Preparation method of didrogesterone

Abstract

The invention discloses a preparation method of didrogesterone, which comprises the following steps: protecting a 20-site carbonyl group by using dithiol, promoting double bond transposition by using a hydrogen chloride solution with lower concentration, and finally removing mercaptan by using iodine to obtain the didrogesterone. In the whole process, formation of chiral isomers caused by conversion from an enol form to a ketone form is avoided, generation of C impurities is eliminated from the mechanism, the yield is greatly increased, and the follow-up refining difficulty is greatly lowered. And the generation of C impurities is eliminated from the mechanism, so that the reaction temperature can be increased to promote double bond transposition, the use of a high-concentration hydrogen chloride solution is avoided, and the process is more environment-friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a preparation method of dydrogesterone. BACKGROUND

[0002] Dydrogesterone, chemical name: 9β,10α-pregn-4,6-dien-3,20-dione, is produced by the Dutch Abbott Company for tocolysis and prevention of abortion and various diseases caused by endogenous progesterone deficiency, such as dysmenorrhea, endometriosis, secondary amenorrhea, irregular menstrual cycle, dysfunctional uterine bleeding, premenstrual syndrome, threatened abortion or habitual abortion caused by progesterone deficiency, and infertility caused by corpus luteum deficiency. At present, there are two products, Duphaston (dydrogesterone tablets) and Femoston (estradiol tablets / estradiol dydrogesterone tablet composite package), which are sold in many countries and regions. The molecular structure formula is as follows:

[0003] Compound 3, chemical name: 9α,10β-pregn-4,6-dien-3,20-diglycol ketal, can be obtained by photochemistry to obtain compound 1, compound 1 is deprotected to obtain compound 2, and compound 2 is prepared into dydrogesterone through double bond shift and other steps, as shown below:

[0004] Report 1: CN110818760A reports that compound 1 is prepared into dydrogesterone in concentrated hydrochloric acid or saturated hydrogen chloride in methanol or ethyl acetate or tetrahydrofuran solution, and the yield is between 80% and 85%.

[0005] Report 2: The literature Recueil des Travaux Chimiques des Pays-bas (1961), 80:43-46 uses a large amount of 37% hydrogen chloride-isopropyl alcohol solution in the double bond isomerization step, while the highest concentration of hydrogen chloride-alcohol solution used in general industry is 35%, so it is necessary to continuously supplement hydrogen chloride gas to ensure the concentration of 37% during the production process.

[0006] Report 3: CN107531746A reports that compound 1 is prepared into dydrogesterone under the action of an alkali containing sodium or potassium, a large amount of compound 1 is not completely converted during the reaction process, and column chromatography separation and purification are also needed, and the actual weight yield is only about 80% at most.

[0007] It is worth noting that in the route of the conventional synthesis of progesterone, compound 1 is subjected to double bond transposition under hydrogen chloride conditions to obtain dydrogesterone, but this method inevitably produces a large amount of 17-carbon chiral inversion impurity C (a pharmacopoeia impurity), and the mechanism of the generation of the impurity is that the 20-carbonyl group undergoes enol tautomerization under strong acidic conditions to form an enol form, the enol form and the ketone form are reversibly tautomeric, and when the enol form is converted into the ketone form, partial inversion of the 17-carbon chiral group occurs, which reduces the acid concentration and reduces the generation of the impurity, but also causes the double bond transposition to be incomplete. SUMMARY

[0008] The present application provides a preparation method of dydrogesterone, which at least solves one of the problems of the prior art, such as the production of impurities in the transposition reaction, the dependence on high-concentration hydrogen chloride alcohol solution, and the difficulty in post-processing.

