A method for preparing antifungal drug

Abstract

The invention discloses a method for preparing an antifungal drug, in particular to a method for preparing ortaconia azole. The method can efficiently obtain ortaconia azole through asymmetric synthesis, and has the advantages of being environmentally friendly, having a short route, high yield, and low cost.

Description

Field of the Invention

[0001] The invention belongs to the field of chemical medicines, and in particular relates to a new preparation method of an antifungal drug. Background Art

[0002] Oteseconazole is an oral antifungal developed by Mycovia Pharmaceuticals. It is the first FDA-approved drug for the treatment of recurrent vulvovaginal candidiasis (RVVC). Oteseconazole is used to reduce the recurrence rate of recurrent vulvovaginal candidiasis (RVVC) in women of no reproductive potential. It effectively binds to and inhibits CYP51 (K d , <39nM); Orteconazole is an azole metalloenzyme inhibitor that targets fungal sterol 14α-demethylase (CYP51), an enzyme that catalyzes an early step in the biosynthetic pathway of ergosterol, a sterol required for fungal cell membrane formation and integrity. Inhibition of CYP51 leads to the accumulation of 14-methylated sterols, some of which are toxic to fungi. By containing a tetrazole metal-binding group, orteconazole has a lower affinity for human CYP enzymes and has no significant effect.

[0003] Recurrent vulvovaginal candidiasis (RVVC), also known as chronic yeast infection, is a disease distinct from vulvovaginal candidiasis (VVC) and is defined as three or more acute episodes of symptomatic yeast infection per year, with primary symptoms including vaginal itching, burning, irritation, and inflammation. Some women may experience abnormal vaginal discharge, dyspareunia, or painful urination, causing varying but often severe discomfort and pain. Nearly 75% of adult women will have at least one yeast infection in their lifetime, and about half of these will have recurring infections. Of these women, up to 9% will develop RVVC. RVVC is a chronic infectious disease that affects nearly 138 million women worldwide each year, including 6 million women in the United States alone, and approximately 29 million RVVC patients in China.

[0004] The approval of orteconazole was based on positive results from three Phase 3 trials that included 875 patients at 232 sites in 11 countries. In one of the clinical studies, 93.3% of women with RVVC treated with orteconazole and 96.1% of women had no recurrence during the 48-week maintenance period, compared with 57.2% and 60.6%, respectively, for women receiving placebo (p<0.001). In another clinical study, 89.7% of women with RVVC treated with orteconazole cleared their initial yeast infection and had no recurrence during the 50-week maintenance period, compared with 57.1% of women with RVVC treated with fluconazole and placebo (p<0.001).

[0005] The Chinese chemical name of Oteconazole: (R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazolyl-1-yl)-1-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-2-propanol, molecular formula: C 23 H 16 F7N5O2, molecular weight: 527.39, CAS registration number: 1340593-59-0, its chemical structure is as follows:

[0006]

[0007] Prior art document patent CN201680061980 reports the synthesis route 1 of oteconazole as follows:

[0008]

[0009] Prior art document CN201180030668 reports the synthesis route 2 of ortaconia as follows:

[0010]

[0011] The above-mentioned oteconazole synthesis route 1 is not only long, but also difficult to implement. Step 2 involves ultra-low temperature reaction, step 3 involves the use of highly toxic nitromethane, step 4 involves pressurized hydrogenation reaction, step 5 involves the use of explosive and dangerous goods azidotrimethylsilane, step 6 involves the use of expensive catalyst PD (DPPF) Cl2, and the overall yield is low, which has little significance for industrialization.

[0012] In the above-mentioned Otaconazole synthesis route 2, step 1 uses diazomethane, a carcinogenic and explosive hazardous substance, and step 5 obtains Otaconazole by splitting. Not only is the route long and the yield low, but the industrial significance is also not great.

[0013] In order to alleviate the accessibility problem of ortaconia, the present invention provides a new method for preparing ortaconia, which can obtain ortaconia of a single configuration with high efficiency through asymmetric synthesis. The new method has not been reported in the prior art. Although it also involves low-temperature reaction, it has the advantages of being environmentally friendly, having a short route, high yield and low cost. Summary of the invention

[0014] The present invention provides a method for preparing an antifungal drug, the method comprising:

[0015]

[0016] Step 1: (2,2,2-trifluoroethoxy)phenylboronic acid pinacol ester (compound of formula a) and compound of formula b are subjected to Suzuki coupling reaction to obtain ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (compound of formula c);

[0017] Step 2, coupling reaction of ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (compound of formula c) with compound of formula d to obtain 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-ethanone (compound of formula e);

[0018] Step 3, 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-ethanone (compound of formula e) and compound of formula f are subjected to an asymmetric synthesis reaction to obtain ortaconia;

[0019] in

[0020] In the compound of formula b, X1 is selected from I, Br and Cl, preferably Br;

[0021] In the compound of formula d, X2 is selected from I, Br and Cl, preferably Br;

[0022] In the compound of formula f, X3 is selected from I, Br and Cl, preferably Br.

