Preparation method of 4-dehydroepiandrosterone

Abstract

The invention relates to the technical field of synthesis of steroids, in particular to a preparation method of 4-dehydroepiandrosterone. According to the method, 4-AD is taken as a starting material and is subjected to cyaniding, silicon etherification, reduction and hydrolysis reaction in sequence to prepare 4-dehydroepiandrosterone, chlorosilane is used for carrying out silicon etherification protection on hydroxyl in a 4-AD cyano compound, the obtained silicon ether compound can tolerate a sodium borohydride reduction system environment, the content of a reduction byproduct is reduced to 0.5% or below, meanwhile, the selectivity of the reduction reaction is accidentally improved, and the yield of the 4-dehydroepiandrosterone is increased. The total yield reaches 75% or above, the product purity is larger than or equal to 98%, in addition, the production cost is greatly reduced, and the method is suitable for industrial large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of steroid synthesis, and particularly relates to a preparation method of 4-dehydroepiandrosterone. BACKGROUND

[0002] Dehydroepiandrosterone (4-androstene-3β-ol-17-one) is a steroid drug intermediate, which can be used to prepare Fasedienol (PH94B), and the Fasedienol (PH94B) is a rapid-acting neurosteroid candidate drug. The preparation of dehydroepiandrosterone is reported in detail in the literature Steroids, 10(4):411-424 (1967) by Klimstra and Colton et al. 4-AD is used as a starting material, and 4-dehydroepiandrosterone is obtained through a 4-AD cyano intermediate and then a 3-position ketone reduction reaction.

[0003] The researchers first tried to directly reduce the 4-AD cyano compound with lithium aluminum hydride or tri (tert-butoxy) aluminum hydride. It was found that in the strong alkaline environment of the reduction system, the 17-hydroxycyano group of the 4-AD cyano compound is easy to lose the cyano group back to the 17-ketone structure, and is further reduced to 17-hydroxyl, and finally generates a by-product 3,17-dihydroxy compound.

[0004]

[0005] Therefore, it is necessary to protect the 17-position hydroxyl group of the 4-AD cyano compound in advance, and after completing the reduction reaction of the 3-position ketone group, the 17-hydroxyl protecting group is removed, and the cyano group is removed by alkaline hydrolysis to obtain the final 3-hydroxyl-17-ketone structure, so as to avoid the reduction of the 17-hydroxycyano group to 17-hydroxyl under alkaline reduction conditions. The researchers then chose to protect the 17-hydroxyl group with tetrahydropyran (THP), and the reduction reaction achieved the expected results, avoiding the generation of 3,17-dihydroxy compounds. However, when the THP protecting group is removed under subsequent acidic conditions, the allyl alcohol structure in the reduction product is easy to dehydrate to form a diene structure under acidic conditions, and the 3,5-diene by-product is inevitably formed.

[0006]

[0007] In view of the instability of allyl alcohol structure in the molecular structure of the reduction product under acidic conditions, the 17-hydroxyl group should be protected by a protecting group that can be removed under weak acid or alkaline conditions. The researchers then used acetate to protect the 17-hydroxyl group, and used lithium tri(tert-butoxy)aluminum hydride to reduce the 3-keto group, and then hydrolyzed the ester group with potassium hydroxide to remove the cyano group, to successfully obtain the target product 4-dehydroepiandrosterone, with a total yield of 52%. Since the reduction reaction uses lithium tri(tert-butoxy)aluminum hydride containing a bulky group, the hydrolysis of 17-hydroxycyanoacetate is avoided. The selectivity of the product is not reported, and the process requires a large amount of expensive reducing agent lithium tri(tert-butoxy)aluminum hydride, which is expensive and not suitable for industrial production.