[0009] Therefore, the present application provides the following solutions: A preparation method of dydrogesterone, comprising the following steps: S1. Compound 1 is mixed with aprotic polar solvent, and dithiol is added, and addition reaction is carried out under stirring by adding p-toluenesulfonic acid, and the product is separated to obtain compound 2; S2. Compound 2 is dissolved, and hydrogen chloride alcohol solution is added to carry out double bond transposition reaction under stirring to obtain compound 3, and then the reaction is quenched; S3. Iodine is added to the reaction product of step S2 to carry out deprotection reaction, and the product is separated after the reaction to obtain dydrogesterone; The dithiol has the structural formula of SH-R-SH, and R is an alkyl group; The reaction route of the preparation method is as follows: .

[0010] Further, in step S1, The ratio of compound 1 to aprotic polar solvent is 1 g: 3 ml to 15 ml; And / or, the aprotic polar solvent is one or more of dichloromethane, ethyl acetate, acetone, tetrahydrofuran, and toluene; The dithiol is 1,2-ethanedithiol or 1,3-propanedithiol; and / or, the ratio of dithiol to compound 1 is (2-3 ml): 1 g.

[0011] Further, in step S1, the addition reaction temperature is 20-80°C, and the reaction time is 4h-24h.

[0012] Further, in step S1, the process of separating the product is as follows: after the reaction is completed, water is added for quenching, the layers are separated, the organic phase is washed with sodium bicarbonate aqueous solution, and then washed with water; after the organic phase is concentrated, it is dissolved in tetrahydrofuran, water is added to precipitate the solid, the solid is filtered, washed with water, and dried to obtain compound 2.

[0013] Further, in step S2: The alcohol in the hydrogen chloride alcohol solution is methanol, ethanol, or isopropanol; And / or, the concentration of hydrogen chloride in the hydrogen chloride alcohol solution is 10-15 wt%; And / or, the solvent is dichloromethane and / or trichloromethane; And / or, the quenching reagent is an organic amine or a carbonate; And / or, in step S2, the double bond isomerization reaction temperature is 20-40℃; preferably 30-40℃, and the reaction time is 10-15h.

[0014] Further, in step S3: The deprotection reagent is iodine or iodosobenzoic acid or NBS; And / or, the deprotection reaction temperature is 0-10℃, and the reaction time is 2-4h; preferably 0-5℃, and the reaction time is 3h.

[0015] And / or, in step S3, the process of separating the product is as follows: after the quenching agent is added, the organic phase is separated, isopropanol is added to the organic phase, the reaction solvent is removed under negative pressure, and the product is precipitated to obtain the compound 2. Preferably, the quenching agent is sodium sulfite or sodium thiosulfate aqueous solution; and / or, the ratio of the amount of isopropanol to the amount of compound 2 is (1.5-3) mL: 1g.

[0016] Compared with the prior art, the present application has the following advantages: The preparation method provided by the present application uses dithiol to first protect the 20-position carbonyl group, uses a lower concentration of hydrogen chloride solution to promote double bond isomerization, and finally uses iodine to remove the dithiol to obtain the compound 2. The whole process avoids the formation of chiral isomers when the enol form is converted to the ketone form, eliminates the generation of C impurities from the mechanism, greatly improves the yield, and reduces the difficulty of subsequent refining. Moreover, since the generation of C impurities is eliminated from the mechanism, the reaction temperature can be increased to promote double bond isomerization, thereby avoiding the use of high-concentration hydrogen chloride solution, and the process is more green and environmentally friendly. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 The C impurity content analysis results of the reaction product obtained after the deprotection reaction in the preparation process of the compound 2 described in an embodiment of the present application.

[0018] Figure 2The analysis result of the content of C impurities in the reaction product of the comparative example of the present application. DETAILED DESCRIPTION

[0019] The technical solutions of the present application will be described clearly and completely below in combination with preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the present application.