[0023] The biggest feature of the present invention is that a new synthesis route of orteconazole is designed, which is different from the new synthesis route of orteconazole reported in the prior art documents CN201680061980 and CN201180030668. The present invention prepares orteconazole through only three steps of reaction, without using highly toxic and explosive materials, with a short route, high yield, and obvious cost and environmental advantages.

[0024] In the present invention, X1 in the compound of formula b is selected from I, Br and Cl, among which the chlorinated structure has weaker activity and lower reaction yield; the iodinated structure has the strongest activity, but the cost is higher; and the brominated structure 2-(5-bromopyridin-2-yl)-2,2-difluoroacetic acid ethyl ester not only has high reaction activity, but is also cheap and easy to purchase, has fewer reaction by-products and higher yield, and is therefore preferred.

[0025] In the present invention, X2 in the compound of formula d is selected from I, Br and Cl, among which the chlorinated structure has weaker activity and lower reaction yield; the iodinated structure has the strongest activity, but the cost is higher; and the brominated structure 2,4-difluorobromobenzene not only has high reaction activity, but is also cheap and easy to purchase, has fewer reaction by-products and higher yield, and is therefore preferred.

[0026] In the present invention, X3 in the compound of formula f is selected from I, Br and Cl, among which the chlorinated structure has weaker activity and lower reaction yield; the iodinated structure has the strongest activity, but the cost is higher; and the brominated structure 1-(2-bromoethyl)-1H-tetrazole not only has high reaction activity, but is also cheap and easy to purchase, has fewer reaction by-products and higher yield, and is therefore preferred.

[0027] The catalyst for the Suzuki coupling reaction in step 1 of the present invention is a palladium catalyst and an inorganic base catalyst, wherein the palladium catalyst is selected from tetrakis(triphenylphosphine)palladium(0), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(tricyclohexylphosphine)palladium(0) or bis(tri-O-toluenephosphine)palladium(0), preferably tetrakis(triphenylphosphine)palladium(0); the inorganic base is selected from cesium carbonate, potassium carbonate, sodium carbonate or lithium carbonate, preferably cesium carbonate or potassium carbonate with greater alkalinity, because the water content in the solvent system is relatively low, the inorganic base catalyst needs to be crushed or directly fed as a powdered material to increase the conversion efficiency of the heterogeneous reaction.

[0028] In the step 1 of the present invention, the compound of formula b in the Suzuki coupling reaction contains an ethyl ester structure. To avoid ester hydrolysis, only a trace amount of water is added to ensure that the reaction proceeds smoothly and to avoid the generation of ester hydrolysis byproducts. In addition, to avoid the generation of ester exchange byproducts of the compound of formula b, the solvent selection needs to avoid the use of other alcohol solvents other than ethanol.

[0029] In the step 2 of the present invention, the Suzuki coupling reaction is carried out under the catalysis of organic lithium at low temperature, and the organic lithium catalyst is selected from n-butyl lithium, tert-butyl lithium, sec-butyl lithium, n-pentyl lithium, and neopentyl lithium, among which n-butyl lithium has the strongest activity and lower cost, and is preferred.

[0030] In the coupling reaction of step 2 of the present invention, the molar feed ratio of the compound of formula c to the compound of formula d is 1:1-1.3:1-1.3, preferably 1:1.1-1.2:1.1-1.2, wherein the main material compound of formula d is appropriately excessive, which can make the compound of formula c react completely, reduce the generation of by-products, and the excess material can be easily removed by post-treatment.

