Method for open-loop fluorination of steroid epoxide

Abstract

The invention discloses a method for ring-opening fluorination of a steroid epoxide, which comprises the following step: carrying out ring-opening fluorination reaction on a low-concentration hydrogen fluoride aqueous solution and the steroid epoxide under the action of organic alkali at the reaction temperature of 0-30 DEG C to obtain a 9alpha-fluoro-11beta-hydroxy steroid compound. According to the method, a high-concentration hydrogen fluoride aqueous solution is not used, the reaction condition is mild, the 9alpha-fluoro-11beta-hydroxy steroid compound with high yield and high purity can be obtained without ultralow-temperature reaction, the safety is high, the production cost is low, and the method is more suitable for industrial mass production.

Description

Technical Field

[0001] The invention relates to medicinal chemistry, in particular to a method for ring-opening fluorination of steroidal epoxides. Background Art

[0002] The product of the steroidal epoxy compound of structural formula I after ring-opening fluorination is 9α-fluoro-11β-hydroxysteroid structural formula II. The 9α-fluoro-11β-hydroxysteroid compound corresponding to structural formula II is usually a more active glucocorticoid steroid drug, such as betamethasone, dexamethasone, fluocinolone, etc. At present, in the reaction of ring-opening fluorination of epoxy compounds to obtain organic fluorides, early fluorination reagents basically use a 70% mass concentration of hydrogen fluoride aqueous solution (supersaturated solution) or a 70% mass concentration of hydrogen fluoride-DMF solution (N,N-dimethylformamide) at ultra-low temperature for ring-opening fluorination.

[0003]

[0004] Existing research discloses the preparation method of dexamethasone and its series of products:

[0005]

[0006] This method not only requires the reaction to be carried out at low temperature, but also uses a large amount of organic solvents in the process, resulting in the subsequent generation of three wastes.

[0007] There are reports of using the following synthesis method of fluorine on betamethasone:

[0008]

[0009] The method uses betamethasone epoxide as a starting material, firstly, hydrogen fluoride gas is introduced into water under ultra-low temperature conditions (-40°C to -30°C) to prepare a supersaturated hydrogen fluoride solution, and then fluorination ring-opening is performed under ultra-low temperature conditions (-25°C to -10°C) to obtain betamethasone; the method requires the use of dangerous hydrogen fluoride gas, which poses a great safety hazard, and the preparation of hydrofluoric acid aqueous solution, the ring-opening fluorination reaction and post-treatment must all be carried out under ultra-low temperature conditions, which has high energy consumption and is not suitable for large-scale production.

[0010] Some studies have also disclosed a method and device for ring-opening and fluorination of steroidal epoxy compounds:

[0011]

[0012] The method uses steroidal pine epoxide as the starting material, aromatic hydrocarbons and water as the medium, and hydrogen fluoride gas as the fluorination agent to form a special liquefied miscible state when the fluorination reaction is carried out at -30°C to -10°C, and implements a multiphase reaction, thereby completing the ring-opening fluorination reaction of the steroidal epoxide to prepare 9α-fluoro-11β-hydroxy steroid compounds. The method requires the use of dangerous hydrogen fluoride gas, which poses a great safety hazard, and requires a special reaction device to achieve a multiphase reaction. The preparation of the hydrofluoric acid aqueous solution and the ring-opening fluorination reaction must be carried out under ultra-low temperature conditions, and the energy consumption is high and is not suitable for large-scale production.

[0013] A method for ring opening of steroidal epoxides:

[0014]

[0015] The method uses betamethasone epoxide or dexamethasone epoxide as the starting material, dichloromethane as the solvent and an antioxidant, and uses a 70% mass concentration hydrogen fluoride aqueous solution as a fluorination reagent to carry out a fluorination reaction at -20°C to -25°C to prepare a 9α-fluoro-11β-hydroxy steroid compound. This method requires the use of a 70% mass concentration hydrogen fluoride aqueous solution, which has a great safety hazard, and requires the use of dichloromethane, which will introduce impurities into the 17-position side chain. In addition, the ring-opening fluorination reaction needs to be carried out under ultra-low temperature conditions, which is energy-intensive and not suitable for large-scale production.

