A process for the preparation of deflazacort

Abstract

The application discloses a preparation method of deflazacort, and the method comprises the following steps: taking 3-(hydrazinecarbonyl) hydrazone-16β, 17β-epoxy imino-1, 4-pregnadiene-11, 20-dione as raw material, and realizing 11β-hydroxyl high selectivity synthesis at-10±2℃ through photocatalysis and diisopinocampyl borane steric hindrance oriented reduction, and the ee value is greater than or equal to 95%. After iodination by N-iodosuccinimide, the product is obtained through quenching by sodium thiosulfate, ring-opening esterification by potassium acetate and recrystallization, and the total yield is 57%, impurities are low, and the method is suitable for industrialization.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically proposes a method for preparing difcote. Background Technology

[0002] Deficotte, as a third-generation glucocorticoid drug, relies on its 11β-hydroxy configuration for its anti-inflammatory activity. However, the stereoselective reduction of the ketone group at the C11 position of the steroid has long faced the technical bottleneck of insufficient purity: traditional chemical reducing agents (such as NaBH4 / CeCl3) are affected by the steric hindrance of the steroid skeleton, and the selectivity of the 11β-OH configuration is only about 80% ee, which is difficult to meet the purity requirements of the drug.

[0003] Currently, domestic synthetic routes are mainly based on fungal dehydrogenases, involving steps such as 11-hydroxyl oxidation, 3-carbonyl protection, ring-opening hydrolysis of 16- and 17-epoxy groups, 11-ketone reduction, hydrazone hydrolysis, and potassium acetate ring-opening. However, the 11-ketone reduction step in this route suffers from low selectivity. Existing technologies using sodium borohydride result in 11α / 11β isomer mixing, primarily because the β-face is blocked by the steric barrier formed by the C18 angular methyl group and C12-H, while the α-face is partially blocked by the C19 angular methyl group. However, the steric hindrance is relatively small, so the ideal β-face attack path of the C11-keto group is blocked by the C18 angular methyl group. Although there are vacancies on the α-face, it is not a thermodynamically dominant configuration. The reduction of sodium borohydride is achieved through the nucleophilic attack of borohydride fluoride ions on the carbonyl carbon. Due to the small size of the hydrogen ion, it can attack from both the α and β faces simultaneously. However, the attack process lacks chiral induction, which means that the attack direction is completely controlled by the substrate space. Therefore, a certain proportion of the product still has the α configuration, which requires multiple purification processes. This also leads to a decrease in the yield of the target configuration product.

[0004] Therefore, it is necessary to optimize the ketone reduction step at position 11 in this synthetic video to improve the selectivity of the 11β configuration. Summary of the Invention

[0005] In view of this, the present invention proposes a method for preparing defcote, which aims to improve the selectivity of the β-configuration product when the ketone group at position 11 is reduced.

[0006] The technical solution of this invention is achieved as follows: This invention provides a method for preparing defcotol, comprising the following steps: S1. Dissolve 3-(hydrazylformyl)hydrazone-16β,17β-epoxyimino-1,4-pregnadiene-11,20-dione in a mixed solvent of acetonitrile and methanol, add 0.5-1.0% of the photosensitizer [Ru(bpy)3]Cl2•6H2O equivalent to the molar amount of 3-(hydrazylformyl)hydrazone-16β,17β-epoxyimino-1,4-pregnadiene-11,20-dione, and activate at 25°C for 1 h under 450 nm blue light irradiation; S2. Add 2.0-3.0 times the molar amount of 3-(hydrazylformyl)hydrazone-16β,17β-epoxyimino-1,4-pregnadiene-11,20-dione to the reaction solution of S1. React at -10±2℃ for 2 hours. Quench with 10% dilute hydrochloric acid. Adjust the pH to 7.0 with saturated sodium bicarbonate. Concentrate the solution by separation to obtain intermediate I. S3. Dissolve intermediate I in acetone, add 3.0 molar amounts of ammonium bisulfate solid of intermediate 1, react at 56°C for 2 hours, cool and dilute with water, extract with dichloromethane, wash the organic phase with water until pH=7.0, and concentrate to obtain intermediate II. S4. Dissolve intermediate II in anhydrous dichloromethane, add 1.05 times the molar amount of N-iodosuccinimide in dichloromethane solution of intermediate II, react at 0°C in the dark for 30 min to generate intermediate III reaction solution. S5. Add a methanol solution of potassium acetate, equivalent to 2.0 moles of intermediate III, to the reaction solution obtained in S4. React at 40°C for 2 hours to achieve ring opening of the epoxy imino group and esterification at C21 position to obtain crude difcote. In S1, the volume ratio of acetonitrile to methanol is (3-5):1, preferably 4:1.

