Preparation method of efinaconazole

Abstract

The invention relates to the field of medicinal chemistry, in particular to a preparation method of efinaconazole. The preparation method comprises the following steps: (1) adding 1, 3-difluorobenzene, S-2-chloropropionyl chloride and a catalyst into an organic solvent A, uniformly mixing, and heating for reaction to obtain a compound 1; (2) adding a compound 1, 4-methylene piperidine into an organic solvent B, and reacting to obtain a compound 2; and (3) adding the compound 2, trimethyl sulfoxide iodide, alkali and 1H-1, 2, 4-triazole into an organic solvent C, mixing, and reacting to obtain the efinaconazole. The preparation method has the advantages of easily available raw materials, simple process and mild reaction conditions, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and specifically relates to a method for preparing efinaconazole. Background Art

[0002] Efinaconazole (English name: Efinaconzole), chemical name (2 R ,3 R )-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1 H -1,2,4-triazole-1-yl)-2-butanol, whose chemical structure is shown in Formula I, is a small molecule triazole antifungal drug and an l4a-demethylase inhibitor with broad-spectrum antifungal activity. In clinical practice, 10% efinaconazole solution is used to treat onychomycosis.

[0003]

[0004] Formula I Chinese invention patent application CN104292214A discloses a method for synthesizing efinaconazole. The synthetic route is as follows: .

[0005] In this route, the racemic mixture 4 is resolved to obtain compound 3, but the yield of compound 3 is greatly lost during the resolution. In addition, there are many side reactions when compound 2 is used to prepare compound 1, and the by-products have similar structures, making it difficult to separate and purify the impurities.

[0006] Chinese invention patent application CN104327047A discloses a method for preparing efinaconazole, and the synthetic route is as follows: .

[0007] This synthetic route uses asymmetric catalysis to obtain chiral intermediate III. The chiral selectivity still needs to be confirmed, and the last step of the cyclization reaction produces a large number of by-products, which are difficult to separate and purify.

[0008] Therefore, it is necessary to develop a method for preparing efinaconazole that has a short process, does not require splitting, does not have harsh reaction conditions, is easy to separate and purify the final product, and is suitable for industrial production. Summary of the Invention

[0009] In view of the shortcomings of the prior art, the present invention provides a method for preparing efinaconazole. The present invention uses 1,3-difluorobenzene as a starting material and reacts it with S-2-chloropropionyl chloride to obtain compound 1; then alkylates it with 4-methylenepiperidine to obtain compound 2; then Chaikovsky epoxidates it with trimethylsulfoxide iodide, and reacts it with 1 HThe one-pot ring opening of 1,2,4-triazole yields efinaconazole. The invention has a short route, does not require separation, and has high purity.

[0010] The present invention is achieved through the following technical solutions: A preparation method of efinaconazole, the synthetic route is as follows:

[0011] The specific steps include: (1) 1,3-difluorobenzene, S-2-chloropropionyl chloride and a catalyst were added to an organic solvent A and mixed evenly, and the temperature was raised to react to obtain compound 1; (2) Compound 1 and 4-methylenepiperidine are added to organic solvent B to react to obtain compound 2; (3) Compound 2, trimethylsulfoxide iodide, base and 1 H -1,2,4-triazole is added into the organic solvent C and mixed, and the reaction is performed to obtain the efinaconazole.

[0012] Furthermore, the molar ratio of 1,3-difluorobenzene, S-2-chloropropionyl chloride and the catalyst in step (1) is 1:1-1.5:1.3-2.7.

[0013] Furthermore, in step (2), the molar ratio of compound 1 to 4-methylenepiperidine is 1:1.3-4.

[0014] Furthermore, in step (3), the compound 2, trimethylsulfoxide iodide, 1 H The molar ratio of 1,2,4-triazole to the base is 1:1.2-1.4:1.2-1.4:2.3-2.7.

[0015] Furthermore, the catalyst in step (1) is selected from any one of aluminum trichloride, ferric trichloride, zinc chloride, H2SO4 and H3PO3; preferably aluminum trichloride.

