A preparation method of otaconazole

Abstract

The present invention relates to the field of organic chemical synthesis, and particularly to a preparation method of ornidazole. The preparation method includes four steps: chiral thiourea-catalyzed Henry reaction, Suzuki coupling reaction, nitro reduction reaction, and tetrazole cyclization reaction, to obtain the target product with high yield and enantioselectivity. This method has good application prospects in the industrial production of ornidazole, is expected to reduce production costs and improve product quality, so as to meet the production requirements.

Description

Technical Field

[0001] The present invention relates to the field of organic chemical synthesis, and particularly to a preparation method of otesaconazole. Technical Background

[0002] The chemical name of otesaconazole is (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol, and its molecular formula is C 23 H 16 7N5O2. This drug was developed by Mycovia Pharmaceuticals and was approved by the FDA for marketing on April 26, 2022, under the trade name Vivjoa.

[0003]

[0004] Otesaconazole inhibits the activity of 14-α demethylase (CYP51), hinders the synthesis of ergosterol, and thus destroys the integrity of fungal cells. At the same time, it causes the accumulation of toxic sterols such as methylated sterols, thereby changing the chemical composition of the fungal cell membrane, affecting its permeability, and inhibiting the growth and reproduction of fungi. Compared with human CYP450 enzymes, otesaconazole has an affinity for fungal CYP51 enzymes that is approximately 2,000 times higher, showing higher selectivity. As an oral drug, otesaconazole can effectively enhance the selective effect on fungal CYP51, demonstrating good efficacy and tolerance, and having broad market prospects.

[0005] There are mainly the following synthetic routes for otesaconazole:

[0006] Patent [Hoekstra, W. J., Yates, C. M., Behnke, M., et al. (2015).Antifungal compound process. WO2015143172A1] uses the key intermediate 2-(5-bromopyridin-2-yl)-1-(2,4-difluorophenyl)-2,2-difluoroethanone as the raw material, and obtains otesaconazole through steps such as epoxidation reaction, ammonia ring opening, chiral resolution, tetrazole cyclization, and Suzuki coupling.

[0007]

[0008] This route uses the method of chiral resolution, with complex processes and waste of raw materials, and is not suitable for industrial production.

[0009] Patent [Wirth, D. D., Yates, C. M., Hoekstra, W. J., et al. (2017). Antifungal compound process. WO2017049080A1] uses the key intermediate 2-(5-bromopyridin-2-yl)-1-(2,4-difluorophenyl)-2,2-difluoroethanone as the raw material, and obtains otaconazole through steps such as asymmetric Henry reaction, hydrogenation reduction reaction, Suzuki coupling reaction, and tetrazole cyclization.

[0010]

[0011] The enantioselectivity of the asymmetric Henry reaction achieved by using a chiral catalyst in the first step of this route is relatively low. The second step involves a hydrogenation reaction, which is not conducive to industrial scale-up. There are by-products of the coupling of amine and boric acid in the third step reaction. Therefore, this route is not conducive to industrial production.

[0012] Patent [Hoekstra, W. J., Yates, C. M., et al. (2015). Antifungal compound process. WO2015143142A1 ] uses the intermediate ethyl 2-(5-bromopyridin-2-yl)-2,2-difluoroacetate as the raw material, and obtains otaconazole through steps such as asymmetric Claisen reaction, decarboxylation reaction, and Henry reaction.

[0013]

[0014] The last step reaction of this route uses a metallated derivative as the reaction substrate, and this reaction substrate is unstable and prone to degradation. Therefore, this method still needs further optimization. Summary of the Invention

[0015] The technical solution and content of the present invention relate to a preparation method of otaconazole shown in the following formula I.