[0016] The prior art also discloses a method for preparing betamethasone: a hydrofluoric acid solution with a mass concentration of 70% reacts with betamethasone epoxide at a temperature of -20 to -15°C, and then a 20% potassium hydroxide solution is added at low temperature, filtered, and 9-fluoro-11β, 17, 21-trihydroxy-16β-methylpregnane-1, 4-diene-3, 20-dione (betamethasone) is obtained. This method also uses a high-concentration hydrofluoric acid aqueous solution, and needs to react at ultra-low temperatures, which has high energy consumption and is not suitable for large-scale production.

[0017] However, in existing research reports, the reaction process has various problems such as the use of ultra-low temperature (below -10°C), large amount of organic solvents, expensive reagents, many impurities, low yield, difficult solvent recovery, and large amount of wastewater. For example, using tetrahydrofuran and dichloromethane as solvents has the problems of large amount of solvents and many impurities; and using 70% hydrofluoric acid solution as a fluorination reagent (70% hydrofluoric acid aqueous solution is a supersaturated solution, so special pressure-resistant containers are required for transportation and storage) has major safety hazards, low reaction temperature, high energy consumption and other problems.

[0018] Currently, the most commonly used fluorinating agents include hydrogen fluoride combined with different electron donors to form stable complexes, such as hydrogen fluoride-pyridine complex (PPHF), Et3N·3HF, Me3N·2HF, etc. However, it can be seen from the prior art that whether hydrogen fluoride aqueous solution or hydrogen fluoride complex is used to open the ring of epoxide, 70% hydrogen fluoride is required, and in the case of using the complex, an organic solvent such as CH 2 Cl 2 .

[0019] Therefore, there is an urgent need to develop a method for producing steroidal epoxides with simple and safe reaction conditions that is suitable for large-scale production. Summary of the invention

[0020] The present invention provides a method for ring-opening fluorination of steroidal epoxides, which comprises the following contents:

[0021]

[0022] Where R is CH 3 or CH 2 OH or CH 2 OAc; R1 is α-methyl or β-methyl; R 2 is F or H;

[0023] The concentration of the hydrogen fluoride aqueous solution is 40% to 60%, preferably 45% to 55%.

[0024] In the present invention, a glucocorticoid steroid drug is obtained after ring-opening fluorination of a steroidal epoxide. The glucocorticoid steroid drug can be at least one of 9-fluoro-11β, 17, 21-trihydroxy-16β-methylpregnane-1, 4-diene-3, 20-dione (betamethasone), 16α-methyl-11β, 17α, 21-trihydroxy-9α-fluoropregnane-1, 4-diene-3, 20-dione (dexamethasone), and 11β-hydroxy-16α, 17-[(1-methylethylidene)-bis(oxygen)]-21-(acetoxy)-6α, 9-difluoropregnane-1, 4-diene-3, 20-dione (fluocinolone).

[0025] In the present invention, a low-concentration hydrogen fluoride aqueous solution and a steroidal epoxide are subjected to a ring-opening fluorination reaction at a reaction temperature of 0°C to 30°C under the action of an organic base to obtain a 9α-fluoro-11β-hydroxy steroid compound.

[0026] Furthermore, the organic base is at least one of diethylamine, trimethylamine, triethylamine, diisopropylamine, and N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine.

[0027] The dosage of the hydrogen fluoride aqueous solution and the organic base is a multiple of the mass of the steroidal epoxide.

[0028] The mass ratio of the steroidal epoxide to the aqueous hydrofluoric acid solution is 1:(3-8), preferably 1:(3-5).

[0029] The mass ratio of the steroidal epoxy compound to the organic base is 1:(0.1-2), preferably 1:1.

[0030] The mass ratio of the organic base to the aqueous hydrogen fluoride solution is 1:(3-80), preferably 1:(3-9), and more preferably 1:4.5.

[0031] In the present invention, the order of adding the aqueous hydrogen fluoride solution and the steroidal epoxide is not limited; the aqueous hydrofluoric acid solution can be added first, followed by the organic base, and then the steroidal epoxide; or the steroidal epoxide can be added first, followed by the organic base, and then the aqueous hydrofluoric acid solution; preferably, the aqueous hydrofluoric acid solution is added first, followed by the organic base, and then the steroidal epoxide.

