Process for the recovery of desogestrel crystallization mother liquors

Abstract

The present application belongs to the field of organic chemistry, and particularly relates to a recovery method of deoxyprogesterone recrystallization mother liquor, aiming at the problem that after the content ratio of delta 3 isomer and deoxyprogesterone in the crystallization mother liquor reaches 40:60, the deoxyprogesterone cannot be further recovered by the ordinary recrystallization method, and the following scheme is proposed, that is, the recrystallization mother liquor is subjected to side chain degradation, reduction, esterification, bromination, elimination, hydrolysis and Birch reduction to obtain a single-component deoxyprogesterone intermediate. The recrystallization mother liquor of deoxyprogesterone is high-yield converted into single-component 18-methyl-11-methylene estradiol-4-ene-17beta-ol, and the main raw material used is the original waste mother liquor in the production of deoxyprogesterone, which not only meets the high atomic utilization rate of the environmental protection production requirement, but also improves the economic benefit.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemistry, and particularly relates to a recovery method of deoxyprogesterone recrystallization mother liquor. BACKGROUND

[0002] Deoxyprogesterone is the third generation of progestogen, which was firstly developed by Holland Oegalong as oral contraceptive, and its trade name is Marvelon. At present, deoxyprogesterone has been listed in most countries in the world. There are three synthetic routes of deoxyprogesterone (Recueil 1975, 35; Recueil 1988, 331; Tetrahedron 1994, 10709), all of which finally involve a 3-deoxy step, and in this step, a double bond isomer impurity-△3 isomer (i.e. impurity A in European Pharmacopoeia 9.0 of deoxyprogesterone) is inevitably produced. After various deoxy treatments reported, the content of △3 isomer in deoxy crude product is usually in the range of 8-25%. Since the structure and properties of this impurity are very similar to those of the main product, it is difficult to purify subsequently, and repeated recrystallization is required. In order to improve the yield, the crystallization mother liquor needs to be recovered and recrystallized. In the production practice, we found that when the content ratio of △3 isomer and deoxyprogesterone in the crystallization mother liquor reaches 40:60, deoxyprogesterone cannot be further recovered by ordinary recrystallization method. SUMMARY

[0003] The purpose of the present application is to solve the shortcomings in the prior art that when the content ratio of △3 isomer and deoxyprogesterone in the crystallization mother liquor reaches 40:60, deoxyprogesterone cannot be further recovered by ordinary recrystallization method, and a recovery method of deoxyprogesterone recrystallization mother liquor is proposed.

[0004] In order to achieve the above purpose, the present application adopts the following technical scheme:

[0005] The recovery method of deoxyprogesterone recrystallization mother liquor is to prepare 18-methyl-11-methylene estr-4-ene-17β-ol (compound 1) from deoxyprogesterone recrystallization mother liquor:

[0006]

[0007] Deoxyprogesterone recrystallization mother liquor (main components: deoxyprogesterone; △ 3 isomer, compound 3; 17-epimer, compound 4) is used as the starting material, and after side chain degradation, reduction, esterification, bromination, elimination, hydrolysis and reduction, 18-methyl-11-methylene estr-4-ene-17β-ol (compound 1) with single component is obtained, which is the main intermediate of deoxyprogesterone;

[0008]

[0009] comprising the steps of:

[0010] S1, treating the desogestrel recrystallization mother liquor in an aprotic solvent with Fetizon reagent to obtain a mixture of 18-methyl-11-methylene-estra-4-ene-17-one and 18-methyl-11-methylene-estra-3-ene-17-one;

[0011] S2, reducing the mixture of 18-methyl-11-methylene-estra-4-ene-17-one and 18-methyl-11-methylene-estra-3-ene-17-one with sodium borohydride or potassium borohydride in a solvent to obtain a mixture of 18-methyl-11-methylene-estra-4-ene-17β-ol and 18-methyl-11-methylene-estra-3-ene-17β-ol;

[0012] S3, reacting the mixture of 18-methyl-11-methylene-estra-4-ene-17β-ol and 18-methyl-11-methylene-estra-3-ene-17β-ol with acetic anhydride in the presence or absence of a solvent to obtain a mixture of 18-methyl-11-methylene-estra-4-ene-17β-ol, 17-acetate and 18-methyl-11-methylene-estra-3-ene-17β-ol, 17-acetate;

