Preparation method of 9-fluoro steroid compound

Abstract

The invention provides a preparation method of a 9-fluorinated steroid compound, which comprises the following steps: a compound I reacts with a fluorination reagent to obtain a 9-fluorinated steroid compound II, the reaction formula is as follows: in the formula I and the formula II, R1 and R2 are respectively and independently selected from hydrogen, hydroxyl or hydroxyl with a protecting group, and the 16-position carbon is R configuration or S configuration and represents a single bond or a double bond; the fluorination reagent is selected from Selectfluor or Selectfluor II, and the fluorination reagent is selected from Selectfluor I and Selectfluor II. According to the preparation method of the 9-fluorinated steroid compound II, the 9-fluorinated steroid compound II is prepared by taking a steroid compound as a raw material through a one-step reaction, after the reaction is completed, a fluorination reagent in a reaction solution is quenched, water is added into the reaction solution, and a solid is separated out by cooling and stirring, so that a target product can be obtained. The preparation method provided by the invention has few steps, does not need to use strong corrosive acid, is simple to operate and is suitable for industrial large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the preparation of organic compounds, more particularly, to a preparation method for obtaining 9-fluorinated steroid compounds by one-step reaction with steroid compound I as raw material. BACKGROUND

[0002] Glucocorticoid drugs (steroidal anti-inflammatory drugs) are widely used in the treatment of inflammatory diseases, autoimmune diseases and allergic reactions, etc. The introduction of fluorine substituent on the 9-position carbon of the molecular structure can significantly enhance its pharmacological activity, such as anti-inflammatory activity and pharmacokinetic stability, making it have more extensive application value in clinical practice.

[0003] At present, the production of 9-fluorinated steroid compounds in industry mainly adopts a multi-step synthesis route. It is generally believed that due to the 9-position carbon of the steroid compound being at the center of the "bowl-shaped" structure of the steroid molecule, there is a very large steric hindrance, and direct fluorination is difficult to achieve high selectivity. So far, people usually prepare 9-fluorinated steroid compounds through the following two paths:

[0004] The epoxy intermediate path: first form a 9,11-epoxy intermediate of the steroid compound, then ring-opening and fluorination under strong acidic conditions, and the 9,11-epoxy intermediate is usually obtained by first introducing bromine and hydroxyl groups at the 9,11 positions of the steroid compound through bromohydration reaction, and then epoxidation under alkaline conditions. This process involves multiple steps (epoxidation → ring-opening → fluorination), has low yield (usually 70-80%), and needs to use dangerous chemicals such as corrosive hydrofluoric acid.

[0005] The bromohydroxy intermediate path: first introduce bromine and hydroxyl groups at the 9,11 positions of the steroid compound through bromohydration reaction, and then replace the bromine atom with a fluorine atom through nucleophilic substitution. This path has problems such as poor selectivity of bromination (9-bromo / 11-bromo ratio is difficult to control), incomplete bromine-fluorine substitution (residual bromine impurities >5%), and additional debromination side reactions, etc., resulting in the purity of the final product being difficult to meet the pharmaceutical standards (usually <95%).

[0006] Both of the two traditional paths need additional 2-3 steps, have low total yield, and produce a large amount of halogen-containing waste, which does not comply with the principles of green chemistry.

[0007] For example, the prior art CN103509075A discloses a preparation method for X compound as shown in route 1, which comprises the steps of: reacting a compound of formula VII with N-bromosuccinimide and water to obtain a compound of formula VIII; epoxidizing the compound of formula VIII under alkaline conditions to obtain a compound of formula IX; and reacting the compound of formula IX with a fluorine reagent to obtain a compound of formula X.

[0008]

[0009] Route 1

[0010] CN107056864A discloses a route similar to Route 1: a method for preparing compound FPA-6 from compound FPA-3, comprising the steps of: reacting compound FPA-3 with dibromohydantoin in the presence of perchloric acid to obtain FPA-4, epoxidizing compound FPA-4 under basic conditions to obtain compound FPA-5, and reacting compound FPA-5 with HF to obtain compound FPA-6.

[0011]

[0012] Route 2

[0013] The above prior art all use a three-step method to obtain the 9-fluorinated product: first, using strong corrosive acids such as perchloric acid, fluoroboric acid, sulfuric acid or p-toluenesulfonic acid, the steroid compound containing a double bond structure is brominated and hydroxylated; then, under strong alkaline conditions, the compound containing bromine and hydroxyl is converted into an epoxide compound; finally, using hydrofluoric acid or its complex, the epoxide compound is fluorinated and opened to obtain the 9-fluorinated product. The fluorination method of the steroid compounds disclosed in these prior arts has obvious defects: the preparation steps are complicated, corrosive reagents are used, the reaction conditions are harsh, the total yield is low (usually only 70-80%) due to multi-step reactions, and there are many impurities in the intermediates and products, which need to be purified by column chromatography, and it is not suitable for industrial large-scale production.

[0014] The prior art CN114685592A discloses a method for fluorinating the 9-position carbon of a steroid compound (see Route 3), comprising the following steps: (a) reacting a compound of formula I with a first brominating reagent, a second brominating reagent and hydrochloric acid to obtain a compound of formula II; (b) reacting the compound of formula II with a fluorinating reagent to obtain a compound of formula III. In this route, strong oxidizing brominating reagents such as dibromohydantoin and potassium bromate are required for the bromohydroxylation step, which has safety hazards and equipment corrosion problems. For the second step of fluorination, although the prior art mentions that nucleophilic fluorine sources such as potassium fluoride and sodium fluoride can be used to complete the bromine-fluorine substitution, this scheme still needs to rely on the above-mentioned strong oxidizing brominating reagents for the bromohydroxylation reaction, and cannot achieve one-step fluorination. It is worth noting that the prior art also mentions that Selectfluor-type electrophilic fluorinating reagents can be used for this conversion, but the inventors have verified that this assumption has a fundamental defect from the chemical principle aspect: the bromine-fluorine substitution is a typical SN2 nucleophilic substitution reaction, which must be driven by a nucleophilic fluorine source (such as F-), while Selectfluor-type reagents are strong electrophilic fluorinating reagents, whose reaction mechanism is completely contrary to the required conversion path. The experimental results of the inventors also confirm that the use of Selectfluor-type reagents cannot achieve effective fluorination of the compound of formula II, and only side reactions such as oxidation can occur.

