Preparation method of oteconazole

Abstract

The invention relates to the field of organic chemical synthesis, in particular to a preparation method of oteconazole. According to the preparation method, the target product is obtained with high yield and enantioselectivity through four steps of chiral thiourea catalysis Henry reaction, Suzuki coupling reaction, nitro reduction reaction and tetrazole cyclization reaction, and the method has a good application prospect in industrial production of oteconazole and is expected to reduce the production cost and improve the product quality, so that the production requirements are met.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and in particular to a method for preparing ortaconia azole. Technical Background

[0002] The chemical name of oteseconazole is (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazolyl-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 F7N5O2. The drug was developed by Mycovia Pharmaceuticals and was approved by the FDA on April 26, 2022 under the trade name Vivjoa.

[0003]

[0004] Otconazole inhibits the activity of 14-α demethylase (CYP51) and hinders the synthesis of ergosterol, thereby destroying the integrity of fungal cells. At the same time, it leads to the accumulation of toxic sterols such as methylated sterols, which in turn changes the chemical composition of fungal cell membranes, affects its permeability, and inhibits the growth and reproduction of fungi. Compared with human CYP450 enzymes, oteconazole has an affinity for fungal CYP51 enzymes of about 2,000 times, showing higher selectivity. As an oral drug, oteconazole can effectively improve the selectivity of fungal CYP51, showing good efficacy and tolerability, and has broad market prospects.

[0005] Otaconia has the following main synthetic routes:

[0006] Patent [Hoekstra, WJ, Yates, CM, 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 oteconazole through epoxidation reaction, aminolysis ring opening, chiral resolution, tetrazole cyclization, Suzuki coupling and other steps.

[0007]

[0008] This route uses a chiral separation method, which has a complicated process and causes waste of raw materials and is not suitable for industrial production.

[0009] Patent [Wirth, DD, Yates, CM, Hoekstra, WJ, 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 oteconazole through asymmetric Henry reaction, hydrogenation reduction reaction, Suzuki coupling reaction, tetrazole cyclization and other steps.

[0010]

[0011] The enantioselectivity of the asymmetric Henry reaction achieved by a chiral catalyst in the first step of this route is low. The second step uses a hydrogenation reaction, which is not conducive to industrial scale-up. The third step reaction produces a by-product of the coupling of amine and boronic acid, so this route is not conducive to industrial production.

[0012] Patent [Hoekstra, WJ, Yates, CM, et al. (2015). Antifungal compound process. WO2015143142A1] uses the intermediate ethyl 2-(5-bromopyridin-2-yl)-2,2-difluoroacetate as a raw material, and obtains oteconazole through asymmetric Claisen reaction, decarboxylation reaction, Henry reaction and other steps.

[0013]

[0014] The last step of this route uses a metal derivative as a reaction substrate. This reaction substrate is unstable and easily degraded, so this method needs further optimization. Summary of the invention

[0015] The technical scheme and content of the present invention relate to a method for preparing ortaconia azole shown in the following formula I.

[0016]

[0017] The above-mentioned method for preparing ortaconia azole comprises the following route:

[0018]

[0019] The above-mentioned synthesis route of oterconazole comprises 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 thiourea catalyst are added to a solvent, the temperature is lowered and stirred, nitromethane is added to the solution, and the mixture is stirred. 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 by 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, and an aqueous solution containing a base is added to the solution under the protection of an inert gas, and the solution is stirred under the protection of an inert gas. After the reaction is completed, post-treatment is performed 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);

[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, and the reaction is stirred. 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 by post-treatment.

[0029] (d) Preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazolyl-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 and stirred. After the reaction is completed, post-treatment is performed to obtain (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazolyl-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (I).

[0032] In the synthetic 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-vinylquinicline-2-yl)methyl)thiourea, and 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 bistriphenylphosphine palladium dichloride, tetrakis(triphenylphosphine)palladium, bis(dibenzylideneacetonepalladium), 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 trifluoromethanesulfonate hydrate or ytterbium oxide, and the solvent is 2-methoxyethanol, acetic acid, propionic acid, N,N-dimethylformamide, etc.

