Purification method of desogestrel

Abstract

The present invention provides a desogestrel refining method, comprising the following steps: mixing a crude desogestrel with a first organic solvent, dissolving it for the first time, and preparing a first solution; mixing the first solution with activated carbon, decolorizing, filtering, taking the filtrate and concentrating it, and preparing a first solute; mixing the first solute with a displacement agent, concentrating it, and preparing a second solute; mixing the second solute with a second organic solvent, dissolving it for the second time, and preparing a second solution; mixing the second solution with a poor solvent, crystallizing, filtering, taking a filter cake, washing, and drying; wherein the poor solvent includes a sodium chloride aqueous solution. The fine desogestrel particles obtained by the refining method are relatively small and have low hardness. The entire crystallization system is very easy to discharge, the stirring paddle will not lock, the pipeline will not be blocked, and the production environment has been significantly improved. In addition, the product yield and purity obtained by the desogestrel refining method have also been significantly improved.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, in particular to a method for refining desogestrel. Background Art

[0002] Desogestrel is a white crystalline powder with a molecular formula of C 22 H 30 O, molecular weight is 310.48, insoluble in water, soluble in ethanol. Desogestrel is a new generation of steroidal contraceptives with high efficiency, low toxicity and no side effects. It was first developed by Organon of the Netherlands in 1992 for oral contraception and has broad market prospects. Desogestrel, as a progestin contraceptive, has strong anti-estrogen activity, has a significant inhibitory effect on ovulation and gonadotropin secretion and endometrial development, can change the concentration of cervical mucus, etc., and is used to prevent pregnancy.

[0003] The classic route for preparing desogestrel is shown below. This method is mature and has a good yield, but it uses stinky ethanedithiol, which has a very adverse effect on research and development and production. In addition, in order to increase the yield, the 17-hydroxyl group is first reduced and then oxidized, which is a bit cumbersome.

[0004]

[0005] There is also a traditional method of first introducing the alkynyl group and then removing the 3-protection, as shown below. The total yield is 37.6% and no obvious side reactions are observed. However, in this method, the ethanedithiol protective agent is used until the end, and the cyclic sulfide is finally removed by a reduction reaction. Therefore, it is impossible to eliminate the odor in the finished product, and it is difficult to adopt it in actual production.

[0006]

[0007] Another traditional method adopts the following preparation route, which is simple and has a total yield of 38%, and is suitable for industrial preparation.

[0008]

[0009] The desogestrel refining steps used in the above preparation method are almost all crystallized in a single solvent, such as a non-polar solvent such as n-hexane. In fact, in the traditional crystallization method of desogestrel, due to the different solubility of desogestrel in various solvents, the crude desogestrel is mostly crystallized in a non-polar solvent, which easily leads to very large particles of desogestrel crystallized, and the problem of the agitator blade being stuck. In addition, the particles are easy to agglomerate and have a very high hardness, making it very difficult to discharge the material in a small test, not to mention the discharge of the material in industrial production.

[0010] There is also a traditional refining step that uses a reactor to dissolve the material, then directly discharges it into a large barrel and uses manual stirring to crystallize it. However, this crystallization method cannot pass the current GMP standards and is extremely unfriendly to the production environment. Summary of the invention

[0011] Based on this, the present invention provides a method for refining desogestrel, wherein the obtained desogestrel fine particles are relatively small, low in hardness, easy to discharge, and have a high yield and purity.

[0012] The present invention is achieved through the following technical solutions.

[0013] A method for refining desogestrel comprises the following steps:

[0014] The crude desogestrel is mixed with a first organic solvent and dissolved for the first time to prepare a first solution;

[0015] The first solution is mixed with activated carbon, decolorized, filtered, and the filtrate is concentrated to prepare a first solute;

[0016] The first solute is mixed with a displacing agent and concentrated to prepare a second solute;

[0017] mixing the second solute with a second organic solvent and dissolving them for a second time to prepare a second solution;

[0018] The second solution is mixed with a poor solvent, crystallized, filtered, the filter cake is taken, washed, and dried; wherein the poor solvent comprises a sodium chloride aqueous solution.

[0019] In one embodiment, the poor solvent further includes water.

[0020] In one of the embodiments, the mass fraction of the sodium chloride aqueous solution is 10% to 30%.

[0021] In one embodiment, the first organic solvent is selected from one or more of dichloromethane, ethanol, methanol and acetone.

