Asymmetric synthesis method of efinaconazole intermediate

Abstract

The invention discloses an asymmetric synthesis method of an efinaconazole intermediate, which comprises the following steps: adding auxiliary materials and water into a reaction bottle, then adding hydrogen peroxide, controlling a certain temperature to dropwise add an organic solution of a substrate I and a catalyst II into the reaction bottle, controlling a certain temperature to carry out a heat preservation reaction, and carrying out post-treatment to obtain a product III. The target product is obtained through the proper chiral catalyst, and the method is mild in condition and high in chiral selectivity.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and in particular relates to a method for synthesizing an efinaconazole intermediate by asymmetric catalysis using a chiral catalyst. Background Art

[0002] Efinaconazole (trade name: Jublia) has the chemical name (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, and its structural formula is as follows:

[0003]

[0004] Efinaconazole is a topical triazole antifungal drug that is applied as a coating and does not cause systemic adverse reactions or acute liver damage. Efinaconazole was developed by Canadian DOW Pharmaceuticals and is used for the topical treatment of toenail tinea caused by Trichophyton rubrum and Trichophyton mentagrophytes. The FDA has approved the marketing of 10% topical solution of Efinaconazole on June 6, 2014 for the treatment of tinea pedis.

[0005] The key to the synthesis of efinaconazole is the construction of two chiral centers. The existing synthesis methods of efinaconazole are also mainly carried out around the synthesis of these two chiral centers. The main synthesis methods are as follows:

[0006] 1. Synthesis of efinaconazole using 2-chloro-2,4-difluoroacetophenone as raw material:

[0007] This route uses 2-chloro-2,4-difluoroacetophenone as the starting material. Under the action of a chiral phosphorus ligand, Gd(HMDS)3 is used to catalyze the addition reaction of ketone and TMS-CN, and then DIBAL-H is used to reduce the cyano group to an aldehyde group; then, Grignard addition reactions are performed in sequence, TMS is removed using an aqueous NaOH solution, and a substitution reaction with 1,2,4-triazole is performed to obtain the key intermediate (2R,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol; the key intermediate is epoxidized under the action of MsCl and NaOH to obtain an epoxide with an ee value of 99.8%, and finally, the epoxide undergoes a ring-opening reaction with 4-methylenepiperidine to obtain efinaconazole, and the total yield of this route is 40%.

[0008]

[0009] 2. Synthesis of efinaconazole using R-methyl lactate as raw material:

[0010] In this route, R-methyl lactate is used as a starting material to react with morpholine to form an amide, which is then reacted with an excess of dihydropyran in the presence of methanesulfonic acid to form (2R)-4-(2-(tetrahydropyran-2-yl)-hydroxypropionyl)morpholine, with a two-step yield of 78%. The product is then reacted with an organomagnesium reagent, 2,4-difluorophenylmagnesium bromide, to form a Grignard reaction, with a yield of 81%. Then, trimethylsulfuryl iodide is added to a THF solution of sodium tert-butoxide to form a sulfur ylide, and the ketone is converted into an epoxide through a sulfur ylide epoxidation reaction. Subsequently, the product is introduced into the reaction mixture. The triazole anion formed by deprotonation of sodium tert-butoxide is used to alkaline open the epoxide to obtain a monoprotected diol. After the THP group is cleaved by methanesulfonic acid, the methanesulfonate of the chiral diol is obtained. The yield of the four-step reaction is 51%, and the purity reaches 99% after recrystallization. The chiral diol is epoxidized under the action of MsCl and NaOH to obtain the epoxide with a yield of 78% and an ee value of 99.8%. Finally, 4-methylenepiperidine is used for ring-opening addition to obtain efinaconazole with a yield of 87%. The total yield of this route is 22%.