[0032] Wherein, after adding the hydrofluoric acid aqueous solution, the temperature is lowered and then the organic base is added.

[0033] The temperature is lowered to -10°C to 20°C, preferably to 0°C to 20°C.

[0034] Wherein, after adding steroidal epoxide, the reaction temperature can be selected from 10°C to 30°C, for example, 10°C to 20°C, 15°C to 25°C, 20°C to 30°C, etc. More specifically, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30°C, etc.

[0035] In the present invention, after the hydrofluoric acid aqueous solution and the steroidal epoxy compound have reacted, they are dispersed with a solvent.

[0036] After the solvent is dispersed, the pH is adjusted to 7-10 using a base, filtered, and dried; preferably, the pH is 7-8.

[0037] The alkali may be selected from sodium hydroxide, potassium hydroxide, and calcium hydroxide, preferably potassium hydroxide.

[0038] The percentage concentration of the alkali is 5% to 25%, preferably 10%.

[0039] The drying temperature is 30°C to 50°C, preferably 40°C to 50°C.

[0040] In the present invention, the drying method can be selected from atmospheric pressure drying, vacuum drying, spray drying and freeze drying, preferably vacuum drying.

[0041] In the present invention, if you want to further improve the purity of the product, you can also use conventional purification methods for purification, and the purity requirement can be adjusted according to your own needs.

[0042] The inventors have tried to use the 70% HF solution of the prior art for ring-opening reaction under room temperature in experimental research. The results show that after 6 hours of reaction, although TLC detection shows that the raw material has reacted completely, the yield is only 72%, and the purity of the product is also very poor. The inventors also found that at room temperature, if 37% hydrogen fluoride triethylamine complex is used, even if the amount of the complex is increased and the complex is 13 times the mass ratio of the complex relative to dexamethasone epoxide, TLC detection shows that the raw material has not reacted after 7 hours of reaction, and the reaction fails; at the same time, the applicants also found that at room temperature, when 70% hydrogen fluoride pyridine complex is used, the mass ratio of 70% hydrogen fluoride pyridine complex to dexamethasone epoxide is increased to 6:1, the reaction can only reach a yield of 85%, and the chromatographic purity of the crude product is only 81.76%. After long-term experimental exploration, the inventor accidentally discovered that by using an HF aqueous solution with a mass concentration of 40% to 60% at room temperature and using an organic base such as diethylamine, trimethylamine, triethylamine, diisopropylamine, N,N-diisopropylethylamine as a catalyst, steroid epoxides can fully and quickly react with hydrogen fluoride to obtain a high-yield steroid ring-opening fluorination product. The effect is better when the mass concentration of the HF aqueous solution is in the range of 45% to 55%, and N,N-diisopropylethylamine is the best organic base.

[0043] The present invention has the following beneficial effects: the method for ring-opening fluorination of steroidal epoxides provided by the present invention no longer uses high-concentration hydrofluoric acid, avoids harsh ultra-low temperature reaction conditions, and also avoids the use of a large amount of organic solvents, thereby achieving the purpose of efficient ring-opening fluorination under mild conditions. The present invention has high safety, low cost, low energy consumption, low pollution, and high reaction yield, and is more suitable for large-scale industrial production.

[0044] The following abbreviations have the following meanings:

[0045] DMF stands for N,N-dimethylformamide;

[0046] DMN1 indicates dexamethasone;

[0047] DMN1-SM1 indicates dexamethasone epoxy;

[0048] DBU stands for 1,8-diazabicycloundec-7-ene;

[0049] DIPEA means N,N-diisopropylethylamine;

[0050] DABCO stands for 1,4-diazabicyclo[2.2.2]octane. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 It is the HPLC spectrogram of Example 1 of the present invention;

[0052] Figure 2 It is the HPLC spectrogram of Example 2 of the present invention;

[0053] Figure 3 It is the HPLC spectrum of Example 3 of the present invention;

[0054] Figure 4 It is the HPLC spectrum of Example 4 of the present invention;