[0008] In view of the problems of existing 4-dehydroepiandrosterone preparation methods, such as easy production of by-products, low yield of target product, and dependence on expensive reducing agents, selecting a suitable hydroxyl protection strategy to make the 17-hydroxycyano structure resistant to the subsequent reduction reaction system environment, while not affecting the 3-hydroxy-4-en structure during the subsequent protection group removal process, is of great significance. SUMMARY

[0009] Therefore, the present application provides a preparation method of 4-dehydroepiandrosterone, which solves the problem that the 17-hydroxycyano structure cannot withstand the reduction reaction system environment by selecting a suitable protection strategy for the 17-hydroxyl group of 4-AD cyano product. The content of the reduction by-product 3,17-dihydroxyl product is reduced to below 0.5%, and the selectivity of the unexpected reduction of the 3-keto group to 3β-hydroxyl is also improved. At the same time, during the hydrolysis reaction, the allyl alcohol structure in the product structure will not be dehydrated to cause the generation of 3,5-diene hydrolysis by-product, thereby improving the yield and purity of 4-dehydroepiandrosterone and greatly reducing the production cost.

[0010] The technical scheme of the present application is as follows: The present application provides a preparation method of 4-dehydroepiandrosterone, which solves the problem that the 17-hydroxycyano structure cannot withstand the reduction reaction system environment by selecting a suitable protection strategy for the 17-hydroxyl group of 4-AD cyano product. The content of the reduction by-product 3,17-dihydroxyl product is reduced to below 0.5%, and the selectivity of the unexpected reduction of the 3-keto group to 3β-hydroxyl is also improved. At the same time, during the hydrolysis reaction, the allyl alcohol structure in the product structure will not be dehydrated to cause the generation of 3,5-diene hydrolysis by-product, thereby improving the yield and purity of 4-dehydroepiandrosterone and greatly reducing the production cost. .

[0011] On the basis of the above technical scheme, preferably, the structures of the siloxane product and the siloxane reduction product are shown in Formula IV and V, respectively, R1, R2 and R3 are all methyl, or two of them are methyl and the other is tert-butyl. Further preferably, R1, R2 and R3 are all methyl.

[0012] On the basis of the above technical scheme, preferably, the silyl etherization reaction includes silyl etherization protection of the hydroxyl group in the 4-AD cyano substance using chlorosilane.

[0013] On the basis of the above technical scheme, preferably, the chlorosilane includes trimethylchlorosilane or tert-butyldimethylchlorosilane. Further preferably, the chlorosilane is trimethylchlorosilane.

[0014] After the 17-position hydroxyl group is protected by trimethylchlorosilane or tert-butyldimethylchlorosilane, the 17-hydroxycyano structure exhibits good stability in the subsequent reduction reaction system, because the alkalinity of sodium borohydride is weak, and the alkalinity is not enough to break the silicon-oxygen bond, ensuring that the silyl ether protecting group can stably exist under reduction conditions.

[0015] On the basis of the above technical scheme, preferably, the molar ratio of the chlorosilane to the 4-AD cyano substance is (1.08-1.32):1.

[0016] On the basis of the above technical scheme, preferably, the silyl etherization reaction is silyl etherization protection of the hydroxyl group in the 4-AD cyano substance by chlorosilane in the presence of imidazole, and the silyl ether substance is obtained by water extraction and concentration.

[0017] On the basis of the above technical scheme, further preferably, under nitrogen protection, 400 ml of dichloromethane, 100 g of 4-AD cyano substance and 44 g of imidazole are added to a 1L reaction bottle, 50 ml of trimethylchlorosilane is slowly added dropwise, after the dropwise addition is completed, the reaction is incubated at 20℃ for 3h, TLC shows that the reaction is complete; 500 ml of water is slowly added to the reaction liquid, and it is concentrated under reduced pressure at 40-50℃, suction filtered, washed with water, suction dried, and dried at 50-60℃ with a blast of air until the weight is constant to obtain the silyl ether substance.

[0018] On the basis of the above technical scheme, preferably, the reduction reaction uses sodium borohydride as a reducing agent and cerium trichloride as a catalyst.

[0019] On the basis of the above technical scheme, preferably, the reduction reaction is selective reduction of the silyl ether substance by sodium borohydride catalyzed by cerium trichloride in a tetrahydrofuran and methanol mixed solvent, and the silyl ether reduction product is obtained by neutralization, extraction concentration and petroleum ether refining.

