Methods and applications of fluorination at the 9-position of steroid compounds

Abstract

This invention provides a method and application for adding fluorine at the 9-position of a steroid compound, relating to the field of chemical synthesis technology. The invention uses a compound of formula I as a starting material, reacting it with a first brominating reagent, a second brominating reagent, and hydrochloric acid to undergo a 9,11-position bromohydroxyl reaction to obtain a compound of formula II. Compound II then undergoes a 9-position substitution reaction with a fluorinating reagent to obtain a 9-position fluorinated steroid compound. This invention utilizes mild reaction conditions, avoiding highly toxic and corrosive reagents such as perchloric acid and hydrogen fluoride solution, making it environmentally friendly, with a short reaction route, easy operation, and greater suitability for industrial production.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method and application of fluorine at the 9-position of a steroid compound. Background Technology

[0002] Steroid hormones have been used to treat inflammation for decades. Steroid compounds bind to glucocorticoid receptors within the cells of the affected tissue, inhibiting inflammatory chemokines and the entire process of inflammation development, thereby achieving an anti-inflammatory effect. Common steroid hormones include fludrosamine, dexamethasone, betamethasone, flumetholone, and diflubenzuron.

[0003] All of the above-mentioned drugs contain fluorine at position 9, making fluorinated steroid compounds at position 9 an important intermediate. Currently, fluorination at position 9 is typically achieved through a reaction involving a bromohydroxyl group at positions 9 and 11, an epoxidation reaction, or a ring-opening fluorination reaction. The reaction formulas are as follows:

[0004]

[0005] For example, patents CN 103509075 A and CN 107056864 A both disclose the use of highly corrosive perchloric acid, fluoroboric acid, sulfuric acid, or p-toluenesulfonic acid in the bromohydroxy reaction, requiring a low-temperature environment of around 0°C, making the reaction conditions harsh; the use of large amounts of alkaline solutions in the epoxide reaction; and the use of highly toxic and corrosive hydrofluoric acid in the ring-opening reaction. These methods use highly toxic and corrosive reagents and involve harsh reaction conditions, which are extremely detrimental to the environment and operators, making them unsuitable for industrial application.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] The main objective of this invention is to provide a method and application for adding fluorine at the 9-position of a steroid compound, in order to at least partially solve at least one of the above-mentioned technical problems.

[0008] As a first aspect of the present invention, the present invention provides a method for fluorinating a steroid compound at the 9-position, comprising the following steps:

[0009] (a) Compound I reacts with a first brominating agent, a second brominating agent and hydrochloric acid to give compound II;

[0010] (b) The compound of formula II reacts with a fluorine reagent to give the compound of formula III;

[0011]

[0012] In this case, R1, R2, R3, and R4, as shown in the structural formulas of compounds I, II, and III, are chosen independently of each other, and:

[0013] R1 = H, methyl, or halogen; halogen = F, Cl, Br, I;

[0014] R2 = H, OH, or methyl;

[0015] R3 = H, OH or OCOR5, where R5 is an alkyl group with six or fewer carbon atoms;

[0016] R4 = CH2R6, R6 = H, OH or OCOR7, R7 is an alkyl group with six or fewer carbon atoms;

[0017] Dashed lines represent double or single bonds.

[0018] Furthermore, this includes the following steps:

[0019] (a) Compound I reacts with a first brominating agent, a second brominating agent and hydrochloric acid to give compound II;

[0020] (b) The compound of formula II reacts with a fluorine reagent to give the compound of formula III;

[0021]

[0022] In this case, R1, R2, R3, and R4, as shown in the structural formulas of compounds I, II, and III, are chosen independently of each other, and:

[0023] R1 = H, methyl, or F;

[0024] R2 = H or methyl;

[0025] R3 = OH or OCOR5, where R5 is an alkyl group with three or fewer carbon atoms;

[0026] R4 = CH2R6, R6 = H, OH or OCOR7, R7 is an alkyl group with three or fewer carbon atoms;

[0027] Dashed lines represent double or single bonds.