[0055] Figure 5 It is the HPLC spectrogram of Example 5 of the present invention;

[0056] Figure 6 It is the HPLC spectrum of Example 6 of the present invention;

[0057] Figure 7 It is the HPLC spectrum of Example 7 of the present invention;

[0058] Figure 8 HPLC spectrum of Comparative Example 1 of the present invention;

[0059] Fig. 9 It is the HPLC spectrum of Comparative Example 3 of the present invention. DETAILED DESCRIPTION

[0060] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with comparative examples and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. In addition, if not clearly stated, all reagents used in the following embodiments are commercially available, or can be synthesized according to this article or known methods, and for the reaction conditions not listed, they are also easily available to those skilled in the art.

[0061] Example 1

[0062] Synthesis of dexamethasone: Add 80g of 50%wt hydrofluoric acid to a 250mL tetrafluoroethylene three-necked round-bottom flask, cool to 0-20°C, control the temperature to be less than 20°C and add 20g of diethylamine. After the addition, add 20g of dexamethasone epoxide at 0-30°C, and stir the reaction at 10-25°C for 5-7h. After the reaction is completed, pour into 600mL of water for dispersion, alkalize to pH 7-8 with 10% potassium hydroxide, filter, and vacuum dry at 40-50°C to obtain 19.19g of dexamethasone, with a yield of 91.1% and a purity of 97.79% (see HPLC spectrum). Figure 1 ).

[0063] Example 2

[0064] Synthesis of dexamethasone: Add 80g of 50%wt hydrofluoric acid to a 250mL tetrafluoroethylene three-necked round-bottom flask, cool to 0-20°C, control the temperature to be less than 20°C and add 20g of DBU. After the addition, add 20g of dexamethasone epoxide at 0-30°C, and stir the reaction at 10-25°C for 5-7h. After the reaction is completed, pour into 600mL of water for dispersion, alkalize to pH 7-8 with 10% potassium hydroxide, filter, and vacuum dry at 40-50°C to obtain 19.38g of dexamethasone, with a yield of 91.9% and a purity of 98.46% (see HPLC spectrum). Figure 2 ).

[0065] Example 3

[0066] Synthesis of dexamethasone: Add 80g of 50%wt hydrofluoric acid to a 250mL tetrafluoroethylene three-necked round-bottom flask, cool to 0-20°C, control the temperature to be less than 20°C, and add 20g of N,N-diisopropylethylamine (DIPEA). After the addition, add 20g of dexamethasone epoxide at 0-30°C, and stir the reaction at 10-25°C for 5-6h. After the reaction is completed, pour into 600mL of water to disperse, alkalize to pH 7-8 with 10% potassium hydroxide, filter, and vacuum dry at 40-50°C to obtain 19.83g of dexamethasone, with a yield of 94.1% and a purity of 98.23% (see HPLC spectrum). Figure 3 ).

[0067] Example 4

[0068] Synthesis of dexamethasone: Add 80g of 50%wt hydrofluoric acid to a 250mL tetrafluoroethylene three-necked round-bottom flask, cool to 0-20°C, control the temperature to be less than 20°C and add 20g of triethylamine. After the addition, add 20g of dexamethasone epoxide at 0-30°C, and stir the reaction at 10-25°C for 5-7h. After the reaction is completed, pour into 600mL of water for dispersion, alkalize with 10% potassium hydroxide to a pH of 7-8, filter, and vacuum dry at 40-50°C to obtain 18.98g of dexamethasone, with a yield of 90.1% and a purity of 97.87% (see HPLC spectrum). Figure 4 ).

[0069] Example 5

[0070] Synthesis of dexamethasone: Add 60g of 50%wt hydrofluoric acid to a 250mL tetrafluoroethylene three-necked round-bottom flask, cool to 0-20°C, control the temperature to be less than 20°C, and add 4g of N,N-diisopropylethylamine. After the addition, add 20g of dexamethasone epoxide at 0-30°C, and stir the reaction at 10-25°C for 7-9h. After the reaction is completed, pour into 600mL of water to disperse, alkalize to pH 7-8 with 10% potassium hydroxide, filter, and vacuum dry at 40-50°C to obtain 19.39g of crude dexamethasone, with a yield of 92.0% and a purity of 97.63% (see HPLC spectrum). Figure 5 ).