[0016] Furthermore, the base in step (3) is selected from triethylamine, N , N - any one of diisopropylethylamine, tripropylamine, triethylenediamine, sodium tert-butoxide and potassium tert-butoxide; preferably N , N -Diisopropylethylamine.

[0017] Furthermore, in step (1), the mixing temperature is 0°C-20°C, the mixing time is 1.5h-2.5h, the reaction temperature is 20°C-40°C, and the reaction time is 2h-6h.

[0018] Furthermore, the reaction temperature in step (2) is 0°C-80°C, and the reaction time is 1h-8h.

[0019] Furthermore, in step (3), the mixing temperature is 0°C-30°C, the mixing time is 1h-2.5h, the reaction temperature is 80°C-100°C, and the reaction time is 5h-7h.

[0020] Furthermore, the mixing described in step (1) is specifically as follows: first, 1,3-difluorobenzene is added to the organic solvent A, and the temperature is lowered to 0°C-20°C, and then the catalyst is added, and the mixture is stirred at this temperature for 0.5-1h; then S-2-chloropropionyl chloride is added, and the mixture is stirred at this temperature for 0.5-1h to complete the mixing.

[0021] Furthermore, the mixing process in step (2) also includes adding alkali.

[0022] Furthermore, the base is selected from triethylamine, N , N - any one of diisopropylethylamine, tripropylamine, triethylenediamine, sodium tert-butoxide and potassium tert-butoxide; preferably N , N -Diisopropylethylamine.

[0023] Furthermore, the molar ratio of the base to compound 1 is 1-2:1.

[0024] Furthermore, the organic solvent A, organic solvent B and organic solvent C are each independently selected from one or more of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers and amides.

[0025] Furthermore, the organic solvent A is any one of dichloromethane, chloroform, tetrahydrofuran and 1,4-dioxane.

[0026] Furthermore, the organic solvent B is tetrahydrofuran, 1,4-dioxane, N , N - Any one of dimethylformamide, acetonitrile and ethanol; Furthermore, the organic solvent C is N , N -dimethylformamide, N,N - Any one of dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane and tetrahydrofuran.

[0027] Furthermore, after the reaction in step (1), the steps of washing with ice water, phase separation, washing the organic phase with water again, phase separation, and distilling the organic phase under reduced pressure are further included.

[0028] Furthermore, after the reaction in step (2), the steps of concentration, extraction with dichloromethane and water, water washing, concentration of the organic phase, and column chromatography purification are also included.

[0029] Furthermore, step (3) comprises the steps of adding dichloromethane and water for extraction, washing with water, concentrating the organic phase and performing secondary crystallization after the reaction.

[0030] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention uses 1,3-difluorobenzene as the starting material and undergoes Friedel-Crafts alkylation, SN2 substitution reaction, configuration inversion, Cchachovsky epoxidation, and ring opening to obtain the target compound, efinaconazole. This route is short in steps, does not require separation, and does not have harsh reaction conditions.

[0031] (2) The present invention achieves a three-step total yield of efinaconazole of nearly 50% and a purity of >99% by optimizing the molar ratio of the initial raw material 1,3-difluorobenzene to S-2-chloropropionyl chloride in the synthesis route, as well as optimizing the temperature of the alkylation reaction, Cchachovsky epoxidation and one-pot ring-opening reaction.

[0032] (3) The raw materials in the present invention are easily available, the process is simple, and the reaction conditions are mild, making it suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is the NMR spectrum of compound 1 in Example 1 of the present invention; Figure 2 is the mass spectrum of compound 1 in Example 1 of the present invention; Figure 3 is the liquid phase spectrum of compound 1 in Example 1 of the present invention; Figure 4 is the NMR spectrum of compound 2 in Example 1 of the present invention; Figure 5 is the mass spectrum of compound 2 in Example 1 of the present invention; Figure 6 is the liquid phase spectrum of compound 2 in Example 1 of the present invention; Figure 7 is the nuclear magnetic spectrum of efinaconazole in Example 1 of the present invention; Figure 8 is the mass spectrum of efinaconazole in Example 1 of the present invention; Figure 9 It is the liquid phase spectrum of efinaconazole in Example 1 of the present invention. DETAILED DESCRIPTION

[0034] The present invention will be further described in detail below with reference to specific examples. The following examples are not intended to limit the present invention but are merely intended to illustrate the present invention. The experimental methods used in the following examples are generally based on conventional conditions unless otherwise specified. The materials and reagents used in the following examples are all commercially available unless otherwise specified.

