Preparation method of deflazacort intermediate

Abstract

The present invention relates to the field of resource recycling technology, and in particular to a method for preparing a deflazacort intermediate, which is characterized by comprising: (a) subjecting compound I to a hydroxyl elimination reaction to obtain compound II; (b) dissolving compound II in a polar solvent, and mixing with an oxidant and a phase transfer catalyst to perform an epoxidation reaction to obtain deflazacort intermediate compound III. The method improves the selectivity of the epoxidation process by optimizing the conditions of the epoxidation process, has a high conversion rate, and reduces by-products.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, in particular to a method for preparing a deflazacort intermediate. Background Art

[0002] Deflazacort is an oral drug used to treat allergic asthma, rheumatoid arthritis, and skin allergies. It can also be used to treat Duchenne muscular dystrophy by reducing inflammation and reducing the activity of the immune system. Its chemical name is 21-acetoxy-11β-hydroxy-2'-methyl-5'H-pregnane-1,4-diene-[17,16-D]oxazole-3,20-dione, and its structural formula is as follows:

[0003]

[0004] The main production method of deflazacort is: turmeric extract saponin is used as the starting material, and diene is obtained through ring-opening hydrolysis, diene is obtained through epoxide hydrolysis and Wohl's oxidation to obtain Wohl's oxide, and then through biological fermentation to obtain mold dehydrogenation product, and mold dehydrogenation product is further subjected to oxidation reaction, protection, amination, cyclization, reduction, hydrolysis, iodination, and replacement to obtain deflazacort. The route is as follows:

[0005]

[0006] The formula (1) (16α)-16,17-epoxypregnane-1,4-diene-3,11,20-trione) is the key intermediate, and the subsequent reaction steps are relatively ideal. However, the preparation process of the key intermediate has the following technical problems:

[0007] The raw material turmeric has limited resources and has been planted for a long time. The content of diosgenin in turmeric is low, and the extraction process consumes a large amount of high-concentration acid and alkali, which is environmentally unfriendly. In the subsequent reaction process of diosgenin, the steps are cumbersome and require biological fermentation, which is time-consuming, labor-intensive and costly. Summary of the invention

[0008] Based on this, the present invention is based on the preparation method in the applicant's prior patent CN114317662A, and uses 11α,17α-dihydroxyprogesterone as a raw material to prepare 17α-hydroxypregna-1,4-diene-3,11,20-trione (specific structure as shown in Formula I), first eliminating the hydroxyl group at position 17, and then epoxidizing 16(17)-ene to obtain the key intermediate compound III of deflazacort.

[0009] The present invention provides a method for preparing a deflazacort intermediate, which specifically comprises:

[0010] (a) subjecting compound I to a hydroxyl elimination reaction to obtain compound II;

[0011] (b) dissolving the compound II in a polar solvent, and mixing it with an oxidant and a phase transfer catalyst to carry out an epoxidation reaction to obtain a deflazacort intermediate compound III;

[0012]

[0013] In one embodiment, the hydroxyl elimination reaction is specifically:

[0014] The compound I is mixed with an elimination solvent / SO2 and a halogenating agent and reacted at -40-0°C for 1-2h. Further, the elimination solvent is any one of pyridine, triethylamine or 4-dimethylaminopyridine. Further, the halogenating agent is chlorosuccinimide or bromosuccinimide. Further, after the hydroxyl elimination reaction, the mixed solution after the hydroxyl elimination reaction is crystallized, filtered, washed and recrystallized to obtain compound II.

[0015] In one embodiment, the polar solvent in step (b) is tetrahydrofuran, dioxane, or acetone.

[0016] In one embodiment, the oxidant is a peracid; the peracid specifically includes: peracetic acid, tert-butyl hydroperoxide, m-chloroperbenzoic acid, and perbenzoic acid.

[0017] In one embodiment, the phase transfer catalyst is tetrabutylammonium bromide or benzyltrimethylammonium hydroxide.

[0018] In one embodiment, the reaction temperature of the epoxidation reaction is 0-40°C.

[0019] In one embodiment, the epoxidation reaction further includes a purification process, including:

[0020] The mixture obtained after the epoxy reaction is concentrated, water is added and stirred to obtain a precipitate, and the filter cake is filtered out and dried and then recrystallized with ethyl acetate to obtain the deflazacort intermediate compound III.

