Preparation method of fluticasone furoate

Abstract

The invention belongs to the technical field of steroid medicine preparation, and particularly relates to a preparation method of fluticasone furoate. By directly increasing the dosage of the furfuryl chloride, the intermediate, namely the compound A with higher activity than that of a traditional intermediate is synthesized, an additional coupling agent and a coupling enhancer do not need to be introduced, impurities, especially dimer impurities, caused by a coupling reaction are avoided, the cost is greatly saved, and the post-treatment difficulty is reduced; the diesterified compound A synthesized by the invention cannot be subjected to intramolecular polymerization, does not use additional special reagents, does not introduce additional side reactions and impurities, reduces the refining process, and reduces the post-treatment difficulty; a one-pot method is adopted, so that the risk of side reaction caused by discharging is avoided. In conclusion, compared with a traditional process, the preparation method provided by the invention reduces generation of impurities and has the advantages of high weight yield and high purity, the purity is 99% or above, and the weight yield is 120% or above.

Description

Technical Field

[0001] The invention belongs to the technical field of steroid drug preparation, and particularly relates to a method for preparing fluticasone furoate. Background Art

[0002] In 1994, GH Phillipps et al. disclosed a method for preparing fluticasone furoate (Journal of Medicinal Chemistry, 37, 3717-3729), which has been widely used by many companies. The main reaction route is as follows:

[0003]

[0004] However, this method inevitably produces more by-products, especially in the steps of preparing compound II and compound III, side reactions are very likely to occur, resulting in excessive impurities in fluticasone furoate, which requires multiple purifications to remove, affecting the product yield.

[0005] Patent WO2004 / 087731 discloses a method for preparing steroidal thiohydroxy acids and derivatives using sodium hydrosulfide, and the main reaction route is as follows:

[0006]

[0007] However, this method uses a large amount of coupling agent or coupling enhancer, and the coupling reaction is prone to produce dimer-type impurities under the coupling effect, and the coupling agent and coupling enhancer will fall off during the reaction, making the impurity situation more complicated.

[0008] In summary, the existing method for preparing fluticasone furoate using compound II has the problems of low weight yield and low purity, wherein the weight yield is about 80-94% and the purity is about 92-98%. Summary of the invention

[0009] The object of the present invention is to provide a preparation method of fluticasone furoate. The preparation method provided by the present invention has the advantages of high weight yield and high purity, with the purity being above 99% and the weight yield being above 120%.

[0010] In order to achieve the above object, the present invention provides the following technical solutions:

[0011] The present invention provides a method for preparing fluticasone furoate, comprising the following steps:

[0012] Compound II, furoyl chloride, an organic base and an organic solvent are mixed for acylation reaction to obtain compound A; the structure of compound II is shown in formula II, and the structure of compound A is shown in formula A:

[0013]

[0014] The mass ratio of furoyl chloride to compound II is 0.8-1.6:1;

[0015] The compound A and sodium hydrosulfide are mixed to carry out a thiocarboxylation reaction to obtain a compound B, the structure of which is shown in Formula B:

[0016]

[0017] The compound B and iodomethane are mixed to carry out fluoromethylation reaction to obtain fluticasone furoate.

[0018] Preferably, the organic base includes one or more of triethylamine, N,N-dimethylaminopyridine and N,N-dimethylaminopropylamine.

[0019] Preferably, the mass ratio of the organic base to compound II is 2.0 to 2.5:1.

[0020] Preferably, the mass ratio of the organic solvent to compound II is 1:2.85-9.48.

[0021] Preferably, the temperature of the acylation reaction is 25-35° C., and the insulation time is 1-2 h.

[0022] Preferably, the mass ratio of sodium hydrosulfide to compound II is 0.15-0.45:1.

[0023] Preferably, the temperature of the thiocarboxylation reaction is 30-40° C., and the insulation time is 2-3 hours.

[0024] Preferably, the mass ratio of fluoroiodomethane to compound II is 0.4-1.2:1.

[0025] Preferably, the temperature of the fluoromethylation reaction is -5 to 5°C, and the insulation time is 1.5 to 3 hours.

[0026] Preferably, after the fluoromethylation reaction, the steps further include adding water to the reaction system, solid-liquid separation and drying.