[0020] On the basis of the above technical scheme, further preferably, under nitrogen protection, 300 ml of tetrahydrofuran and 300 ml of methanol are added to a 2L reaction bottle, 130 g of cerium trichloride and 19 g of sodium borohydride are added in batches, after addition, the temperature is controlled below 10℃, a tetrahydrofuran solution containing the silyl ether substance (121 g of silyl ether substance dissolved in 363 ml of tetrahydrofuran) is added dropwise, and the reaction is stirred at 0-10℃ for 2h, TLC shows that the reaction is complete. The reaction solution is poured into an acetic acid aqueous solution (30 ml of glacial acetic acid is diluted in 1200 ml of ice water) to quench, extracted with ethyl acetate, and the organic phase is concentrated under reduced pressure to near dryness. 600 ml of petroleum ether is added to the concentrate, stirred for 2 h, suction filtered, and air-dried at 50-60 DEG C to constant weight to obtain the silyl ether reduction product.

[0021] On the basis of the above technical solutions, preferably, the cyanation reaction is that 4-AD and acetone cyanohydrin undergo a cyanation reaction in a sodium carbonate aqueous solution, and 4-AD cyano product is obtained after acid hydrolysis.

[0022] On the basis of the above technical solutions, further preferably, 100 g of 4-AD, a sodium carbonate aqueous solution (8 g of sodium carbonate is dissolved in 150 ml of water), and 70 ml of acetone cyanohydrin are added to a 500 ml reaction flask, and the mixture is reacted at 20-30 DEG C for 20 h; TLC shows that the reaction is complete; a dilute hydrochloric acid solution (16.5 ml of concentrated hydrochloric acid is diluted in 100 ml of water) is added dropwise to the reaction solution, and the mixture is stirred at room temperature for 1 h; suction filtered, washed with water, and suction dried, and air-dried at 50-60 DEG C to constant weight to obtain the 4-AD cyano product.

[0023] On the basis of the above technical solutions, preferably, the hydrolysis reaction is that the silyl ether reduction product is hydrolyzed with potassium hydroxide in a methanol and water mixed solvent; 4-didehydroepiandrosterone crude product is obtained after water hydrolysis, and 4-didehydroepiandrosterone is obtained after recrystallization in methanol and water.

[0024] On the basis of the above technical solutions, further preferably, 1 L of methanol, 107 g of silyl ether reduction product, and a potassium hydroxide aqueous solution (32.1 g of potassium hydroxide is dissolved in 321 ml of water) are added to a 3 L reaction flask, and the mixture is reacted at 20-25 DEG C for 2 h; TLC shows that the reaction is complete; 1.07 L of water is slowly added to the reaction solution, and the mixture is stirred for 1 h; filtered, washed with water, and suction dried to obtain a crude product; 214 ml of methanol and 107 ml of water are added to the crude product, and the mixture is stirred at 0-10 DEG C for 1 h; filtered, suction dried, and air-dried at 40-50 DEG C to constant weight to obtain 4-didehydroepiandrosterone.

[0025] The preparation method of 4-didehydroepiandrosterone has the following beneficial effects compared with the prior art: (1) In the present application, the 17-hydroxyl group is protected by selecting a silyl ether, and sodium borohydride is used for reduction. It is found that when this protection strategy is used, the 17-hydroxyl cyan group structure can better tolerate the reduction reaction system. This is related to the fact that the silyl ether is not reduced by sodium borohydride, and the alkalinity of sodium borohydride is weak, which can effectively control the generation of 3,17-dihydroxyl byproducts. At the same time, it is accidentally found that silyl ether protection can significantly improve the selectivity of 3-keto reduction, significantly improve the overall process yield and product purity of 4-didehydroepiandrosterone prepared from 4-AD, and the final yield is more than 75%, and the product purity is ≥98%; (2) using sodium borohydride system for reduction, greatly reduce the production cost, suitable for large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0026] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed to be used in the embodiments or prior art description will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application, and all other embodiments obtained by those skilled in the art without creative labor based on these drawings also belong to the protection scope of the present application.