[0028] Furthermore, in step (a), the first brominating agent is selected from one or more of NBS (N-bromosuccinimide), dibromohydantoin, N-bromoacetamide, or bromide salts.

[0029] Furthermore, in step (a), the bromide salt is selected from one or more of sodium bromide, potassium bromide, or ammonium bromide.

[0030] Furthermore, in step (a), the second brominating agent is selected from bromate.

[0031] Furthermore, in step (a), the bromate is selected from sodium bromate or potassium bromate.

[0032] Furthermore, in step (a), the organic solvent used is selected from one or more of acetone, acetonitrile, tetrahydrofuran, dichloromethane, toluene, or isopropyl acetate.

[0033] Furthermore, in step (a), the mass-to-volume ratio of the hydrochloric acid to the compound of formula I is (0.1–0.5):1 g / mL.

[0034] In this invention, in step (a), the typical but non-limiting mass-to-volume ratio of hydrochloric acid to the compound of formula I can be, for example, 0.1:1 g / mL, 0.2:1 g / mL, 0.3:1 g / mL, 0.4:1 g / mL or 0.5:1 g / mL.

[0035] Furthermore, the molar ratio of the first brominating reagent, the second brominating reagent, and the compound of formula I is (1.5–4.0):(1.5–2):1.

[0036] In this invention, in step (a), the typical but non-limiting molar ratio of the first brominating agent, the second brominating agent and the compound of formula I can be, for example, 1.5:2:1, 2:2:1, 3:2:1, 4:1.5:1, 4:2:1, 3:1.5:1, 1:3:1, 5:1:2 or 3:2:1.

[0037] Furthermore, in step (a), the reaction temperature is 15–50°C.

[0038] In this invention, the typical single non-limiting temperature of the reaction in step (a) can be, for example, 15°C, 18°C, 20°C, 22°C, 25°C, 28°C, 30°C, 15°C, 32°C, 35°C, 40°C, 42°C, 45°C, 48°C, or 50°C.

[0039] Furthermore, in step (b), the fluorine reagent is selected from one or more of metal fluorides, selective fluorine reagent I, or selective fluorine reagent II.

[0040] Furthermore, in step (b), the alkali metal fluoride is selected from one or more of potassium fluoride, silver fluoride, or sodium fluoride.

[0041] Furthermore, in step (b), the organic solvent is selected from one or more of acetonitrile, acetone, DMF (N,N-dimethylformamide), DME (dimethyl ether), or tetrahydrofuran.

[0042] Furthermore, in step (b), the molar ratio of the fluorine reagent to the compound of formula II is (1.0 to 5.0):1.

[0043] In this invention, in step (b), the typical single non-limiting molar ratio of the fluorine reagent to the compound of formula II can be, for example, 1.0:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2.0:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3.0:1, 3.2:1, 1.0:1, 1.0:1, 1.0:1, 1.0:1, 1.0:1, 1.0:1, 1.0:1, 1.0:1, 1.0:1, 1.0:1, 1.0:1, 1.0:1, 1.0:1.

[0044] Furthermore, in step (b), the reaction temperature is 15–70°C.

[0045] In this invention, the typical single non-limiting temperature of the reaction in step (b) can be, for example, 15°C, 18°C, 20°C, 22°C, 25°C, 28°C, 30°C, 15°C, 32°C, 35°C, 40°C, 42°C, 45°C, 48°C, 50°C, 55°C, 58°C, 60°C, 62°C, 65°C, 68°C, or 70°C.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] This invention uses a compound of formula I as a starting material, which reacts with a first brominating reagent, a second brominating reagent, and hydrochloric acid at the 9,11 position to yield a compound of formula II. Compound II then undergoes a 9-position substitution reaction with a fluorine reagent to yield a 9-fluorosteroid compound. This invention utilizes mild reaction conditions, avoids highly toxic and corrosive reagents such as perchloric acid and hydrogen fluoride solution, is environmentally friendly, has a short reaction route, is easy to operate, and is more suitable for industrial production. Detailed Implementation

[0048] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions were applied in the examples. Reagents or instruments used, unless otherwise specified, are all commercially available products.