[0027] The present invention provides a method for preparing fluticasone furoate. The present invention synthesizes an intermediate compound A with higher activity than the traditional intermediate by directly increasing the amount of furoyl chloride, without introducing additional coupling agents and coupling enhancers, avoiding impurities caused by coupling reactions, especially dimer impurities, greatly saving costs and reducing the difficulty of post-processing; the double-esterified compound A synthesized by the present invention can no longer undergo intramolecular polymerization, and does not use additional special reagents (such as NMI (N-methylimidazole), DCI (4,5-dioxyimidazole), NHS (N-hydroxysuccinimide) or sulfo-NHS (N-hydroxysulfosuccinimide)), does not introduce additional side reactions and impurities, reduces the refining process, and reduces the difficulty of post-processing; the present invention adopts a one-pot method to avoid the risk of side reactions caused by discharging. In summary, compared with the traditional process, the preparation method provided by the present invention reduces the generation of impurities and has the advantages of high weight yield and high purity. Among them, the purity is above 99% and the weight yield is above 120%. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0029] Figure 1 The invention provides a synthetic route diagram of the preparation method of fluticasone furoate. DETAILED DESCRIPTION

[0030] The present invention provides a method for preparing fluticasone furoate, comprising the following steps:

[0031] Compound II, furoyl chloride, an organic base and an organic solvent are mixed for acylation reaction to obtain compound A; the structure of compound II is shown in formula II, and the structure of compound A is shown in formula A:

[0032]

[0033] The compound A and sodium hydrosulfide are mixed to carry out a thiocarboxylation reaction to obtain a compound B, the structure of which is shown in Formula B:

[0034]

[0035] The compound B and iodomethane are mixed to carry out fluoromethylation reaction to obtain fluticasone furoate.

[0036] The main process route for preparing fluticasone furoate of the present invention is as follows Figure 1As shown, the present invention first uses compound II to synthesize compound A, then uses compound A to synthesize compound B, and then uses compound B to synthesize fluticasone furoate.

[0037] In the present invention, compound II, furoyl chloride, an organic base and an organic solvent are mixed (referred to as the first mixing) for acylation reaction to obtain compound A. In the present invention, the mass ratio of furoyl chloride to compound II is preferably 0.8 to 1.6:1, specifically 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1 or 1.6:1.

[0038] In the present invention, the organic base preferably includes one or more of triethylamine, N,N-dimethylaminopyridine and N,N-dimethylaminopropylamine; the mass ratio of the organic base to compound II is preferably 2.0 to 2.5:1, specifically 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1 or 2.5:1.

[0039] In the present invention, the organic solvent preferably includes one or two of N,N-dimethylformamide (DMF) and tetrahydrofuran; the mass ratio of the organic solvent to compound II is preferably 1:2.85-9.48, specifically 1:2.85, 1:3.75, 1:4.74, 1:5.66, 1:6.58, 1:7.49, 1:8.42 or 1:9.48.

[0040] In the present invention, the first mixing is preferably: premixing compound II, an organic solvent and an organic base to obtain a premixed liquid, and then dropping furoyl chloride into the premixed liquid.

[0041] In the present invention, the temperature of the first mixing is preferably room temperature; the rate of the dropping is preferably 60 to 100 s / mL, specifically 60 s / mL, 70 s / mL, 80 s / mL, 90 s / mL or 100 s / mL.

[0042] In the present invention, the temperature of the acylation reaction is preferably 25-35°C, specifically 25°C, 27°C, 29°C, 31°C, 33°C or 35°C, and the insulation time is preferably 1-2h, specifically 1h, 1.5h or 2h; the acylation reaction is preferably monitored by TLC.

[0043] In the present invention, after the acylation reaction, the reaction system is preferably cooled; the cooling rate is preferably 20-30°C / h, specifically 20°C / h, 22°C / h, 24°C / h, 26°C / h, 28°C / h or 30°C / h; the final temperature of the cooling is preferably 10-20°C, specifically 10°C, 15°C or 20°C.

[0044] After obtaining the compound A, the present invention mixes the compound A and sodium hydrosulfide to carry out a thiocarboxylation reaction to obtain compound B. In the present invention, the mass ratio of the sodium hydrosulfide to the compound II is preferably 0.15 to 0.45:1, specifically 0.15:1, 0.18:1, 0.21:1, 0.24:1, 0.27:1, 0.30:1, 0.35:1, 0.40:1 or 0.45:1.

[0045] In the present invention, the temperature of the thiocarboxylation reaction is preferably 30-40°C, specifically 30°C, 32°C, 34°C, 36°C, 38°C or 40°C, and the insulation time is preferably 2-3h, specifically 2h, 2.2h, 2.4h, 2.6h, 2.8h or 3h; the thiocarboxylation reaction is preferably monitored by TLC.

[0046] After obtaining the compound B, the present invention mixes the compound B and iodofluoromethane for fluoromethylation reaction to obtain fluticasone furoate. In the present invention, the mass ratio of iodofluoromethane to compound II is preferably 0.4 to 1.2:1, specifically 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1 or 1.2:1.