[0020] In one embodiment, a preparation method of dydrogesterone is provided, and the steps include: S1. Compound 1 is mixed with an aprotic polar solvent, dithiol is added, and addition reaction is carried out under stirring by adding p-toluenesulfonic acid, and the product is separated to obtain compound 2; S2. Compound 2 is dissolved, and double bond isomerization reaction is carried out by adding hydrogen chloride alcohol solution under stirring to obtain compound 3, and then the reaction is quenched; S3. Iodine is added to the reaction product of step S2 to carry out deprotection reaction, and the product is separated after the reaction is completed to obtain dydrogesterone; The dithiol has a structural formula of SH-R-SH, R is an alkyl group, preferably a linear alkyl group, and the mercapto groups are respectively substituted on different carbon atoms, and at least two adjacent carbon atoms; optionally, the dithiol includes but is not limited to 1,2-ethanedithiol or 1,3-propanedithiol.

[0021] Taking 1,2-ethanedithiol as an example, the reaction route of the preparation method is as follows: .

[0022] In the above embodiments, the dithiol is used to first protect the 20-position carbonyl group, a lower concentration of hydrogen chloride solution is used to promote the double bond isomerization, and then iodine is used to deproton to obtain dydrogesterone. In the whole process, the formation of chiral isomers caused by the transformation of enol form into ketone form is avoided, the generation of C impurities is significantly eliminated from the mechanism, the yield is greatly improved, and the difficulty of subsequent refining is reduced. Moreover, since the generation of C impurities is eliminated from the mechanism, the reaction temperature can be increased to promote the double bond isomerization, thereby avoiding the use of high-concentration hydrogen chloride solution, and the process is more green and environmentally friendly.

[0023] In some embodiments, the content of C impurities in the reaction product obtained after the deprotection reaction of step S3 of the above preparation route can be reduced to 1.7% or less, and the HPLC detection result is as shown in Figure 1 .

[0024] Embodiment 1

[0025] 1) Add 10g of compound 1, 100mL of toluene, 20mL of ethylenedithiol, and 3g of p-toluenesulfonic acid to the reaction flask in sequence. Keep the mixture at 50℃ and stir for 20h. Monitor the reaction by TLC. After the reaction is complete, add 20mL of drinking water, stir for 0.5h, let stand for 10min, separate the organic layer, add 50mL of 10% sodium bicarbonate solution to the organic layer, stir for 0.5h, let stand for 10min, separate the organic layer, add 20mL of drinking water to the organic layer, stir for 0.5h, let stand for 10min, separate the organic layer, concentrate all solvents to dryness in a water bath at 45℃, add 20mL of tetrahydrofuran and stir to dissolve, add 100mL of water to precipitate the solid, stir for 1h, filter, wash with a small amount of water, and dry at 45℃ to obtain 12.1g of compound 2 with an HPLC purity of 98.9%. 2) Add 10g of compound 2, 50mL of dichloromethane, and 50mL of hydrogen chloride ethanol solution (hydrogen chloride content 10%) to the reaction flask in sequence. Heat to 40℃ and reflux for 12h. Monitor the reaction by TLC. After the reaction is complete, add 60g of sodium carbonate to quench the hydrogen chloride, add 12g of iodine, and react at 0~5℃ for 3h. Add 500mL of saturated sodium sulfite aqueous solution to quench the reaction. Discard the aqueous phase, add 20mL of isopropanol to the organic phase, and dichloromethane is distilled off under negative pressure at 35~40℃. The material precipitates, is filtered, and 7.6g of dydrogesterone with a purity of 99.7% is obtained.

[0026] Example 2

[0027] 1) Add 100g of compound 1, 1000mL of toluene, 200mL of ethylenedithiol, and 30g of p-toluenesulfonic acid to the reaction flask in sequence. Keep the mixture at 50℃ and stir for 20h. Monitor the reaction by TLC. After the reaction is complete, add 200mL of drinking water, stir for 0.5h, let stand for 10min, and separate the organic layer. Add 500mL of 10% sodium bicarbonate solution to the organic layer, stir for 0.5h, let stand for 10min, and separate the organic layer. Add 200mL of drinking water to the organic layer, stir for 0.5h, let stand for 10min, and separate the organic layer. Concentrate all solvents to dryness in a water bath at 45℃, add 200mL of tetrahydrofuran and stir to dissolve. Add 1000mL of water to precipitate the solid, stir for 1h, filter, wash with a small amount of water, and dry at 45℃ to obtain 123g of compound 2 with an HPLC purity of 98.4%.