[0027] Figure 1 HPLC chromatogram of the silylether prepared for the present application embodiment 2; Figure 2 Silylether prepared for the present application embodiment 2 1 H-NMR spectrum; Figure 3 MS spectrum of the silylether prepared for the present application embodiment 2; Figure 4 HPLC chromatogram of the silylether prepared for the present application embodiment 6; Figure 5 Silylether prepared for the present application embodiment 6 1 H-NMR spectrum; Figure 6 MS spectrum of the silylether prepared for the present application embodiment 6; Figure 7 HPLC chromatogram of the 4-dehydroepiandrosterone prepared for the present application embodiment 7; Figure 8 4-Dehydroepiandrosterone prepared for the present application embodiment 7 1 H-NMR spectrum; Figure 9 MS spectrum of the 4-dehydroepiandrosterone prepared for the present application embodiment 7. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present application will be described clearly and completely below in combination with the embodiments of the present application. Obviously, the described embodiments are only some embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor also belong to the protection scope of the present application.

[0029] The 4-AD used in the present application is from Hubei Joint Pharmaceutical Co., Ltd.; acetone cyanohydrin is from BURUN DEHUA Chemical Industry; sodium borohydride is from Shanghai Lingfeng Chemical Reagent Co., Ltd.; imidazole, trimethylchlorosilane, tert-butyl dimethylchlorosilane, and cerium trichloride are all from Adamas.

[0030] The HPLC detection conditions in the application are as follows: Chromatographic column: Agilent- InfinityLab Poroshell 120 EC-C18 (4.6x150 mm, 4 um), Mobile phase: water and acetonitrile are configured in different gradients, as shown in Table 1: Table 1 Mobile phase ratio

[0031] Detector: ultraviolet detector (VWD) Wavelength: 210 nm Column oven temperature: 35 ℃ Injection volume: 10 uL Collection time: 21 min Preparation of test solution: take the sample, accurately weigh and dissolve in acetonitrile to prepare a solution of about 1 mg / mL as the test sample.

[0032] Example 1: Preparation of 4-AD cyanophore-cyanation reaction In a 500 ml reaction bottle, add 100 g of 4-AD, sodium carbonate aqueous solution (8 g of sodium carbonate dissolved in 150 ml of water) and 70 ml of acetone cyanohydrin, and react at 25 ℃ for 20 h. TLC shows that the reaction is complete (developing agent: PE / EA=2 / 1, UV 254 nm color development).

[0033] Add dilute hydrochloric acid solution (16.5 ml of concentrated hydrochloric acid diluted in 100 ml of water) dropwise to the reaction solution, stir at room temperature for 1 h; suction filtration, water washing, suction drying, 55 ℃ air drying to constant weight, to obtain 4-AD cyanophore white solid 105.1 g, yield 95.8%, purity 98.32%.

[0034] Example 2: Preparation of siloxane-siloxane reaction Under nitrogen protection, in a 1L reaction bottle, add 400ml of dichloromethane, 100g of 4-AD cyanophore prepared in Example 1 and 44g of imidazole, slowly add 50ml of trimethylsilyl chloride (abbreviated as TMCS or TMSCl), that is, the molar ratio of trimethylsilyl chloride to 4-AD cyanophore is 1.2:1, after the addition is completed, incubate at 20 ℃ for 3h, TLC shows that the reaction is complete (developing agent: petroleum ether / ethyl acetate=3 / 1, UV 254 nm color development).

[0035] The reaction solution was slowly added with 500 ml of water, concentrated under reduced pressure at 45°C, suction filtered, washed with water, suction dried, and air-dried at 55°C to constant weight to obtain the silylether product in white solid 121.0 g, with a yield of 98.4% and a purity of 99.15%. The HPLC spectrum of the prepared silylether product is shown in FIG. 1, 1 The H-NMR spectrum and the MS spectrum are shown in FIGS. Figure 1 , 2 and 3, respectively. The structural formula thereof is .