[0021] Beneficial effects of the present invention:

[0022] The invention adopts hydroxyl elimination and epoxidation process to prepare the key intermediate of deflazacort, optimizes the conditions of the epoxidation process, cooperates with a specific solvent, oxidant and phase transfer catalyst, improves the selectivity of the epoxidation process, has a high conversion rate, reduces by-products, and has mild reaction conditions and a simple post-treatment process, making the production more economical and safer, and is suitable for industrial promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1This is the HPLC spectrum of compound III obtained in Example 2 of the present invention;

[0024] Figure 2 The compound III obtained in Example 2 of the present invention 1 HNMR spectrum;

[0025] Figure 3 The compound IV obtained in Example 2 of the present invention 1 HNMR spectrum. DETAILED DESCRIPTION

[0026] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below in conjunction with the accompanying drawings. In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed below.

[0027] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present invention, the meaning of "plurality" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

[0029] The present invention provides a method for preparing a deflazacort intermediate, which specifically comprises:

[0030] (a) subjecting compound I to a hydroxyl elimination reaction to obtain compound II;

[0031] (b) dissolving the compound II in a polar solvent, and mixing it with an oxidant and a phase transfer catalyst to carry out an epoxidation reaction to obtain a deflazacort intermediate compound III;

[0032]

[0033] In a specific example, the hydroxyl elimination reaction process is specifically as follows:

[0034] The compound I is mixed with the elimination solvent / SO2 and the halogenating agent and reacted at -40 to 0°C for 1-2h; the preferred temperature is -30 to -20°C. Further, the elimination solvent is any one of pyridine, triethylamine or 4-dimethylaminopyridine or a mixture thereof. Further, the halogenating agent is chlorosuccinimide or bromosuccinimide. Further, after the hydroxyl elimination reaction, the mixed solution after the hydroxyl elimination reaction is crystallized, filtered, washed and recrystallized to obtain compound II; specifically, the mixed solution after the hydroxyl elimination reaction is introduced into a hydrochloric acid aqueous solution (20%), crystallized at 0 to 5°C for 2h, filtered, rinsed with water to the core, the solid is dried at about 50°C, and the solid is recrystallized from ethyl acetate to obtain a white solid compound II.

[0035] In one embodiment, the polar solvent in step (b) is tetrahydrofuran or acetone.

[0036] In one embodiment, the oxidant is a peracid; the peracid specifically includes: peracetic acid, tert-butyl hydroperoxide, m-chloroperbenzoic acid, perbenzoic acid, preferably tert-butyl hydroperoxide.

[0037] In one embodiment, the phase transfer catalyst is tetrabutylammonium bromide or benzyltrimethylammonium hydroxide or benzyltriethylammonium chloride.

[0038] The preferred combination includes: the polar solvent is tetrahydrofuran, the oxidant is tert-butyl peracetic acid and the phase transfer catalyst is benzyltrimethylammonium hydroxide.

[0039] In one embodiment, the reaction temperature of the epoxidation reaction is 0-40°C. Preferably, the reaction temperature of the epoxidation reaction is 0-5°C.

[0040] Compound II has three double bonds. Peroxy acid is an electrophilic reagent. When the double bond carbon atom is connected to a donor group, the more donor groups are connected, the easier the reaction is. If two different olefinic bonds exist in the same molecule, the olefinic bond with a higher electron cloud density is easy to oxidize; when the olefinic bond is conjugated with a carbonyl group, its activity will decrease. Based on structural analysis, selectivity can be improved by selecting a weaker peroxy reagent, a polar solvent, and adding a suitable phase transfer catalyst.

[0041] Organic peroxyacids (referred to as peracids) are often used as epoxidation reagents in laboratories to react with alkenes to generate 1,2-epoxides. Commonly used peroxyacids include peroxyformic acid, peroxyacetic acid, peroxybenzoic acid, peroxym-chlorobenzoic acid, peroxytrifluoroacetic acid, etc. When the peroxyacid molecule contains electron-withdrawing substituents, its reactivity is much more active than that of alkyl peroxyacids. The order of oxidizing properties of peroxyacids is: peroxytrifluoroacetic acid > peroxym-chlorobenzoic acid > peroxybenzoic acid > peroxyacetic acid > tert-butyl hydroperoxide. Weaker peracids can significantly improve the selectivity of epoxides.