[0013] S4, reacting the mixture of 18-methyl-11-methylene-estra-4-ene-17β-ol, 17-acetate and 18-methyl-11-methylene-estra-3-ene-17β-ol, 17-acetate with bromine or pyridinium tribromide in a solvent to obtain a mixture of 18-methyl-11-methylene-estra-4,5-dibromo-17β-ol, 17-acetate and 18-methyl-11-methylene-estra-3,4-dibromo-17β-ol, 17-acetate;

[0014] S5, reacting the mixture of 18-methyl-11-methylene-estra-4,5-dibromo-17β-ol, 17-acetate and 18-methyl-11-methylene-estra-3,4-dibromo-17β-ol, 17-acetate with an organic base in the presence or absence of an aprotic solvent to obtain a mixture of 18-methyl-11-methylene-estra-3,5-diene-17β-ol, 17-acetate and 18-methyl-11-methylene-estra-2,4-diene-17β-ol, 17-acetate;

[0015] S6, a mixture of 18-methyl-11-methylene-estra-3,5-dien-17β-ol, 17-acetate and 18-methyl-11-methylene-estra-2,4-dien-17β-ol, 17-acetate is treated with a strong acid in a solvent to isomerize the latter conjugated double bond, followed by removal of the 17-protecting group with a base to form the single component 18-methyl-11-methylene-estra-3,5-dien-17β-ol;

[0016] S7, 18-methyl-11-methylene-estra-3,5-dien-17β-ol is subjected to a Birch reaction to reduce the conjugated double bond by 1,4-addition of hydrogen to form 18-methyl-11-methylene-estra-4-en-17β-ol.

[0017] Preferably, in S1, the aprotic solvent refers to one or more of the aprotic solvents commonly used in the field of organic synthesis, such as benzene, toluene, n-hexane, cyclohexane, dimethylformamide, dimethyl sulfoxide.

[0018] Preferably, in S1, the reaction temperature is 100-120°C.

[0019] Preferably, in S2, the solvent refers to a commonly used ether or alcohol, such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, and the reaction temperature is 0-20°C.

[0020] Preferably, in S3, the solvent refers to one or more of toluene, dichloromethane, chloroform, acetic acid, and the reaction temperature is 0-20°C.

[0021] Preferably, in S4, the solvent refers to one or more of dichloromethane, chloroform, carbon tetrachloride, acetic acid, and the reaction temperature is 0-20°C.

[0022] Preferably, in S5, the aprotic solvent is one or more of benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and the organic base is one or more of trimethylpyridine, quinoline, 2-methylquinoline, DBU, and the reaction temperature is 120-140°C.

[0023] Preferably, in the S6, the solvent refers to one or more of methyl alcohol, ethanol, isopropyl alcohol, strong acid such as sulfuric acid, hydrochloric acid, perchloric acid, p-toluene sulfonic acid, the reaction temperature is 40-60℃, the base is inorganic base such as ammonia, potassium carbonate, potassium hydroxide, sodium hydroxide, and the reaction temperature is 20-60℃. Preferably, the mixture of the products 18-methyl-11-methylene-estra-3,5-dien-17β-ol, 17-acetate and 18-methyl-11-methylene-estra-2,4-dien-17β-ol, 17-acetate in S5 is not subjected to acid isomerization, and the mixture obtained by directly removing the protection with base is subjected to Birch reaction, and 18-methyl-11-methylene-estra-4-en-17β-ol can also be obtained as the main product, because the 4-double bond end steric hindrance in the 2,4-dien structure is large, and the lithiation is not easy to generate, so that the 1,2-addition is mainly generated, and the 4-en structure is also generated.

[0024] Compared with the prior art, the present application has the beneficial effects that:

[0025] The present application converts the deoxyprogesterone recrystallization mother liquor into 18-methyl-11-methylene-estra-4-en-17β-ol with single component at high yield, and the main raw material used is the originally discarded mother liquor in the production of deoxyprogesterone, which not only meets the high atomic utilization rate of the environmental protection production requirement, but also improves the economic benefit. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 The synthesis route map of the deoxyprogesterone recrystallization mother liquor recovery method proposed in the present application. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments.

[0028] Example one side chain degradation:

[0029] Deoxyprogesterone mother liquor (brown oil, dry product, containing 53% deoxyprogesterone, 34% Δ3 isomer and 9% 17-epimer, GC) 30g, according to the method in J.C.S. Chem. Comm. 1972, 468, brown oil 27.3g (containing 57% 18-methyl-11-methylene-estra-4-en-17-ketone and 37% 18-methyl-11-methylene-estra-3-en-17-ketone, GC) is obtained.