[0022] In one embodiment, the displacer and the second organic solvent are both non-polar solvents.

[0023] In one embodiment, the displacer and the second organic solvent are independently selected from one or more of n-heptane, n-hexane, n-pentane, isooctane, chloroform, benzene and toluene.

[0024] In one embodiment, the temperature condition of the second dissolution is 55°C to 70°C.

[0025] In one embodiment, the crystallization conditions include: temperature of 0°C to 5°C and time of 1h to 2h.

[0026] In one embodiment, the mass ratio of the crude desogestrel to the first organic solvent is 1:(5-10); and / or

[0027] The mass volume ratio of the crude desogestrel to the second organic solvent is 1 g:(2 mL to 3 mL).

[0028] In one embodiment, the mass volume ratio of the crude desogestrel to the poor solvent is 1 g:(1 mL to 2 mL).

[0029] Compared with the prior art, the desogestrel refining method of the present invention has the following beneficial effects:

[0030] The desogestrel purification method of the present invention is to dissolve, decolorize and concentrate the desogestrel crude product in sequence, and then make the product concentrated to dry be dissolved in an organic solvent, and then add sodium chloride aqueous solution to the dissolved purification system for crystallization, the solid separated out is in the organic phase, and the density of the organic phase is less than that of the sodium chloride aqueous solution, and is in the upper layer, so that it will not be blocked in the discharge port. At the same time, the sodium chloride aqueous solution is used as a poor solvent to significantly reduce the chance of solid particles colliding together during the crystallization process, and the solid particles finally separated out are relatively small, so that the problem of the locking of the stirring paddle in the refining process can not only be avoided, but also the situation of the particle agglomeration can be reduced, and the hardness will also be reduced. In summary, the desogestrel fine particles obtained by the desogestrel purification method of the present invention are relatively small, low in hardness, and the whole crystallization system is very easy to discharge, the stirring paddle will not lock, and the pipeline will not be blocked, and the production environment has been significantly improved.

[0031] In addition, the yield and purity of the product obtained by the desogestrel purification method of the present invention are also significantly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0033] Figure 1 A diagram of mechanical stirring provided by the present invention;

[0034] Figure 2 The mechanical stirring diagram provided by the present invention. DETAILED DESCRIPTION

[0035] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. The preferred embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present invention more thorough and comprehensive.

[0036] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the invention, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of the present invention, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0037] The words "preferably", "more preferably", etc. in the present invention refer to embodiments of the present invention that may provide certain beneficial effects in certain circumstances. However, other embodiments may also be preferred under the same circumstances or other circumstances. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not applicable, nor is it intended to exclude other embodiments from the scope of the present invention.

[0038] When a numerical range is disclosed herein, the above range is considered to be continuous and includes the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be combined. In other words, unless otherwise indicated, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0039] Unless otherwise specified, all percentages, fractions and ratios are calculated by the total mass of the composition of the present invention. Unless otherwise specified, all masses of the listed ingredients are given to the content of active substances, so they do not include solvents or by-products that may be contained in commercially available materials. The term "mass percentage content" herein can be represented by the symbol "%". Unless otherwise specified, all molecular weights in this article are weight average molecular weights expressed in Daltons. Unless otherwise specified, all formulations and tests in this article occur in an environment of 25°C. "Including", "including", "containing", "containing", "having" or other variants herein are intended to cover non-closed inclusions, and these terms are not distinguished. The term "comprising" means that other steps and ingredients that do not affect the final result can be added. The composition and method / process of the present invention include, consist of and are essentially composed of the necessary elements and restrictions described herein and any additional or optional ingredients, components, steps or restrictions described herein. The terms "efficacy", "performance", "effect" and "efficacy" are not distinguished between herein.

[0040] The weight of the relevant components mentioned in the description of the embodiments of the present invention may not only refer to the specific content of each component, but also indicate the weight ratio between the components. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the description of the embodiments of the present invention, it is within the scope disclosed in the description of the embodiments of the present invention. Specifically, the weight described in the description of the embodiments of the present invention may be a mass unit known in the chemical industry such as ug, mg, g, kg, etc.

