Method for preparing dienogest by one-pot method

Abstract

The invention provides a method for preparing dienogest through a one-pot method, and belongs to the technical field of medicine synthesis. The method comprises the following steps: forming ethyl cyano anions from n-butyllithium and acetonitrile under an ultra-low temperature condition, carrying out addition reaction on a compound in a formula (1), quenching with acid after the reaction is finished, and then directly dropwise adding concentrated hydrochloric acid to carry out deprotection-transposition reaction, so as to prepare a compound in a formula (2); and after the reaction is finished, adding a sodium bicarbonate aqueous solution to carry out elutriation, and carrying out secondary refining on an obtained crude product to obtain a refined dienogest product. The dienogest is prepared through the addition and deprotection-transposition reaction one-pot method, the solvent dosage can be effectively reduced, meanwhile, solid waste is reduced, the process cost is reduced, and green chemical industrial production of the dienogest is achieved.

Description

Technical Field

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

[0002] The chemical name of dienogest is 17α-cyanomethyl-17β-hydroxy-13β-methylsteroid-4,9-diene-3-one, and its structural formula is: It has the dual properties of 19-nortestosterone derivatives and progesterone derivatives, and thus has a powerful ovulation inhibitory effect. It has the characteristics of exact curative effect in contraception, small toxic and side effects, high and reliable drug efficacy, small adverse reactions, and good tolerance.

[0003] Currently, in the synthesis route of dienogest, basically 19-hydroxymethyl-androst-4-ene-3,17-dione or diene diketone is used as the raw material, and dienogest is obtained through multiple steps of reaction. No matter which route, it at least includes the following steps: The difference lies only in the intermediate reaction steps of the two.

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

[0005]

[0006] In the above technology, n-butyllithium and acetonitrile form an acetonitrile anion under ultra-low temperature conditions, and an addition reaction is carried out on compound (III) to obtain compound (II). Then, deprotection with fluoroboric acid and double bond rearrangement are carried out to obtain the crude product of dienogest, that is, compound (I). The crude product is refined with activated carbon and 4-methyl-tetrahydropyran to obtain dienogest, with a yield of 76% and a purity of 99.6%. Although this synthesis route overcomes the problems of low purity of the crude product, dark color, and cumbersome process in the traditional synthesis process, in fact, it still needs to purify compound (III) after synthesizing compound (II), and then carry out deprotection reaction by acidolysis to obtain dienogest. Therefore, it is only limited to the one-pot synthesis of compound (I) dienogest from compound (II), rather than the one-pot synthesis of dienogest from compound (III). In addition, the fluoroboric acid and solvent acetonitrile used in its deprotection-rearrangement reaction are expensive and not easy to recycle, and the solvent used for refining is also expensive, and solid waste activated carbon is generated. Summary of the Invention

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

[0008] The present invention is realized as follows:

[0009] A method for preparing dienogest by a one-pot method, and the reaction formula of the method is as shown below:

[0010]

[0011] The method includes: adding the compound of formula (1) and cyanomethyl anion for an addition reaction under an ultra-low temperature environment, quenching with an acid after the reaction ends; and then directly adding concentrated hydrochloric acid for a deprotection-transposition reaction to obtain the compound of formula (2).

[0012] Preferably, the method further includes crude preparation of dienogest and purification of dienogest.

[0013] Preferably, the crude preparation of dienogest includes:

[0014] Adjusting the pH of the product of the deprotection-transposition reaction to neutral with a sodium bicarbonate solution to obtain a reaction solution;

[0015] Slowly pouring the reaction solution into water, filtering after stirring and salting out, and drying the filter cake at 50°C to 60°C to obtain crude dienogest.

[0016] Preferably, the purification of dienogest includes: dissolving the crude dienogest in ethanol, heating to 50°C to 80°C and stirring for reaction, cooling to 0°C to 5°C to precipitate, and after solid-liquid separation, obtaining a refined mother liquor and high-quality dienogest.

[0017] The purification of dienogest further includes: extracting high-quality dienogest from the refined mother liquor.

[0018] Preferably, the extraction of high-quality dienogest from the refined mother liquor includes:

[0019] Concentrating the refined mother liquor to obtain an oily substance, adding tetrahydrofuran and stirring until clear, then dropping concentrated hydrochloric acid, and carrying out a reaction while controlling the temperature at 20°C to 40°C;

[0020] Adjusting the pH of the reaction system to neutral with a sodium bicarbonate solution, slowly pouring it into water, filtering after stirring and salting out, and drying the filter cake at 50°C to 60°C to obtain crude dienogest;

[0021] Dissolving the crude dienogest in ethanol, heating to 50°C to 80°C and stirring for 2 hours, cooling to 0°C to 5°C to precipitate, and after solid-liquid separation, obtaining high-quality dienogest.

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

[0023] Controlling the temperature and dropping tetrahydrofuran in a n-butyllithium solution at -60°C to -80°C, and then dropping a mixed solution of acetonitrile and tetrahydrofuran;

[0024] Then dropping the compound of formula (1) and a tetrahydrofuran solution, controlling the temperature at -60°C to -80°C for reaction after dropping, and dropping dilute hydrochloric acid to terminate the reaction after the reaction is completed.