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

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

[0040] In step (b), the solvent is preferably tetrahydrofuran, the catalyst is preferably bistriphenylphosphine 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] In step (d), the catalyst is preferably ytterbium trifluoromethanesulfonate hydrate, and the solvent is preferably 2-methoxyethanol.

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

[0044] The present invention will be further described below with reference to specific embodiments, but the present invention is not limited thereto. Example

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

[0046] 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-vinylquiniclin-2-yl)methyl)thiourea (292 mg, 0.6 mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran, cooled to 0°C, nitromethane (3.66 g, 60 mmol) was slowly added dropwise to the solution, and stirred at 0°C overnight.

[0047] The solvent was concentrated under reduced pressure and the residue was passed 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 H-NMR (300 MHz, DMSO-d6): δ 8.62 (d, , 1 H), 7.95 (dd, J 1 = 8.4Hz,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, 2H), 5.76 (d, , 1 H), 5.18 (d, , 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] (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 bistriphenylphosphine palladium dichloride (280 mg, 0.4 mmol) were added to tetrahydrofuran (30 ml). Under nitrogen protection, an aqueous solution (10 mL) containing sodium carbonate (2.12 g, 20 mmol) was added to the solution. Under nitrogen protection, the temperature was raised to 70 °C and the reaction was carried out for 8 h.

[0051] The temperature was lowered to room temperature, ethyl acetate (120 mL) was added to the reaction, the organic phase was separated, washed with 1N HCl (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered through diatomaceous earth, and the organic phase was concentrated under reduced pressure and passed through a silica gel column (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 H-NMR (300 MHz, DMSO-d6): δ 8.60 (d, , 1 H), 7.95 (dd, J 1 = 8.4Hz,J 1 = 2.1 Hz, 1 H), 7.86 (d, , 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, , 2 H), 6.80 (m, 2 H), 5.76 (d, , 1 H), 5.18 (d, , 1 H), 4.84 (q, , 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] 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 (3.0 g, 6 mmol) to 20 mL of n-butanol, add Raney nickel (71 mg, 1.2 mmol) to the solution, add hydrazine hydrate solution (2.4 g, 48 mmol, 80% aqueous solution) dropwise in an ice-water bath, and after the addition is complete, heat to 90°C and react overnight.

[0055] The mixture was cooled, filtered through activated white clay, and concentrated under reduced pressure to give (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, , 1 H), 7.86 (dd, J 1 = 8.4Hz,J 1 = 2.1 Hz, 1 H), 7.82 (d, , 2 H), 7.46 (m, 1 H), 7.30 (m , 1 H), 7.16 (d, , 2 H), 6.80 (m, 2 H), 5.20 (s, 2 H), 4.84 (q, J = 7.5Hz, 2 H), 3.86 (d, , 1 H), 3.48 (d, , 1 H).

[0057] Preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazolyl-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 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, washed with saturated potassium carbonate sodium solution (30 mL * 2), washed with saturated sodium chloride solution (30 mL * 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 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-tetrazolyl-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 H-NMR (300 MHz, DMSO-d6): δ 9.16 (s, 1 H), 8.96 (d, , 1 H),8.22 (m, 1 H), 7.86 (d, , 2 H), 7.55 (d, , 1 H), 7.30 (d, , 1 H), 7.29 (m, 1 H), 7.22 (d, , 1 H), 7.18 (d, J = 6.6 Hz, 1 H), 6.90 (m, 1 H), 5.72 (d, , 1 H), 5.15 (d, , 1H), 4.88 (q, , 2 H).

[0061] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several simple adjustments or improvements can be made without departing from the concept of the present invention, which should be regarded as falling within the scope of protection of the present invention.

