper sulphate, dipropanesulfonic acid group N, N-carbonyl copper imidazole sulphate and dipropanesulfonic acid group pyridine copper sulphate were 80% or higher, and the aldehyde oxidative decarbonylation yield of organic amine, hexamethyl tetraamine copper tetrasulphate was 86% or higher.

Example 3 The example made further attempt on the conclusion basis of obtaining organic amine, hexamethyl tetraamine copper tetrasuiphate with better catalysis effect based on experimental results obtained in Example 2.

Steps were the same with those of preparing the ion liquid catalyst in Example 1, and species (CuO, Cu20 or ZnO, FeCl3, AICI3, CuCl2, Cu2CI2 or ZnClI2) of metal oxides or metal chlorides in the reaction system were changed while other conditions were kept unchanged, so that different acidic functional ion liquids including ([TshxH][(*2Cu2+)S042-]4, [TshxH]{(Cu+)SO42-]4, [TshxH}{((4Zn2+)SO42-]4, {TshxH][(FeCl4)]4, [TshxH][(AICI4)}4, [TshxH}{(CuC13)]4, [TshxH][ (Cu2CI3)}4 and [TshxHi[ (ZnCI3)]4)could be prepared.

Different catalysts prepared in the Example were selected, and operating examples were performed in accordance with a method of preparing progesterone by catalysis through the acidic controllable ion liquid catalyst disclosed in the Example 2, so that finally obtained aldehyde oxidative decarbonylation results were as shown in Table 2.

Table 2 Aldehyde oxidative decarbonylation results of different metal salt catalysts Catalyst species ___|Aldehyde oxidative decarbonylation yield ( %) [TshxH][ (*2Cu2+)S042-]4 86.1 I [TshxH][(Cu+)SO42-)4 (702 0 [TshxH][(7Zn2+)S042-j4 60.3 N LL - [TshxH][ (FeCl4]4 _ 532 _ [TshxH]{(CuCI3)]4 2831 ee [TshxH][(CuCi2)}4 mz [TshxH][(ZnCI3)j4 60.6 [TshxHj[(AICI4)}4 ~~ 59.2 0) Metal salts with good catalysis effect can be copper oxide or copper dichloride according to the results of Table 2.

Example 4 The example made further attempt on the conclusion basis of obtaining metal salt with better catalysis effect as copper oxide based on experimental results obtained in Example 3.

Steps were the same with those of preparing the ion liquid catalyst in Example 1, and Brensted-Lewis acidic functional ion liquids [TshxH][ (AH*+ACu**)SO4*14, [TShx(KH*+-4Cu2*}][ (%CU?)SO4*-]a and[Tshx(H Cu?) (2Cu?*)S04%]s with different Bronsted acidic sites and Lewis acidic sites could be prepared by changing amount (0.1 mol, 0.3 mol and 0.4 mol) of copper oxide in the reaction system while other conditions were not changed.

Different catalysts prepared in the Example and catalyst TshxH][ (MCu?)SO4?]4 prepared in the Example 1 were selected, and operating examples were performed in accordance with a method of preparing progesterone by catalysis through the acidic controllable ion liquid catalyst disclosed in the Example 2, so that finally obtained aldehyde oxidative decarbonylation results were as shown in Table 3.

Table 3 Aldehyde oxidative decarbonylation results of copper oxide catalyst in different proportions Dosageof | lonLiqud Aldehyde Copper Oxide Oxidative Decarbonylation I Yield (%)

0.1mol [TshxH][ (~H++%Cu2+)SO42-4 684

0.2mol(Example|[TshxH][ (2Cu2+)S042-}4 86.1 0 preparation) So . nn

0.3mol [Tshx(H++4CU2+)][ (2Cu2+)SO42-j46 79.6 a

0.4mol [Tshx(2Cu2+)][ (2Cu2+)S042-]4 75.9 According to the results of Table 3, [TshxH][ (2Cu2+)S042-]4- and [Tshx(2H++4Cu2+)][ (7Cu2+)S042-]4 had better catalysis effect, where catalysis effect of the [TshxH][ (2Cu2+)S0O42-]4- catalyst was the best.

Example 5 20g of raw material (20S)-20- hydroxymethylpregna-4-ene-3-keone, 100 mL of the solvent N, N-dimethylformamide (DMF) and catalyst

[TshxH][ (*2Cu2+)S042-]4 were sequentially added into the threes-neck flask with air, and were quickly stirred for 6 hours at 40 ©. While the reaction was ended, the catalyst and the reaction system were layered, and the catalyst was repeatedly used after being washed with ethyl acetate and dried in air; the upper organic layer was taken and distilled under normal pressure to remove fractions at a temperature lower than 200 ©, was added with water to separate solids after being cooled, and was filtered to obtain a progesterone crude product which was re-crystallized to obtain a progesterone fine product. Amount of the catalyst was changed to obtain an aldehyde oxidative decarbonylation yield as shown in Table 4.

Table 4 Aldehyde oxidative decarbonylation reaction results obtained by different catalyst dosages Catalyst dosage (g) ) Catalyst dosage (wt%) |Aldehyde ‘oxidative 1 ______. (decarbonylation yield (%) 08 222 4 79.2

1.0 Pv BL 12 00008 86.1 14 7 869 ~~ 16 ) 8 0 868 00h According to the results of Table 4, better catalysis effects could be achieved while a ratio of dosage of catalysts to mass of the (20S)-20-hydroxymethylpregna-4-ene-3-keone was within 4%-8%, with catalysis efficiency being 80% or higher; and the catalysis effects were better if the ratio was 6%-8%, where the aldehyde oxidative decarbonylation yield could be 86% or higher.

