Process for the one-pot preparation of dienogest

Abstract

The application provides a method for preparing dienogest by one-pot method, and belongs to the technical field of drug synthesis. The reaction formula of the method is as follows: the method comprises the following steps: under the condition of ultralow temperature, ethynyl carbanion is formed by n-butyllithium and acetonitrile, addition reaction is carried out on a compound of formula (1), after the reaction is completed, an acid is used for quenching, then concentrated hydrochloric acid is directly added dropwise for deprotection-transposition reaction, a compound of formula (2) is prepared; after the reaction is completed, sodium bicarbonate aqueous solution is added for water analysis, and dienogest fine product is obtained by secondary refining of the obtained crude product. The dienogest is prepared by the addition reaction, deprotection-transposition reaction one-pot method, solvent consumption can be effectively reduced, solid waste can be reduced, process cost can be reduced, and green chemical industrial production of dienogest can be realized.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug synthesis, and particularly relates to a method for preparing dienogest by one-pot method. BACKGROUND

[0002] Dienogest is chemically named as 17alpha-cyanomethyl-17beta-hydroxy-13beta-methylgona-4,9-dien-3-one, and its structural formula is as follows: It has the dual properties of 19-nortestosterone derivatives and progesterone derivatives, and further has a strong ovulation inhibiting effect. It has the characteristics of accurate curative effect, small toxic and side effects, high and reliable drug efficacy, small adverse reactions, and good tolerance in the aspect of contraception.

[0003] At present, the synthesis route of dienogest is basically to take 19-hydroxymethyl-androst-4-ene-3,17-dione or dienone as a raw material, and dienogest is prepared through multiple steps. No matter which route, at least the following step is included: The difference is only in the step of the intermediate reaction.

[0004] For example, the patent application for invention with the publication number CN112209987A discloses a synthesis route of dienogest, as shown below:

[0005]

[0006] In the above-mentioned technology, ethynyl carbanion is formed by n-butyl lithium and acetonitrile under ultra-low temperature conditions, and addition reaction is carried out on compound (III) to obtain compound (II), then fluoroboric acid is used for deprotection and double bond transposition to obtain dienogest crude product, i.e. compound (I), and the crude product is refined by activated carbon and 4-methyl-tetrahydro-pyran to obtain dienogest, with a yield of 76% and a purity of 99.6%. Although the synthesis route overcomes the problems of low purity, deep color and complicated process in the traditional synthesis process, it still needs to purify compound (II) after synthesizing compound (II) from compound (III), and then dienogest is prepared by acidolysis deprotection reaction, so it is limited to one-pot synthesis of compound (I) dienogest from compound (II), but not one-pot synthesis of dienogest from compound (III). In addition, fluoroboric acid and solvent acetonitrile used in deprotection-transposition reaction are expensive and difficult to recover, and the solvent used in refining is also expensive, and solid waste activated carbon is generated. SUMMARY

[0007] In view of this, the present application aims to provide a method for preparing dienogest by one-pot method, and aims to solve at least one technical problem in the background art.

[0008] The present application is implemented as follows:

[0009] The method for preparing dienogest by one-pot method, and the reaction formula of the method is as follows:

[0010]

[0011] The method comprises: addition reaction of the compound of formula (1) and ethyleneglycol anion in an ultralow temperature environment, and quenching with an acid after the reaction; and directly adding concentrated hydrochloric acid for deprotection-transposition reaction to prepare the compound of formula (2).

[0012] Preferably, the method further comprises denogest crude preparation and denogest refining.

[0013] Preferably, the denogest crude preparation comprises:

[0014] The pH of the deprotection-transposition reaction product is adjusted to neutral by using a sodium bicarbonate solution to obtain a reaction solution;

[0015] The reaction solution is slowly poured into water, and after stirring and water separation, filtration is performed, and the filter cake is dried at 50-60 DEG C to obtain denogest crude product.

[0016] Preferably, the denogest refining comprises: dissolving the denogest crude product in ethanol, heating to 50-80 DEG C and stirring for reaction, cooling to 0-5 DEG C to precipitate, and after solid-liquid separation, obtaining refined mother liquor and denogest fine product.

[0017] The denogest refining further comprises: extracting the denogest fine product from the refined mother liquor.