[0035] Example 1 A preparation method of efinaconazole comprises the following steps: Step 1: Weigh 5.00g of 1,3-difluorobenzene and 30mL of dichloromethane into a 100mL three-necked flask. Stir the reaction mixture, cool it to 0-5°C, then add 8.76g of aluminum chloride and maintain the temperature at 0-5°C with stirring for 1 hour. Add 6.12g of S-2-chloropropionyl chloride dropwise to the reaction mixture, maintain the temperature at 0-5°C, and continue stirring for 1 hour to produce a brown liquid. Then, raise the temperature to 20-25°C and stir for 3 hours. The reaction is complete. Add 30mL of ice water to the reaction mixture, stir and wash for 0.5 hour, and then separate the phases. Add 30mL of water to the organic phase, stir and wash for 0.5 hour, and then separate the phases. The organic phase is then distilled under reduced pressure until no liquid is released, yielding 7.67g of a pale yellow oil (Compound 1) with a yield of 85.60% and a purity of 98.83%.

[0036] 1 H NMR: 1 HNMR (400MHz, CDCl3): δ=7.91-7.83(1H, m), 6.93-6.79(2H, m), 5.11(1H, dd, J = 16.0, 8.0Hz), 1.64(3H, d, J=8.0Hz).

[0037] MS: [M+H] + The theoretical value is 205.02 and the measured value is 205.22.

[0038] Among them, the NMR spectrum, mass spectrum and liquid chromatography of compound 1 are shown in Figure 1-Figure 3 .

[0039] Step 2: 1.00 g of compound 1, 10 mL of 1,4-dioxane, 1.26 g of DIPEA, and 0.65 g of 4-methylenepiperidine were weighed and added to a 100 mL three-necked flask. The reaction was stirred and heated to 55-60°C for 6 hours. Upon completion, a light yellow, transparent solution was obtained. For post-processing, the solution was concentrated under reduced pressure until no liquid remained. 20 mL of dichloromethane and 10 mL of water were added, stirred for 0.5 hour, and the phases separated. 10 mL of water was added to the organic phase, stirred and washed for 0.5 hour, and the phases separated. The organic phase was concentrated under reduced pressure until no liquid remained. The crude product was purified by silica gel column chromatography to yield 0.82 g of a light yellow solid (compound 2) with a yield of 63.56% and a purity of 99.68%.

[0040] 1H NMR: (400MHz, CDCl3): δ=7.88(1H, t, J = 12.0Hz), 6.72-6.68(1H, m), 6.51-6.45(1H, m), 5.23(1H, dd, J = 16.0, 8.0Hz), 4.83(2H, s), 3.48(4H, t, J =8.0Hz), 2.34(4H, t, J = 8.0Hz), 1.72(3H, d, J = 12.0Hz).

[0041] MS: [M+H] + The theoretical value is 266.13 and the measured value is 266.35.

[0042] Among them, the NMR spectrum, mass spectrum and liquid chromatography of compound 2 are shown in Figure 4-Figure 6 .

[0043] Step 3: Weigh 1.40 g of trimethylsulfoxide iodide, 1 H 0.45 g of -1,2,4-triazole and 10 mL of DMSO solvent were added to a 100 mL three-necked flask, the reaction was stirred and cooled to 5°C, 1.49 g of potassium tert-butoxide was added, and the reaction was stirred for 1 h. Then 1.50 g of compound 2 was added, the temperature was raised to 25°C, and stirred for 1 h; the reaction temperature was raised to 80-85°C, and the temperature was kept stirred for 5 h. The reaction was completed. 20 mL of water and 20 mL of ethyl acetate were added to the reaction solution, stirred and extracted for 0.5 h, and the phases were separated; 10 mL of water was added to the organic phase, stirred and washed for 0.5 h, and the phases were separated; the organic phase was concentrated under reduced pressure until no liquid flowed out, 10 mL of ethanol was added and stirred to dissolve a clear transparent solution, 8 mL of water was added dropwise to precipitate an off-white solid crude product; the crude product and 3 mL of ethanol were added to a 25 mL single-necked flask, stirred to dissolve, 6 mL of water was added dropwise, the temperature was lowered to 20-25°C, stirred and crystallized for 1 h, and filtered to obtain 1.77 g of a white solid (ifinaconazole) with a yield of 89.85%, a purity of 99.78%, and a specific rotation of 88.8°.