Example 6 20g of raw material (20S)-20-hydroxymethylpregna-4-ene-3-keone, 100 mL of the solvent N, N-dimethylformamide (DMF) and a 1.4 g of catalyst [TshxH][ (4Cu2+)S042-]4 were sequentially added into the threes-neck flask with air, and were quickly stirred for 6 hours at certain temperature. While the reaction was ended, the catalyst and the reaction system were layered, and the catalyst was repeatedly used after being washed with ethyl acetate and dried in air; the upper organic layer was taken and distilled under normal pressure to remove fractions at a temperature lower than 200 C, was added with water to separate solids after being cooled, and was filtered to obtain a progesterone crude product which was re-crystallized to obtain a progesterone fine product. Aldehyde oxidative decarbonylation yield results were as shown in Table 5 by changing the reaction temperature. Reaction temperature (°C) |Aldehyde oxidative decarbonylation yield (%) 0 &o5 » : 863 4 0 86,9 000 ee 45 ——— 87.8 ER hs WELL ———— a —— LIL 56 876 Table 5 showed aldehyde oxidative decarbonylation reaction results at different reaction temperatures.

According to the results of the Table 5, the aldehyde oxidative decarbonylation yield could be 80% or higher at a lower reaction temperature, and was gradually increased along with temperature rise.

> LU102541 The results of the examples showed that in the progesterone preparation method, better catalysis activity and a high aldehyde oxidative decarbonylation yield were displayed while dosage of the catalyst was relatively low, and reaction time was greatly shortened, post-treatment was simple, and pollution was less, and thus, the preparation method belonged to a green chemical technology.

It should be noted that problems such as a complex process, different difficulty, severe pollution, poor safety and high cost usually occur in an existing progesterone production process. In order to solve the problems, the invention discloses an acidic controllable ion liquid based catalyst which has strong designability and small green pollution; while the acidic controllable ion liquid catalyst is taken as the catalyst, the reacted catalyst and the product are automatically layered, and acidic controllability and regeneration of the catalyst can be realized through simple treatment after the catalyst is recycled for many times; and the catalyst with better catalysis effect is a [TshxH][ (2Cu2+)5042-]4 ion liquid catalyst.

The above-mentioned examples are merely illustrative of several embodiments of the invention, and the description thereof is more specific and detailed, but is not to be construed as limit to the scope of the invention. It should be noted that a number of variations and modifications may be made by those skilled in the art without departing from the spirit and scope of the invention, and shall be subject to the protection scope of the invention. the protective scope of the invention should correspond to the scope of claims in the application patent.

Claims (10)

1. A preparation method for progesterone, characterized by comprising the following steps: reacting in a solvent by taking (20S)-20- hydroxymethylpregna-4-ene-3-keone as a raw material and an acidic ion liquid catalyst as a catalyst; after the reaction is ended, separating the catalyst to obtain reaction liquid which is sequentially subjected to normal-pressure compression, separation-out of solids by adding water and filtration so as to obtain a progesterone crude product; and re-crystallizing the progesterone crude product to obtain a progesterone fine product.

2. The preparation method according to claim 1, wherein dosage of the catalyst is 4%-8% of the mass of (20S)-20-hydroxymethylpregna-4-ene-3-keone.

3. The preparation method according to claim 1, wherein the reaction temperature is 30-50 °C.

4. The preparation method according to claim 1, wherein the reaction time lasts for 4-8 hours.

5. The preparation method according to claim 1, wherein the solvent is one of methanol, n-buty! alcohol and DMF.

6. The preparation method according to claim 1, wherein the separated catalyst is washed by ethyl acetate, dried in vacuum and directly used for next-time reaction after reaction is ended.

7. The preparation method according to claim 1, wherein the acidic ion liquid based catalyst is prepared by the following method: filtering, washing and drying in vacuum after reaction is ended to obtain an ion liquid intermediate by taking 1,3- propane sultone and organic amine as raw materials; drying, washing and drying in vacuum after reaction is ended to obtain sulfonated organic amine hydrogen sulphate or sulfonated organic amine hydrochloride by taking the ionic liquid intermediate and acid as raw materials, where the acid is concentrated sulfuric acid or concentrated hydrochloric acid; and drying, and drying in vacuum after reaction is ended to obtain a sulfonated organic amine metal salt, namely an acidic ion liquid based catalyst by taking sulfonated organic amine hydrogen sulphate and metal oxides as raw materials or sulfonated organic amine hydrochloride and metal chlorides as raw materials.

8. The preparation method according to claim 7, wherein the organic amine is hexamethylene tetramine, N, N-carboxyl diimidazole, pyridine, triethylamine, N-methylimidazole, tributylamine, piperidine, quinoline, pyrazine or indole; and the metal oxides are CuO, Cu20 or ZnO; and the metal chlorides are FeCl3, AICI3, CuCl2, Cu2CI2 or ZnCI2.

9. The preparation method according to claim 7, wherein the 1,3-propane sultone and the organic amine are in a molar ratio of (1-4) to 1; the ion liquid intermediate and acid are in a molar ratio of 1 to (1-4); the sulfonated organic amine hydrogen sulphate and the metal oxides are in a molar ratio of 1 to

(1-4); and the sulfonated organic amine hydrochloride and the metal oxides are in molar ratio of 1 to (1-4).

10. The preparation method according to claim 7, wherein the organic amine is hexamethylene tetramine; the acid is concentrated sulfuric acid, and the metal oxides are CuO; and the sulfonated organic amine hydrogen sulphate and the metal oxides are in a molar ratio of 1 to 2.