[0015]

[0016] Route 3

[0017] Therefore, there is a need in the art for a method for preparing 9-fluorinated steroidal compounds which is suitable for industrial large-scale production and simple to operate. SUMMARY

[0018] In view of the problems in fluorination of the 9-position carbon of steroidal compounds in the prior art, the present application provides a method for preparing 9-fluorinated steroidal compounds II from steroidal compounds I and fluorinating reagents through one step, wherein the obtained reaction solution is quenched with a reducing agent to remove residual fluorinating reagents, then cooled to make the product precipitate, and filtered to obtain the target compound. The preparation method has fewer steps, does not need strong corrosive acid, and has simple post-treatment, and is very suitable for industrial large-scale production.

[0019] The method for preparing 9-fluorinated steroidal compounds II provided by the present application comprises the step of: reacting compound I with a fluorinating reagent to obtain 9-fluorinated steroidal compounds II, and the reaction formula is as follows:

[0020]

[0021] In formula I and formula II, R1 and R2 are hydrogen, hydroxyl or hydroxyl with a protecting group,

[0022] the 16-position carbon is in R configuration or S configuration,

[0023] represents a single bond or a double bond;

[0024] the fluorinating reagent is selected from Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) and / or Selectfluor II (1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane tetrafluoroborate)

[0025] In another preferred embodiment, the protecting group is selected from C1-C4 alkyl, substituted C1-C4 alkyl, acyl or silyl.

[0026] In another preferred embodiment, the hydroxyl with a protecting group is an ether-containing ring structure.

[0027] In another preferred embodiment, the alkyl is selected from methyl, ethyl or propyl.

[0028] In another preferred embodiment, the substituted alkyl is selected from benzyl (Bn), p-methoxybenzyl (PMB) or trityl (Trt), 3-methoxypropyl (MOP) or 1-methoxymethyl (MOM).

[0029] In another preferred embodiment, the acyl group is selected from acetyl (Ac), benzoyl (Bz), pivaloyl (Piv), or methoxyacetyl (MEM).

[0030] In another preferred embodiment, the silyl group is selected from tert-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), or tert-butyldiphenylsilyl (TBDPS).

[0031] In another preferred embodiment, the ether-containing ring structure is selected from tetrahydropyranyl (THP).

[0032] In another preferred embodiment, the reaction temperature for the reaction of Compound I with the fluorinating agent is -10 to 20 °C, more preferably 0 to 10 °C, and most preferably 0 to 5 °C.

[0033] In another preferred embodiment, the molar ratio of Compound I to the fluorinating agent is 1 : 1.0 to 3.0, more preferably 1 : 2.0 to 2.5.

[0034] In another preferred embodiment, the solvent used for the reaction of Compound I with the fluorinating agent is selected from polar aprotic solvents.

[0035] In another preferred embodiment, the polar aprotic solvent is selected from acetonitrile (CH3CN), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF) dioxane, acetone, methyltetrahydrofuran, or a combination thereof, more preferably CH3CN.

[0036] In another preferred embodiment, the water content in the solvent used is < 0.1%, more preferably < 0.05%.

[0037] In another preferred embodiment, the solvent used is treated with 4A molecular sieves for > 24 hours, more preferably > 48 hours, prior to use.

[0038] In another preferred embodiment, the water content in the solvent used is maintained at < 0.1%, more preferably < 0.05%, during the reaction by molecular sieves or azeotropic dehydration. In another preferred embodiment, the method of preparation further comprises the steps of:

[0039] quenching the residual (unreacted) fluorinating agent in the reaction mixture with a reducing agent or an aqueous solution of a reducing agent; and

[0040] cooling the quenched reaction mixture to -5 to 10 °C to precipitate the product, filtering, and drying to obtain the 9-fluorinated steroid compound II.

[0041] In another preferred embodiment, the reducing agent is selected from sodium thiosulfate, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium dithionite, or a combination thereof.

[0042] In another preferred embodiment, the aqueous solution of the reducing agent has a mass concentration of 10-40%, more preferably 25-35%.

[0043] In another preferred embodiment, the volume ratio of the solvent used in the reaction to the aqueous solution of the reducing agent is 1:0.1-1, more preferably 1:0.2-0.5.

[0044] In another preferred embodiment, the compound I has the following structural formula:

[0045]

[0046] In another preferred embodiment, the present application provides a method for preparing the 9-fluorinated steroid compound II from the compound I in one step, comprising the step of: reacting the compound I with a fluorinating reagent to obtain the 9-fluorinated steroid compound II, and the reaction formula is as follows:

[0047]

[0048]

[0049] or

[0050] BRIEF DESCRIPTION OF DRAWINGS

[0051] Figure 1-a is the HPLC chromatogram of the reaction solution of the steroid compound II-1 obtained in Examples 1-8;

[0052] Figure 1-b is the HPLC chromatogram of the steroid compound II-1 obtained in Examples 1-8;

[0053] Figure 1-c is the nuclear magnetic hydrogen spectrum of the steroid compound II-1 obtained in Examples 1-8;

[0054] Figure 1-d is the high-resolution mass spectrum of the steroid compound II-1 obtained in Examples 1-8;

[0055] Figure 1-e is the HPLC chromatogram of the steroid compound II-1 obtained in Example 2;