[0031] The most important feature of this patent is that a single-configuration oteconazole is efficiently prepared by an asymmetric synthesis reaction in step 3 of the present invention, wherein the asymmetric reaction catalyst is selected from (R)-1,1'-binaphthol or 3,3'-disubstituted aryl binaphthol, wherein (R)-1,1'-binaphthol has stronger selectivity, better reaction effect, and low price, and is the first choice. In addition, this reaction requires the addition of Grignard reagent isopropylmagnesium chloride lithium chloride to catalyze the coupling reaction, and the catalyst is also a Lewis acid; isopropylmagnesium chloride lithium chloride first activates the formula f compound, and then under the catalysis of the asymmetric synthesis catalyst (R)-1,1'-binaphthol, it undergoes a coupling reaction with the carbonyl group in 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridine-2-yl)-ethanone (formula e compound) to generate an absolutely single R-configuration oteconazole, which is the biggest highlight of the present invention.

[0032] In the asymmetric synthesis reaction of step 3 of the present invention, any excess of the main material will cause the generation of by-products. A slightly excess of isopropyl magnesium chloride and lithium chloride catalyst is beneficial to the reaction, and the asymmetric reaction catalyst (R)-1,1'-binaphthol only needs 1 / 10 equivalent of the main material. Excess not only increases the cost, but also leads to an increase in by-products. After optimization, it is finally confirmed that the molar feed ratio of the compound of formula e, the compound of formula f, isopropyl magnesium chloride and lithium chloride and the asymmetric reaction catalyst (R)-1,1'-binaphthol in the material is 1:0.9-1.1:1.0-1.5:0.08-0.12, preferably 1:0.95-1.05:1.1-1.3:0.09-0.11, which can ensure the smooth progress of the reaction, while controlling the by-products to a minimum, and obtaining an absolutely single R-configuration oteconazole with a low cost.

[0033] The present invention provides a new synthesis method of ortaconia azole with the advantages of short route, high yield, environmental friendliness, etc., which has obvious advantages over the prior art documents and can benefit from them. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 :The synthetic route of the present invention 2024-12-7 2023106568953 Specific implementation methods

[0035] The technical solutions in the embodiments of the present invention will be described in detail below in conjunction with the embodiments of the present invention. However, the following embodiments are only used to understand the present invention and cannot limit the present invention. The present invention can be implemented in a variety of different ways as defined and covered by the claims.

[0036] The novel synthesis method of ortaconia and the advantages of the method will be further described below in conjunction with Examples 1 and 10 of the present invention.

[0037] Example 1: Synthesis of ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (compound of formula C)

[0038]

[0039] Under nitrogen protection, the compound p-(2,2,2-trifluoroethoxy)phenylboronic acid pinacol ester (Formula a, 151 g, 0.5 mol), ethyl 2-(5-bromopyridin-2-yl)-2,2-difluoroacetate (Formula bI, 140 g, 0.5 mol), tetrakis(triphenylphosphine)palladium(0) (28.9 g, 25 mmol), powdered anhydrous potassium carbonate (79.5 g, 0.75 mol), 1 L of toluene, 200 ml of anhydrous ethanol and 5 ml of water were placed in a three-necked flask, refluxed for 12 h, cooled, 1.2 L of water and 500 ml of ethyl acetate were added, stirred and separated, the organic phase was washed with 1 L of water, the organic phase was dried, and concentrated under reduced pressure to about 1 / 5 of the volume, the residue was cooled, filtered, and the filter cake was dried to obtain the compound of formula c (159 g, yield 85%), Ms m / z 376.1 (M+1). 1 H NMR (300MHz d6-DMSO): 1.23 (t, 3H), 4.18 (q, 2H), 4.50 (m, 2H), 7.01 (d, 2H), 7.45 (d, 1H), 7.73 (d, 2H), 7.95 (d, 1H), 8.79 (d, 1H).

[0040] Example 2: Synthesis of ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (compound of formula C)

[0041]

[0042] Under nitrogen protection, compound p-(2,2,2-trifluoroethoxy)phenylboronic acid pinacol ester (Formula a, 75.5 g, 0.25 mol), ethyl 2-(5-bromopyridin-2-yl)-2,2-difluoroacetate (Formula bI, 70 g, 0.25 mol), (1,1'-bis(diphenylphosphino)ferrocene) palladium dichloride (18.2 g, 25 mmol), powdered anhydrous cesium carbonate (122 g, 0.375 mol), 600 ml of dimethylformamide and 2 ml of water were placed in a three-necked flask, the temperature was controlled at 80-90°C for reaction for 8 h, cooled, 1 L of water and 1.2 L of ethyl acetate were added, stirred and separated, the organic phase was washed with 500 ml of water, the organic phase was dried, most of the solvent was concentrated under reduced pressure, 200 ml of n-hexane was added to the residue, refluxed to dissolve, cooled for crystallization, filtered, and the filter cake was dried to obtain a compound of formula c (67.6 g, yield 72%), Ms m / z 376.1 (M+1).