[0049] To help to better understand the present invention, the technical solution of the present invention will be further described below in conjunction with embodiments.

[0050] Example 1: Preparation of Compound II

[0051] Example 1-1

[0052]

[0053] Under nitrogen protection, 200 mL of acetone, 10.0 g (0.028 mol) of compound I, 1 mL of hydrochloric acid, 7.5 g of NBS, and 9.4 g of potassium bromate were added to a reaction flask. The reaction was maintained at 15 °C, and TLC monitoring showed no remnants of compound I. 100 mL of a 10% sodium sulfite aqueous solution was added to the system, and the mixture was stirred for 0.5–1 h. The mixture was then filtered, washed with water, and dried to obtain 12.6 g of compound II, with a yield of 99.1% and an HPLC purity of 99.1%.

[0054] Examples 1-2

[0055]

[0056] Under nitrogen protection, 200 mL of tetrahydrofuran, 10.0 g (0.021 mol) of compound I, 2 mL of hydrochloric acid, 12.2 g of dibromohydantoin, and 6.4 g of sodium bromate were added to a reaction flask. The reaction was maintained at 20 °C, and TLC monitoring showed no change in compound I. 100 mL of 10% sodium sulfite aqueous solution was added to the system, and the mixture was stirred for 0.5–1 h. After filtration, washing with water, and drying, 11.9 g of compound II was obtained, with a yield of 98.6% and an HPLC purity of 98.7%.

[0057] Examples 1-3

[0058]

[0059] Under nitrogen protection, 200 mL of acetonitrile, 10.0 g (0.025 mol) of compound I, 3 mL of hydrochloric acid, 13.3 g of N-bromoacetamide, and 8.4 g of potassium bromate were added to a reaction flask. The reaction was maintained at 25 °C, and TLC monitoring showed no remnants of compound I. 100 mL of 10% sodium sulfite aqueous solution was added to the system, and the mixture was stirred for 0.5–1 h. The mixture was then filtered, washed with water, and dried to obtain 12.4 g of compound II, with a yield of 99.4% and an HPLC purity of 99.5%.

[0060] Examples 1-4

[0061]

[0062] Under nitrogen protection, 200 mL of dichloromethane, 10.0 g (0.029 mol) of compound I, 4 mL of hydrochloric acid, 13.8 g of potassium bromide, and 7.4 g of potassium bromate were added to a reaction flask. The reaction was maintained at 30 °C, and TLC monitoring showed no change in compound I. 100 mL of 10% sodium sulfite aqueous solution was added to the system, and the mixture was stirred for 0.5–1 h. The mixture was then filtered, washed with water, and dried to obtain 12.7 g of compound II, with a yield of 98.5% and an HPLC purity of 98.3%.

[0063] Examples 1-5

[0064]

[0065] Under nitrogen protection, 200 mL of toluene, 10.0 g (0.027 mol) of compound I, 5 mL of hydrochloric acid, 11.1 g of sodium bromide, and 9.0 g of potassium bromate were added to a reaction flask. The reaction was maintained at 40 °C, and TLC monitoring showed no remnants of compound I. 100 mL of a 10% sodium sulfite aqueous solution was added to the system, and the mixture was stirred for 0.5–1 h. The mixture was then filtered, washed with water, and dried to obtain 12.6 g of compound II, with a yield of 98.8% and an HPLC purity of 99.4%.

[0066] Examples 1-6

[0067]

[0068] Under nitrogen protection, 200 mL of isopropyl acetate, 10.0 g (0.030 mol) of compound I, 3 mL of hydrochloric acid, 8.9 g of ammonium bromide, and 7.6 g of potassium bromate were added to a reaction flask. The reaction was maintained at 50 °C, and TLC monitoring showed no remnants of compound I. 100 mL of 10% sodium sulfite aqueous solution was added to the system, and the mixture was stirred for 0.5–1 h. The mixture was then filtered, washed with water, and dried to obtain 12.6 g of compound II, with a yield of 99.0% and an HPLC purity of 99.2%.