[0056] Figure 2 is the HPLC chromatogram of the steroid compound II-2 obtained in Example 3;

[0057] Figure 3 is the HPLC chromatogram of the steroid compound II-3 obtained in Example 4;

[0058] Figure 4is the HPLC chromatogram of the steroid compound II-4 obtained in Example 5;

[0059] Figure 5 is the HPLC chromatogram of the steroid compound II-5 obtained in Example 6;

[0060] Figure 6 is the HPLC chromatogram of the steroid compound II-6 obtained in Example 7;

[0061] Figure 7 is the HPLC chromatogram of the steroid compound obtained in Comparative Example 1;

[0062] Figure 8 is the HPLC chromatogram of the steroid compound obtained in Comparative Example 2;

[0063] Figure 9 is the HPLC chromatogram of the steroid compound obtained in Comparative Example 3. DETAILED DESCRIPTION

[0064] In the prior art, there is no report on a method for directly synthesizing 9a-fluorinated steroid compounds from 9,11-double bond structure. So far, all the synthesis of 9-fluorinated steroids in the prior art relies on an indirect path: first constructing a 9,11-epoxide or 9,11-bromohydroxyl intermediate, and then introducing a fluorine atom through ring opening or substitution. Although Selectfluor or Selectfluor II is a known fluorinating agent, its application in direct fluorination at the 9 position of a steroid has never been reported. Based on the strong oxidizing property of Selectfluor or Selectfluor II fluorinating agent, a person skilled in the art would generally expect it to initiate double bond epoxidation or over-fluorination, rather than high-selectivity monofluorination. However, the inventors of the present application surprisingly found that, in a specific polar aprotic solvent with strict control of water content, Selectfluor or Selectfluor II can directly perform high-selectivity electrophilic fluorination on the 9,11-double bond structure without any intermediate, which is the first report in the field of steroid chemistry. Moreover, after the reaction is completed, the reaction solution only needs to be quenched with a reducing agent to remove residual fluorinating agent, and then cooled to make the product precipitate, so that the target compound can be obtained by filtration.

[0065] Process for the preparation of 9-fluorinated steroid compounds II

[0066] In one specific embodiment of the present application, the preparation method comprises reacting compound I with a fluorinating agent to obtain a 9-fluorinated steroid compound II, and the reaction formula is as follows:

[0067]

[0068] In formula I and formula II, R1 and R2 are hydrogen, hydroxyl or hydroxyl with a protecting group, the carbon at 16 position is R configuration or S configuration,

[0069] represents a single bond or a double bond; wherein the protecting group includes but is not limited to C1-C4 alkyl, substituted C1-C4 alkyl, acyl or silyl; or the hydroxyl with a protecting group is an ether-containing ring structure.

[0070] The fluorinating agent is Selectfluor (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) or Selectfluor II (1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane tetrafluoroborate). The amount of the fluorinating agent is preferably 2.0-2.5:1 in molar ratio to compound I.

[0071] The solvent used in the reaction is a polar aprotic solvent containing no water or very low amount of water, including but not limited to acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone, tetrahydrofuran, dioxane, acetone, methyl tetrahydrofuran, etc.

[0072] The reaction temperature is preferably 0-10℃,

[0073] In the description of the present application, "C1-C4 alkyl" refers to an alkyl group containing 1-4 carbons.

[0074] In the description of the present application, "substituted" or "substituted" means that the group can be substituted by one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, alkoxy, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, etc. Compared with the prior art method for preparing 9-fluorinated steroid compounds from steroid compounds containing 9,11-double bond structure, the present application has the following advantages:

[0075] 1. The present application uses steroid compound I containing 9,11-double bond structure as raw material, and only one step of fluorination reaction is needed to obtain 9-fluorinated steroid compound. After the reaction is completed, the residual fluorinating agent in the reaction solution is quenched, the product is precipitated by cooling, and the target compound with purity ≥99.0% can be obtained by filtration. The steps are less and the post-treatment is simple.

[0076] 2. The method for preparing 9-fluorinated steroid compounds of the present application does not need to use dangerous chemicals such as strong corrosive hydrofluoric acid and perchloric acid, and the operation safety is high.

[0077] The application will be further described in connection with specific examples. It should be understood that these examples are only used to illustrate the application and not used to limit the scope of the application. The experimental methods in the following examples, if not otherwise specified, are usually carried out under conventional conditions

[0078] The structure of the epoxy by-product mentioned in the following examples is:

[0079]

[0080] The structure of the difluoro by-product is:

[0081]

[0082] In the following Table 1, Table 2, Table 3 and Table 4, for the examples marked [a], the content of 9α-fluoro product, the content of epoxy by-product and the content of difluoro by-product refer to the content of these compounds in the reaction solution determined by HPLC. The target product is not present or has a low content in the reaction solution obtained from these examples, and no further treatment is carried out. "-" indicates that the reaction solution is not treated to obtain the product, and no yield of target product is obtained. For the examples marked [b], the content of 9α-fluoro product, the content of epoxy by-product and the content of difluoro by-product refer to the content of these compounds in the reaction product obtained by treating the reaction solution. The content of target product in the reaction solution obtained from these examples is relatively high, and further treatment is carried out to obtain the reaction product, and the purity of which is detected.

[0083] Example 1

[0084] A three-necked round-bottom flask is charged with solvent, about 25 mL, and compound I-1 (1.0 g, 1.0 eq) is added, and the solution is stirred to dissolve under nitrogen protection, and the temperature of the solution is reduced to 2.5±0.2 ℃. The fluorination reagent (2.0 eq) is added to the solution in three portions with an interval of 6 minutes each time, and the temperature of the system is strictly maintained at 2.5±0.2 ℃. After the addition is completed, the reaction is incubated until the residual raw material in the reaction solution is less than 0.10% detected by HPLC, and the reaction is stopped.