[0044] The total yield of efinaconazole in the above preparation process is 48.89%.

[0045] 1 H NMR: 1HNMR (400MHz, CDCl3): δ=8.02(1H, s), 7.78(1H, s), 7.55-7.47(1H,m), 6.82-6.70(2H, m), 5.44(1H, s), 4.91-4.78(2H, dd, J = 32, 20Hz), 4.64(2H,s), 2.96-2.88(1H, m), 2.74-2.66(2H, m), 2.41-2.15(6H, m), 0.96(3H, d, J =12Hz).

[0046] MS: [M+H] + The theoretical value is 349.18 and the measured value is 349.74.

[0047] Example 2 A preparation method of efinaconazole comprises the following steps: Step 1: Weigh 15.00g of 1,3-difluorobenzene and 60mL of dichloromethane into a 250mL three-necked flask. Stir the reaction mixture, cool to 10-15°C, then add 52.56g of aluminum chloride and maintain the temperature at 10-15°C with stirring for 1 hour. Add 18.36g of S-2-chloropropionyl chloride dropwise to the reaction mixture, maintain the temperature at 10-15°C with stirring for 1 hour until a brown liquid forms. Raise the temperature to 35-40°C and stir for 2 hours to complete the reaction. Wash the organic phase with 60mL of ice water and separate the phases. Wash the organic phase with 60mL of water and separate the phases. Evaporate under reduced pressure until no liquid remains, yielding 25.09g of a pale yellow oil (Compound 1) with a yield of 93.30% and a purity of 99.53%.

[0048] Step 2: 5.00g of compound 1, 50mL of ethanol, and 3.56g of 4-methylenepiperidine were weighed and stirred in a 100mL three-necked flask. The reaction mixture was cooled to 5-10°C, and a solution of 2.58g of sodium tert-butoxide (diluted with 5mL of ethanol) in ethanol was added dropwise. The reaction was incubated for 1h, resulting in a light yellow, transparent solution. For post-processing, the solution was concentrated under reduced pressure until no liquid emanated. 35mL of dichloromethane and 20mL of water were added, stirred for 0.5h, and the phases separated. 15mL of water was added to the organic phase, stirred and washed for 0.5h, and the phases separated. The organic phase was concentrated under reduced pressure until no liquid emanated. The solution was purified by column chromatography to obtain compound 2 as a light yellow solid (4.49g), with a yield of 69.29% and a purity of 99.87%.

[0049] Step 3: Weigh 1.89 g of trimethylsulfoxide iodide, 1 H0.59 g of -1,2,4-triazole and 10 mL of DMF were added to a 100 mL three-necked flask, and the reaction was stirred and cooled to 5°C; then 1.58 g of sodium tert-butoxide was added and stirred for 1.5 h; finally, 2.00 g of compound 2 was added, the temperature was raised to 25°C, and the reaction was stirred for 1 h; the reaction temperature was raised to 80-90°C, and the temperature was kept stirred for 5 h. The reaction was completed. 20 mL of water and 30 mL of dichloromethane were added to the reaction solution, stirred and extracted for 0.5 h, and the phases were separated; 20 mL of water was added to the organic phase, stirred and washed for 0.5 h, and the phases were separated; the organic phase was concentrated under reduced pressure until no liquid flowed out, 10 mL of isopropanol was added, and 3 mL of water was added dropwise with stirring to precipitate an off-white solid crude product. The crude product and 5 mL of ethanol were added to a 25 mL single-necked flask, stirred to dissolve, 9 mL of water was added dropwise, the temperature was lowered to 10-15°C, stirred and crystallized for 1 h, and filtered to obtain 2.21 g of a white solid (ifinaconazole) with a yield of 84.03% and a purity of 99.86%.