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0042] The present invention provides a method for refining desogestrel, comprising the following steps:

[0043] The crude desogestrel is mixed with a first organic solvent and dissolved for the first time to prepare a first solution;

[0044] The first solution is mixed with activated carbon, decolorized, filtered, and the filtrate is concentrated to prepare a first solute;

[0045] The first solute is mixed with a displacing agent and concentrated to prepare a second solute;

[0046] mixing a second solute with a second organic solvent and dissolving the second solute for a second time to prepare a second solution;

[0047] The second solution is mixed with a poor solvent, crystallized, filtered, the filter cake is taken, washed, and dried; wherein the poor solvent comprises a sodium chloride aqueous solution.

[0048] The present invention adds sodium chloride aqueous solution to the dissolved refining system for crystallization. Desogestrel is almost insoluble in sodium chloride aqueous solution, so it can be used as a poor solvent for crystallization. The precipitated solid is in the organic phase, and the density of the organic phase is smaller than that of the sodium chloride aqueous solution, and it is in the upper layer, so it will not be blocked at the discharge port, the stirring paddle will not be locked, and the pipeline will not be blocked. At the same time, the use of sodium chloride aqueous solution as a poor solvent can significantly reduce the chance of solid particles colliding together during the crystallization process, and the solid particles finally precipitated are smaller, which can not only avoid the problem of the stirring paddle being locked during the refining process, but also reduce the situation of particle agglomeration, and the hardness will also be reduced.

[0049] In a specific example, the poor solvent also includes water.

[0050] It can be understood that the poor solvent is a sodium chloride aqueous solution, or a mixture of a sodium chloride aqueous solution and water.

[0051] More specifically, the poor solvent is a mixture of sodium chloride aqueous solution and water in a volume ratio of 1:1.

[0052] In a specific example, the mass fraction of the sodium chloride aqueous solution is 10% to 30%.

[0053] It can be understood that in the present invention, the mass fraction of sodium chloride aqueous solution includes but is not limited to 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, and 30%.

[0054] In a specific example, the first organic solvent is selected from one or more of dichloromethane, ethanol, methanol and acetone.

[0055] In a specific example, both the displacer and the second organic solvent are non-polar solvents.

[0056] Sodium chloride aqueous solution and non-polar solvents are insoluble in each other and can be separated into layers.

[0057] In a specific example, the displacer and the second organic solvent are independently selected from one or more of n-heptane, n-hexane, n-pentane, isooctane, chloroform, benzene and toluene.

[0058] In a specific example, the temperature condition of the second dissolution is 55°C to 70°C.

[0059] It can be understood that in the present invention, the temperature of the second dissolution includes but is not limited to 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, and 70°C.

[0060] In a specific example, the crystallization conditions include: a temperature of 0° C. to 5° C. and a time of 1 h to 2 h.

[0061] It can be understood that the crystallization temperature includes but is not limited to 0℃, 0.5℃, 1℃, 1.5℃, 2℃, 2.5℃, 3℃, 3.5℃, 4℃, 4.5℃, and 5℃; the crystallization time includes but is not limited to 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, and 2h.

[0062] In a specific example, the mass ratio of the crude desogestrel to the first organic solvent is 1:(5-10).

[0063] It can be understood that in the present invention, the mass ratio of the crude desogestrel to the first organic solvent includes but is not limited to 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, and 1:10.

[0064] In a specific example, the mass volume ratio of the crude desogestrel to the second organic solvent is 1 g:(2 mL to 3 mL).

[0065] It can be understood that in the present invention, the mass volume ratio of the crude desogestrel to the second organic solvent includes but is not limited to 1g:2mL, 1g:2.1mL, 1g:2.2mL, 1g:2.3mL, 1g:2.4mL, 1g:2.5mL, 1g:2.6mL, 1g:2.7mL, 1g:2.8mL, 1g:2.9mL, and 1g:3mL.

[0066] In a specific example, the mass volume ratio of crude desogestrel to poor solvent is 1 g:(1 mL to 2 mL).

[0067] It can be understood that in the present invention, the mass volume ratio of crude desogestrel to poor solvent includes but is not limited to 1g:1mL, 1g:1.1mL, 1g:1.2mL, 1g:1.3mL, 1g:1.4mL, 1g:1.5mL, 1g:1.6mL, 1g:1.7mL, 1g:1.8mL, 1g:1.9mL, 1g:2mL.

[0068] In a specific example, the reagent used for washing is a non-polar solvent.

[0069] More specifically, the reagent used for washing is selected from one or more of n-heptane, n-hexane, n-pentane, isooctane, chloroform, benzene and toluene.