[0018] Preferably, the extraction of the denogest fine product from the refined mother liquor comprises:

[0019] The refined mother liquor is concentrated to obtain an oily substance, tetrahydrofuran is added, stirring is performed until the solution is clear, concentrated hydrochloric acid is added dropwise, and temperature control reaction is performed at 20-40 DEG C;

[0020] The pH of the reaction system is adjusted to neutral by using a sodium bicarbonate solution, and the reaction solution is slowly poured into water, and after stirring and water separation, filtration is performed, and the filter cake is dried at 50-60 DEG C to obtain denogest crude product;

[0021] The denogest crude product is dissolved in ethanol, heated to 50-80 DEG C and stirred for 2 hours, cooled to 0-5 DEG C to precipitate, and after solid-liquid separation, denogest fine product is obtained.

[0022] Preferably, the specific operation of the addition reaction comprises:

[0023] In a n-butyllithium solution at -60-80 DEG C, tetrahydrofuran is added dropwise, and then a mixed solution of acetonitrile and tetrahydrofuran is added dropwise;

[0024] Then, the compound of formula (1) and a tetrahydrofuran solution are added dropwise, and after the dropwise addition is completed, temperature control reaction is performed at -60-80 DEG C, and after the reaction is completed, dilute hydrochloric acid is added dropwise to terminate the reaction.

[0025] Preferably, the temperature of the deprotection-translocation reaction is 20-40℃.

[0026] Compared with the prior art, the present application includes the following beneficial effects:

[0027] 1. The present application can effectively reduce the amount of solvent, reduce solid waste, reduce process cost, and realize the green chemical industrial production of dienogest by one-pot method of addition, deprotection-translocation reaction.

[0028] 2. The synthesis method of the present application not only simplifies the process steps, but also improves the yield.

[0029] 3. The synthesis process of the present application uses cheap and readily available acid and solvent, without high-risk, high-corrosion and expensive reagents such as fluoroboric acid, reduces the use of adsorbents such as activated carbon in the refining process, and further saves the cost. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 is the high performance liquid chromatogram of the product after the first stage of refining in Example 1 of the present application;

[0031] Figure 2 is the hydrogen nuclear magnetic resonance spectrum of the product after the first stage of refining in Example 1 of the present application;

[0032] Figure 3 is the carbon nuclear magnetic resonance spectrum of the product after the first stage of refining in Example 1 of the present application;

[0033] Figure 4 is the mass spectrum of the product after the first stage of refining in Example 1 of the present application;

[0034] Figure 5 is the high performance liquid chromatogram of the product after the second stage of refining in Example 1 of the present application. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical scheme and advantages of the present application clearer, the present application will be further described in detail below with examples. It should be understood that the specific implementation examples described herein are only used to explain the present application, and are not used to limit the present application.

[0036] Example 1

[0037] In this embodiment, dienogest is synthesized by one-pot method of addition reaction and deprotection-translocation reaction, and high-purity and high-yield dienogest is obtained after purification. The specific steps are as follows:

[0038] (1) One-pot synthesis of dienogest

[0039] The synthesis route is as follows:

[0040]

[0041] Addition reaction: In a reaction vessel, 2.5 mol / L n-butyllithium 2.8 L was added, and the temperature was lowered to -60°C to -80°C. Tetrahydrofuran 5 L was added dropwise while controlling the temperature. After the completion of the dropwise addition, a mixed solution of acetonitrile and tetrahydrofuran (0.29 kg and 0.6 L of tetrahydrofuran) was added dropwise. After the completion of the dropwise addition, a solution of the compound of formula (1) and tetrahydrofuran (1 kg of the compound of formula (1) and 3.5 L of tetrahydrofuran) was added dropwise. After the completion of the dropwise addition, the reaction was carried out at -60°C to -80°C for 30 minutes. After the completion of the reaction, 150 g of 1N dilute hydrochloric acid was added dropwise to terminate the reaction.

[0042] Deprotection-transposition reaction: In the addition reaction product, 0.5 kg of 37 wt.% concentrated hydrochloric acid was directly added dropwise while controlling the temperature at 20°C to 40°C. The reaction was carried out for 2 hours.

[0043] (2) Preparation of crude dienogest

[0044] After the completion of the deprotection-transposition reaction, an aqueous sodium bicarbonate solution (0.5 kg of sodium bicarbonate and 6 L of water) was added to adjust the pH to neutral. The reaction solution was slowly poured into 15 L of water, and water was separated by stirring. The filter cake was dried at 50°C to 60°C for 20 hours to obtain crude dienogest 0.9 kg.