[0028] 2) Add 100g of compound 2, 500mL of dichloromethane, and 500mL of hydrogen chloride ethanol solution (hydrogen chloride content 10%) to the reaction flask in sequence. Heat to 40℃ and reflux for 12h. Monitor the reaction by TLC. After the reaction is complete, add 600g of sodium carbonate to quench the hydrogen chloride, add 120g of iodine, and react at 0~5℃ for 3 hours. Add 5000mL of saturated sodium sulfite aqueous solution to quench the reaction. Discard the aqueous phase, add 200mL of isopropanol to the organic phase, and dichloromethane is distilled off under negative pressure at 35~40℃. The material precipitates out, is filtered, and 78g of dydrogesterone with a purity of 99.8% is obtained.

[0029] Example 3

[0030] 1) Add 10g of compound 1 to the reaction flask sequentially, followed by 50mL of ethyl acetate, 20mL of 1,3-propanedithiol, and then 3g of p-toluenesulfonic acid. Incubate at 60℃ and stir for 20h. Monitor the reaction by TLC. After the reaction is complete, add 20mL of drinking water, stir for 0.5h, let stand for 10min, and separate the organic layer. Add 50mL of 10% sodium bicarbonate solution to the organic layer, stir for 0.5h, let stand for 10min, and separate the organic layer. Add 20mL of drinking water to the organic layer, stir for 0.5h, let stand for 10min, and separate the organic layer. Concentrate all solvents to dryness in a water bath at 45℃, add 20mL of tetrahydrofuran and stir until dissolved. Add 100mL of water to precipitate the solid, stir for 2h, filter, wash with a small amount of water, and dry at 45℃ to obtain 11.9g of compound 2 with an HPLC purity of 98.9%.

[0031] 2) Add 10g of compound 2 to the reaction flask sequentially, followed by 50mL of chloroform and 50mL of isopropanol hydrochloride solution (hydrogen chloride content 10%). Reflux at 40℃ for 12h, monitored by TLC. After the reaction is complete, add 60g of sodium carbonate to quench the hydrogen chloride, then add 10g of iodine. React at 0~5℃ for 3h. Quench the reaction with 500mL of saturated sodium thiosulfate aqueous solution. Discard the aqueous phase, add 20mL of isopropanol to the organic phase, and dichloromethane is distilled off under negative pressure at 35~40℃. The material precipitates, is filtered, and 7.8g of dydrogesterone with a purity of 99.7% is obtained.

[0032] Example 4

[0033] 1) Add 10g of compound 1 to the reaction flask sequentially, followed by 50mL of dichloromethane, 20mL of 1,3-propanedithiol, and then 4g of p-toluenesulfonic acid. Incubate at 40℃ and stir for 16h. Monitor the reaction by TLC. After the reaction is complete, add 20mL of drinking water, stir for 0.5h, let stand for 10min, and separate the organic layer. Add 50mL of 10% sodium bicarbonate solution to the organic layer, stir for 0.5h, let stand for 10min, and separate the organic layer. Add 20mL of drinking water to the organic layer, stir for 0.5h, let stand for 10min, and separate the organic layer. Concentrate all solvents to dryness in a water bath at 45℃, add 20mL of tetrahydrofuran and stir until dissolved, add 100mL of water to precipitate the solid, stir for 3h, filter, wash with a small amount of water, and dry at 45℃ to obtain 11.9g of compound 2 with an HPLC purity of 98.9%.