[0047] In the present invention, the temperature of the fluoromethylation reaction is preferably -5 to 5°C, specifically -5°C, -3°C, -1°C, 0°C, 1°C, 3°C or 5°C, and the insulation time is preferably 1.5 to 3h, specifically 1.5h, 2h, 2.5h or 3h; the fluoromethylation reaction is preferably monitored by TLC.

[0048] In the present invention, the fluoromethylation reaction preferably further comprises adding water to the reaction system, solid-liquid separation and drying in sequence. The present invention terminates the reaction by adding water to the reaction solution, quenches fluoroiodomethane, and the product precipitates from the water.

[0049] In the present invention, the solid-liquid separation is preferably filtration.

[0050] In the present invention, the drying is preferably oven drying; the drying is preferably forced air drying; the drying temperature is preferably 40-50°C, specifically 40°C, 43°C, 47°C or 50°C, until the product has constant weight, preferably 8-12h, specifically 8h, 10h or 12h.

[0051] In a specific embodiment of the present invention, the calculation formula of weight yield is as follows:

[0052] Weight yield = product weight / starting material weight × 100%;

[0053] In the formula, the starting material is compound II.

[0054] In order to further illustrate the present invention, the scheme of the present invention is described in detail below in conjunction with the accompanying drawings and embodiments, but they should not be understood as limiting the protection scope of the present invention.

[0055] Example 1

[0056] The starting material (Compound II) (10 g, 25.23 mmol) was added to 50 mL of DMF, and an organic base N,N-dimethylaminopyridine (6.2 g, 50.46 mmol) was added, and furoyl chloride (9.9 g, 75.68 mmol) was added dropwise. The mixture was reacted at 30°C for 1 h, and the reaction was complete by TLC. Sodium hydrosulfide (2.1 g, 37.84 mmol) was added, and the mixture was reacted at 35°C for 2 h, and the reaction was complete by TLC. The mixture was cooled to 0°C, and iodomethane (6.1 g, 37.85 mmol) was added, and the mixture was reacted for 2 h, and the reaction was complete by TLC. 50 mL of water was added, and the mixture was filtered and dried to obtain 12.2 g of fluticasone furoate with a weight yield of 122% and a purity of 99.3%, wherein dimer impurities were not detected.

[0057] Example 2

[0058] The starting material (Compound II) (20 g, 50.46 mmol) was added to 100 mL of DMF, and an organic base N,N-dimethylaminopropylamine (13 g, 126.16 mmol) was added, and furoyl chloride (19.8 g, 151.36 mmol) was added dropwise, and the mixture was reacted at 30°C for 1 h. The reaction was complete by TLC. Sodium hydrosulfide (4.62 g, 83.17 mmol) was added, and the mixture was reacted at 35°C for 2 h. The reaction was complete by TLC. The mixture was cooled to 0°C, and iodomethane (12.2 g, 75.69 mmol) was added, and the mixture was reacted for 2 h. The reaction was complete by TLC. 100 mL of water was added, and the mixture was filtered and dried to obtain 24.16 g of fluticasone furoate with a weight yield of 120.8% and a purity of 98.8%. No dimer impurities were detected.

[0059] Example 3

[0060] The starting material (Compound II) (4 g, 10.09 mmol) was added to 20 mL of DMF, and an organic base potassium carbonate (2.78 g, 20.18 mmol) was added, and furoyl chloride (3.96 g, 30.27 mmol) was added dropwise, and the mixture was reacted at 30°C for 1 h. The reaction was complete by TLC. Sodium hydrosulfide (0.84 g, 15.14 mmol) was added, and the mixture was reacted at 35°C for 2 h. The reaction was complete by TLC. The mixture was cooled to 0°C, and iodomethane (2.44 g, 15.14 mmol) was added, and the mixture was reacted for 2 h. The reaction was complete by TLC. 20 mL of water was added, and the mixture was filtered and dried to obtain 4.77 g of fluticasone furoate with a weight yield of 119.3% and a purity of 99.1%. No dimer impurities were detected.