[0045] (3) Secondary refinement

[0046] First-stage refinement: To crude dienogest, 9 L of ethanol was added, and the temperature was raised to 50°C to 80°C. The mixture was stirred for 2 hours, and then the temperature was lowered to 0°C to 5°C to obtain dienogest 0.77 kg and a refined mother liquor. The HPLC purity of the dienogest was 99.85%, and the high-performance liquid chromatography (HPLC) spectrum, hydrogen nuclear magnetic resonance (HNMR) spectrum, carbon nuclear magnetic resonance (CNMR) spectrum, and mass spectrum (MS) thereof are shown in FIGS. 1 to 4, respectively. Figures 1 to 4

[0047] 1 H NMR (400 MHz, CDCl3) δ H / ppm: 5.70 (s, 1H), 2.96 (m, 1H), 2.92-2.84 (m, 2H), 2.66-2.62 (d, J = 16.0 Hz, 1H), 2.54-2.50 (d, J = 16.0 Hz, 1H), 2.48-2.31 (m, 6H), 2.20-2.09 (m, 2H), 2.02-1.91 (m, 2H), 1.81-1.69 (m, 2H), 1.50-1.46 (m, 1H), 1.33-1.24 (m, 3H), 1.09 (s, 3H).

[0048] 13 C NMR (100 MHz, CDCl3) δ C ​ppm: 199.99, 157.22, 145.06, 126.07, 122.35, 118.69, 81.47, 51.12, 46.28, 40.09, 36.97, 36.90, 31.71, 30.79, 28.23, 27.27, 25.81, 25.52, 23.49, 13.58.

[0049] MS (ESI) m / z calcd for C 20 H 25 NO2 + (M+H) + : 312.2 found: 312.1.

[0050] Second stage refining: the refining mother liquor was concentrated to obtain 0.14 kg of oil, 1.4 L of tetrahydrofuran was added and stirred to dissolve the clear solution, then 0.07 kg of concentrated hydrochloric acid was added dropwise, the temperature was controlled at 20-40°C, and the reaction was carried out for 1 hour. After the reaction was completed, 0.07 kg of sodium bicarbonate and 0.84 L of water were added to adjust the pH to neutral. The reaction liquid was slowly poured into 2.1 L of water, stirred to precipitate, filtered, and the filter cake was dried at 50-60°C for 20 hours to obtain 0.11 kg of crude denogest. 1.1 L of ethanol was added and warmed to 50-80°C, stirred for 2 hours, cooled to 0-5°C, and filtered to obtain 0.086 kg of fine denogest with a purity of 99.73% by HPLC. The high performance liquid chromatography (HPLC) spectrum is shown in Figure 2. Figure 5

[0051] The first stage refining and the second stage refining obtained a total of 0.856 kg of fine denogest with an average purity of 99.84% by HPLC, and the total yield was 86.4%.

[0052] Comparative Example 1

[0053] The difference between this comparative example 1 and example 1 is that the addition reaction and the deprotection-transposition reaction in step (1) were synthesized by two-pot method.

[0054] The synthetic route of step (1) of this comparative example 1 is as follows:

[0055]

[0056] Step (1) of this comparative example 1 is as follows:

[0057] ​Addition reaction: in a reactor, 2.5 mol / L n-butyllithium 2.8 L was added, and the temperature was lowered to -60℃ to -80℃, and then tetrahydrofuran 5 L was added dropwise under temperature control. After the dropwise addition was completed, the mixture of acetonitrile and tetrahydrofuran (0.29 kg acetonitrile and 0.6 L tetrahydrofuran) was added dropwise, and then the solution of compound of formula (1) and tetrahydrofuran (1 kg compound of formula (1) and 3.5 L tetrahydrofuran) was added dropwise. After the dropwise addition was completed, the temperature was controlled at -60℃ to -80℃ for 30 minutes. After the reaction was completed, 150 g of 1N dilute hydrochloric acid was added dropwise to terminate the reaction, and then the organic phase was separated and concentrated under reduced pressure to obtain a light yellow oil, which was the compound of formula (3);

[0058] Deprotection-translocation reaction: the compound of formula (3) obtained above was added into a reactor, 10 L tetrahydrofuran was added, and then 0.5 kg of concentrated hydrochloric acid was added dropwise under stirring. The temperature was controlled at 20℃ to 40℃, and the reaction was carried out for 2 hours to obtain the compound of formula (2).