[0043] Example 3: Synthesis of ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (compound of formula C)

[0044]

[0045] Under nitrogen protection, the compound p-(2,2,2-trifluoroethoxy)phenylboronic acid pinacol ester (Formula a, 60.4 g, 0.2 mol), ethyl 2-(5-iodopyridin-2-yl)-2,2-difluoroacetate (Formula bI, 65.4 g, 0.2 mol), tetrakis(triphenylphosphine)palladium(0) (11.6 g, 10 mmol), powdered anhydrous potassium carbonate (31.8 g, 0.3 mol), 400 ml of toluene, 80 ml of anhydrous ethanol and 2 ml of water were placed in a three-necked flask, refluxed for 6 h, cooled, 480 ml of water and 200 ml of ethyl acetate were added, stirred and separated, the organic phase was washed with 400 ml of water, the organic phase was dried, and concentrated under reduced pressure to about 1 / 5 of the volume, the residue was cooled, filtered, and the filter cake was dried to obtain the compound of formula c (75.1 g, yield 87%), Ms m / z 376.1 (M+1).

[0046] Example 4: Synthesis of ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (compound of formula C)

[0047]

[0048] Under nitrogen protection, compound p-(2,2,2-trifluoroethoxy)phenylboronic acid pinacol ester (Formula a, 30.2 g, 0.1 mol), ethyl 2-(5-chloropyridin-2-yl)-2,2-difluoroacetate (Formula bI, 23.6 g, 0.1 mol), tetrakis(triphenylphosphine)palladium(0) (11.6 g, 10 mmol), powdered anhydrous cesium carbonate (65.2 g, 0.2 mol), 200 ml of toluene, 40 ml of anhydrous ethanol and 1 ml of water were placed in a three-necked flask, refluxed for 18 h, cooled, added with 240 ml of water and 100 ml of ethyl acetate, stirred for separation, the organic phase was washed with 200 ml of water, dried, concentrated to dryness under reduced pressure, 100 ml of ethyl acetate and 150 ml of n-hexane were added to the residue, heated to dissolve, cooled for crystallization, filtered, and the filter cake was dried to obtain a compound of formula c (21.8 g, yield 58%), Ms m / z 376.1(M+1).

[0049] Example 5: Synthesis of 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-ethanone (compound of formula e)

[0050]

[0051] Under argon atmosphere, tetrahydrofuran (100 ml, manufacturer: BASF) and 2,4-difluorobromobenzene (formula dI, 44.4 g, 0.23 mol) were added to a 1000 ml dry three-necked flask, cooled to -75 to -70 ° C, and n-BuLi (2.5 M n-hexane solution, 92 mL, 0.23 mol) was added dropwise at -75 to -55 ° C. After the addition was completed, the mixture was stirred and cooled to -75 to -70 ° C. The temperature was controlled at -75 to -65 ° C. A 150 ml tetrahydrofuran solution of ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (formula c, 75 g, 0.2 mol) was added dropwise. After the addition was completed, the temperature was controlled and stirred for 1 h, and a 1 M hydrochloric acid solution (250 mL) was added dropwise to quench the reaction, and the pH was adjusted with a saturated sodium carbonate solution. 7-8, methyl tert-butyl ether was added and extracted twice (300 ml each time), the organic phases were combined, washed with 300 ml of purified water, the organic phase was dried over anhydrous MgSO4, filtered, the organic phase was refluxed for 3-4 hours, and then concentrated to dryness under reduced pressure, n-hexane was added to the residue to precipitate solid, filtered, and the filter cake was recrystallized with anhydrous ethanol-n-hexane (100 ml / 300 ml) to obtain the compound of formula e (66.4 g, yield 75%, purity 98.8%), Ms m / z 444.1 (M+1), 1 H NMR(300MHz d6-DMSO): 5.14(d, 2H), 5.70(s, 1H), 6.91–6.95(m, 1H), 7.21(d, 1H), 7.23–7.25(d, 2H), 7 .23-7.29 (m, 1H), 7.30 (d, 1H), 7.53 (d, 1H), 7.83 (d, 2H), 8.20–8.22 (m, 1H), 8.90 (d, 1H).