[0030] Example two reduction:

[0031] Into a 1000 ml three-necked round bottom flask, add the oil obtained from Example 1, 25 g, and stir to dissolve in 500 ml of methanol. Add 10 g of sodium borohydride in portions at room temperature. Monitor the progress of the reaction by TLC. After the reaction is complete, acidify with acetic acid, evaporate the solvent, and extract with water and dichloromethane. Concentrate the organic layer to dryness to obtain 24.3 g of brown oil.

[0032] Example Three Esterification:

[0033] Stir the oil obtained from the above reduction step, 24.3 g, with 120 ml of acetic anhydride. Add 1.2 g of p-toluenesulfonic acid at room temperature. Monitor the progress of the reaction by TLC. After the reaction is complete, add 2 ml of pyridine, and then pour into 500 ml of ice water. Stir for 2 hours. Extract with dichloromethane, wash the organic layer with water, and concentrate to dryness to obtain 26.1 g of brown oil.

[0034] Example Four Bromination:

[0035] Into a 1000 ml three-necked round bottom flask, add the oil obtained from Example 3, 26.1 g, and stir to dissolve in 500 ml of dichloromethane. Add 26 g of pyridinium tribromide in portions at room temperature. Monitor the progress of the reaction by TLC. After the reaction is complete, wash with water. Concentrate the organic layer to dryness to obtain 36.9 g of semisolid.

[0036] Example Five Elimination:

[0037] Add the semisolid obtained from the bromination step, 36.9 g, to 400 ml of xylene and 70 ml of 2-methylquinoline. Reflux under nitrogen for 2 hours. Determine the end point of the reaction by UV after sampling and processing. Add dilute hydrochloric acid and stir vigorously for 30 minutes. Separate the layers, and wash the organic layer with water until it is neutral. Evaporate to dryness under reduced pressure to obtain a light brown oil which crystallizes slowly at room temperature.

[0038] Example Six Hydrolysis:

[0039] Stir the semisolid obtained from the elimination step, 22.3 g, in 500 ml of methanol. Add 6 ml of concentrated hydrochloric acid. Reflux under nitrogen for 2 hours. Determine the end point of the reaction by UV. Cool the reaction mixture and adjust the pH to >11 by adding sodium hydroxide. Stir at room temperature overnight. Neutralize with acetic acid, dilute with 500 ml of water, filter, wash with water, and dry under vacuum to obtain 22.3 g of crude light brown powder. Recrystallize a small amount from methanol to obtain white needle-like crystals with a melting point of 145-148°C. [α] 20 D +21° (c = 1, chloroform)

[0040] Example Seven Birch Reduction:

[0041] In 1000ml four-port round bottom flask, condense ammonia about 200ml under argon protection, add hydrolysis crude product tetrahydrofuran solution (10g / 100ml) and t-butyl alcohol 40ml dropwise, control the internal temperature below -40℃, add 2g lithium batchwise, continue to react for 1 hour, add ethanol dropwise to terminate the reaction, discharge ammonia, increase to room temperature, add glacial acetic acid aqueous solution to adjust pH=5-6, filter the filtrate, evaporate organic solvent under reduced pressure, add water to filter, and vacuum dry to obtain light brown powder 9.7g, recrystallize with n-hexane to obtain white crystalline powder 7.2g, HPLC purity >93%, which can be directly used for subsequent preparation of desogestrel.

[0042] The above description is merely preferred specific embodiments of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art can make equivalent replacements or changes according to the technical solution and the inventive concept of the present application within the technical range disclosed by the present application, which should be covered within the protection scope of the present application.