[0059] The other steps and parameters of Comparative Example 1 were the same as those of Example 1.

[0060] Comparative Example 1 obtained 0.88 kg of crude denogest, and 0.75 kg of denogest of the first grade was obtained by the first grade refining. The HPLC purity was 99.75%, and 0.1 kg of denogest of the second grade was obtained by the second grade refining, and the HPLC purity was 99.73%.

[0061] The total amount of denogest of the first and second grades was 0.85 kg, and the average HPLC purity was 99.75%, and the total yield was 85.8%.

[0062] As can be seen from the comparison between Comparative Example 1 and Example 1, although the separation of the product after the addition reaction was omitted in Example 1, the one-pot addition reaction and deprotection-translocation reaction can obtain denogest of the first grade with higher purity and higher yield.

[0063] The above examples only express several embodiments of the present application, and the description is more specific and detailed, but it cannot be understood as a limitation on the scope of the patent of the present application. It should be pointed out that for ordinary skilled persons in the art, several modifications and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application should be subject to the appended claims.

Claims

1. A process for the one-pot preparation of dienogest, characterized in that, The method reaction formula is shown as follows: The method comprises: addition reaction of a compound of formula (1) with ethyl cyanide anion in an ultralow temperature environment, and after the reaction is completed, quenching with an acid; and then directly adding concentrated hydrochloric acid to perform deprotection-translocation reaction to prepare a compound of formula (2); The specific operation of the addition reaction comprises: In a n-butyllithium solution at -60 to -80 DEG C, a temperature-controlled tetrahydrofuran is added dropwise, and then a mixed solution of acetonitrile and tetrahydrofuran is added dropwise; Then, the compound of formula (1) and a tetrahydrofuran solution are added dropwise, and after the dropwise addition is completed, a reaction is performed at a temperature of -60 to -80 DEG C, and after the reaction is completed, dilute hydrochloric acid is added dropwise to terminate the reaction; The temperature of the deprotection-translocation reaction is 20 to 40 DEG C; The method further comprises denogest crude preparation and denogest refining; the denogest crude preparation comprises adding sodium bicarbonate aqueous solution to adjust the pH after the deprotection-translocation reaction is completed, and water separation to obtain denogest crude product; and the denogest refining comprises secondary refining of the denogest crude product to obtain denogest fine product.

2. The process for one pot preparation of dienogest as claimed in claim 1 wherein, The denogest crude preparation comprises: Sodium bicarbonate solution is used to adjust the pH of the deprotection-translocation reaction product to neutral to obtain a reaction liquid; The reaction liquid is slowly poured into water, and after stirring and water separation, filtration is performed, and the filter cake is dried at 50 to 60 DEG C to obtain denogest crude product.

3. The process for one pot preparation of dienogest as claimed in claim 2 wherein, The denogest refining comprises: the denogest crude product is dissolved in ethanol, heated to 50 to 80 DEG C and stirred to react, cooled to 0 to 5 DEG C to precipitate, and after solid-liquid separation, a refining mother liquor and denogest fine product are obtained.

4. The process for one pot preparation of dienogest as claimed in claim 3 wherein, The denogest refining further comprises: extraction of denogest fine product from the refining mother liquor.

5. The process for one pot preparation of dienogest as claimed in claim 4 wherein, The extraction of denogest fine product from the refining mother liquor comprises: The refining mother liquor is concentrated to obtain an oily substance, concentrated hydrochloric acid is added after stirring and dissolving in tetrahydrofuran, and a reaction is performed at a temperature of 20 to 40 DEG C; Sodium bicarbonate solution is used to adjust the pH of the reaction system to neutral, and the reaction system is slowly poured into water, and after stirring and water separation, filtration is performed, and the filter cake is dried at 50 to 60 DEG C to obtain denogest crude product; The denogest crude product is dissolved in ethanol, heated to 50 to 80 DEG C and stirred for 2 hours, cooled to 0 to 5 DEG C to precipitate, and after solid-liquid separation, denogest fine product is obtained.

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