[0007] The reaction formula is as follows: .

[0008] Intermediate I is 3-(hydrazylformyl)hydrazone-11β-hydroxy-16β,17β-epoxyimino-1,4-pregnadien-20-one; Intermediate II is 1β-hydroxy-16β,17β-epoxyimino-1,4-pregnadiene-3,20-dione; Intermediate III is 11β-hydroxy-21-iodo-16β,17β-epoxyimino-1,4-pregnadiene-3,20-dione.

[0009] In some embodiments, the temperature is maintained at -10±2°C when diisopinepineborane is added dropwise to S2.

[0010] In some embodiments, the dichloromethane solution of N-iodosuccinimide is added dropwise for ≥10 min in step S4, and the reaction progress is monitored by TLC. The developing solvent is n-hexane:ethyl acetate = 3:1, and the Rf value is 0.62 for intermediate II and 0.48 for intermediate III.

[0011] In some embodiments, after the reaction in step S4 is completed, a saturated sodium thiosulfate solution is slowly added dropwise to the reaction solution, and the reaction is maintained at 0°C for 10-15 minutes. The amount of sodium thiosulfate used is 1.5-2.0 times the molar amount of N-iodosuccinimide.

[0012] In some embodiments, after the addition is complete, an equal volume of deionized water equal to that of saturated sodium thiosulfate solution is added, the pH is adjusted to 6.5-7.0 with 1M sodium hydroxide solution, the mixture is transferred to a separatory funnel and allowed to stand for separation, and the organic phase is collected.

[0013] In some embodiments, the organic phase is dried with anhydrous sodium sulfate for 10-15 minutes, with the amount of anhydrous sodium sulfate being 10 g / 100 ml of the organic phase. The desiccant is removed by filtration, and the phase is concentrated under reduced pressure to 1 / 3 of its original volume.

[0014] In some embodiments, after the S5 reaction is completed, the solvent is removed by vacuum concentration, and a mixture of ethyl acetate and water in a volume ratio of 1:1 is added for separation. The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain crude defcodone.

[0015] In some embodiments, the process further includes S6, where the crude product is dissolved in a mixed solvent of dichloromethane and methanol in a volume ratio of 8:1, 5% w / w activated carbon is added for decolorization for 30 minutes, the product is filtered and concentrated, and then recrystallized in a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 3:1 to obtain purified difcote.

[0016] In some embodiments, the particle size of ammonium bisulfate in S3 is 100-200 mesh.

[0017] This application uses diisopinepineborane, in which the isopine group has a large spatial occupancy, which can completely seal the α-face, allowing hydrogen ions to attack only from the β-face. At the same time, the reaction condition of -10℃ can effectively suppress molecular thermal motion and enhance the spatial guidance effect. The photocatalytic process polarizes the 11-keto group, enhancing the directional binding with borane.

[0018] The present invention has the following advantages over the prior art: Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0020] Figure 1 This is the reaction formula of the present invention. Detailed Implementation

[0021] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments of this invention pertain. If any definition stated in this section is contrary to or otherwise inconsistent with a definition stated in a patent, patent application, published patent application, or other publication incorporated herein by reference, the definitions listed here shall prevail over those incorporated herein by reference.

[0023] Unless otherwise specified, the methods used in the following embodiments are conventional methods. Unless otherwise specified, the materials, reagents, and instruments used are conventional materials, reagents, and instruments in the art, and can be obtained commercially by those skilled in the art.