[0042] The epoxidation reaction of olefins is usually carried out in an inert solvent (such as chloroform, dichloromethane, ether, toluene), but the reaction effect of compound II in these solvents is poor due to solubility and polarity. Tetrahydrofuran and acetone are preferred as solvents, which can take into account the above advantages and disadvantages.

[0043] Phase transfer catalyst plays an important role in the reaction, which can accelerate the reaction rate and thus improve the reaction selectivity. If the reaction time is long, the transition epoxy product will increase.

[0044] In one embodiment, the epoxidation reaction further includes a purification process, including:

[0045] The mixture obtained after the epoxy reaction is concentrated, water is added and stirred to obtain a precipitate, and the filter cake is filtered out and dried and then recrystallized with ethyl acetate to obtain the deflazacort intermediate compound III.

[0046] During the above hydroxyl elimination and epoxidation reaction, TLC detection was used to track the reaction until the reaction was complete.

[0047] The present invention is described in detail below in conjunction with specific embodiments, which are used to understand but not to limit the present invention.

[0048] In the examples of the present invention, the starting material compound I: 17α-hydroxypregna-1,4-diene-3,11,20-trione is homemade, and other reagents are commercially available.

[0049] Starting material compound I: 17α-hydroxypregnane-1,4-diene-3,11,20-trione was prepared by referring to patent CN114317662A. Its hydrogen spectrum and carbon spectrum data are as follows:

[0050] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=10.2Hz, 1H), 6.19 (dd, J=10.2, 2.0Hz, 1H), 6.06 (d, J=1.8Hz, 1H),3.36(d,J=8.3Hz,1H),2.84–2.70(m,2H),2.48(ddd,J=13.6,5.1,1.6Hz,1H),2.43–2.29( m,2H),2.24(d,J=0.9Hz,3H),2.10(d,J=12.2Hz,2H),1.98(s,3H),1.74(ddd,J=15.2,9.5,6. 1Hz,1H),1.49(td,J=12.1,6.1Hz,1H),1.42(s,3H),1.34–1.19(m,1H),0.72(d,J=1.1Hz,3H).

[0051] 13 C NMR(101MHz, CDCl3)δδ210.42,209.41,186.39,166.57,166.53,155.24,155.22,127.64,124.65,88.5 8,60.12,51.54,51.53,49.77,49.29,42.34,36.09,33.89,33.64,32.23,27.62,23.54,18.85,16.26.

[0052] Example 1

[0053] Compound II: Preparation of pregnane-1,4,16-triene-3,11,20-trione.

[0054] The reaction formula is:

[0055]

[0056] Preparation process: In a 250mL three-necked flask, add 10.0g of compound I, 10.0g of chlorosuccinimide, and 50mL of pyridine at a time, cool to -20~-30℃ under nitrogen protection, slowly add 30% SO2 / pyridine (20mL) dropwise, react for 1 hour, and detect by TLC. After the reaction is complete, pour the reaction solution into a hydrochloric acid aqueous solution (20%, 60mL), crystallize at 0~5℃ for 2 hours, filter, rinse with water until neutral, and dry the solid at about 50℃; the solid is recrystallized from ethyl acetate to obtain 8.2g of white solid, with a yield of 82.0%, HPLC purity of 98.5%, and identification by hydrogen spectrum and carbon spectrum is as follows:

[0057] 1 H NMR (400MHz, CDCl3) δ7.72(d,J=10.3Hz,1H),6.73(dd,J=3.4,1.8Hz,1H),6.14(dd,J=10.3,2.0Hz,1H),6.02(t,J=1.7Hz,1H),3.08(d,J=12.9Hz,1H ),2.56–2.42(m,2H),2.41–2.29(m,2H),2.22(s,3H),2.21–1.95(m,5H),1 .90(dd,J=11.1,0.9Hz,1H),1.40(s,3H),1.35–1.20(m,2H),0.85(s,3H).