[0085] For the examples in which the reaction solution needs to be treated to obtain the product, the treatment process of the reaction solution is as follows:

[0086] A 30% aqueous solution of sodium thiosulfate is added dropwise to the reaction solution (the temperature of the reaction solution is controlled to be ≤5 ℃ during the addition), and the residual fluorination reagent is quenched until the potassium iodide test paper shows no color reaction, indicating that the residual fluorination reagent is completely quenched, the addition of the aqueous sodium thiosulfate solution is stopped, and the stirring is continued for 0.5 hours. 5 mL of water is added to the quenched reaction solution, the temperature is reduced to 0 ℃, and the stirring is maintained at this temperature for 2 hours to precipitate the product, which is filtered, the filter cake is washed with water twice, and the wet product is dried at 40-50 ℃ to obtain a white solid product. The HPLC purity of the product is detected, and the yield is calculated.

[0087] The used solvents, fluorinating reagents, purity of 9-fluorinated product (9a-fluorinated product) in the obtained product, content of epoxide by-product, content of difluoro by-product, and yield are shown in Table 1.

[0088] Table 1

[0089]

[0090]

[0091] Note: In Table 1, NFSI is the abbreviation of N-fluorobenzenesulfonimide, CAS No. 133745-75-2; Selectfluor is the abbreviation of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), CAS No. 140681-55-6; Selectfluor II is the abbreviation of 1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane tetrafluoroborate, CAS No. 159269-48-4; NFTh is the abbreviation of 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), CAS No. 162241-33-0; [BMIm][BF4] is the abbreviation of 1-butyl-3-methylimidazolium tetrafluoroborate, CAS No. 174501-65-6.

[0092] As can be seen from Table 1, Selectfluor is the best fluorinating reagent, and acetonitrile is the best solvent. As an electrophilic fluorinating reagent, Selectfluor can form a specific solvation layer with polar aprotic solvents due to its quaternary ammonium salt structure, and F + is stably released in the solvent, which selectively attacks the a face of the 9 position of the steroid, while other electrophilic fluorinating reagents (such as NFSI, NFTh) cannot achieve high selectivity.

[0093] The HPLC spectrum of the reaction solution of Examples 1-8 is shown in Figure 1-a , where RT = 14.355 is the 9a-fluorinated product. The HPLC spectrum of the reaction solution shows that there is no other impurity peak near the retention time of the target product, especially no interfering peak in the region with similar polarity, indicating that the reaction has excellent selectivity, less by-products, and high separation degree from the main product; the HPLC spectrum of the product obtained by treating the reaction solution is shown in Figure 1-b , where RT = 14.341 is the 9a-fluorinated product; the nuclear magnetic hydrogen spectrum of the product is shown in Figure 1-c ; and the high-resolution mass spectrum of the product is shown in Figure 1-d .

[0094] The nuclear magnetic hydrogen spectrum data of the product are as follows:

[0095] 1H NMR: δ 7.27 (1H), 6.20 (1H), 6.00 (1H), 5.15 (1H), 5.05 (1H), 4.35 (2H), 4.12 (2H), 2.63 (1H), 2.42 (2H), 2.00 (2H), 1.82 (3H), 1.50 (3H), 1.37 (2H), 1.08 (4H), 0.98 (3H).

[0096] ESI-MS data of the product: m / z = 415.25 [M+Na + ]。

[0097] Based on Table 1, the inventors further screened solvents for Selectfluor as fluorinating reagent, and screened its analogues as fluorinating reagent, and the experimental process was as follows (Examples 1-22 to 1-34):

[0098] A three-necked round-bottom flask was charged with solvent (about 25 mL) (the organic solvents used in Examples 1-22 to 1-34 were treated with 4A molecular sieves for 48 hours before use to fully remove water therein), compound I-1 (1.0 g, 2.8 mmol) was added, and the solution was stirred under nitrogen protection until the temperature dropped to 2.5±0.2°C. The fluorinating reagent (2.0 eq, i.e. the molar ratio of fluorinating reagent to compound I-1 was 2:1) was added in three portions with an interval of 3 minutes each, and the system temperature was strictly maintained at 2.5±0.2°C. After the addition was completed, the reaction was incubated until the residual raw material in the reaction solution was <0.10% as detected by HPLC, and the reaction was stopped.

[0099] For examples that required treatment of the reaction solution to obtain the product, the treatment process of the reaction solution was as follows:

[0100] To the reaction solution, 30% aqueous sodium thiosulfate solution was added dropwise (the temperature of the reaction solution was controlled to be ≤5°C during the dropwise addition process), and the residual fluorinating reagent was quenched until the potassium iodide test paper showed no color reaction, indicating that the residual fluorinating reagent was completely quenched. The dropwise addition of aqueous sodium thiosulfate solution was stopped, and stirring was continued for 0.5 hours. To the quenched reaction solution, 5 mL of water was added, and the temperature was lowered to 0°C and maintained at this temperature for 2 hours to precipitate the product. The product was filtered, the filter cake was washed with water twice, and the wet product was dried at 40-50°C for 2 hours to obtain a white solid. The purity was detected by HPLC, and the yield was calculated.

[0101] The solvents used in the reaction, the purity of the 9α-fluorine product, the content of the epoxide by-product, the content of the difluoro by-product, and the yield are shown in Table 2.