[0024] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1 to 5” is disclosed, the described range should be interpreted as including ranges “1 to 4”, “1 to 3”, “1 to 2”, “1 to 2 and 4 to 5”, “1 to 3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range. In this specification and claims, range definitions may be combined and / or interchanged, unless otherwise stated, these ranges include all subranges contained therein.

[0025] Example 1 Preparation of Difucoid S1, photosensitizer activation 3-(hydrazylformyl)hydrazone-16β,17β-epoxyimino-1,4-pregnadiene-11,20-dione (5.0 g, 12.8 mmol) was dissolved in acetonitrile:methanol (4:1 v:v, 60 mL), and [Ru(bpy)3]Cl2・6H2O (0.06 g, 0.1 mmol, 0.8 mol%) was added. The mixture was activated by stirring at 25 °C for 1 h under 450 nm blue light (10 W power), and the system turned orange-red.

[0026] S2, reduction with diisopinepineborane The temperature was lowered to -10℃, and diisopinepineborane (1.0 MTHF solution, 38.4 mL, 38.4 mmol, 3.0 eq) was added dropwise. The reaction was maintained at -10 ± 2℃ for 2 h. TLC monitoring (developing solvent n-hexane: ethyl acetate = 3:1) showed that the starting material Rf = 0.62 disappeared, and intermediate I Rf = 0.45 appeared.

[0027] Quenching was performed with 10% dilute hydrochloric acid (10 mL), pH was adjusted to 7.0 with saturated sodium bicarbonate, and the mixture was extracted with dichloromethane (3 × 50 mL). The organic phase was dried and concentrated to obtain intermediate I (4.5 g, yield 91%, ee value 95.8%).

[0028] S3, Ammonium bisulfate reaction Intermediate I (4.0 g, 10.2 mmol) was dissolved in acetone (40 mL), and ammonium bisulfate (100 mesh, 4.3 g, 30.6 mmol, 3.0 eq) was added. The mixture was refluxed at 56 °C for 2 h.

[0029] After cooling, water (50 mL) was added, and the mixture was extracted with dichloromethane. The organic phase was washed with water until pH=7, and then concentrated to obtain intermediate II (3.6 g, yield 93%).

[0030] S4, NIS iodination reaction Intermediate II (3.5 g, 9.4 mmol) was dissolved in anhydrous dichloromethane (35 mL). A solution of N-iodosuccinimide (2.7 g, 10.0 mmol, 1.05 eq) in dichloromethane (15 mL) was added dropwise at 0 °C in the dark over a period of 15 min. The reaction was carried out for 30 min. TLC showed that intermediate II disappeared and intermediate III appeared with Rf = 0.48.

[0031] Add 15 mL of saturated sodium thiosulfate solution (1.8 eq NIS equivalent) at 0 °C, react for 15 min, and detect no free iodine with starch test paper.

[0032] Add deionized water (15 mL), adjust the pH to 6.8 with 1 M sodium hydroxide, separate the liquid and dry the organic phase with anhydrous sodium sulfate (3.5 g) for 15 min, filter and concentrate to 12 mL (1 / 3 of the original volume).

[0033] S5, potassium acetate ring-opening esterification A methanol solution (20 mL) of potassium acetate (1.4 g, 14.8 mmol, 2.0 eq) was added to the concentrate, and the reaction was carried out at 40 °C for 2 h. HPLC analysis showed that the epoxy ring-opening was complete.

[0034] Concentrate under reduced pressure, add ethyl acetate:water (1:1, 50mL), separate the liquid, dry and concentrate the organic phase to obtain crude defcodone (3.2g).

[0035] S6, recrystallization purification The crude product was dissolved in dichloromethane:methanol (8:1, 30mL), and decolorized with 5% activated carbon (0.16g) for 30min. After filtration and concentration, it was recrystallized with n-hexane:ethyl acetate (3:1) to give white crystals of defcote (2.8g, total yield 57%, HPLC purity 99.3%, ee value 95.8%).