[0016]

[0017] The above-mentioned preparation method of otaconazole includes the following route:

[0018]

[0019] The above-mentioned synthesis route of otaconazole includes the following specific steps:

[0020] (a) Preparation of (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol (III)

[0021]

[0022] Compound II and a thiourea catalyst are added to a solvent, the temperature is lowered and stirred, nitromethane is added to the solution, stirred, and after the reaction is completed, (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol (III) is obtained through post-treatment;

[0023] (b) Preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (IV)

[0024]

[0025] Compound III, 4-(2,2,2-trifluoroethoxy)phenylboronic acid, and a catalyst are added to a solvent. Under the protection of an inert gas, an aqueous solution containing a base is added to the solution, and it is stirred under the protection of an inert gas. After the reaction is completed, (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (IV) is obtained through post-treatment;

[0026] (c) Preparation of (R)-3-amino-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (V)

[0027]

[0028] Compound IV and a catalyst are added to a solvent, the temperature is lowered and stirred, hydrazine hydrate is added, stirred, and after the reaction is completed, (R)-3-amino-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (V) is obtained through post-treatment;

[0029] (d) Preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (I)

[0030]

[0031] Compound V, triethyl orthoformate, sodium azide and a catalyst are added to a solvent, stirred, and after the reaction is completed, (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (I) is obtained through post-treatment.

[0032] In the synthesis route of the present invention:

[0033] The solvent in step (a) is tetrahydrofuran, methyl tert-butyl ether, dichloromethane, chloroform, toluene, etc., and the thiourea catalyst is 1-((R)-1-phenylethyl)-3-((1R)-quinolin-4-yl((2S)-8-vinylquinicolin-2-yl)methyl)thiourea. The structural formula of the thiourea catalyst is as follows;

[0034] ;

[0035] The solvent in step (b) is tetrahydrofuran, n-butanol, N,N-dimethylformamide, N-methyl-2-pyrrolidone, etc., the catalyst is bis(triphenylphosphine)palladium dichloride, tetrakis(triphenylphosphine)palladium, bis(dibenzylideneacetone)palladium, etc., the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, etc., and the inert gas is nitrogen, argon, etc.;

[0036] The solvent in step (c) is n-butanol, isopropanol, methanol, ethanol, etc., and the catalyst is Raney nickel, iron powder, etc.;

[0037] The catalyst in step (d) is ytterbium(III) trifluoromethanesulfonate hydrate, ytterbium(III) oxide, and the solvent is 2-methoxyethanol, acetic acid, propionic acid, N,N-dimethylformamide, etc.

[0038] In the synthesis route of the present invention:

[0039] The solvent in step (a) is preferably tetrahydrofuran, and the thiourea catalyst is preferably 1-((R)-1-phenylethyl)-3-((1R)-quinolin-4-yl((2S)-8-vinylquinicolin-2-yl)methyl)thiourea;

[0040] The solvent in step (b) is preferably tetrahydrofuran, the catalyst is preferably bis(triphenylphosphine)palladium dichloride, the base is preferably sodium carbonate, and the inert gas is preferably nitrogen;

[0041] The solvent in step (c) is preferably n-butanol, and the catalyst is preferably Raney nickel;

[0042] The catalyst in step (d) is preferably ytterbium(III) trifluoromethanesulfonate hydrate, and the solvent is preferably 2-methoxyethanol.

[0043] The present invention obtains the target product through four steps: a chiral thiourea-catalyzed Henry reaction, Suzuki coupling reaction, nitro reduction reaction, and tetrazole cyclization reaction, with high yield and enantioselectivity, which makes this method have good application prospects in the industrial production of clotrimazole. This preparation method is expected to reduce production costs and improve product quality, thus meeting production requirements. Embodiment

[0044] The present invention will be further described below in conjunction with specific embodiments, but it is not a limitation of the present invention. Example

[0045] Preparation of (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol (III)

[0046] Dissolve 2-(5-bromopyridin-2-yl)-1-(2,4-difluorophenyl)-2,2-difluoroethanone (3.47 g, 10 mmol) and 1-((R)-1-phenylethyl)-3-((1R)-quinolin-4-yl((2S)-8-vinylquinuclidin-2-yl)methyl)thiourea (292 mg, 0.6 mmol) in 20 mL of anhydrous tetrahydrofuran, cool to 0 °C, and slowly add nitromethane (3.66 g, 60 mmol) dropwise to the solution, and stir at 0 °C overnight.

[0047] Concentrate the solvent under reduced pressure, and pass through a silica gel column (PE:EA = 5:1) to obtain (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol (III) (3.77 g, y = 92.2%, ee = 90%).