[0102] Table 2

[0103]

[0104] As can be seen from Table 2, both Selectfluor and Selectfluor II can be used for the fluorination of compound I-1. Acetonitrile, DMF, DMSO, NMP and other aprotic polar solvents can be used as the solvent for the above reaction, but the presence of water in the solvent affects the reaction. Table 2 shows that the presence of water causes a sharp increase in the content of the epoxy by-product (the content of the epoxy by-product in the reaction solution in Example 1-30 is 56%; the content of the epoxy by-product in the reaction solution in Example 1-31 is 72%), which is probably due to the reorientation of the reaction path by water molecules: under anhydrous condition, Selectfluor directly releases F + 9α electrophilic fluorination; and in the presence of water, the nitrogen center of Selectfluor is probably coordinated with H2O through hydrogen bonding, which weakens the polarity of the N-F bond and promotes the oxygen transfer path to dominate—water molecules bridge the C9-C11 double bond, and the oxygen atom attacks to form an epoxy structure. Even a trace amount of water (0.1% in Example 1-30) is enough to change the dissociation mode of Selectfluor, leading to an imbalance in the competition between fluorination / epoxidation paths, which proves that water molecules restructure the reactivity of the fluorination reagent through coordination effect.

[0105] Based on the examples in Table 2, the inventors studied the amount of Selectfluor used as the fluorination reagent (Examples 1-35 to 1-46), and the specific experimental process is as follows:

[0106] A three-necked round-bottom flask was charged with acetonitrile (about 25 mL, treated with 4A molecular sieves for 72 hours), and compound I-1 (1.0 g, 2.8 mmol) was added and stirred to dissolve under nitrogen protection, and the temperature of the solution was reduced to 2.5±0.2°C. The fluorination reagent was added to the solution in three portions with an interval of 3 minutes, and the temperature of the system was strictly maintained at 2.5±0.2°C. After the addition was completed, the reaction was incubated until the residual raw material in the reaction solution was less than 0.10% as detected by HPLC, and the reaction was stopped.

[0107] For examples in which the reaction solution needs to be treated to obtain the product, the treatment process of the reaction solution is as follows:

[0108] A 30% aqueous solution of sodium thiosulfate was added dropwise to the reaction solution (the temperature of the reaction solution was controlled to be ≤5°C during the dropwise addition), and the residual fluorination reagent was quenched until the potassium iodide test paper showed no color reaction, indicating that the residual fluorination reagent was completely quenched, and the dropwise addition of the aqueous sodium thiosulfate solution was stopped, and stirring was continued for 0.5 hours. 5 mL of water was added to the quenched reaction solution, which was cooled to 0°C and stirred at this temperature for 2 hours to precipitate the product, which was filtered, and the filter cake was washed with water twice, and the wet product was dried at 40-50°C for 2 hours to obtain a white solid. The HPLC purity of the product was detected, and the yield was calculated.

[0109] The fluorination reagent, its amount, the purity of the 9α-fluorine product, the content of the epoxy by-product, the content of the difluoro by-product and the yield are shown in Table 3.

[0110] Table 3

[0111]

[0112]

[0113] From Table 3, it can be seen that when Selectfluor and Selectfluor II are used for the fluorination of compound I-1, the optimal ratio of compound I-1 to fluorination reagent is 2.0-2.5, and more amount of fluorination reagent cannot obviously increase the yield and reaction speed.

[0114] On the basis of the examples in Table 3, the inventors studied the reaction temperature when Selectfluor is used as the fluorination reagent, and the specific experimental process is as follows (Examples 1-37 to 1-58).

[0115] Into a three-necked round-bottom flask was added acetonitrile (about 25 mL, treated with 4A molecular sieves for 72 hours), and compound I-1 (1.0 g, 1.0 eq) was added and stirred to dissolve under nitrogen protection, and the solution was cooled to a specific temperature. The fluorination reagent (2.0 eq) was added in three portions with an interval of 3 minutes each time, and the system temperature was strictly maintained at 2.5±0.2°C. After the addition was completed, the reaction was incubated until the residual raw material in the reaction solution was less than 0.10% as detected by HPLC, and the reaction was stopped.

[0116] For examples in which the reaction solution needs to be treated to obtain the product, the treatment process of the reaction solution is as follows:

[0117] To the reaction solution was added dropwise a 30% aqueous sodium thiosulfate solution (the temperature of the reaction solution was controlled to be ≤5°C during the dropwise addition process), and the residual fluorination reagent was quenched until the potassium iodide test paper showed no color reaction, indicating that the residual fluorination reagent was completely quenched, the dropwise addition of the aqueous sodium thiosulfate solution was stopped, and stirring was continued for 0.5 hours. To the quenched reaction solution was added 5 mL of water, and the temperature was lowered to 0°C and maintained at this temperature for 2 hours for the product to precipitate, and the precipitate was filtered, the filter cake was washed with water twice, and the wet product was dried at 40-50°C for 2 hours to obtain a white solid, which was detected for purity by HPLC and the yield was calculated.

[0118] The reaction temperature, the fluorination reagent used, the purity of the 9α-fluorine product, the content of the epoxide by-product, the content of the difluoro by-product, and the yield are shown in Table 4.

[0119] Table 4

[0120]

[0121]

[0122] From Table 4, it can be seen that the reaction temperature of 0-10°C is the preferred reaction temperature, too low temperature, the reaction rate is slow, the yield is low, too high temperature, impurities increase significantly, the yield has no obvious difference.

[0123] Example 2

[0124]

[0125] Into a 5000 mL three-necked flask, add CH3CN (2500 mL) which has been dehydrated by molecular sieve (water content ≤0.05%), and then put in compound I-1 (100.0 g, 280.54 mmol). Stir to dissolve under nitrogen protection, and reduce the temperature of the solution to 2.5±0.2°C. Add Selectfluor (197.65 g, 557.91 mmol) to the solution in 5 portions, with an interval of 6 minutes each time, and strictly maintain the temperature of the system at 2.5±0.2°C. After the addition is completed, keep the reaction for 60 minutes, and stop the reaction when the HPLC detection of the residual raw material is <0.10%.