[0050] The total yield of efinaconazole in the above preparation process is 54.32%.

[0051] Example 3 A preparation method of efinaconazole comprises the following steps: Step 1: Weigh 8.33g of 1,3-difluorobenzene and 40mL of dichloromethane into a 250mL three-necked flask. Stir the reaction mixture and cool to -10-0°C. Then add 19.38g of aluminum chloride and stir at -10-0°C for 1 hour. Add 12.12g of S-2-chloropropionyl chloride dropwise to the reaction mixture and stir at -10-0°C for 1 hour to produce a brown liquid. Raise the temperature to 15-20°C and stir for 6 hours to complete the reaction. Wash the organic phase with 40mL of ice water and separate the phases. Wash the organic phase with 30mL of water and separate the phases. Distill the organic phase under reduced pressure until no liquid remains, yielding 13.66g of a pale yellow oil (Compound 1) with a yield of 91.43% and a purity of 98.57%.

[0052] Step 2: 3.00g of compound 1, 20ml of ethanol, and 5.59g of 4-methylenepiperidine were weighed and added to a 100ml three-necked flask. The reaction mixture was heated to 75-80°C and stirred for 8 hours. The reaction was completed, resulting in a light yellow transparent solution. For post-processing, the reaction solution was concentrated under reduced pressure until no liquid emanated. 15ml of dichloromethane and 10ml of water were added, stirred, and extracted for 1 hour. The phases were separated. 10ml of water was added to the organic phase, stirred and washed for 0.5 hour, and the phases were separated. The organic phase was concentrated under reduced pressure until no liquid emanated. The solution was purified by column chromatography to obtain 2.53g of a light yellow solid (compound 2) with a yield of 65.03% and a purity of 99.96%.

[0053] Step 3: Weigh 1.62g of trimethylsulfoxide iodide, 1H 0.51 g of 1,2,4-triazole and 5 mL of DMF were added to a 50 mL three-necked flask. The reaction mixture was stirred and cooled to 0-5°C. 1.36 g of sodium tert-butoxide was added and stirred for 1 hour. Then, 1.50 g of compound 2 was added, and the temperature was raised to 90-95°C and stirred for 7 hours. The reaction was complete. 12 mL of water and 20 mL of dichloromethane were added to the reaction mixture, and the mixture was extracted with stirring for 0.5 hour. The phases were separated. 10 mL of water was added to the organic phase, and the mixture was washed with stirring for 0.5 hour. The phases were separated. The organic phase was concentrated under reduced pressure until no liquid flowed out. 7 mL of isopropanol was added with stirring, and 3 mL of water was added dropwise with stirring to precipitate an off-white crude solid. The crude product and 2 mL of ethanol were added to a 25 mL single-necked flask, stirred to dissolve, and 3 mL of water was added dropwise. The temperature was lowered to 0-5°C and stirred for 1 hour to crystallize. Filtration afforded 1.60 g of a white solid (efinaconazole) with a yield of 81.21% and a purity of 99.71%.

[0054] The total yield of efinaconazole in the above preparation process is 48.28%.

[0055] Example 4 This example differs from Example 1 only in that 5.55 g of S-2-chloropropionyl chloride is used in Step 1 (the molar ratio of 1,3-difluorobenzene to S-2-chloropropionyl chloride is 1:1). 6.32 g of a yellow oil (Compound 1) is obtained, with a yield of 70.45% and a purity of 92.68%. The total yield is 40.23%.

[0056] Example 5 This example differs from Example 1 only in that the reaction temperature in Step 2 is different, specifically 30-40°C. 0.41 g of a yellow solid (Compound 2) is obtained, with a yield of 31.78% and a purity of 98.64%. The total yield is 24.44%.

[0057] Example 6 This example differs from Example 1 only in that the reaction temperature in step 3 is different, specifically 100-105°C. 0.93 g of a white solid (efinaconazole) is obtained, with a yield of 47.21% and a purity of 97.11%. The total yield is 25.68%.