[0036] 1 H NMR (600 MHz, CDCl3):δ 5.74 (s, 1H), 2.47 – 2.34 (m, 4H), 2.21 –2.27 (m, 1H), 2.07 – 2.03 (m, 1H), 2.02 – 1.97 (m,1H), 1.87 – 1.84 (m, 1H),1.82 – 1.70 (m, 2H), 1.68 – 1.60 (m, 2H), 1.59 – 1.53 (m, 3H), 1.47 – 1.33(m, 2H), 1.20 (s, 3H), 1.15 – 1.08 (m, 1H), 1.00 – 0.96 (m, 1H), 0.95 (s,3H), 0.23 (s, 9H)。

[0037] MS (ESI): m / z = 386.4 [M+1] + .

[0038] Example 3: Preparation of silylether product of formula (IV) – silyletherification reaction This example is basically the same as the preparation method of Example 2, except that 59.5 g of tert-butyldimethylsilyl chloride (abbreviated as TBDMSCl or TBSCl) is used instead of trimethylsilyl chloride, and the molar ratio of trimethylsilyl chloride to 4-AD cyano product remains the same as in Example 2. The silylether product obtained is white solid 135.4 g, with a yield of 99.2% and a purity of 99.31%. The structural formula of the prepared silylether product is: .

[0039] Example 4: Preparation of silylether product of formula (IV) – silyletherification reaction This example is basically the same as the preparation method of Example 2, except that the amount of trimethylsilyl chloride used is 45 mL, i.e. the molar ratio of trimethylsilyl chloride to 4-AD cyano product is 1.08:1. The silylether product obtained is white solid 118.5 g, with a yield of 96.3% and a purity of 97.26%.

[0040] Example 5: Preparation of the silyl ether of formula (IV) - silyl etherification reaction The preparation method of this example is basically the same as that of Example 2, except that the amount of trimethylsilyl chloride is 55 mL, i.e. the molar ratio of trimethylsilyl chloride to 4-AD cyano compound is 1.32:1. A white solid of silyl ether, 120.5 g, is finally prepared with a yield of 97.9% and a purity of 99.20%.

[0041] Comparative Example 1: The preparation method of this example is basically the same as that of Example 2, except that the amount of trimethylsilyl chloride is 42 mL, i.e. the molar ratio of trimethylsilyl chloride to 4-AD cyano compound is 1:1. A white solid of silyl ether, 117.1 g, is finally prepared with a yield of 95.2% and a purity of 98.92%. When the amount of trimethylsilyl chloride is less than 1.08 equivalents, the reaction is incomplete and the yield begins to decrease.

[0042] Comparative Example 2: The preparation method of this example is basically the same as that of Example 2, except that the amount of trimethylsilyl chloride is 60 mL, i.e. the molar ratio of trimethylsilyl chloride to 4-AD cyano compound is 1.4:1. A white solid of silyl ether, 119.8 g, is finally prepared with a yield of 97.4% and a purity of 99.08%. When the amount of trimethylsilyl chloride is greatly excessive, the yield of the product does not increase, and therefore, the molar ratio of trimethylsilyl chloride to 4-AD cyano compound needs to be controlled within an appropriate range.

[0043] Example 6: Preparation of the silyl ether reduction product of formula (V) - reduction reaction Under nitrogen protection, 300 ml of tetrahydrofuran and 300 ml of methanol were added to a 2 L reaction flask, 130 g of cerium trichloride and 19 g of sodium borohydride were added in batches, and after addition, the temperature was controlled below 10°C. A tetrahydrofuran solution containing the silyl ether prepared in Example 2 (121 g of silyl ether dissolved in 363 ml of tetrahydrofuran) was added dropwise, and the reaction was stirred at 8°C for 2 h. TLC showed that the reaction was complete (developing agent: petroleum ether / ethyl acetate = 3:1, phosphomolybdic acid coloration).