[0069] Examples 1-7

[0070]

[0071] Under nitrogen protection, 200 mL of acetonitrile, 10.0 g (0.025 mol) of compound I, 3 mL of hydrochloric acid, 4.4 g of N-bromoacetamide, and 11.8 g of potassium bromate were added to a reaction flask. The reaction was maintained at 25 °C, and TLC monitoring showed no change in compound I. 100 mL of 10% sodium sulfite aqueous solution was added to the system, and the mixture was stirred for 0.5–1 h. The mixture was then filtered, washed with water, and dried to obtain 11.8 g of compound II, with a yield of 94.4% and an HPLC purity of 97.3%.

[0072] Examples 1-8

[0073]

[0074] Under nitrogen protection, 200 mL of acetonitrile, 10.0 g (0.025 mol) of compound I, 3 mL of hydrochloric acid, 11.1 g of N-bromoacetamide, and 2.1 g of potassium bromate were added to a reaction flask. The reaction was maintained at 25 °C, and TLC monitoring showed no remnants of compound I. 100 mL of 10% sodium sulfite aqueous solution was added to the system, and the mixture was stirred for 0.5–1 h. After filtration, washing with water, and drying, 11.6 g of compound II was obtained, with a yield of 93.4% and an HPLC purity of 97.8%.

[0075] Examples 1-9

[0076]

[0077] Under nitrogen protection, 200 mL of acetonitrile, 10.0 g (0.025 mol) of compound I, 3 mL of hydrochloric acid, 13.3 g of N-bromoacetamide, and 8.4 g of potassium bromate were added to a reaction flask. The reaction was maintained at 10 °C, and TLC monitoring showed no change in compound I. 100 mL of 10% sodium sulfite aqueous solution was added to the system, and the mixture was stirred for 0.5–1 h. After filtration, washing with water, and drying, 10.2 g of compound II was obtained, with a yield of 81.7% and an HPLC purity of 97.4%.

[0078] Examples 1-10

[0079]

[0080] Under nitrogen protection, 200 mL of acetonitrile, 10.0 g (0.025 mol) of compound I, 3 mL of hydrochloric acid, 13.3 g of N-bromoacetamide, and 8.4 g of potassium bromate were added to a reaction flask. The reaction was maintained at 70 °C, and TLC monitoring showed no remnants of compound I. 100 mL of a 10% sodium sulfite aqueous solution was added to the system, and the mixture was stirred for 0.5–1 h. The mixture was then filtered, washed with water, and dried to obtain 10.7 g of compound II, with a yield of 85.7% and an HPLC purity of 97.3%.

[0081] Example 2 Preparation of Compound III

[0082] Example 2-1

[0083]

[0084] Under nitrogen protection, 50 mL of acetonitrile, 10.0 g (0.022 mol) of compound II, and 2.8 g of silver fluoride were added to the reaction flask. The reaction was maintained at 15 °C, and TLC monitoring showed no remnants of compound II. The reaction solution was diluted in 1000 mL of ice water, stirred for 1 h, filtered, washed with water, and dried at 60–70 °C for 20 h to obtain 8.6 g of compound III (betamethasone), with a yield of 98.8% and an HPLC purity of 98.7%.

[0085] Example 2-2

[0086]

[0087] Under nitrogen protection, 50 mL of acetone, 10.0 g (0.018 mol) of compound II, and 2.0 g of potassium fluoride were added to the reaction flask. The reaction was maintained at 20 °C, and TLC monitoring showed no remnants of compound II. The reaction solution was diluted in 1000 mL of ice water, stirred for 1 h, filtered, washed with water, and dried at 60–70 °C for 20 h to obtain 8.9 g of compound III (betamethasone propionate), with a yield of 99.2% and an HPLC purity of 99.0%.