[0025] Preferably, the temperature of the deprotection-transposition reaction is 20 °C to 40 °C.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1. The present invention prepares dienogest by a one-pot method of addition, deprotection-transposition reaction, which can effectively reduce the solvent consumption, reduce solid waste at the same time, lower the process cost, and realize the green chemical industrial production of dienogest.

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

[0029] 3. The synthesis process of the present invention uses cheap and easily available acids and solvents, without high-risk, highly corrosive and expensive reagents such as fluoboric acid, and reduces the use of adsorbents such as activated carbon in the refining process, further saving costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is the high performance liquid chromatography of the product after the first-stage refining in Example 1 of the present invention;

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

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

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

[0034] Figure 5 It is the high performance liquid chromatography of the product after the second-stage refining in Example 1 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0035] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0036] Example 1

[0037] In this example, a one-pot method is used for the addition reaction and the deprotection-transposition reaction to synthesize dienogest, and high-purity and high-yield dienogest fine products are obtained after purification. The specific steps are as follows:

[0038] (1) Synthesis of dienogest by one-pot method

[0039] The synthesis route is:

[0040]

[0041] Carry out the addition reaction: In a reaction kettle, add 2.8 L of 2.5 mo1 / L n-butyllithium, cool down to -60 °C to -80 °C, control the temperature and dropwise add 5 L of tetrahydrofuran. After the addition is complete, start to dropwise add a mixed solution of acetonitrile and tetrahydrofuran (0.29 kg and 0.6 L of tetrahydrofuran). After the addition is complete, start to dropwise add the compound of formula (1) and a tetrahydrofuran solution (1 kg of the compound of formula (1) and 3.5 L of tetrahydrofuran). After the addition is complete, control the temperature at -60 °C to -80 °C and react for 30 minutes. After the reaction is complete, dropwise add 150 g of 1N dilute hydrochloric acid to terminate the reaction;

[0042] Deprotection-transposition reaction: In the addition reaction product, directly dropwise add 0.5 kg of 37 wt.% concentrated hydrochloric acid, control the temperature at 20 °C to 40 °C, and react for 2 hours.

[0043] (2) Preparation of crude dienogest

[0044] After the deprotection-transposition reaction is complete, add an aqueous sodium bicarbonate solution (0.5 kg of sodium bicarbonate and 6 L of water) to adjust the pH to neutral. Slowly pour the reaction solution into 15 L of water, stir for precipitation, filter, and dry the filter cake at 50 °C to 60 °C for 20 hours to obtain 0.9 kg of crude dienogest.

[0045] (3) Secondary refining

[0046] First-stage refining: Add 9 L of ethanol to the crude dienogest, heat up to 50 °C to 80 °C, stir for 2 hours, cool down to 0 °C to 5 °C and filter to obtain 0.77 kg of high-quality dienogest and refined mother liquor. The HPLC purity of the high-quality dienogest is 99.85%. Its high-performance liquid chromatography (HPLC) spectrum, nuclear magnetic resonance hydrogen spectrum (HNMR), carbon spectrum (CNMR), and mass spectrum (MS) are respectively as Figures 1 to 4 shown;

[0047] 1 H NMR(400MHz,CDCl 3 )δ H / ppm:5.70(s,1H),2.96(m,1H),2.92 - 2.84(m,2H),2.66 - 2.62(d,J = 16.0Hz,1H),2.54 - 2.50(d,J = 16.0Hz,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(100MHz,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 NO 2 + (M + H) + : 312.2 found: 312.1。

[0050] Secondary purification: The refined mother liquor was concentrated to obtain 0.14 kg of an oily substance. After adding 1.4 L of tetrahydrofuran and stirring until dissolved clearly, 0.07 kg of concentrated hydrochloric acid was added dropwise. The temperature was controlled at 20 °C - 40 °C, and the reaction was carried out for 1 hour. After the reaction was complete, an aqueous sodium bicarbonate solution (0.07 kg of sodium bicarbonate and 0.84 L of water) was added to adjust the pH to neutral. The reaction solution was slowly poured into 2.1 L of water, stirred for water precipitation, filtered, and the filter cake was dried at 50 °C - 60 °C for 20 hours to obtain 0.11 kg of crude dienogest. Then 1.1 L of ethanol was added and the temperature was raised to 50 °C - 80 °C, stirred for 2 hours, and then cooled to 0 °C - 5 °C and filtered to obtain 0.086 kg of high-quality dienogest with an HPLC purity of 99.73%. Its high-performance liquid chromatography (HPLC) spectrum is as Figure 5 shown.

[0051] A total of 0.856 kg of high-quality dienogest was obtained from the first-stage purification and the second-stage purification, with an average HPLC purity of 99.84% and a total yield of 86.4%.

[0052] Comparative Example 1

[0053] The difference between this Comparative Example 1 and Example 1 is that in step (1), the addition reaction and the deprotection-rearrangement reaction were synthesized by a two-pot method.