[0048] 1 1H-NMR (300 MHz, DMSO-d6): δ 8.62 (d, J = 2.1 Hz, 1 H), 7.95 (dd, J 1 = 8.4 Hz, J 1 = 2.1 Hz, 1 H), 7.46 (m, 1 H), 7.33 (dd, J 1 = 8.4 Hz, J 1 = 2.1 Hz, 1H), 6.80 (m, 2 H), 5.76 (d, J = 12.6 Hz, 1 H), 5.18 (d, J = 12.6 Hz, 1 H).

[0049] Preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (IV)

[0050] Add (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol (3.27 g, 8 mmol), 4-(2,2,2-trifluoroethoxy)phenylboronic acid (1.94 g, 8.8 mmol), and bis(triphenylphosphine)palladium(II) dichloride (280 mg, 0.4 mmol) to tetrahydrofuran (30 ml). Under nitrogen protection, add an aqueous solution (10 mL) containing sodium carbonate (2.12 g, 20 mmol) to the solution. Under nitrogen protection, heat the mixture to 70 °C and react for 8 h.

[0051] Cool to room temperature, add ethyl acetate (120 mL) to the reaction mixture, separate the organic phase, wash the organic phase with 1N HCl (20 mL), saturated brine (20 mL), dry over anhydrous sodium sulfate, filter through diatomaceous earth, concentrate the organic phase under reduced pressure, and purify by silica gel column chromatography (PE:EA = 5:1) to obtain (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (IV) (3.54 g, y = 87.8 %).

[0052] 1 1H-NMR (300 MHz, DMSO-d6): δ 8.60 (d, J = 2.1 Hz, 1 H), 7.95 (dd, J 1 = 8.4 Hz, J 1 = 2.1 Hz, 1 H), 7.86 (d, J = 6.6 Hz, 2 H), 7.46 (m, 1 H), 7.33 (dd, J 1 = 8.4 Hz, J 1 = 2.1 Hz, 1 H), 7.19 (d, J = 6.6 Hz, 2 H), 6.80 (m, 2 H), 5.76(d, J = 12.6 Hz, 1 H), 5.18 (d, J = 12.6 Hz, 1 H), 4.84 (q, J = 7.5 Hz, 2 H).

[0053] Preparation of (R)-3-Amino-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (V)

[0054] (R)-2-(2,4-Difluorophenyl)-1,1-difluoro-3-nitro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (3.0 g, 6 mmol) was added to 20 mL of n-butanol. Raney nickel (71 mg, 1.2 mmol) was added to the solution, and hydrazine hydrate solution (2.4 g, 48 mmol, 80% aqueous solution) was added dropwise in an ice-water bath. After the addition was complete, the temperature was raised to 90 °C and the reaction was carried out overnight.

[0055] After cooling, it was filtered through activated clay, and concentrated under reduced pressure to obtain (R)-3-Amino-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (2.67 g, y = 94%).

[0056] 1 H-NMR (300 MHz, DMSO-d6): δ 8.60 (d, J = 2.1 Hz, 1 H), 7.86 (dd, J 1 = 8.4 Hz, J 1 = 2.1 Hz, 1 H), 7.82 (d, J = 6.6 Hz, 2 H), 7.46 (m, 1 H), 7.30 (m , 1 H), 7.16 (d, J = 6.6 Hz, 2 H), 6.80 (m, 2 H), 5.20 (s, 2 H), 4.84 (q, J = 7.5 Hz, 2 H), 3.86 (d, J = 13.8 Hz, 1 H), 3.48 (d, J = 13.8 Hz, 1 H).

[0057] Preparation of (R)-2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (I)

[0058] (R)-3-Amino-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (1.5 g, 3.2 mmol), triethyl orthoformate (3.5 mmol), sodium azide (3.5 mmol) and ytterbium(III) trifluoromethanesulfonate hydrate (0.64 mmol) were stirred in 2-methoxyethanol (15 mL) at 60 °C overnight.

[0059] 100 mL of ethyl acetate was added to the reaction solution, and it was washed with saturated potassium sodium carbonate solution (30 mL × 2) and saturated sodium chloride solution (30 mL × 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was slurried in ethanol / water (10 mL / 10 mL) to obtain white (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (I) (1.61 g, y = 95.3%, ee = 97.8%).