[0058] The above detailed description is a specific description of one feasible embodiment of the present invention. This embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not depart from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for preparing efinaconazole, characterized in that: The synthetic route is as follows: The specific steps include: (1) 1,3-difluorobenzene, S-2-chloropropionyl chloride and a catalyst were added to an organic solvent A and mixed evenly, and the temperature was raised to react to obtain compound 1; (2) Compound 1 and 4-methylenepiperidine are added to organic solvent B to react to obtain compound 2; (3) Compound 2, trimethylsulfoxide iodide, base and 1 H -1,2,4-triazole is added into the organic solvent C and mixed, and the reaction is performed to obtain the efinaconazole.

2. The preparation method according to claim 1, characterized in that The molar ratio of 1,3-difluorobenzene, S-2-chloropropionyl chloride and catalyst in step (1) is 1:1-1.5:1.3-2.7; and / or the molar ratio of compound 1 to 4-methylenepiperidine in step (2) is 1:1.3-4; and / or the compound 2, trimethylsulfoxide iodide, 1 in step (3) H The molar ratio of 1,2,4-triazole to the base is 1:1.2-1.4:1.2-1.4:2.3-2.

7.

3. The preparation method according to claim 1, characterized in that The catalyst in step (1) is selected from any one of aluminum chloride, ferric chloride, zinc chloride, H2SO4 and H3PO3; preferably aluminum chloride; And / or the base in step (3) is selected from triethylamine, N , N - any one of diisopropylethylamine, tripropylamine, triethylenediamine, sodium tert-butoxide and potassium tert-butoxide; preferably N , N -Diisopropylethylamine.

4. The preparation method according to claim 1, characterized in that In step (1), the mixing temperature is 0°C-20°C, the mixing time is 1.5h-2.5h, the reaction temperature is 20°C-40°C, and the reaction time is 2h-6h; And / or the reaction temperature in step (2) is 0°C-80°C, and the reaction time is 1h-8h; And / or in step (3), the mixing temperature is 0°C-30°C, the mixing time is 1h-2.5h, the reaction temperature is 80°C-100°C, and the reaction time is 5h-7h.

5. The preparation method according to claim 4, characterized in that The mixing described in step (1) is specifically: First, add 1,3-difluorobenzene to organic solvent A, cool to 0°C-20°C, then add the catalyst, and stir at this temperature for 0.5-1h; then add S-2-chloropropionyl chloride and continue stirring at this temperature for 0.5-1h to complete the mixing.

6. The preparation method according to claim 1, characterized in that The mixing process in step (2) also includes adding a base; the base is selected from triethylamine, N , N - any one of diisopropylethylamine, tripropylamine, triethylenediamine, sodium tert-butoxide and potassium tert-butoxide; preferably N , N -Diisopropylethylamine.

7. The preparation method according to claim 6, characterized in that The molar ratio of the base to compound 1 is 1-2:

1.

8. The preparation method according to claim 1, characterized in that The organic solvent A, organic solvent B and organic solvent C are independently selected from one or more of aromatic hydrocarbons, aliphatic hydrocarbons, halogenated hydrocarbons, ethers and amides.

9. The preparation method according to claim 8, characterized in that The organic solvent A is any one of dichloromethane, chloroform, tetrahydrofuran and 1,4-dioxane; And / or the organic solvent B is tetrahydrofuran, 1,4-dioxane, N , N - Any one of dimethylformamide, acetonitrile and ethanol; And / or the organic solvent C is N , N -dimethylformamide, N,N - Any one of dimethylacetamide, dimethyl sulfoxide, 1,4-dioxane and tetrahydrofuran.

10. The preparation method according to claim 1, characterized in that After the reaction in step (1), the process further comprises the steps of washing with ice water, separating the phases, washing the organic phase with water again, separating the phases, and distilling the organic phase under reduced pressure; And / or after the reaction in step (2), the method further comprises the steps of concentration, extraction with dichloromethane and water, washing with water, concentration of the organic phase, and purification by column chromatography; And / or step (3) comprises the steps of adding dichloromethane and water for extraction, washing with water, concentrating the organic phase and performing secondary crystallization after the reaction.

Images