[0058] 13C NMR (101MHz, CDCl3) δ208.50,195.76,186.19,166.17,155.22,152.48,144.12,127.57,12 4.83,61.78,54.59,53.67,48.38,42.55,35.12,33.27,32.22,31.80,26.89,18.92,17.40.

[0059] Example 2

[0060] Preparation of compound III

[0061] The reaction formula is:

[0062]

[0063] Preparation process: Tetrahydrofuran (100.0 mL), compound II (10.0 g) obtained in the example and tetrabutylammonium bromide (0.5 g) were added to a clean and dry 250 mL three-necked flask in sequence, the temperature was lowered to 0-5°C, tert-butyl hydroperoxide (5.0 g, 70% aqueous solution) was slowly added dropwise, and after the addition, the reaction was stirred and the reaction was detected to be complete by TLC (it should be understood that the reaction to completion means that the reaction product no longer increases, not that all compound II is completely reacted). The system was added to a sodium sulfite aqueous solution (50 mL, 5%), and potassium iodide starch paper was used to detect the non-oxidizing property. The system was concentrated under reduced pressure, replaced once with water (50 mL), filtered, rinsed with water (50 mL), and the filter cake was dried to obtain 9.2 g of the target compound III and a small amount of by-product IV, with an HPLC purity of 96.8% (a small amount of peroxide is present), and a yield of 92.0%; the crude product was recrystallized from ethyl acetate with a purity of 99%; the HPLC spectrum is as follows Figure 1 shown.

[0064] The peak results are shown in Table 1:

[0065]

[0066] Compound III hydrogen spectrum (spectrum as shown Figure 2 The carbon spectrum is identified as follows:

[0067] 1H NMR (400MHz, CDCl3) δ7.64(d,J=10.3Hz,2H),6.11(dd,J=10.2,2.0Hz,2H),5.99(t,J=1.7Hz,2H),3.77(s,2H),2.69(d,J=12.4Hz,2H), 2.55–2.28(m,7H),2.26–1.53(m,21H),1.45(ddd,J=12.9,11.7,1.1Hz,2H),1.36(s,6H),1.33–1.10(m,4H),0.98(s,6H),0.63(s,1H).

[0068] 13 C NMR (100MHz, CDCl3) δ207.73,203.46,186.08,165.95,154.92,127.61,124.78,68.88,61 .21,60.71,50.17,44.15,44.00,42.37,34.16,32.85,32.11,27.09,25.57,18.94,16.01.

[0069] The hydrogen spectrum of compound IV (spectrum as shown Figure 3 As shown), carbon spectrum identification is as follows:

[0070] 1 H NMR (400MHz, CDCl3) δ5.63(s,1H),4.26(dd,J=18.4,4.1Hz,1H),3.79(s,1H),3.47–3.11(m,2H),2.73(t,J=9.1Hz,1H),2.44(dd,J=20.9,1 1.5Hz,2H),2.26(d,J=11.6Hz,2H),2.17–2.06(m,2H),2.03–1.71(m,8H),1.42(d,J=17.6Hz,5H),1.27–1.12(m,2H),0.99(d,J=5.3Hz,4H).

[0071] 13 C NMR (101MHz, CDCl3) δ207.87,203.52,193.71,163.63,120.80,68.98,60.73,60.52,59. 29,55.01,50.07,44.07,43.84,40.27,34.08,32.33,31.70,27.04,25.61,18.71,16.02.

[0072] Example 3-12

[0073] The key intermediate compound III of deflazacort was prepared according to the method of Example 2. The selection, proportion and reaction temperature of each reagent are shown in Table 1; and the yield and purity of the isolated product are shown in Table 2.

[0074] Table 1 Preparation conditions of Examples 3-12

[0075]

[0076] Wherein, THF: tetrahydrofuran; TBHP: tert-butyl hydroperoxide; TRITON B: benzyltrimethylammonium hydroxide; TBAB: tetrabutylammonium bromide.