[0060] 1 1H-NMR (300 MHz, DMSO-d6): δ 9.16 (s, 1 H), 8.96 (d, J = 0.9 Hz, 1 H), 8.22 (m, 1 H), 7.86 (d, J = 6.6 Hz, 2 H), 7.55 (d, J = 6.6 Hz, 1 H), 7.30 (d, J = 3.3 Hz, 1 H), 7.29 (m, 1 H), 7.22 (d, J = 6.6 Hz, 1 H), 7.18 (d, J = 6.6 Hz, 1 H), 6.90 (m, 1 H), 5.72 (d, J = 11.7 Hz, 1 H), 5.15 (d, J = 11.7 Hz, 1H), 4.88 (q, J = 7.5 Hz, 2 H).

[0061] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the idea of the present invention, several simple adjustments or improvements can be made, which should all be regarded as belonging to the protection scope of the present invention.

Claims

1. A preparation method of otaconazole, characterized in that Comprising the following steps: (a) Preparation of (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol (III) ； Compound II and a thiourea catalyst are added to the solvent tetrahydrofuran, cooled and stirred, nitromethane is added to the solution, stirred, and after the reaction is completed, (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol (III) is obtained through post-treatment; The thiourea catalyst is 1-((R)-1-phenylethyl)-3-((1R)-quinolin-4-yl((2S)-8-vinylquinuclidin-2-yl)methyl)thiourea, and the structural formula of the thiourea catalyst is as follows; ； (b) Preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (IV) ； Compound III, 4-(2,2,2-trifluoroethoxy)phenylboronic acid, and the catalyst bis(triphenylphosphine)palladium dichloride are added to the solvent tetrahydrofuran. Under the protection of an inert gas, an aqueous solution containing sodium carbonate is added to the solution, stirred under the protection of an inert gas, and after the reaction is completed, (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (IV) is obtained through post-treatment; (c) Preparation of (R)-3-amino-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (V) ； Compound IV and the catalyst Raney nickel are added to the solvent n-butanol, cooled and stirred, hydrazine hydrate is added, stirred, and after the reaction is completed, (R)-3-amino-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (V) is obtained through post-treatment; (d) Preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (I) ； Compound V, triethyl orthoformate, sodium azide, and the catalyst ytterbium(III) trifluoromethanesulfonate hydrate are added to the solvent 2-methoxyethanol, stirred, and after the reaction is completed, (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (I) is obtained through post-treatment.

2. The preparation method according to claim 1, wherein: Step (a): Dissolve 2-(5-bromopyridin-2-yl)-1-(2,4-difluorophenyl)-2,2-difluoroethanone and 1-((R)-1-phenylethyl)-3-((1R)-quinolin-4-yl((2S)-8-vinylquinuclidin-2-yl)methyl)thiourea in anhydrous tetrahydrofuran, cool the temperature to 0 °C, add nitromethane to the solution, stir at 0 °C, concentrate the solvent under reduced pressure, and obtain (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol (III) by passing through a flash silica gel column; Step (b): Add (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol, 4-(2,2,2-trifluoroethoxy)phenylboronic acid, and bis(triphenylphosphine)palladium dichloride to tetrahydrofuran. Under nitrogen protection, add an aqueous solution containing sodium carbonate to the solution. Under nitrogen protection, heat the solution to 70 °C for reaction, cool to room temperature, add ethyl acetate to the reaction, separate the organic phase, wash the organic phase with HCl, wash with saturated brine, dry with anhydrous sodium sulfate, filter through diatomaceous earth, concentrate the organic phase under reduced pressure, and obtain (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (IV) by passing through a flash silica gel column; Step (c): Add (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol to 20 mL of n-butanol, add Raney nickel to the solution, dropwise add hydrazine hydrate solution in an ice-water bath. After the addition is complete, heat the temperature to 90 °C, stir, cool, filter through activated clay, and concentrate under reduced pressure to obtain (R)-3-amino-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol; Step (d): Add (R)-3-amino-2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol, triethyl orthoformate, sodium azide, and ytterbium(III) trifluoromethanesulfonate hydrate to 2-methoxyethanol, stir at 60 °C, add ethyl acetate to the reaction solution, wash with saturated potassium sodium carbonate solution, wash with saturated sodium chloride solution, collect the organic phase, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and obtain (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (I) by pulping the crude product in ethanol / water.

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