[0036] Comparative Example 1 This comparative example differs from Example 1 in that: S4, NIS iodination reaction Intermediate II (3.5 g, 9.4 mmol) was dissolved in anhydrous dichloromethane (35 mL). A solution of N-iodosuccinimide (2.7 g, 10.0 mmol, 1.05 eq) in dichloromethane (15 mL) was added dropwise at 0°C in the dark over 15 min. The reaction proceeded for 30 min. TLC showed that intermediate II disappeared and intermediate III appeared with an Rf of 0.48. No further quenching was performed, and the reaction solution was used directly for reaction S5.

[0037] After recrystallization and purification, 2.5 g of defcodone was obtained with an HPLC purity of 92.1%. An iodine impurity at position C21 (4.7%) was detected, and the yield was 50%, which was 7% lower than that in Example 1, and the impurity content was higher.

[0038] Comparative Example 2 This comparative example is based on Example 1, where S2 uses conventional sodium borohydride for reduction. In S2, NaBH4 (0.48 g, 12.8 mmol, 1.0 eq) was used instead of diisopinepineborane, and the reaction was carried out at 0 °C for 2 h. The remaining steps were the same as in Example 1.

[0039] Results: Intermediate I yielded 75% with an ee value of 81.2%, and the final yield of defcodone was 42%, with an HPLC purity of 91.5%. It required three additional recrystallizations to reach pharmaceutical standards.

[0040] Comparative Example 3 This comparative example is based on Example 1, omitting S1. In S1, no photosensitizer [Ru(bpy)3]Cl2・6H2O is added; the mixture is stirred directly in the dark, and the remaining steps are the same as in Example 1.

[0041] Results: The ee value of intermediate I was 88.3%, and the final efcotol ee value was 87.9%, which was 7.9% lower than that of Example 1, with a yield of 52%.

[0042] The data from the above embodiments and comparative examples are compared in the table below:

[0043] Example 2 Diisopinepineborane equivalent optimization Based on Example 1, the equivalent of diisopinepineborane in S2 was adjusted to 2.0 eq, 2.5 eq, and 3.0 eq, respectively, while the other steps were the same as in Example 1.

[0044] The results are compared in the table below:

[0045] Example 3 Photosensitizer concentration gradient Based on Example 1, the amount of photosensitizer in S1 was adjusted to 0.5 mol%, 0.8 mol%, and 1.0 mol, respectively, while other conditions remained the same as in Example 1.

[0046] The results are compared in the table below:

[0047] 0.8 mol% is the optimal dosage, verifying the scientific validity of the 0.5-1.0 mol% range in the claims. Excessive dosage will lead to a self-quenching effect.

[0048] Example 4 S2 reaction temperature fluctuation test Based on Example 1, the reaction temperatures in S2 were adjusted to -5℃, -10℃, and -15℃, respectively, while the other steps were the same as in Example 1.

[0049] The results are compared in the table below:

[0050] Selectivity and stability are optimal at -10℃, while fluctuations of ±5℃ can lead to a decrease in ee value or reagent decomposition.

[0051] Comparative Example 4 This comparative example is based on Example 1, but the dropping time in step S4 is shortened to 5 minutes, while other conditions are the same as in Example 1.

[0052] Results: The content of iodinated byproducts increased to 3.2% (0.5% in Example 1), and the yield of intermediate III decreased to 82%, demonstrating the importance of a dropping time ≥10 min for suppressing excessively high local concentrations.

[0053] Comparative Example 5 This comparative example is based on Example 1, except that the particle size of ammonium bisulfate in step S3 is adjusted to 50 mesh, 200 mesh, and 250 mesh, while other conditions are the same as in Example 1.

[0054] The results are compared below:

[0055] A particle size of 100-200 mesh can balance reaction rate and dispersibility. The essence of ammonium bisulfate particle size control is to achieve a balance between reaction rate, selectivity and process feasibility by optimizing the synergistic effect of surface area, mass transfer and acid strength, so as to meet the kinetic requirements and suppress side reactions.