Claims

1. A method for preparing ortaconia, characterized in that The steps include: (a) Preparation of (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol (III) ； Compound II and thiourea catalyst are added to a solvent, the temperature is lowered and stirred, nitromethane is added to the solution, and the mixture is stirred. 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 by post-treatment; (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 a catalyst are added to a solvent, and an aqueous solution containing a base is added to the solution under the protection of an inert gas, and the solution is stirred under the protection of an inert gas. After the reaction is completed, post-treatment is performed 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); (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 a catalyst are added to a solvent, the temperature is lowered and stirred, hydrazine hydrate is added, and the reaction is stirred. 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 by post-treatment. (d) Preparation of (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazolyl-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (I) ； Compound V, triethyl orthoformate, sodium azide and a catalyst are added to a solvent and stirred. After the reaction is completed, post-treatment is performed to obtain (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazolyl-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (I).

2. The preparation method according to claim 1, characterized in that: The solvent in step (a) is tetrahydrofuran, methyl tert-butyl ether, dichloromethane, chloroform or toluene, and the thiourea catalyst is 1-((R)-1-phenylethyl)-3-((1R)-quinolin-4-yl((2S)-8-vinylquinicline-2-yl)methyl)thiourea, and the structural formula of the thiourea catalyst is as follows: ； The solvent in step (b) is tetrahydrofuran, n-butanol, N,N-dimethylformamide or N-methyl-2-pyrrolidone, the catalyst is bistriphenylphosphine palladium dichloride, tetrakis(triphenylphosphine)palladium or bis(dibenzylideneacetonepalladium), the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide, and the inert gas is nitrogen or argon; The solvent in step (c) is n-butanol, isopropanol, methanol or ethanol, and the catalyst is Raney nickel or iron powder; The catalyst in step (d) is ytterbium trifluoromethanesulfonate hydrate or ytterbium oxide, and the solvent is 2-methoxyethanol, acetic acid, propionic acid or N,N-dimethylformamide.

3. The preparation method according to claim 1 or 2, characterized in that: The solvent of step (a) is tetrahydrofuran, and the thiourea catalyst is 1-((R)-1-phenylethyl)-3-((1R)-quinolin-4-yl((2S)-8-vinylquinicline-2-yl)methyl)thiourea; In step (b), the solvent is tetrahydrofuran, the catalyst is bistriphenylphosphine palladium dichloride, the base is sodium carbonate, and the inert gas is nitrogen; In step (c), the solvent is n-butanol and the catalyst is Raney nickel; In step (d), the catalyst is ytterbium trifluoromethanesulfonate hydrate, and the solvent is 2-methoxyethanol.

4. The preparation method according to claim 1 or 2, characterized in that: Step (a) 2-(5-bromopyridin-2-yl)-1-(2,4-difluorophenyl)-2,2-difluoroethanone and 1-((R)-1-phenylethyl)-3-((1R)-quinolin-4-yl((2S)-8-vinylquinicline-2-yl)methyl)thiourea are dissolved in anhydrous tetrahydrofuran, cooled to 0°C, nitromethane is added to the solution, and stirred at 0°C. The solvent is concentrated under reduced pressure, and the solution is passed through a rapid silica gel column to obtain (R)-1-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-1,1-difluoro-3-nitropropan-2-ol (III); Step (b) (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 bistriphenylphosphine palladium dichloride are added to tetrahydrofuran, and under nitrogen protection, an aqueous solution containing sodium carbonate is added to the solution, and under nitrogen protection, the temperature is raised to 70° C. for reaction, and the temperature is lowered to room temperature, and ethyl acetate is added to the reaction, and the organic phase is separated, and the organic phase is washed with HCl, washed with saturated brine, dried over anhydrous sodium sulfate, filtered through diatomaceous earth, and the organic phase is concentrated under reduced pressure. The organic phase is passed through a rapid silica gel column 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); Step (c) adding (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, adding Raney nickel to the solution, adding hydrazine hydrate solution dropwise in an ice-water bath, and after the addition is complete, heating to 90° C., stirring, cooling, filtering with activated white earth, and concentrating 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) (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 trifluoromethanesulfonate hydrate are added to 2-methoxyethanol and stirred at 60° C. Ethyl acetate is added to the reaction solution, and the mixture is washed with a saturated potassium carbonate solution and a saturated sodium chloride solution. The organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is slurried in ethanol / water to 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).

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