[0061] Comparative Example 1

[0062] Reference is made to the preparation method disclosed by GH Phillipps et al. in Journal of Medicinal Chemistry, 37, 3717-3729:

[0063] Add 10 g of flumethasone, the starting material (Compound I), to 50 mL of THF, add 8.4 g of aqueous periodic acid solution, react at 0°C for 3 h, and the reaction is complete by TLC; add 150 mL of water, filter, and dry to obtain Compound II; add Compound II to 50 mL of THF, add 6 g of triethylamine and 7.5 g of furoyl chloride, react at 30°C for 1 h, and the reaction is complete by TLC, add 5 g of diethylamine and 150 mL of water, filter, and dry to obtain Compound III; add Compound III to 50 mL of THF, add Add 5 g of N,N-dimethylaminothiocarbonyl chloride, react at 30°C for 2 h, and the reaction is complete by TLC; add 150 mL of water, filter, and dry to obtain compound IV; add 50 mL of methanol and 5 g of potassium carbonate to compound IV, react at 50°C for 4 h, and the reaction is complete by TLC to obtain compound V; cool to 0°C, add 8 g of bromofluoromethane, react for 3 h, and the reaction is complete by TLC, add 150 mL of water, filter, and dry to obtain 8.2 g of fluticasone furoate, with a weight yield of 82.0%, a purity of 94.6%, and a total impurity of 5.4%.

[0064] Comparative Example 2

[0065] Referring to the preparation methods disclosed in Alfama's patents CN 1798757A and WO2004 / 087731:

[0066] 5 g of the starting material flumethasone was added to 25 mL of THF, and 5.55 g of aqueous periodic acid solution was added, and the mixture was reacted at 0°C for 3 h. The reaction was complete by TLC. 150 mL of water was added, filtered, and dried to obtain compound II. Compound II was added to 30 mL of acetone, and 3 g of triethylamine and 5 g of furoyl chloride were added, and the mixture was reacted at 0°C for 2 h. The reaction was complete by TLC. 10 g of diethylamine was added, and the mixture was continued to react at 0°C for 1 h. The reaction was complete by TLC. 100 mL of water was added, filtered, and dried to obtain compound III. Compound III was added to 50 mL of DMA, and 4 g of EDC and 3 g of NHS were added, and the mixture was heated at 50°C. The reaction was completed after 4 hours of TLC to obtain compound VI; the temperature was lowered to 35°C, 8 g of sodium hydrosulfide hydrate was added, the reaction was continued for 0.5 h, the temperature was lowered to 25°C, bromofluoromethane was introduced for reaction for 1 h, the reaction was completed after TLC, 100 mL of 10% aqueous sodium carbonate solution and 200 mL of water were added, the mixture was filtered, the obtained solid was added to 300 mL of methanol, the temperature was raised to reflux and filtered, 300 mL of warm water (40-50°C) was added, the temperature was gradually lowered to 0°C, the mixture was filtered and dried to obtain 4.45 g of fluticasone furoate with a weight yield of 89.0% and a purity of 98.1%, wherein the content of dimer impurities was greater than 0.3%.

[0067] It can be seen from the above examples that the preparation method provided by the present invention reduces the generation of impurities and has the advantages of high weight yield and high purity, with the purity being above 99% and the weight yield being above 120%.

[0068] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing fluticasone furoate, characterized in that: The following steps are involved: Compound II, furoyl chloride, an organic base and an organic solvent are mixed for acylation reaction to obtain compound A; the structure of compound II is shown in formula II, and the structure of compound A is shown in formula A: The mass ratio of furoyl chloride to compound II is 0.8-1.6:1; The compound A and sodium hydrosulfide are mixed to carry out a thiocarboxylation reaction to obtain a compound B, the structure of which is shown in Formula B: The compound B and iodomethane are mixed to carry out fluoromethylation reaction to obtain fluticasone furoate.

2. The preparation method according to claim 1, characterized in that: The organic base includes one or more of triethylamine, N,N-dimethylaminopyridine and N,N-dimethylaminopropylamine.

3. The preparation method according to claim 1 or 2, characterized in that: The mass ratio of the organic base to compound II is 2.0-2.5:

1.

4. The preparation method according to claim 1, characterized in that: The mass ratio of the organic solvent to compound II is 1:2.85-9.

48.

5. The preparation method according to claim 1 or 4, characterized in that: The temperature of the acylation reaction is 25-35° C., and the insulation time is 1-2 hours.

6. The preparation method according to claim 1, characterized in that: The mass ratio of the sodium hydrosulfide to compound II is 0.15-0.45:

1.

7. The preparation method according to claim 1 or 6, characterized in that: The temperature of the thiocarboxylation reaction is 30-40° C., and the insulation time is 2-3 hours.

8. The preparation method according to claim 1, characterized in that: The mass ratio of the fluoroiodomethane to compound II is 0.4-1.2:

1.

9. The preparation method according to claim 1 or 8, characterized in that: The temperature of the fluoromethylation reaction is -5 to 5°C, and the insulation time is 1.5 to 3 hours.

10. The preparation method according to claim 9, characterized in that: After the fluoromethylation reaction, the process further includes sequentially adding water to the reaction system, solid-liquid separation and drying.

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