[0044] The reaction solution was poured into an aqueous acetic acid solution (30 ml of glacial acetic acid diluted in 1200 ml of ice water) and quenched, and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to near dryness. HPLC detection showed that the silyl ether reduction product in the concentrate accounted for 85.3%, the impurity 3,17-dihydroxy compound accounted for 0.5%, and the 3α-isomer accounted for 5.2%.

[0045] The concentrate was added with 600 ml petroleum ether, stirred for 2 h, suction filtered, and air-dried at 55 °C to constant weight to obtain a silylether-reduced product in the form of white solid 107.4 g, with a yield of 88.3%, purity of 97.98%, impurity 3, 17-dihydroxy product of 0.44%, and 3a-isomer of 0.72%. The HPLC spectrum of the prepared silylether-reduced product is shown in FIG. 1, 1 The H-NMR spectrum and MS spectrum are shown in FIGS. Figure 4 , 5 and 6.

[0046] 1 H NMR (600 MHz, CDCl3): δ 5.30 (m, 1H), 4.15 – 4.13 (m, 1H), 2.37 –2.32 (m, 1H), 2.23 – 2.18 (m, 1H), 2.05 – 2.02 (m, 1H), 1.98 – 1.93 (m, 2H),1.78 – 1.71 (m, 3H), 1.63 – 1.53 (m, 3H), 1.51 – 1.44 (m, 3H), 1.38 – 1.30(m, 3H), 1.05 (s, 3H), 0.99 – 0.95 (m, 1H), 0.92 (s, 3H), 0.80 – 0.75 (m,1H), 0.22 (s, 9H).

[0047] MS (ESI): m / z = 280.4 [M-72-18-18+1] + .

[0048] By calculation, when the 17-hydroxycyanosilylether product is reduced by using a sodium borohydride + cerium trichloride system, the selectivity of the target product 3β-hydroxy-4-ene product to the isomer impurity 3a-hydroxy-4-ene product is as high as 16.4:1, and the structural formulas of the target product 3β-hydroxy-4-ene product and the isomer impurity 3a-hydroxy-4-ene product are as follows: .

[0049] Example 7: Preparation of 4-dehydroepiandrosterone by hydrolysis reaction In a 3 L reaction bottle, 1 L of methanol, 107 g of the silylether-reduced product prepared in Example 6, and an aqueous potassium hydroxide solution (32.1 g of potassium hydroxide dissolved in 321 ml of water) were added, and reacted at 23 °C for 2 h. TLC showed that the reaction was complete (developing agent: petroleum ether / ethyl acetate = 3 / 1, phosphomolybdic acid coloration).

[0050] To the reaction solution, 1.07 L of water was slowly added, stirred for 1 h, filtered, washed with water, and dried under suction to obtain a crude product; 214 ml of methanol and 107 ml of water were added to the crude product, stirred at 8°C for 1 h, filtered, dried under suction, and dried at 45°C with air blowing until the weight was constant to obtain 4-dehydroepiandrosterone white solid 71.1 g with a yield of 89.3% and a purity of 99.06% (210 nm). The HPLC spectrum of the prepared 4-dehydroepiandrosterone is shown in FIG. 1. 1 The H-NMR spectrum and the MS spectrum are shown in FIGS. Figure 7 、 8 and 9.

[0051] 1 H NMR (600 MHz, CDCl3): δ 5.32 (s, 1H), 4.17 – 4.14 (m, 1H), 2.47-2.43 (m, 1H), 2.26 – 2.21 (m, 1H), 2.1 – 2.04 (m, 2H), 1.97 – 1.92 (m, 2H),1.87 – 1.81 (m, 2H), 1.73 – 1.70 (m, 1H), 1.67 – 1.61 (m, 2H), 1.55 – 1.51(m, 1H), 1.47 – 1.38 (m, 2H), 1.30 – 1.21 (m, 3H), 1.08 (s, 3H), 1.00 – 0.93(m, 1H), 0.89 (s, 3H), 0.83 – 0.78 (m, 1H)。

[0052] MS (ESI): m / z = 271.3 [M-18+1] + .