[0126] Add 30% sodium thiosulfate aqueous solution dropwise to the reaction solution to quench the residual fluorinating agent (control the temperature of the reaction solution to ≤5°C during the dropping process), until the potassium iodide test paper shows no color reaction, indicating that the residual fluorinating agent is completely quenched, stop dropping the sodium thiosulfate aqueous solution, and continue stirring for 0.5 hours.

[0127] Add 500 mL water to the quenched reaction solution, and reduce the temperature to 0°C, and keep stirring at this temperature for 2 hours to precipitate the product. Filter, wash the filter cake with water twice, and dry the wet product at 40-50°C for 10 hours to obtain 87.6 g (223.31 mmol) of white solid, with a HPLC purity of 99.7% and a yield of 80%. No epoxy by-product is detected in the product, and no difluoro by-product is detected (see Figure 1-e ).

[0128] Example 3

[0129]

[0130] Into a 5000 mL three-necked flask, add CH3CN (2500 mL) which has been dehydrated by molecular sieve (water content ≤0.05%), and then put in compound I-1 (100.0 g, 280.54 mmol). Stir to dissolve under nitrogen protection, and reduce the temperature of the solution to 2.5±0.2°C. Add Selectfluor (197.65 g, 557.91 mmol) to the solution in 5 portions, with an interval of 6 minutes each time, and strictly maintain the temperature of the system at 2.5±0.2°C. After the addition is completed, keep the reaction for 60 minutes, and stop the reaction when the HPLC detection of the residual raw material is <0.10%.

[0131] Add 30% sodium thiosulfate aqueous solution dropwise to the reaction solution (controlling the temperature of the reaction solution to ≤5℃ during the dropwise addition process) to quench the residual fluorinating reagent. Continue until no color reaction is observed on the potassium iodide test paper, indicating that the residual fluorinating reagent has been completely quenched. Stop adding sodium thiosulfate aqueous solution dropwise and continue stirring for 0.5 hours.

[0132] Add 500 mL of water to the quenched reaction solution and cool to 0 °C. Maintain stirring at this temperature for 2 hours to allow the product to precipitate. Filter, wash the filter cake twice with water, and dry the wet product at 40–50 °C to obtain 89.01 g (225.65 mmol) of a white solid with an HPLC purity of 99.6% and a yield of 81%. No epoxy byproducts or difluorinated byproducts were detected in the product (see [link to product description]). Figure 2 The 1H NMR data of the product are as follows:

[0133] 1 H NMR: δ5.78(1H),5.35(3H),4.43(2H),4.14(1H),2.69(1H),2.53(2H),2.42(2H),2. 36(1H),1.98(2H),1.96(2H),1.66(2H),1.61(1H),1.59(2H),1.13(6H),0.99(3H).

[0134] Example 4

[0135]

[0136] Add 2500 mL of DMSO (water content ≤0.05%), which has been pre-dehydrated by molecular sieve treatment, to a 5000 mL three-necked flask. Add compound I-3 (100.0 g, 220.40 mmol), and stir to dissolve under nitrogen protection, allowing the solution temperature to drop to 2.5 ± 0.2 °C. Add Selectfluor (156.16 g, 440.80 mmol) to the solution in 5 portions, 6 minutes apart, strictly maintaining the system temperature at 2.5 ± 0.2 °C. After the addition is complete, maintain the reaction temperature until HPLC analysis shows that the residual reactants in the reaction solution are <0.20%, at which point the reaction is stopped.

[0137] Add 30% sodium bisulfite aqueous solution dropwise to the reaction solution (controlling the temperature of the reaction solution to ≤5℃ during the dropwise addition process) to quench the residual fluorinating reagent. Continue until no color reaction is observed on the potassium iodide test paper, indicating that the residual fluorinating reagent has been completely quenched. Stop adding sodium thiosulfate aqueous solution dropwise and continue stirring for 0.5 hours.

[0138] Add 500 mL of water to the quenched reaction solution and cool to 0 °C. Maintain stirring at this temperature for 2 hours to allow the product to precipitate. Filter, wash the filter cake twice with water, and dry the wet product at 40–50 °C to obtain 85.92 g (175.44 mmol) of a white solid with an HPLC purity of 99.5% and a yield of 80%. No epoxy byproducts or difluorinated byproducts were detected in the product (see [link to product description]). Figure 3 The 1H NMR data of the product are as follows:

[0139] 1 H NMR: δ7.29(1H),6.29(1H),6.02(1H),5.34(1H),4.20(1H),3.97(4H),3.95(4H),2.77(1H),2.40(2 H),2.31(1H),1.97(2H),1.52(1H),1.51(2H),1.45(3H),1.43(2H),1.34(9H),1.13(3H),0.99(3H).

[0140] Example 5

[0141]

[0142] In a 5000 mL three-necked flask, NMP (water content ≤0.05%, 2500 mL) pre-treated with molecular sieves for dehydration was added, followed by compound I-4 (100.0 g, 262.13 mmol). The mixture was stirred and dissolved under nitrogen protection, and the temperature of the solution was lowered to 2.5 ± 0.2 °C. Selectfluor (185.72 g, 524.26 mmol) was added to the solution in five portions, with each portion spaced 6 minutes apart, while strictly maintaining the system temperature at 5 ± 0.2 °C. After the addition was complete, the reaction was maintained at this temperature until HPLC analysis showed that the residual reactants in the reaction solution were <0.12%.

[0143] Add 30% sodium dithionite aqueous solution dropwise to the reaction solution (controlling the temperature of the reaction solution to ≤5℃ during the dropwise addition process) to quench the residual fluorinating reagent. Continue until no color reaction is observed on the potassium iodide test paper, indicating that the residual fluorinating reagent has been completely quenched. Stop adding sodium thiosulfate aqueous solution dropwise and continue stirring for 0.5 hours.