[0071] Example 6

[0072] Synthesis of dexamethasone: Add 60g of 50%wt hydrofluoric acid to a 250mL tetrafluoroethylene three-necked round-bottom flask, cool to 0-20°C, control the temperature to be less than 20°C, and add 24g of N,N-diisopropylethylamine. After the addition, add 12g of dexamethasone epoxide at 0-30°C, and stir the reaction at 10-25°C for 7-9h. After the reaction is completed, pour into 200mL of water to disperse, alkalize to pH 7-8 with 10% potassium hydroxide, filter, and vacuum dry at 40-50°C to obtain 11.21g of crude dexamethasone, with a yield of 88.5% and a purity of 95.64% (see HPLC spectrum). Figure 6 ).

[0073] Example 7

[0074] Synthesis of dexamethasone: Add 60g of 50%wt hydrofluoric acid to a 250mL tetrafluoroethylene three-necked round-bottom flask, cool to 0-20°C, control the temperature to be less than 20°C and add 38.4g of N,N-diisopropylethylamine. After the addition, add 12g of dexamethasone epoxide at 0-30°C, stir and react at 10-25°C for 23h, take a sample and send it to HPLC for inspection, which shows that 82.64% of the material remains, indicating that the reaction has failed. (HPLC spectrum see Figure 7 ).

[0075] Comparative Example 1

[0076] Synthesis of dexamethasone: Add 80g of 50%wt hydrofluoric acid to a 250ml tetrafluoroethylene three-necked round-bottom flask, cool to 10-15°C, add 20g of dexamethasone epoxide, and keep stirring at 10-25°C for 19h. TLC detection shows that there is still a large amount of dexamethasone epoxide that has not reacted. Samples are taken and sent for HPLC inspection, which shows: 25.81% of dexamethasone epoxide and 64.86% of dexamethasone (HPLC spectrum is shown in Figure 8 ).

[0077] Comparative Example 2

[0078] Synthesis of dexamethasone: Add 260g of hydrogen fluoride triethylamine complex (content 37%) into a 250ml tetrafluoroethylene three-necked round-bottom flask, cool to 10-15°C, add 20g of dexamethasone epoxide, and stir at 10-25°C for 7h. TLC detection shows that the raw material has not reacted and the reaction has failed.

[0079] Comparative Example 3

[0080] Synthesis of dexamethasone: Add 120g of hydrogen fluoride pyridine complex (hydrogen fluoride content: 70%) to a 250ml tetrafluoroethylene three-necked round-bottom flask, cool to 10-15°C, add 20g of dexamethasone epoxide, and stir and react at 10-25°C for 7-9h. After the reaction is completed, pour into 800mL of water for dispersion, alkalize to pH 7-8 with 10% potassium hydroxide, filter, and vacuum dry at 40-50°C to obtain 17.9g of crude dexamethasone, with a yield of 85.0% and a purity of 81.76% (see HPLC spectrum). Fig. 9 ).

[0081] Comparative Example 4

[0082] Synthesis of dexamethasone: Add 120g of 50%wt hydrofluoric acid to a 250mL tetrafluoroethylene three-necked round-bottom flask, cool to 0-20°C, and add 20g of pyridine at a temperature below 20°C. After the addition, add 20g of dexamethasone epoxide at 0-30°C, stir and react at 10-25°C for 16h to obtain 8.7g of crude dexamethasone with a yield of 41.38%. Samples were taken for inspection and HPLC showed that 32.86% of the material remained.

[0083] Comparative Example 5

[0084] Synthesis of dexamethasone: Add 120g of 50%wt hydrofluoric acid to a 250mL tetrafluoroethylene three-necked round-bottom flask, cool to 0-20°C, and add 20g of DABCO at a temperature below 20°C. After the addition, add 20g of dexamethasone epoxide at 0-30°C, stir at 10-25°C for 19h, and TLC detection shows that the raw material has not reacted, and the reaction has failed.