[0088] Example 2-3

[0089]

[0090] Under nitrogen protection, 50 mL of tetrahydrofuran, 10.0 g (0.020 mol) of compound II, and 21.4 g of selective fluorine reagent I were added to the reaction flask. The reaction was maintained at 25 °C, and TLC monitoring showed no remnants of compound II. The reaction solution was diluted in 1000 mL of ice water, stirred for 1 h, filtered, washed with water, and dried at 60–70 °C for 20 h to obtain 8.8 g of compound III (dexamethasone acetate), with a yield of 99.8% and an HPLC purity of 99.5%.

[0091] Examples 2-4

[0092]

[0093] Under nitrogen protection, 50 mL LME, 10.0 g (0.023 mol) of compound II, and 29.3 g of selective fluorine reagent II were added to the reaction flask. The reaction was maintained at 30 °C, and TLC monitoring showed no remnants of compound II. The reaction solution was diluted in 1000 mL of ice water, stirred for 1 h, filtered, washed with water, and dried at 60–70 °C for 20 h to obtain 8.5 g of compound III (fluorometholone), with a yield of 98.5% and an HPLC purity of 98.3%.

[0094] Examples 2-5

[0095]

[0096] Under nitrogen protection, 50 mL of acetonitrile, 10.0 g (0.021 mol) of compound II, and 4.4 g of sodium fluoride were added to the reaction flask. The reaction was maintained at 50 °C, and TLC monitoring showed no remnants of compound II. The reaction solution was diluted in 1000 mL of ice water, stirred for 1 h, filtered, washed with water, and dried at 60–70 °C for 20 h to obtain 8.6 g of compound III (difluorometholone), with a yield of 98.2% and an HPLC purity of 99.0%.

[0097] Examples 2-6

[0098]

[0099] Under nitrogen protection, 50 mL of DMF, 10.0 g (0.024 mol) of compound II, and 4.1 g of potassium fluoride were added to the reaction flask. The reaction was maintained at 50 °C, and TLC monitoring showed no remnants of compound II. The reaction solution was diluted in 1000 mL of ice water, stirred for 1 h, filtered, washed with water, and dried at 60–70 °C for 20 h to obtain 8.7 g of compound III (fluoroprogesterone), with a yield of 99.1% and an HPLC purity of 98.6%.

[0100] Examples 2-7

[0101]

[0102] Under nitrogen protection, 50 mL of tetrahydrofuran, 10.0 g (0.020 mol) of compound II, and 21.4 g of selective fluorine reagent I were added to the reaction flask. The reaction was maintained at 15 °C, and TLC monitoring showed no presence of compound II. The reaction solution was diluted in 1000 mL of ice water, stirred for 1 h, filtered, washed with water, and dried at 60–70 °C for 20 h to obtain 8.5 g of compound III (dexamethasone acetate), with a yield of 96.5% and an HPLC purity of 96.3%.

[0103] Examples 2-8

[0104]

[0105] Under nitrogen protection, 50 mL of tetrahydrofuran, 10.0 g (0.020 mol) of compound II, and 21.4 g of selective fluorine reagent I were added to the reaction flask. The reaction was maintained at 50 °C, and TLC monitoring showed no remnants of compound II. The reaction solution was diluted in 1000 mL of ice water, stirred for 1 h, filtered, washed with water, and dried at 60–70 °C for 20 h to obtain 8.6 g of compound III (dexamethasone acetate), with a yield of 98.8% and an HPLC purity of 95.8%.

[0106] Examples 2-9

[0107]

[0108] Under nitrogen protection, 50 mL of tetrahydrofuran, 10.0 g (0.020 mol) of compound II, and 3.6 g of selective fluorine reagent I were added to the reaction flask. The reaction was maintained at 25 °C, and TLC monitoring showed no remnants of compound II. The reaction solution was diluted in 1000 mL of ice water, stirred for 1 h, filtered, washed with water, and dried at 60–70 °C for 20 h to obtain 8.5 g of compound III (dexamethasone acetate), with a yield of 96.5% and an HPLC purity of 96.3%.