[0070] In a specific example, the drying temperature is 45°C to 50°C.

[0071] In a specific example, the drying time is 5 hours to 10 hours.

[0072] The desogestrel purification method of the present invention is further described in detail below in conjunction with specific examples. The raw materials used in the following examples, unless otherwise specified, are all commercially available products.

[0073] Example 1

[0074] This embodiment provides a method for refining desogestrel, and the specific steps are as follows:

[0075] Take a three-necked flask, add 700g of dichloromethane and 100g of crude desogestrel into the flask, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate to dryness under reduced pressure, and then replace with 50mL of n-heptane to dryness. Add 300mL of n-heptane solvent into the reaction flask, heat to 55℃~70℃, stir mechanically to dissolve the materials, and when the reaction liquid is clear, begin to drop 100mL of 10% saline solution by mass, and after the drop is complete, begin to cool down to 0℃~5℃, and crystallize for 1 hour to 2 hours (the particles are fine, and the stirring paddle does not lock). Figure 1 Then filter (good filtration), rinse the filter cake with about 5 mL of n-heptane, spin dry, spread on a plate, and dry at 45°C to 50°C for 7 hours to obtain 93.0 g of desogestrel fine product with a yield of 93.0% and a purity of more than 99%, which meets the requirements of the pharmacopoeia.

[0076] Example 2

[0077] This embodiment provides a method for refining desogestrel, and the specific steps are as follows:

[0078] Take a three-necked flask, add 700g of dichloromethane and 100g of crude desogestrel into the three-necked flask, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate under reduced pressure to dryness, and then replace with 50mL of n-heptane to dryness. Add 300mL of n-heptane solvent to the reaction flask, heat to 55℃ to 70℃, mechanically stir to dissolve the material, and when the reaction liquid is clear, start to drop 100mL of purified water and 100mL of 20% saline solution by mass, drop after drop, start cooling, cool to 0℃ to 5℃, crystallize for 1 hour to 2 hours (fine particles, stirring paddle does not appear locked), filter (very good filtration), rinse the filter cake with about 5mL of n-heptane, spin dry, spread on a plate, dry at 45℃ to 50℃ for 7 hours, and obtain 92.3g of desogestrel fine product, with a yield of 92.3%, a purity greater than 99%, and meet the requirements of the pharmacopoeia.

[0079] Example 3

[0080] This embodiment provides a method for refining desogestrel, and the specific steps are as follows:

[0081] Take a three-necked flask, add 700g of dichloromethane and 100g of crude desogestrel into the three-necked flask, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate to dryness under reduced pressure, and then replace with 50mL of n-heptane to dryness. Add 200mL of n-heptane solvent to the reaction flask, heat to 55℃~70℃, mechanically stir to dissolve the material, and when the reaction liquid is clear, start to drop 100mL of 30% saline solution by mass, drop after drop, start cooling, cool to 0℃~5℃, crystallize for 1 hour to 2 hours (the particles are fine, and the stirring paddle does not appear to be stuck), filter (very good filtration), rinse the filter cake with about 5mL of n-heptane, spin dry, spread on a plate, dry at 45℃~50℃ for 7 hours, and obtain 92g of desogestrel fine product, with a yield of 93%, a purity greater than 99%, and an ignition exceeding the standard.

[0082] Example 4

[0083] This embodiment provides a method for refining desogestrel, and the specific steps are as follows:

[0084] Take a reactor, add 140kg of dichloromethane and 20kg of crude desogestrel into the reactor, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate to dryness under reduced pressure, and then replace with 1L of n-heptane to dryness. Add 60L of n-heptane solvent into the reaction bottle, heat to 55℃~70℃, mechanically stir to dissolve the material, and when the reaction liquid is clear, start to drop 20L of 10% saline solution by mass, drop after drop, start cooling, cool to 0℃~5℃, crystallize for 1 hour to 2 hours (the particles are fine, and the stirring paddle does not appear to be stuck), filter (better filtration), rinse the filter cake with about 5mL of n-heptane, spin dry, spread on a plate, and dry at 45℃~50℃ for 7 hours to obtain 18.8g of desogestrel fine product, with a yield of 94% and a purity greater than 99%, which meets the requirements of the pharmacopoeia.