[0054] The synthesis route of step (1) in this Comparative Example 1 is as follows:

[0055]

[0056] Step (1) in this Comparative Example 1 is specifically as follows:

[0057] Addition reaction: In the reaction kettle, 2.8 L of 2.5 mo1 / L n-butyllithium was added, and the temperature was lowered to -60 °C to -80 °C. 5 L of tetrahydrofuran was added dropwise while controlling the temperature. After the addition was completed, a mixed solution of acetonitrile and tetrahydrofuran (0.29 kg of acetonitrile and 0.6 L of tetrahydrofuran) was added dropwise. After the addition was completed, a compound of formula (1) and a tetrahydrofuran solution (1 kg of the compound of formula (1) and 3.5 L of tetrahydrofuran) were added dropwise. After the addition was completed, the reaction was carried out at -60 °C to -80 °C for 30 minutes. After the reaction was completed, 150 g of 1N dilute hydrochloric acid was added dropwise to terminate the reaction. After liquid separation, the organic phase was concentrated under reduced pressure to a pale yellow oily substance to obtain the refined product of the compound of formula (3);

[0058] Deprotection-transposition reaction: The refined product of the above-mentioned compound of formula (3) was added to the reaction kettle, 10 L of tetrahydrofuran was added, and after stirring to dissolve clearly, 0.5 kg of concentrated hydrochloric acid was added dropwise. The temperature was controlled at 20 °C to 40 °C, and the reaction was carried out for 2 hours to form the compound of formula (2);

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

[0060] 0.88 kg of crude dienogest was obtained in Comparative Example 1; 0.75 kg of refined dienogest was obtained in the first-stage refining; HPLC purity was 99.75%; 0.1 kg of refined dienogest was obtained in the second-stage refining, and HPLC purity was 99.73%;

[0061] A total of 0.85 kg of refined dienogest was obtained in the first-stage refining and the second-stage refining, the average HPLC purity was 99.75%, and the total yield was 85.8%.

[0062] It can be seen from the comparison between Comparative Example 1 and Example 1 that although the separation of the product after the addition reaction was omitted in Example 1 of the present invention, the refined product of dienogest with higher purity and higher yield can be obtained by using the one-pot method for the addition reaction and the deprotection-transposition reaction.

[0063] The above-described embodiments only represent several embodiments of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

Claims

1. A method for preparing dienogest by a one-pot process, characterized in that: The reaction formula of the method is as follows: The method comprises: performing an addition reaction between a compound of formula (1) and an acetonitrile anion in an ultra-low temperature environment, quenching with acid after the reaction is completed; and then directly adding concentrated hydrochloric acid to perform a deprotection-transposition reaction to obtain a compound of formula (2).

2. The method for preparing dienogest by one-pot method according to claim 1, characterized in that: The method also includes crude dienogest and refined dienogest.

3. The one-pot method for preparing dienogest according to claim 2, characterized in that: The crude dienogest comprises: adjusting the pH of the deprotection-transposition reaction product to neutral using a sodium bicarbonate solution to obtain a reaction solution; The reaction solution was slowly poured into water, stirred for water precipitation and then filtered, and the filter cake was dried at 50° C. to 60° C. to obtain a crude product of dienogest.

4. The method for preparing dienogest by one-pot method according to claim 3, characterized in that: The dienogest refining process comprises: dissolving the crude dienogest in ethanol, heating to 50°C to 80°C for stirring and reacting, cooling to 0°C to 5°C for precipitation, and obtaining a refined mother liquor and a fine dienogest product after solid-liquid separation.

5. The one-pot method for preparing dienogest according to claim 4, characterized in that: The dienogest refining further comprises: extracting the dienogest fine product from the refined mother liquor.

6. The one-pot method for preparing dienogest according to claim 5, characterized in that: The refined mother solution for extracting the fine product of dienogest comprises: The mother liquor was concentrated and refined to obtain an oily substance, tetrahydrofuran was added, stirred to dissolve, and concentrated hydrochloric acid was added dropwise, and the reaction was controlled at 20°C to 40°C; The pH of the reaction system is adjusted to neutral with a sodium bicarbonate solution, which is slowly poured into water, stirred for water precipitation, and then filtered, and the filter cake is dried at 50° C. to 60° C. to obtain a crude dienogest; The crude dienogest is dissolved in ethanol, heated to 50°C to 80°C and stirred for 2 hours, cooled to 0°C to 5°C to precipitate, and after solid-liquid separation, a fine dienogest product is obtained.

7. The one-pot method for preparing dienogest according to claim 1, characterized in that: The specific operation of the addition reaction includes: In a n-butyl lithium solution at -60°C to -80°C, tetrahydrofuran is added dropwise under temperature control, and then a mixed solution of acetonitrile and tetrahydrofuran is added dropwise; Then, the compound of formula (1) and tetrahydrofuran solution are added dropwise, and after the addition is completed, the temperature is controlled at -60°C to -80°C for reaction. After the reaction is completed, dilute hydrochloric acid is added dropwise to terminate the reaction.

8. The one-pot method for preparing dienogest according to claim 1, characterized in that: The temperature of the deprotection-transposition reaction is 20°C to 40°C.

Images