[0077] Table 2 Statistical table of results of Examples 3-12

[0078]

[0079] Comparative Example 1

[0080] Compound II (1 g) was added to dichloromethane (1 mL) and methanol (6 mL), and the temperature was lowered to about 0°C, and tert-butyl hydroperoxide (0.45 g) and tetrabutylammonium bromide solution (0.03 g) were added dropwise in sequence. TLC tracking detection was performed. After the reaction was completed, acetic acid (2.5 mL) was added to quench the reaction, and the reaction was concentrated. 10 mL of water was added for replacement, and the reaction was filtered and dried to obtain 0.85 g of a crude product. The purity of the isolated product was: 83.6% for compound III and 12.1% for the diepoxy product (compound IV).

[0081] Comparative Example 2

[0082] Compound II (2.0 g) was added to tetrahydrofuran (10 mL), and the temperature was lowered to about 0°C. Tert-butyl hydroperoxide (0.9 g) was added, and the reaction was carried out for about 2 h. According to TLC detection, 20% of the raw materials remained. The reaction time was further extended to 6 hours until the reaction product no longer increased. After quenching, the mixture was concentrated, replaced with water, filtered, and dried to obtain 1.63 g of a crude product. The purity of compound III was 85.3% by HPLC, the proportion of diepoxy product (compound IV) was 6.3%, and the raw materials remained 4.5%.

[0083] According to the above-mentioned Example 11 and Comparative Examples 1 and 2, the ratio of reactants in Comparative Examples 1 and 2 is the same as that in Example 11, but the solvent is changed to a mixed solution of dichloromethane and methanol in Comparative Example 1, and no phase transfer catalyst is added in Comparative Example 2. By comparing the purity of each substance in the product obtained in Example 11 and Comparative Examples 1 and 2, it can be known that the type of solvent and the phase transfer catalyst will greatly affect the selectivity and reaction conversion rate of the reaction. According to Examples 2-12, when the type of organic peracid and the phase transfer catalyst are different, the reaction selectivity and reaction conversion rate are greatly different. Therefore, the reaction in the present invention is an organic whole, and the raw materials, reaction environment and various parameters in the reaction process affect each other. Through the limitation of the relevant conditions of the present invention, a method for preparing a deflazacort intermediate with high yield and good reaction selectivity is obtained.

[0084] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0085] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be based on the attached claims, and the description and drawings can be used to interpret the content of the claims.

Claims

1. A method for preparing a deflazacort intermediate, characterized in that: Specifically include: (a) subjecting compound I to a hydroxyl elimination reaction to obtain compound II; (b) dissolving the compound II in a polar solvent, and mixing with an oxidant and a phase transfer catalyst to carry out an epoxidation reaction to obtain the deflazacort intermediate compound III; the polar solvent in the step (b) is tetrahydrofuran or acetone, the oxidant in the step (b) is tert-butyl hydroperoxide, the phase transfer catalyst in the step (b) is tetrabutylammonium bromide or benzyltrimethylammonium hydroxide, and the reaction temperature of the epoxidation reaction in the step (b) is 0 to 40°C; 2. The method for preparing a deflazacort intermediate according to claim 1, characterized in that: The step of the hydroxyl elimination reaction comprises: The compound I is mixed with a solvent, SO2 and a halogenating agent and reacted at -40-0°C for 1-2 hours.

3. The method for preparing a deflazacort intermediate according to claim 2, characterized in that: The solvent is any one of pyridine, triethylamine or 4-dimethylaminopyridine.

4. The method for preparing a deflazacort intermediate according to claim 2, characterized in that: The halogenating agent is chlorosuccinimide or bromosuccinimide.

5. The method for preparing a deflazacort intermediate according to any one of claims 1 to 4, characterized in that: After the hydroxyl elimination reaction, the method further comprises: crystallizing, filtering, washing and recrystallizing the mixed solution after the hydroxyl elimination reaction to obtain compound II.

6. The method for preparing a deflazacort intermediate according to any one of claims 1 to 4, characterized in that: The temperature of the epoxidation reaction is 0-5°C.

7. The method for preparing a deflazacort intermediate according to any one of claims 1 to 4, characterized in that: The epoxidation reaction also includes a purification process, including: The mixture obtained after the epoxy reaction is concentrated, water is added and stirred to obtain a precipitate, and the filter cake is filtered and dried and then recrystallized with ethyl acetate to obtain the deflazacort intermediate compound III.

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