[0085] Example 5

[0086] This embodiment provides a method for refining desogestrel, and the specific steps are as follows:

[0087] Take a three-necked flask, add 700g of dichloromethane and 100g of crude desogestrel into the three-necked flask, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate to dryness under reduced pressure, and then replace with 50mL of n-heptane to dryness. Add 300mL of n-heptane solvent to the reaction flask, heat to 55℃~70℃, mechanically stir to dissolve the material, and when the reaction liquid is clear, start to drip 100mL of 5% saline solution by mass, after dripping, start cooling, cool to 0℃~5℃, crystallize for 1 hour to 2 hours (fine particles, no locking of the stirring paddle). Then filter (easy to filter), rinse the filter cake with about 5mL of n-heptane, spin dry, spread on a plate, dry at 45℃~50℃ for 7 hours, and obtain 88.0g of desogestrel fine product, with a yield of 88% and a purity greater than 99%, which meets the requirements of the pharmacopoeia.

[0088] Example 6

[0089] This embodiment provides a method for refining desogestrel, and the specific steps are as follows:

[0090] Take a three-necked flask, add 700g of dichloromethane and 100g of crude desogestrel into the three-necked flask, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate to dryness under reduced pressure, and then replace with 50mL of n-heptane to dryness. Add 300mL of n-heptane solvent to the reaction flask, heat to 55℃~70℃, mechanically stir to dissolve the material, and when the reaction liquid is clear, start to drop 100mL of 50% saline solution by mass, drop after drop, start cooling, cool to 0℃~5℃, crystallize for 1 hour to 2 hours (fine particles, no locking of the stirring paddle). Then filter (better filtration), rinse the filter cake with about 5mL of n-heptane, spin dry, spread on a plate, dry at 45℃~50℃ for 7 hours, and obtain 90.1g of desogestrel fine product, with a yield of 90.1% and a purity greater than 99%, which meets the requirements of the pharmacopoeia.

[0091] Example 7

[0092] This embodiment provides a method for refining desogestrel, and the specific steps are as follows:

[0093] Take a three-necked flask, add 700g of dichloromethane and 100g of crude desogestrel into the three-necked flask, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate to dryness under reduced pressure, and then replace with 50mL of n-hexane to dryness. Add 300mL of n-hexane solvent to the reaction flask, heat to 55℃~70℃, mechanically stir to dissolve the material, and when the reaction liquid is clear, start to drip 100mL of 10% saline solution by mass, after dripping, start cooling, cool to 0℃~5℃, crystallize for 1 hour to 2 hours (fine particles, no locking of the stirring paddle). Then filter (better filtration), rinse the filter cake with about 5mL of n-hexane, spin dry, spread on a plate, dry at 45℃~50℃ for 7 hours, and obtain 85.6g of desogestrel fine product, with a yield of 85.6% and a purity greater than 99%, which meets the requirements of the pharmacopoeia.

[0094] Example 8

[0095] This embodiment provides a method for refining desogestrel, and the specific steps are as follows:

[0096] Take a three-necked flask, add 700g of dichloromethane and 100g of crude desogestrel into the three-necked flask, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate to dryness under reduced pressure, and then replace with 50mL of n-heptane to dryness. Add 300mL of n-heptane solvent to the reaction flask, heat to 55℃~70℃, mechanically stir to dissolve the material, and when the reaction liquid is clear, start to drip 100mL of 10% saline solution by mass, after dripping, start cooling, cool to 10℃, crystallize for 1 hour to 2 hours (fine particles, no locking of the stirring paddle). Then filter (easy to filter), rinse the filter cake with about 5mL of n-heptane, spin dry, spread on a plate, dry at 45℃~50℃ for 7 hours, and obtain 89.6g of desogestrel fine product, with a yield of 89.6% and a purity greater than 99%, which meets the requirements of the pharmacopoeia.

[0097] Example 9

[0098] This embodiment provides a method for refining desogestrel, and the specific steps are as follows:

[0099] Take a three-necked flask, add 700g of dichloromethane and 100g of crude desogestrel into the flask, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate to dryness under reduced pressure, and then replace with 50mL of n-heptane to dryness. Add 200mL of n-heptane solvent into the reaction flask, heat to 55℃~70℃, stir mechanically to dissolve the material, and when the reaction liquid is clear, begin to drop 100mL of 10% saline solution by mass, and after the drop is complete, begin to cool down to 0℃~5℃, and crystallize for 1 hour to 2 hours (the particles are fine, and the stirring paddle does not lock). Figure 1 Then filter (preferably filter), rinse the filter cake with about 5 mL of n-heptane, spin dry, spread on a plate, and dry at 45°C to 50°C for 7 hours to obtain 92.5 g of desogestrel fine product with a yield of 92.5% and a purity of more than 99%, which meets the requirements of the pharmacopoeia.