[0011]

[0012] 3. Synthesis of efinaconazole using methyl 2-bromoacetate as raw material:

[0013] This route uses methyl 2-bromoacetate as a starting material, and sequentially reacts with 1,2,4-triazole to obtain methyl 2-(1H-1,2,4-triazol-1-yl)acetate through a substitution reaction, and then reacts with morpholine through an amidation reaction, reacts with 2,4-difluorophenylmagnesium bromide through a Grignard addition reaction, and reacts with nitroethane through an addition reaction to obtain a racemic mixture of nitro compounds, and then undergoes chiral resolution to obtain the desired chiral alcohol compound, and then reduces the nitro group, and finally undergoes a substitution reaction with 1,5-dibromo-3-methylenepentane to obtain efinaconazole.

[0014]

[0015] 4. Synthesis of efinaconazole using alanine as raw material:

[0016] This route uses alanine as a starting material, and sequentially undergoes substitution reactions with di-tert-butyl dicarbonate and N-methyl-N-methoxy hydrochloride, and then undergoes a Grignard reaction with 2,4-difluorobromobenzene, and then undergoes an epoxidation reaction to obtain ((1R)-1-(2-(2-,2,4-difluorophenyl)oxirane-2-yl)ethyl)carbamic acid tert-butyl ester, and then undergoes a ring-opening reaction and a deprotection reaction with 1,2,4-triazole to obtain (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, and finally undergoes a substitution reaction with 1,5-dibromo-3-methylenepentane to obtain efinaconazole.

[0017]

[0018] In summary, in order to obtain two chiral centers, we either need to construct them separately through chiral synthesis methods (synthetic route 1); or we need to introduce a chiral intermediate through the raw materials, and then use the chiral synthesis method to construct another chiral center in the process (synthetic routes 2 and 4); or we need to obtain them through chiral separation methods (synthetic route 3). Relatively speaking, the processes are cumbersome, some process conditions are harsh, and the overall yield is not high.

[0019] Therefore, if we can find a method to construct two chiral centers at one time to obtain chiral epoxides, the process steps will be greatly reduced, which is very beneficial to industrial production. Summary of the invention

[0020] The purpose of the present invention is to overcome the problems of complicated process conditions, low material yield and high production cost of the existing asymmetric synthesis process of efinaconazole intermediates, and provide a method for asymmetric catalytic synthesis of efinaconazole intermediates using a chiral catalyst. The molar yield of the method can reach more than 95%, and the chiral purity can reach more than 98%ee. In addition, the reaction conditions of the reaction method are mild, and the reaction temperature is between -20 and 40°C, which is very conducive to implementation in industrial production.

[0021] The technical solution of the present invention is as follows:

[0022] An asymmetric synthesis method of an efinaconazole intermediate, wherein substrate I is subjected to hydrogen peroxide epoxidation reaction under the catalysis of catalyst II to obtain product III, and the chemical reaction equation is as follows:

[0023]

[0024] The structure of the catalyst II is shown below:

[0025]

[0026] An asymmetric synthesis method of an efinaconazole intermediate comprises the following steps:

[0027] 1) Add water, auxiliary materials and hydrogen peroxide into the reaction bottle and control the reaction system at a certain temperature (-20℃~40℃);

[0028] 2) Add the solution of substrate I and catalyst II to the reaction flask, and stir at room temperature for 6 to 24 hours;

[0029] 3) After the reaction is completed, the product III is obtained by extraction, washing, evaporation and column chromatography of the distillation residue.

[0030] The auxiliary materials in step 1) are potassium carbonate and EDTA; potassium carbonate increases the alkalinity of the reaction system, and EDTA serves as a ligand of the catalyst;

[0031] The molar ratio of potassium carbonate, EDTA and substrate I is 3.2-2.8:0.0008-0.0006:1;

[0032] The molar ratio of hydrogen peroxide to substrate I is 4.2 to 3.8:1;

[0033] In step 1), the reaction temperature is preferably controlled at 0°C to 20°C.

[0034] The structure of catalyst II in step 2) is shown below:

[0035]

[0036] In step 2), the molar ratio of catalyst II to substrate I is between 0.1:1 and 0.3:1;

[0037] Step 2) The solution of substrate I and catalyst II is a solution obtained by dissolving substrate I and catalyst II in an organic solvent, wherein the organic solvent is selected from one or a mixture of the following: acetonitrile, ethanol, and dichloromethane;

[0038] The organic solvent is a mixed solvent of acetonitrile, ethanol and dichloromethane in a volume ratio of 1:1:2.