[0085] Comparative Example 6

[0086] Synthesis of dexamethasone: 100 g of 70% wt aqueous hydrofluoric acid solution was added to a 250 mL tetrafluoroethylene three-necked round-bottom flask, cooled to 10-20° C., the internal temperature was controlled to be less than 25° C., 20 g of dexamethasone epoxide was added, and the reaction was stirred at 15-25° C. for 6 h. TLC detection showed that the raw materials were completely reacted (but the color of the reaction system was dark reddish brown). The reaction solution was slowly poured into 800 mL of water for dispersion, alkalized to pH 7-8 with 10% potassium hydroxide, filtered, and vacuum dried at 40-50° C. to obtain 15.16 g of crude dexamethasone with a yield of 72.0%.

[0087] The reaction was carried out under the conditions of reaction temperature of 10°C to 25°C and reaction time of 3h to 19h in Examples 1 to 7 and Comparative Examples 1 to 5; after the reaction, the mixture was alkalized to pH 7 to 8 with 10% potassium hydroxide aqueous solution, filtered, and vacuum dried at 45 to 55°C to obtain crude dexamethasone. Examples 1 to 7 studied the effects of the type and amount of organic base and the amount of hydrofluoric acid on the ring-opening fluorination reaction, and Comparative Examples 1 to 6 investigated the reaction conditions under different fluorine sources, whether to add organic base, the type of organic base, the amount of organic base, etc. The results are shown in Table 1:

[0088] Table 1

[0089]

[0090] Note: NA means that the substance was not added to the reaction; “ / ” means that the reactivity was very poor or not detected.

[0091] It can be seen from Table 1 that in Comparative Example 1, only a low concentration of 50%wt hydrofluoric acid aqueous solution is used for ring-opening fluorination reaction without using an organic base. Although the amount of hydrofluoric acid aqueous solution used is 2 to 3 times that of Examples 1 to 5, and the reaction time is extended to 19h, there are still many raw materials that have not reacted, indicating that a special amount of organic base can significantly increase the reaction rate; in addition, when the organic base is diethylamine, DBU, DIPEA, triethylamine and N, N-diisopropylethylamine, the yield is more than 90%. Especially when the mass of N, N-diisopropylethylamine: the mass of dexamethasone epoxide is 1, the yield can reach more than 94% and the purity can reach more than 98%. However, from Examples 3 and 5, the amount of organic base used and the amount ratio of hydrofluoric acid aqueous solution are also very important, which will directly affect the final yield and purity.

Claims

1. A method for ring-opening fluorination of steroidal epoxides, wherein the specific reaction formula is as follows: in, R is CH3 or CH2OH or CH2OAc; R1 is α-methyl or β-methyl; R2 is F or H; The concentration of the hydrogen fluoride aqueous solution is 40% to 60%, preferably 45% to 55%.

2. The method according to claim 1, characterized in that: The organic base is at least one of diethylamine, trimethylamine, triethylamine, diisopropylamine and N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine.

3. The method according to claim 1, characterized in that: The amount of the hydrogen fluoride aqueous solution used is a multiple of the mass of the steroidal epoxide.

4. The method according to claim 1, characterized in that: The mass ratio of the steroidal epoxide to the hydrofluoric acid aqueous solution is 1:(3-8), preferably 1:(3-5).

5. The method according to claim 1, characterized in that: The mass ratio of the organic base to the aqueous hydrogen fluoride solution is 1:(3-80), preferably 1:(3-9), and more preferably 1:4.

5.

6. The method according to claim 1, characterized in that: Firstly, a hydrofluoric acid aqueous solution is added, the temperature is lowered, an organic base is added, and then the steroidal epoxide is added and stirred for reaction.

7. The method according to claim 6, characterized in that: The temperature is lowered to -10°C to 20°C, preferably 0°C to 20°C.

8. The method according to claim 1, characterized in that: The reaction temperature is 10°C to 25°C.

9. The method according to claim 1, characterized in that: The reaction time is 3 h to 19 h, preferably 3 h to 9 h.

10. The method according to claim 1, characterized in that: After the reaction is completed, the pH is adjusted to 7-10, preferably 7-8.

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