[0052] Example 6: Synthesis of 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-ethanone (compound of formula e)

[0053]

[0054] Under argon atmosphere, tetrahydrofuran (50 ml, manufacturer: BASF) and 2,4-difluoroiodobenzene (Formula d-II, 26.4 g, 0.11 mol) were added to a 500 ml dry three-necked flask, cooled to -75 to -70 ° C, and n-BuLi (2.5 M n-hexane solution, 44 mL, 0.11 mol) was added dropwise at -75 to -55 ° C. After the addition was completed, the mixture was stirred and cooled to -75 to -70 ° C. The temperature was controlled at -75 to -65 ° C. 80 ml of tetrahydrofuran solution of ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (Formula c, 37.5 g, 0.1 mol) was added dropwise. After the addition was completed, the temperature was controlled and stirred for 0.5 h. A 1 M hydrochloric acid solution (125 mL) was added dropwise to quench the reaction, and the pH was adjusted with a saturated sodium carbonate solution. 7-8, add methyl tert-butyl ether and extract twice (150 ml each time), combine the organic phases, wash with 150 ml of purified water, dry the organic phase over anhydrous MgSO4, filter, reflux the organic phase for 3 hours, and concentrate to dryness under reduced pressure. Add n-hexane to the residue to precipitate a solid, filter, and recrystallize the filter cake with anhydrous ethanol-n-hexane (50 ml / 150 ml) to obtain the compound of formula e (35.9 g, yield 81%, purity 99.1%), Ms m / z 444.1 (M+1).

[0055] Example 7: Synthesis of 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-ethanone (compound of formula e)

[0056]

[0057] Under argon atmosphere, tetrahydrofuran (50 ml, manufacturer: BASF) and 2,4-difluorochlorobenzene (Formula d-II, 26.4 g, 0.13 mol) were added to a 200 ml dry three-necked flask, cooled to -75 to -70 ° C, and n-BuLi (2.5 M n-hexane solution, 23 mL, 57.5 mmol) was added dropwise at -75 to -55 ° C. After the addition was completed, the mixture was stirred and cooled to -75 to -70 ° C. The temperature was controlled at -75 to -65 ° C. 40 ml of tetrahydrofuran solution of ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (Formula c, 18.8 g, 50 mmol) was added dropwise. After the addition was completed, the temperature was controlled and stirred for 1 h. A 1 M hydrochloric acid solution (70 mL) was added dropwise to quench the reaction, and the pH was adjusted with a saturated sodium carbonate solution. 7-8, add methyl tert-butyl ether and extract twice (80 ml each time), combine the organic phases, wash with 80 ml of purified water, dry the organic phase over anhydrous MgSO4, filter, reflux the organic phase for 3 hours, and concentrate to dryness under reduced pressure. Add n-hexane to the residue to precipitate solid, filter, and recrystallize the filter cake with anhydrous ethanol-n-hexane (30 ml / 70 ml) to obtain the compound of formula e (16.0 g, yield 72%, purity 97.5%), Ms m / z 444.1 (M+1).

[0058] Embodiment 8: the synthesis method 1 of Otconazole

[0059]

[0060] Under argon atmosphere, add 1-(2-bromomethyl)-1H-tetrazole (Formula fI, 17.7 g) and 90 ml of tetrahydrofuran into a 500 ml dry three-necked flask, cool to -35°C, and add 1.3 M isopropylmagnesium chloride lithium chloride tetrahydrofuran solution (110 ml, 0.12 mol) dropwise at -35 to -15°C. After the addition, continue to control the temperature at -25 to -15°C and stir to react for 1 hour. Cool to -25°C, control the temperature at -25 to -15°C, add dropwise a mixed solution of 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-ethanone (Formula e, 44.3 g, 0.1 mol) and (R)-1,1'-binaphthol (2.9 g, 10 mmol) in tetrahydrofuran (150 ml), after addition, control the temperature at -25°C to -15°C to react for 1 h, stop the reaction, add 10% citric acid aqueous solution to the reaction solution, The mixture was stirred for 2 h and then filtered. The filter cake was recrystallized from 200 ml of anhydrous ethanol to obtain the title product, pure ortaconia azole (41.1 g, yield 78%, chemical purity 98.6%, ee value 98.2%), Ms m / z 528.1 (M+1), 1 HNMR(300MHz d6-DMSO): 4.86 (q, 2H), 5.11 (d, 2H), 5.68 (s, 1H), 6.93–6.89 (m, 1H), 7.19 (d, 1H), 7.23–7.21 (d, 2H), 7 .27–7.21 (m, 1H), 7.29 (d, 1H), 7.52 (d, 1H), 7.80 (d, 2H), 8.22–8.20 (m, 1H), 8.93 (d, 1H), 9.15 (s, 1H).