[0039] The present invention provides a novel method for preparing a key precursor of efinaconazole. After the efinaconazole intermediate III is prepared, efinaconazole can be prepared by the following route:

[0040]

[0041] Beneficial effects:

[0042] The present invention selects an effective catalyst, so that the steps of obtaining the chiral intermediate are greatly reduced. The molar yield of the method is at most above 95%, and the chiral purity can reach at most above 98%ee. In addition, the reaction conditions of the reaction method are mild, and the reaction temperature is between -20 and 40°C, which is very conducive to implementation in industrial production. DETAILED DESCRIPTION

[0043] In order to better understand the present invention, the following will be described in detail through specific examples. It should be noted that the following examples are not intended to limit the scope of the present invention. Obviously, ordinary technicians in the field can make various modifications and changes to the present invention within the scope of the present invention based on the description herein, and these modifications and changes are also included in the scope of the present invention.

[0044] The structure of the catalyst II used in the following examples is shown below:

[0045]

[0046] The catalyst synthesis method is described in Journal of Organic Chemistry, 2001, 66, 521.

[0047] The substrate I used in the following examples was prepared by the following method:

[0048]

[0049] Add 2-chloro-2',4'-difluoroacetophenone (10g, 52.5mmol) and anhydrous toluene (25ml) to the reaction flask, cool to 0-5°C, and slowly drop EtMgBr (3M ether solution) (21ml, 62.9mmol). After the addition, continue the reaction for 2h. After the reaction, pour it into 1M HCl (50ml) solution and stir for 30min. Let stand for stratification, wash the combined organic phase once with brine (50ml), dry with Na2SO4 and concentrate under reduced pressure. Yield: 11.6g. The crude product can be used in the next step without additional purification.

[0050]

[0051] To a solution of the above (6.6 g, 29.9 mmol) in toluene (30 ml) was added H2SO4 (50%) (5.34 g, 4.11 ml, 29.9 mmol). After addition, the reaction mixture was heated to reflux and water was distilled using a Dean-Stark apparatus. After the reaction was complete, the reaction mixture was cooled to room temperature. Toluene (50 ml) was added, washed three times with water (50 ml each time), then washed once with brine, dried over Na2SO4, and then the solvent was evaporated. Yield: 5.83 g. The crude product was used in the next step without additional purification.

[0052] H NMR (CDC13, 400MHz) & 7.26-7.14 (1H, m); 6.85-6.75 (2H, m); 5.88-5.83 (1H, dd, J = 7.2, J = 6.8Hz); 4.42 (2H, s); 1.88 (3H, d, J = 6.8Hz).

[0053] Example 1

[0054]

[0055] Add 15ml of water, potassium carbonate (4.15g, 30.0mmol), EDTA (0.002g, 0.007mmol), and hydrogen peroxide (30%, 4ml, 40.0mmol) to the reaction flask. Add 5ml of acetonitrile, 5ml of ethanol, and 10ml of dichloromethane to the prepared beaker, then add substrate I (2.03g, 10.0mmol) and catalyst II (0.77g, 3.0mmol) to the beaker and stir to dissolve. Lower the temperature in the reaction flask to 0℃. When the temperature reaches, add the mixed solution in the beaker to the reaction flask. After the addition is completed, control the temperature and stir for 16 hours until the reaction is complete. Extract the reaction solution with n-hexane (15ml*3), combine the n-hexane phases, wash with 1M sodium sulfite aqueous solution, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, separate the crude product by column chromatography, and spin-dry to obtain product III (2.08g. Yield 95%, 98% ee).

[0056] 1H-NMR:1.66(3H,d,J=5.6Hz),3.21(1H,q,J=5.6Hz),4.43-4.50(1H,m),4.87 -4.94(1H,m),6.71-6.85(2H,m),6.98-7.09(1H,m),7.83(1H,s),8.00(1H,s).