[0109] Example 2-10

[0110]

[0111] Under nitrogen protection, 50 mL of tetrahydrofuran, 10.0 g (0.020 mol) of compound II, and 50.0 g of selective fluorine reagent I were added to the reaction flask. The reaction was maintained at 25 °C, and TLC monitoring showed no remnants of compound II. The reaction solution was diluted in 1000 mL of ice water, stirred for 1 h, filtered, washed with water, and dried at 60–70 °C for 20 h to obtain 8.4 g of compound III (dexamethasone acetate), with a yield of 95.4% and an HPLC purity of 95.8%.

[0112] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for the fluorination of the 9-position of a steroid compound, characterized in that, comprising the steps of: (a) reacting a compound of formula I with a first brominating agent, a second brominating agent and hydrochloric acid to obtain a compound of formula II; (b) reacting the compound of formula II with a fluorinating agent to obtain a compound of formula III; wherein R1, R2, R3and R4in the structural formula of compound I, compound II and compound III are selected independently, and: R1= H, methyl or halogen, halogen = F, CI, Br or I; R2= H, OH or methyl; R3= H, OH or OCOR5, R5is an alkyl group within six carbons; R4= CH2R6, R6= H, OH or OCOR7, R7is an alkyl group within six carbons; the dotted line is a double bond or a single bond; in the step (a), the first brominating agent is selected from one or more of NBS, dibromohydantoin, N-bromoacetamide or bromide salt; the second brominating agent is selected from bromate salt; the bromide salt is selected from one or more of sodium bromide, potassium bromide or ammonium bromide; the bromate salt is selected from sodium bromate or potassium bromate; in the step (b), the fluorinating agent is selected from one or more of alkali metal fluoride, selective fluorinating agent I or selective fluorinating agent II; the alkali metal fluoride is selected from one or more of potassium fluoride, silver fluoride or sodium fluoride.

2. The method for fluorination at position 9 of a steroid compound according to claim 1, comprising the steps of: (a) reacting a compound of formula I with a first brominating agent, a second brominating agent and hydrochloric acid to obtain a compound of formula II; (b) reacting the compound of formula II with a fluorinating agent to obtain a compound of formula III; wherein R1, R2, R3and R4in the structural formula of compound I, compound II and compound III are selected independently, and: R1= H, methyl or F; R2= H or methyl; R3= OH or OCOR5, R5is an alkyl group within three carbons; R4= CH2R6, R6= H, OH or OCOR7, R7is an alkyl group within three carbons; the dotted line is a double bond or a single bond.

3. The method for fluorination at position 9 of a steroid compound according to claim 1, in the step (a), the mass volume ratio of hydrochloric acid to compound of formula I is (0.1-0.5): 1 g / mL; the molar ratio of the first brominating agent, the second brominating agent to compound of formula I is (1.5-4.0):(1.5-2):

1. in the step (a), the temperature of the reaction is 15-50 °C.

4. The method of fluorination at position 9 of a steroid compound according to any one of claims 1 to 3, characterized in that, in the step (b), the molar ratio of the fluorinating agent to compound of formula II is (1.0-5.0):

1.

5. The method of fluorination at position 9 of a steroid compound according to any one of claims 1, 2, 3, characterized in that, in the step (b), the temperature of the reaction is 15-70 °C.

6. The method of fluorination at the 9-position of a steroid compound according to claim 5, wherein, in the step (a), the organic solvent used is selected from one or more of acetone, acetonitrile, tetrahydrofuran, dichloromethane, toluene or isopropyl acetate; 7. The method of fluorination at the 9-position of a steroid compound according to any one of claims 1, 2, 3 or 6, wherein, in the step (b), the organic solvent used is selected from one or more of acetonitrile, acetone, DMF, DME or tetrahydrofuran.

8. Use of the preparation method according to any one of claims 1-7 in the preparation of a 9-fluorinated steroid compound. ​

Images