[0100] Comparative Example 1

[0101] This comparative example provides a method for refining desogestrel, and the specific steps are as follows:

[0102] Take a three-necked flask, add 700g of dichloromethane and 100g of crude desogestrel, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate to dryness under reduced pressure, and then replace with 50mL of n-heptane to dryness. Add 200mL of n-heptane solvent to the reaction flask, heat to 55℃~70℃, mechanically stir to dissolve the material, and cool down to about 30℃ while stirring. The mechanical stirring is stuck and can no longer be stirred. Figure 2As shown, continue to cool to 0°C ~ 5°C, crystallize for 1 hour to 2 hours, filter (the solid particles are large and hard, and cannot be discharged, so they can only be crushed with an iron spoon), rinse the filter cake with about 5 mL of n-heptane, spin dry, spread on a plate, and dry at 45°C ~ 50°C for 7 hours to obtain desogestrel with a yield of 90% and a purity of more than 99%, which meets the requirements of the pharmacopoeia.

[0103] Comparative Example 2

[0104] This comparative example provides a method for refining desogestrel, and the specific steps are as follows:

[0105] Take a three-necked flask, add 700g of dichloromethane and 100g of crude desogestrel into the three-necked flask, stir to dissolve it completely, then add activated carbon, stir for 1 hour to 1.5 hours, filter, concentrate to dryness under reduced pressure, and then replace with 50mL of n-heptane to dryness. Add 300mL of n-heptane solvent to the reaction flask, heat to 55℃~70℃, mechanically stir to dissolve the material, and when the reaction liquid is clear, start to drop 100mL of purified water, drop after, start cooling, cool to 0℃~5℃, crystallize for 1 hour to 2 hours (the particles are fine, and the stirring paddle does not appear to be stuck), filter (very good filtering), rinse the filter cake with about 5mL of n-heptane, dry, spread on a plate, dry at 45℃~50℃ for 7 hours, and obtain 85g of desogestrel fine product, with a yield of 85%, a purity greater than 99%, and meet the requirements of the pharmacopoeia.

[0106] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0107] The above-described embodiments only express several implementation methods of the present invention, which are convenient for understanding the technical solutions of the present invention in detail, but they cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present invention are all within the protection scope of the claims attached to the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the contents of the attached claims, and the description and drawings can be used to interpret the contents of the claims.

Claims

1. A method for refining desogestrel, characterized in that: The steps include: Mixing the crude desogestrel with a first organic solvent and dissolving them for the first time to prepare a first solution; wherein the first organic solvent is selected from dichloromethane; The first solution is mixed with activated carbon, decolorized, filtered, and the filtrate is concentrated to prepare a first solute; The first solute is mixed with a displacing agent and concentrated to prepare a second solute; The second solute is mixed with a second organic solvent and dissolved for a second time to prepare a second solution; the displacing agent and the second organic solvent are independently selected from one or more of n-heptane, n-hexane, n-pentane and isooctane; The second solution is mixed with a poor solvent, crystallized, filtered, the filter cake is taken, washed, and dried; wherein the poor solvent comprises a sodium chloride aqueous solution.

2. The method for refining desogestrel according to claim 1, characterized in that: The mass fraction of the sodium chloride aqueous solution is 10% to 30%.

3. The method for refining desogestrel according to claim 1, characterized in that: The displacing agent and the second organic solvent are independently selected from n-heptane or n-hexane.

4. The method for refining desogestrel according to claim 1, characterized in that: The temperature condition for the second dissolution is 55°C to 70°C.

5. The method for refining desogestrel according to claim 1, characterized in that: The crystallization conditions include: temperature of 0°C to 5°C and time of 1h to 2h.

6. The method for refining desogestrel according to claim 1, characterized in that: The mass ratio of the crude desogestrel to the first organic solvent is 1:(5-10); and / or The mass volume ratio of the crude desogestrel to the second organic solvent is 1 g:(2 mL to 3 mL).

7. The method for refining desogestrel according to claim 1, characterized in that: The mass volume ratio of the crude desogestrel to the poor solvent is 1 g:(1 mL to 2 mL).

Images