[0053] Comparative Example 3: The target product 4-dehydroepiandrosterone was prepared by using the method reported in the literature Steroids, 10(4): 411-424 (1967) to protect the 17-position hydroxyl group with an acetate and reduce the 3-position ketone group with lithium tri(tert-butoxy)aluminum hydride, and then hydrolyzed with potassium hydroxide to remove the ester group and decyano group at the same time, and the reaction route is as follows, and the total yield is 55.4%: .

[0054] The reduction reaction was repeated, and the results showed that the selectivity 3β / 3α = 9.55:1 was obviously lower than that in Example 6 of the present application. Moreover, the process needs to use a large amount of expensive reducing agent lithium tri(tert-butoxy)aluminum hydride, which is expensive and not suitable for industrial production.

[0055] Comparative Example 4: On the basis of the comparative example 3, the lithium tri (t-butoxy) aluminum hydride is replaced by sodium borohydride, the ketone group of 3-position of 17-hydroxycyanophenyl acetic ester is reduced, it is found that the structure of 17-hydroxycyanophenyl acetic ester can be reduced by sodium borohydride + cerium trichloride structure, most of the raw materials are converted into 3,17-bishydroxy by-products during the reduction reaction, and the content is as high as 62%, and the reaction is as follows: .

[0056] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A process for the preparation of 4-dehydroepiandrosterone, characterized in that: The 4-AD is used as a starting material, and is subjected to cyanation to obtain a 4-AD cyano compound, silylation to obtain a silyl ether compound, reduction to obtain a silyl ether reduction compound, and hydrolysis to obtain 4-dehydroepiandrosterone. The structure of the 4-AD is shown in Formula II: ; The structure of the 4-dehydroepiandrosterone is shown in formula I: .

2. The process for preparing 4-dehydroepiandrosterone according to claim 1, characterized in that: The structures of the silyl ether compound and the silyl ether reduction compound are shown in Formulas IV and V, respectively: ； R1, R2 and R3 are all methyl groups, or two of them are methyl groups and the other is a tert-butyl group.

3. The process for preparing 4-dehydroepiandrosterone according to claim 1, wherein: The silylation comprises silyl ether protection of the hydroxyl group in the 4-AD cyano compound using chlorosilane.

4. The process for preparing 4-dehydroepiandrosterone according to claim 3, characterized in that: The chlorosilane comprises trimethylchlorosilane or tert-butyldimethylchlorosilane.

5. The process for the preparation of 4-dehydroepiandrosterone according to claim 4, characterized in that: The molar ratio of the chlorosilane to the 4-AD cyano compound is (1.08-1.32):

1.

6. The process for the preparation of 4-dehydroepiandrosterone according to claim 3, characterized in that: The silylation comprises silyl ether protection of the hydroxyl group in the 4-AD cyano compound using chlorosilane in the presence of imidazole, and the silyl ether compound is obtained by water extraction and concentration.

7. The process for preparing 4-dehydroepiandrosterone according to claim 1, wherein: The reduction reaction uses sodium borohydride as a reducing agent and cerium trichloride as a catalyst.

8. The process for preparing 4-dehydroepiandrosterone according to claim 6, characterized in that: The reduction reaction comprises selective reduction of the silyl ether compound by sodium borohydride catalyzed by cerium trichloride in a tetrahydrofuran and methanol mixed solvent, and the silyl ether reduction compound is obtained by neutralization, extraction and concentration, and petroleum ether refining.

9. The process for the preparation of 4-dehydroepiandrosterone according to claim 1, characterized in that: The cyanation reaction comprises cyanation of 4-AD and acetone cyanohydrin in a sodium carbonate aqueous solution, and the 4-AD cyano compound is obtained by acid water extraction.

10. The process for the preparation of 4-dehydroepiandrosterone according to claim 1, characterized in that: The hydrolysis reaction comprises hydrolysis of the silyl ether reduction compound by potassium hydroxide in a methanol and water mixed solvent, and the 4-dehydroepiandrosterone crude product is obtained by water extraction, and the 4-dehydroepiandrosterone is obtained by methanol water recrystallization.

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