[0144] Add 500 mL of water to the quenched reaction solution and cool to 0 °C. Maintain stirring at this temperature for 2 hours to allow the product to precipitate. Filter, wash the filter cake twice with water, and dry the wet product at 40–50 °C to obtain 95.45 g (228.63 mmol) of a white solid with an HPLC purity of 99.7% and a yield of 87%. No epoxy byproducts or difluorinated byproducts were detected in the product (see [link to product description]). Figure 4 The 1H NMR data of the product are as follows:

[0145] 1H NMR: δ7.27(1H),6.26(1H),6.10(1H),5.35(1H),4.97(2H),4.07(1H),2.75(1H),2.41(2H),2. 31(1H),2.12(3H),2.03(2H),1.58(1H),1.49(2H),1.45(3H),1.43(2H),1.13(3H),0.99(3H).

[0146] Example 6

[0147]

[0148] Add THF (water content ≤0.05%, 2500mL) that has been pre-dehydrated by molecular sieve to a 5000mL reaction flask, add compound I-5 (100.0g, 225.96mmol), stir to dissolve under nitrogen protection, and lower the temperature of the solution to -5℃.

[0149] Selectfluor (160.10 g, 451.93 mmol) was added in three portions, with an 8-minute interval between each addition. The system temperature was strictly maintained at 0°C. After the addition was complete, the reaction was kept at this temperature for 1.5 minutes until HPLC confirmed that the starting material was <0.10%, at which point the reaction was stopped.

[0150] Add 30% sodium metabisulfite aqueous solution dropwise to the reaction solution to quench the residual fluorinating reagent (control the temperature of the reaction solution to ≤5℃ during the dropwise addition process). Continue until no color reaction is observed on the potassium iodide test paper, indicating that the residual fluorinating reagent has been completely quenched. Stop adding sodium thiosulfate aqueous solution dropwise and continue stirring for 0.5 hours.

[0151] Add 500 mL of water to the quenched reaction solution and cool to 0 °C. Maintain stirring at this temperature for 2 hours to allow the product to precipitate. Filter, wash the filter cake twice with water, and dry the wet product at 40–50 °C to obtain 87.57 g (182.98 mmol) of a white solid with an HPLC purity of 99.6% and a yield of 81%. No epoxy byproducts or difluorinated byproducts were detected in the product (see [link to product description]). Figure 5 The 1H NMR data of the product are as follows:

[0152] 1 H NMR: δ7.27(1H),6.26(1H),6.10(1H),5.35(1H),4.95(2H),4.70(2H),4.13(1H),3.35(3H),2.81(1H),2. 47(2H),2.37(1H),2.09(3H),1.97(2H),1.54(1H),1.53(2H),1.47(3H),1.45(2H),1.13(3H),0.99(3H).

[0153] Example 7

[0154]

[0155] Add CH3CN (water content ≤0.05%, 2500 mL), which has been pre-dehydrated by molecular sieve treatment, to a 5000 mL reaction flask. Add compound I-6 (100.0 g, 219.43 mmol), and stir to dissolve under nitrogen protection, allowing the solution temperature to drop to -5 °C. Add Selectfluor II (102.26 g, 438.86 mmol) to the solution in three portions, 8 minutes apart, while strictly maintaining the system temperature at 0 °C. After the addition is complete, maintain the reaction temperature until HPLC confirms that the reactant content in the reaction solution is <0.10%.

[0156] Add 30% sodium thiosulfate aqueous solution dropwise to the reaction solution (controlling the temperature of the reaction solution to ≤5℃ during the dropwise addition process) to quench the residual fluorination reagent. Continue until no color reaction is observed on the potassium iodide test paper, indicating that the residual fluorination reagent has been completely quenched. Stop adding sodium thiosulfate aqueous solution dropwise and continue stirring for 0.5 hours.

[0157] Add 500 mL of water to the quenched reaction solution and cool to 0 °C. Maintain stirring at this temperature for 2 hours to allow the product to precipitate. Filter, wash the filter cake twice with water, and dry the wet product at 40–50 °C to obtain 86.08 g (175.05 mmol) of a white solid with an HPLC purity of 99.7% and a yield of 80%. No epoxy byproducts or difluorinated byproducts were detected in the product (see [link to product description]). Figure 6 The 1H NMR data of the product are as follows:

[0158] 1 H NMR: δ5.73(1H),5.39(1H),4.20(1H),4.04(4H),4.02(4H),2.77(1H),2.44(2H),2.42(2H),2. 38(1H),2.12(2H),2.03(2H),1.77(2H),1.62(1H),1.60(2H),1.41(9H),1.13(6H),0.99(3H).

[0159] Comparative Example 1 (Traditional Process)

[0160] Following the method disclosed in Example 1 of CN117924397A, the target product was prepared from betamethasone epoxy hydrolysate as the starting material through a multi-step reaction process including esterification-fluorination, fluorination-hydrolysis, esterification, and purification. In the fluorination step, pyridine hydrogen fluoride was used as the fluorinating agent, and the ring-opening reaction was carried out at -15°C. The overall yield was only 14%, and two recrystallizations (first with methanol, then with acetone / water) were required to achieve a purity of 99.4%. HPLC chromatograms (see...) Figure 7 The results show that there are multiple impurity peaks with similar polarity around the main peak, indicating that there are many side reactions and that separation is difficult.

[0161] This method is not only cumbersome in its process steps and uses highly toxic and corrosive pyridine hydrogen fluoride, but also requires complex post-processing and multiple purifications, resulting in high production costs and large amounts of waste. In contrast, the one-step direct fluorination of steroidal compounds to obtain 9-fluorosteroidal compounds using Selectfluor and Selectfluor II as fluorinating agents eliminates the need for epoxy precursors, avoids the use of highly corrosive reagents, and allows the crude product to precipitate directly from the quenched reaction solution with a purity of ≥99.5% and a yield as high as 80%, significantly outperforming the existing technology CN117924397A and demonstrating clear advantages for industrial applications.