[0061] Embodiment 9: the synthesis method 2 of Otconazole

[0062]

[0063] Under argon atmosphere, add 1-(2-iodomethyl)-1H-tetrazole (Formula f-II, 11.2 g) and 90 ml of tetrahydrofuran into a 250 ml dry three-necked flask, cool to -35°C, and add 1.3 M isopropylmagnesium chloride lithium chloride tetrahydrofuran solution (55 ml, 60 mmol) dropwise at -35 to -15°C. After the addition, continue to control the temperature at -25°C to -15°C and stir the reaction for 0.5 h. Cool to -25°C, control the temperature at -25 to -15°C, add dropwise a mixed solution of 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-ethanone (Formula e, 22.2 g, 50 mmol) and (R)-1,1'-binaphthol (1.5 g, 5 mmol) in tetrahydrofuran (80 ml), after addition, control the temperature at -25°C to -15°C to react for 0.5 h, stop the reaction, add 10% citric acid aqueous solution to the reaction solution, The mixture was added with 100 ml of n-hexane to obtain pure ortacazole (21.1 g, yield 80%, chemical purity 99.1%, ee value 98.5%), Ms m / z 528.1 (M+1).

[0064] Embodiment 10: the synthesis method 3 of Otconazole

[0065]

[0066] Under argon atmosphere, add 1-(2-chloromethyl)-1H-tetrazole (Formula f-III, 29.1 g) and 180 ml of tetrahydrofuran into a 1L dry three-necked flask, cool to -35°C, and add 1.3M isopropylmagnesium chloride lithium chloride tetrahydrofuran solution (138 ml, 0.26 mol) dropwise at -35 to -15°C. After the addition, continue to control the temperature at -25°C to -15°C and stir the reaction for 1.5 hours. Cool to -25°C, control the temperature at -25 to -15°C, add dropwise a mixed solution of 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-ethanone (Formula e, 88.6 g, 0.2 mol) and (R)-1,1'-binaphthol (5.8 g, 20 mmol) in tetrahydrofuran (300 ml), after addition, control the temperature at -25°C to -15°C to react for 1.5 h, stop the reaction, add 10% citric acid aqueous solution to the reaction solution, The mixture was added with 400 ml of n-hexane and stirred to disperse, and the filter cake was recrystallized twice with 300 ml of anhydrous ethanol to obtain the title product, pure ortaconia azole (71.7 g, yield 68%, chemical purity 97.6%, ee value 97.2%), Ms m / z 528.1 (M+1).

[0067] Compared with the synthesis method of orteconazole provided in the comparative example, the synthesis methods of Examples 1-10 of the present invention have a shorter route, a higher yield, reduced health damage to production operators, and are more environmentally friendly.

[0068] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing an antifungal drug, orteconazole, characterized in that: The method is: Step 1: (2,2,2-trifluoroethoxy)phenylboronic acid pinacol ester (compound of formula a) and compound of formula b are subjected to Suzuki coupling reaction to obtain ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (compound of formula c); Step 2, coupling reaction of ethyl 2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)acetate (compound of formula c) with compound of formula d to obtain 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-ethanone (compound of formula e); Step 3, 1-(2,4-difluorophenyl)-2,2-difluoro-2-(5-(4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)-ethanone (compound of formula e) and compound of formula f are subjected to an asymmetric synthesis reaction to obtain ortaconia; in In the compound of formula b, X1 is selected from I, Br and Cl; In the compound of formula d, X2 is selected from I, Br and Cl; In the compound of formula f, X3 is selected from I, Br and Cl; The catalyst for the coupling reaction in step 1 is a palladium catalyst and an inorganic base catalyst, wherein the palladium catalyst is selected from tetrakis(triphenylphosphine)palladium(0), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(tricyclohexylphosphine)palladium(0) or bis(tri-O-toluenephosphine)palladium(0); the inorganic base is selected from cesium carbonate, potassium carbonate, sodium carbonate or lithium carbonate; The coupling reaction catalyst in step 2 is an organic lithium, wherein the organic lithium catalyst is selected from n-butyl lithium, tert-butyl lithium, sec-butyl lithium, n-pentyl lithium or neopentyl lithium; The asymmetric synthesis reaction in step 3 requires the addition of an asymmetric reaction catalyst and a coupling reaction catalyst. The asymmetric reaction catalyst is selected from (R)-1,1'-binaphthol, and the coupling reaction catalyst is isopropylmagnesium chloride and lithium chloride.

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