[0034] 2) Add 10g of compound 2 to the reaction flask sequentially, followed by 50mL of dichloromethane and 50mL of isopropanol hydrochloride solution (hydrogen chloride content 15%). Heat to 35℃ and react for 24h. Monitor the reaction by TLC. After the reaction is complete, add 60g of sodium carbonate to quench the hydrogen chloride, add 11g of iodine, and react at 0~5℃ for 3h. Add 500mL of saturated sodium sulfite aqueous solution to quench the reaction. Discard the aqueous phase, add 20mL of isopropanol to the organic phase, and dichloromethane is distilled off under negative pressure at 35~40℃. The material precipitates, is filtered, and 7.9g of dydrogesterone with a purity of 99.7% is obtained.

[0035] Comparative Example

[0036] 10g of Compound 1 was added sequentially to the reaction flask, followed by 50mL of dichloromethane and 50mL of isopropanol hydrochloride solution (hydrogen chloride content 37%). The mixture was heated to 35℃ and reacted for 24 hours under TLC monitoring. After the reaction was complete, 60g of sodium carbonate was added to quench the hydrogen chloride. The organic phase was analyzed by HPLC, and the results are as follows: Figure 2 As shown, the impurity content in Pharmacopoeia C is approximately 19%.

[0037] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing dydrogesterone, characterized in that the steps include... include: S1. Compound 1 was mixed with an aprotic polar solvent, dithiol was added, and p-toluenesulfonic acid was added under stirring to carry out an addition reaction. The product was separated to obtain compound 2. S2. After dissolving compound 2, add hydrochloric acid solution and stir to carry out double bond transposition reaction to obtain compound 3, and quench the reaction after completion; S3. Iodine is added to the product of step S2 to carry out a deprotection reaction. After the reaction is completed, the product is separated to obtain dydrogesterone. The dithiol has the structural formula SH-R-SH, where R is an alkyl group; The reaction route for the preparation method is as follows: 。 2. The preparation method according to claim 1, characterized in that, In step S1, the ratio of compound 1 to the aprotic polar solvent is 1g: 3ml to 15ml; And / or, the aprotic polar solvent is one or more of dichloromethane, ethyl acetate, acetone, tetrahydrofuran, and toluene; And / or, the dithiol is 1,2-ethanedithiol or 1,3-propanedithiol; And / or, the ratio of the dithiol to compound 1 is (2-3 ml): 1 g.

3. The preparation method according to claim 1, characterized in that, In step S1, the addition reaction temperature is 20–80°C, and the reaction time is 4–24 h.

4. The preparation method according to claim 1, characterized in that, In step S1, the process of separating the product is as follows: after the reaction is completed, water is added to quench the reaction, the product is separated into layers, washed with sodium bicarbonate aqueous solution, washed with water, the organic phase is separated and concentrated, tetrahydrofuran is dissolved, water is added to precipitate the solid, filtered, washed with water, and dried to obtain compound 2.

5. The preparation method according to claim 1, characterized in that, In step S2, the alcohol in the hydrogen chloride solution is methanol, ethanol, or isopropanol; And / or, the concentration of hydrogen chloride in the hydrogen chloride alcohol solution is 10~15wt%.

6. The preparation method according to claim 1, characterized in that, In step S2, the solvent is dichloromethane and / or trichloromethane; And / or, the quenching agent used is an organic amine or a carbonate.

7. The preparation method according to claim 1, characterized in that, In step S2, the double bond translocation reaction temperature is 20~40℃.

8. The preparation method according to claim 1, characterized in that, In step S3, the reagent used for deprotection is iodine, iodophenyl diacetic acid, or NBS; And / or, the deprotection reaction temperature is 0~10℃.

9. The preparation method according to claim 1, characterized in that, In step S3, the process of separating the product is as follows: after adding a quencher, the organic phase is separated, isopropanol is added to the organic phase, the reaction solvent is removed by negative pressure concentration, and dydrogesterone is obtained by material precipitation.

10. The preparation method according to claim 9, characterized in that, The quenching agent is an aqueous solution of sodium sulfite or sodium thiosulfate. And / or, the ratio of the amount of isopropanol to compound 2 is (1.5~3) mL: 1 g.

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