Claims

1. Process for the recovery of desogestrel crystallization mother liquors, characterized in that, Preparation of 18-methyl-11-methylene-estra-4-ene-17β-ol from deoxyprogesterone recrystallization mother liquor, i.e. compound 1: Preparation of 18-methyl-11-methylene-estra-4-ene-17β-ol from deoxyprogesterone recrystallization mother liquor containing deoxyprogesterone, △3 isomer, 17-epimer, via side chain degradation, reduction, esterification, bromination, elimination, hydrolysis and reduction to obtain single component 18-methyl-11-methylene-estra-4-ene-17β-ol; Comprising the following steps: S1, deoxyprogesterone recrystallization mother liquor is treated with Fetizon reagent in an aprotic solvent to obtain a mixture of 18-methyl-11-methylene-estra-4-en-17-one and 18-methyl-11-methylene-estra-3-en-17-one; S2, the mixture of 18-methyl-11-methylene-estra-4-en-17-one and 18-methyl-11-methylene-estra-3-en-17-one is reduced to a mixture of 18-methyl-11-methylene-estra-4-en-17β-ol and 18-methyl-11-methylene-estra-3-en-17β-ol with sodium borohydride or potassium borohydride in a solvent; S3, the mixture of 18-methyl-11-methylene-estra-4-en-17β-ol and 18-methyl-11-methylene-estra-3-en-17β-ol is reacted with acetic anhydride in the presence or absence of a solvent to form a mixture of 18-methyl-11-methylene-estra-4-en-17β-acetate and 18-methyl-11-methylene-estra-3-en-17β-acetate; S4, the mixture of 18-methyl-11-methylene-estra-4-en-17β-acetate and 18-methyl-11-methylene-estra-3-en-17β-acetate is reacted with bromine or pyridinium tribromide in a solvent to form a mixture of 18-methyl-11-methylene-estra-4,5-dibromo-17β-acetate and 18-methyl-11-methylene-estra-3,4-dibromo-17β-acetate; S5, the mixture of 18-methyl-11-methylene-estra-4,5-dibromo-17β-acetate and 18-methyl-11-methylene-estra-3,4-dibromo-17β-acetate is reacted with an organic base in the presence or absence of an aprotic solvent to form a mixture of 18-methyl-11-methylene-estra-3,5-diene-17β-acetate and 18-methyl-11-methylene-estra-2,4-diene-17β-acetate; S6, the mixture of 18-methyl-11-methylene-estra-3,5-diene-17β-acetate and 18-methyl-11-methylene-estra-2,4-diene-17β-acetate is treated with a strong acid in a solvent to isomerize the latter conjugated double bond, and then the 17-protecting group is removed with a base to form single component 18-methyl-11-methylene-estra-3,5-diene-17β-ol; S7, 18-methyl-11-methylene-estra-3,5-diene-17β-ol is subjected to 1,4-addition reduction of conjugated double bond by Birch reaction to obtain 18-methyl-11-methylene-estra-4-en-17β-ol.

2. The method for recovering a desogestrel crystallization mother liquor according to claim 1, characterized in that, The S1, the aprotic solvent refers to the aprotic solvent commonly used in the field of organic synthesis, which is one or more of benzene, toluene, n-hexane, cyclohexane, dimethylformamide, dimethyl sulfoxide.

3. The method for recovering a desogestrel crystallization mother liquor according to claim 1, characterized in that, In the S1, the reaction temperature is 100-120℃.

4. The method for recovering a desogestrel crystallization mother liquor according to claim 1, characterized in that, In the S2, the solvent refers to ether or alcohol, and the reaction temperature is 0-20℃.

5. The method for recovering a desogestrel crystallization mother liquor according to claim 1, characterized in that, In the S3, the solvent refers to one or more of toluene, dichloromethane, chloroform, acetic acid, and the reaction temperature is 0-20℃.

6. The method for recovering a desogestrel crystallization mother liquor according to claim 1, characterized in that, In the S4, the solvent refers to one or more of dichloromethane, chloroform, carbon tetrachloride, acetic acid, and the reaction temperature is 0-20℃.

7. The method for recovering a desogestrel crystallization mother liquor according to claim 1, characterized in that, In the S5, the aprotic solvent is benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and the organic base is one or more of trimethylpyridine, quinoline, 2-methylquinoline, DBU, and the reaction temperature is 120-140℃.

8. The method for recovering a desogestrel crystallization mother liquor according to claim 1, characterized in that, In the S6, the solvent refers to one or more of methanol, ethanol, isopropanol, the strong acid is sulfuric acid, hydrochloric acid, perchloric acid, p-toluenesulfonic acid, the reaction temperature is 40-60℃, the base is an inorganic base selected from ammonia, potassium carbonate, potassium hydroxide, sodium hydroxide, and the reaction temperature is 20-60℃.

9. The method for recovering deoxyprogesterone recrystallization mother liquor according to claim 1, characterized by, The mixture of 18-methyl-11-methylene-estra-3, 5-diene-17β-acetic acid ester and 18-methyl-11-methylene-estra-2, 4-diene-17β-acetic acid ester in S5 does not perform acid isomerization, and the mixture obtained by removing the protection with base directly performs Birch reaction to obtain 18-methyl-11-methylene-estra-4-ene-17β-alcohol.

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