[0162] Comparative Example 2 (according to CN114685592A method)

[0163] Following the method disclosed in prior art CN114685592A, compound I-1 was used as the starting material, and bromohydroxylation was performed using dibromohydantoin / potassium bromate, followed by treatment with Selectfluor. No target fluorinated product was detected in the reaction solution (HPLC chromatogram of the reaction solution is shown in [reference needed]). Figure 8 The main products are oxidation byproducts (products with RT = 12.866).

[0164] This indicates that the electrophilic fluorinating agent Selectfluor cannot complete SN2-type bromine-fluorine substitution, and the existing technical solution has a fundamental flaw.

[0165] Comparative Example 3 (solvent water content 2%)

[0166] CH3CN (2% water content, 2500 mL) was added to a 5000 mL reaction flask, followed by compound I-1 (100.0 g, 280.54 mmol). The mixture was stirred and dissolved under nitrogen protection, and the solution temperature was lowered to 2.5 °C. Selectfluor (197.65 g, 557.91 mmol) was added to the solution in three portions, with an 8-minute interval between each addition. The system temperature was strictly maintained at 2.5 ± 0.2 °C. After the additions were complete, the reaction was maintained at this temperature for 1.5 hours. HPLC confirmed that the starting material content was <0.10%.

[0167] Add 30% sodium thiosulfate aqueous solution dropwise to the reaction solution (controlling the temperature of the reaction solution to ≤5℃ during the dropwise addition process) to quench the residual fluorination reagent. Continue until no color reaction is observed on the potassium iodide test paper, indicating that the residual fluorination reagent has been completely quenched. Stop adding sodium thiosulfate aqueous solution dropwise and continue stirring for 0.5h.

[0168] 500 mL of water was added to the quenched reaction solution, and the temperature was lowered to 0 °C and stirred at this temperature for 2 hours to allow the product to precipitate. The product was filtered, the filter cake was washed twice with water, and the wet product was dried at 40–50 °C to obtain 85.50 g (229.56 mmol) of a white solid, with a yield of 82%. However, the white solid was an epoxy byproduct, and its HPLC chromatogram is shown below. Figure 9 Process for the preparation of 9-fluorinated steroid compounds II .

[0169] This comparative example shows that when the water content of acetonitrile increases to 2%, the reaction completely shifts to the epoxidation pathway, generating epoxide byproducts. The reason for this may be that water molecules directly participate in the reaction system, acting as nucleophiles to attack the C9-C11 double bond of the steroid, initiating the epoxidation reaction; simultaneously, water molecules coordinate with the nitrogen center of Selectfluor, weakening its ability to release fluoride ions and inhibiting the electrophilic fluorination pathway. This result confirms that solvent water content is a key threshold factor controlling the reaction pathway; highly selective 9-position electrophilic fluorination can only be achieved under strictly controlled water conditions (≤0.05%).

[0170] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Process for the preparation of 9-fluorinated steroidal compounds II, characterized in that, The method comprises the step of: reacting compound I with a fluorinating agent to obtain a 9-fluorinated steroid compound II, and the reaction formula is as follows: In formula I and formula II, R1 and R2 are hydrogen, hydroxyl or hydroxyl with a protective group, the 16-carbon is in R configuration or S configuration, “---·” represents a single bond or a double bond, the fluorinating agent is selected from Selectfluor, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), and / or Selectfluor II, 1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane tetrafluoroborate.

2. The production method according to claim 1, characterized by, the protective group is selected from C1-C4 alkyl, substituted C1-C4 alkyl, acyl, silyl or ester group, or, the hydroxyl with a protective group is an ether-containing ring structure.

3. The preparation method according to claim 3, wherein, the C1-C4 alkyl is selected from methyl, ethyl, propyl or isopropyl; and / or the substituted C1-C4 alkyl is selected from benzyl, p-methoxybenzyl, trityl, 3-methoxypropyl or 1-methoxymethyl; and / or the acyl is selected from acetyl, benzoyl, pivaloyl or methoxyacetyl; and / or the silyl is selected from tert-butyldimethylsilyl, triisopropylsilyl or tert-butyldiphenylsilyl; and / or the ether-containing ring structure is selected from tetrahydropyranyl.

4. The preparation method according to claim 1 or 2, wherein, the reaction temperature of the reaction of compound I with the fluorinating agent is -10-20°C, more preferably 0-10°C, and / or the molar ratio of compound I to the fluorinating agent is 1:1.0-3.0, more preferably 1:2.0-2.

5.

5. The production method according to claim 1 or 2, characterized by, the solvent used for the reaction of compound I with the fluorinating agent is selected from polar aprotic solvents, more preferably, the polar aprotic solvent is selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran, dioxane, acetone, methyltetrahydrofuran, or a combination thereof, and most preferably acetonitrile.

6. The production method according to claim 5, wherein The water content in the solvent used is ≤0.1%, more preferably ≤0.05%.

7. The production method according to claim 1 or 2, characterized by, The preparation method further comprises the steps of: after the reaction is completed, quenching the residual fluorinating agent in the reaction solution with a reducing agent or an aqueous solution of a reducing agent; and cooling the quenched reaction solution to -5-10°C to precipitate the product, and filtering and drying to obtain the 9-fluorinated steroid compound II.

8. The production method according to claim 7, characterized by, the reducing agent is selected from sodium thiosulfate, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium dithionite or a combination thereof.

9. The preparation method according to claim 7, characterized in that, the mass concentration of the aqueous solution of the reducing agent is 10-40%, more preferably 25-35%.

10. The production method according to claim 1 or 2, characterized by, The structural formula of the compound I is as follows:

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