[0057] Example 2

[0058] Add 15ml of water, potassium carbonate (4.42g, 32.0mmol), EDTA (0.002g, 0.007mmol), and hydrogen peroxide (30%, 3.8ml, 38.0mmol) to the reaction flask. Add 5ml of acetonitrile, 5ml of ethanol, and 10ml of dichloromethane to the prepared beaker, then add substrate I (2.03g, 10.0mmol) and catalyst II (0.77g, 3.0mmol) to the beaker and stir to dissolve. Lower the temperature in the reaction flask to 0℃. When the temperature reaches, add the mixed solution in the beaker to the reaction flask. After the addition is completed, control the temperature and stir for 15 hours until the reaction is complete. Extract the reaction solution with n-hexane (15ml*3), combine the n-hexane phases, wash with 1M sodium sulfite aqueous solution, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, separate the crude product by column chromatography, and spin-dry to obtain product III (2.10g. Yield 96%, 98% ee).

[0059] Example 3

[0060] Add 15ml of water, potassium carbonate (3.87g, 28.0mmol), EDTA (0.002g, 0.007mmol), and hydrogen peroxide (30%, 4.2ml, 42.0mmol) to the reaction flask. Add 5ml of acetonitrile, 5ml of ethanol, and 10ml of dichloromethane to the prepared beaker, then add substrate I (2.03g, 10.0mmol) and catalyst II (0.77g, 3.0mmol) to the beaker and stir to dissolve. Lower the temperature in the reaction flask to 0℃. When the temperature reaches, add the mixed solution in the beaker to the reaction flask. After the addition is completed, control the temperature and stir for 16 hours until the reaction is complete. Extract the reaction solution with n-hexane (15ml*3), combine the n-hexane phases, wash with 1M sodium sulfite aqueous solution, dry with anhydrous sodium sulfate, filter, spin-dry the filtrate, separate the crude product by column chromatography, and spin-dry to obtain product III (2.06g. Yield 94%, 98% ee).

Claims

1. An asymmetric synthesis method of an efinaconazole intermediate, characterized in that: Under the catalysis of catalyst II, substrate I undergoes hydrogen peroxide epoxidation reaction to obtain product III. The chemical reaction equation is as follows: The structure of the catalyst II is shown below:

2. The asymmetric synthesis method of an efinaconazole intermediate according to claim 1, characterized in that: The molar ratio of catalyst II to substrate I is 0.1-0.3:

1.

3. The asymmetric synthesis method of an efinaconazole intermediate according to claim 1, characterized in that: Catalyst II and substrate I are dissolved in an organic solvent and then added dropwise into a reaction bottle containing hydrogen peroxide.

4. The asymmetric synthesis method of an efinaconazole intermediate according to claim 1, characterized in that: The epoxidation reaction temperature is -20°C to 40°C.

5. The asymmetric synthesis method of an efinaconazole intermediate according to claim 1, characterized in that: The epoxidation reaction time is 6 to 24 hours.

6. The asymmetric synthesis method of an efinaconazole intermediate according to claim 1, characterized in that: The hydrogen peroxide has a concentration of 20 to 30%.

7. The asymmetric synthesis method of an efinaconazole intermediate according to claim 1, characterized in that: The molar ratio of hydrogen peroxide to substrate I is 4.2-3.8:

1.

8. The asymmetric synthesis method of an efinaconazole intermediate according to claim 3, characterized in that: The organic solvent is selected from the following one or a mixture of several: acetonitrile, ethanol, and dichloromethane.

9. The asymmetric synthesis method of an efinaconazole intermediate according to claim 7, characterized in that: The organic solvent is a mixed solvent of acetonitrile, ethanol and dichloromethane in a volume ratio of 1:1:

2.

10. The asymmetric synthesis method of an efinaconazole intermediate according to claim 3, characterized in that: The reaction bottle of the hydrogen peroxide also includes auxiliary materials potassium carbonate and EDTA.

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