[0056] Comparative Example 6 Quenching and Type Replacement in S4 This comparative example is based on Example 1, except that the quenching agent used in the S4 quenching step is sodium sulfite (1.8 eq), and other conditions are the same as in Example 1.

[0057] Results: The NIS residue was 1.2% (0.1% in Example 1), and methyl esterification byproducts (2.3%) appeared in S5, demonstrating the selective reduction advantage of sodium thiosulfate (sodium sulfite has weak reducing power and cannot completely quench NIS).

[0058] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing defcotol, characterized in that... It includes the following steps: S1. Dissolve the starting material A with the following structure in a mixed solvent of acetonitrile and methanol, add 0.5-1.0% of photosensitizer [Ru(bpy)3]Cl2·6H2O equivalent to the molar amount of the starting material A, and activate it at 25°C for 1 h under 450nm blue light irradiation; S2. Add 2.0-3.0 times the molar amount of starting material A to the reaction solution of S1, react at -10±2℃ for 2 hours, quench with 10% dilute hydrochloric acid, adjust the pH to 7.0 with saturated sodium bicarbonate, and concentrate by separation to obtain intermediate I. S3. Dissolve intermediate I in acetone, add 3.0 times the molar amount of ammonium bisulfate solid of intermediate I, react at 56°C for 2 hours, cool and dilute with water, extract with dichloromethane, wash the organic phase with water until pH=7.0, and concentrate to obtain intermediate II. S4. Dissolve intermediate II in anhydrous dichloromethane, and add dropwise a dichloromethane solution of N-iodosuccinimide equivalent to 1.05 molar amounts of intermediate II. The dropwise addition time of the dichloromethane solution of N-iodosuccinimide is ≥10 min. React at 0°C in the dark for 30 min to generate the reaction solution of intermediate III. After the S4 reaction is complete, slowly add saturated sodium thiosulfate solution dropwise to the reaction solution, maintain the reaction temperature at 0℃ for 10-15 min, and use sodium thiosulfate at a rate of 1.5-2.0 times the molar amount of N-iodosuccinimide. After the addition is complete, add an equal volume of deionized water to the saturated sodium thiosulfate solution, adjust the pH to 6.5-7.0 with 1M sodium hydroxide solution, transfer to a separatory funnel and allow to stand for separation, then take the organic phase. Dry the organic phase with anhydrous sodium sulfate for 10-15 min, using 10 g of anhydrous sodium sulfate per 100 mL of organic phase, filter to remove the desiccant, and concentrate under reduced pressure to 1 / 3 of the original volume. S5. Add a methanol solution of potassium acetate, equivalent to 2.0 moles of intermediate III, to the reaction solution obtained in S4. React at 40°C for 2 hours to achieve acetic acid esterification at C21 and obtain crude difcote. 。 2. The method for preparing defcotol as described in claim 1, characterized in that... When adding diisopinepineborane dropwise to S2, the temperature is maintained at -10±2℃.

3. The method for preparing defcotol as described in claim 1, characterized in that... In step S4, the reaction progress was monitored by TLC. The developing solvent was n-hexane:ethyl acetate = 3:1, and the Rf value was 0.62 for intermediate II and 0.48 for intermediate III.

4. The method for preparing defcotol as described in claim 1, characterized in that... After the S5 reaction is completed, the solvent is removed by concentration under reduced pressure. A mixture of ethyl acetate and water in a volume ratio of 1:1 is added and the mixture is separated. The organic phase is dried over anhydrous sodium sulfate and concentrated to obtain crude defcodone.

5. The method for preparing defcotol as described in claim 1, characterized in that... It also includes S6. The crude product is dissolved in a mixed solvent of dichloromethane and methanol in a volume ratio of 8:1, and 5% w / w activated carbon is added for decolorization for 30 minutes. After filtration, it is concentrated and recrystallized in a mixed solvent of n-hexane and ethyl acetate in a volume ratio of 3:1 to obtain purified difcote.

6. The method for preparing defcotol as described in claim 1, characterized in that... The particle size of ammonium bisulfate in S3 is 100-200 mesh.

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