A method for the synthesis of an antifungal drug

Abstract

The present application relates to a kind of synthetic methods of antifungal drugs, which comprises the following steps: (1) the compound of formula II is removed Boc in the presence of acid in reaction solvent to generate the compound of formula III;And (2) adding sulfuric acid to the compound of formula III obtained in step (1) to convert into the sulfate compound of formula I, wherein the compound of formula II, the compound of formula III are as described in the specification.The synthetic method of the present application avoids the degradation of the compound of formula IV obtained by removing Boc with HCl in the prior art, and reduces the generation of by-product of formula V when removing Boc with HCl, H2SO4, TFA and other solvents in the prior art, the impurity can be controlled below 0.10% without purification, the process operation is simple, the total purity can reach more than 99%, and each index is qualified.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a synthesis method of an antifungal drug, and particularly to a synthesis method of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate. BACKGROUND

[0002] 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate is a prodrug for the treatment of invasive aspergillosis and invasive mucormycosis developed by Astellas and Basilea, and was approved for marketing by FDA in March 2015.

[0003] 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2- hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2- yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate is a triazole antifungal drug, which is a prodrug form of 4-(2-((2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)thiazol-4-yl)benzonitrile. Compared with other triazole antifungal drugs, 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate has strong water solubility, so it does not need to add β-cyclodextrin to its preparation to improve the solubility, eliminating the possibility of kidney toxicity caused by the addition of cyclodextrin. At the same time, the absorption of its oral preparation is not affected by food and gastric acid, and it has high bioavailability. 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate has low metabolic toxicity, and the urine solubility of the drug is negligible after oral administration, and the urine concentration is only slightly improved after intravenous administration. Patients with reduced kidney function can use it normally. In addition, 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate has good safety and tolerability, and the common side effects are headache and mild gastrointestinal symptoms. The liver toxicity caused by the drug is reversible and can be recovered by stopping the drug.

[0004] Since 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium has thermal instability, leading to difficulties in recrystallization purification, and contains multiple salt-forming sites in the structure, making it difficult to control the number of sulfate groups, therefore, the salt type conversion from halogen to hydrogen sulfate salt of the quaternary ammonium salt of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium is a technical difficulty of the process, and in the existing reported synthesis or purification process of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate, most of them are optimized for the above problems, for example, Chinese patent application CN106467534A reports a purification method of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate, CN106916152A reports a method for accurately controlling the number of sulfate groups by oxidation-reduction reaction, etc.

[0005] As for the deprotection of the protecting group Boc, it is mainly still following the process reported in the original research US7459561B2, i.e. deprotecting the compound of formula II by HCl solution to obtain the compound of formula IV, as shown below:

[0006]

[0007] The process of the original research US7459561B2 has two problems, one is that the compound of formula IV is hydrochloride form, which is very easy to absorb moisture, and needs to strictly control the moisture of the experimental environment, which brings many inconveniences to the operation and increases the cost of the control process; the second is that the strong acidity of HCl will lead to the generation of process impurity 1-((2R,3R)-3-(4-(4-(tert-butoxy(imino)methyl)phenyl)thiazol-2-yl)-2-(2,5-difluorophenyl)-2-hydroxybutyl)-4-(1-((methyl(3-(((methylamino)oxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl)-1H-1,2,4-triazol-4-ium (compound of formula V) during the reaction. This impurity is generated by the reaction of the tert-butyl ion generated when the compound of formula II is de-Boc with 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium, which is difficult to remove by simple purification and needs to be removed by column chromatography or preparative purification.

[0008]

[0009] In summary, there is an urgent need to develop a new synthesis method of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate salt which can avoid the moisture-absorbing intermediate compound of formula IV and control the generation of by-product compound of formula V when the compound of formula II is de-Boc, and which is simple to operate and easy to industrialize. SUMMARY

[0010] The object of the present application is to provide a synthesis method of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate, comprising deprotecting Boc of a compound of formula II in trifluoroacetic acid and hexafluoroisopropanol to obtain a compound of formula III, and converting the salt of the compound of formula III to obtain a compound of formula I. The synthesis method of the present application avoids the compound of formula IV obtained by deprotecting Boc with HCl in the prior art process, which is prone to moisture absorption and degradation, and reduces the generation of by-product of formula V when deprotecting Boc with HCl, H2SO4, TFA and other solvents in the prior art process. The impurity can be controlled below 0.10% without purification, the process operation is simple, and the total purity can reach more than 99%, and the indicators are qualified.

[0011] The technical solution of the present application is as follows:

[0012] A synthesis method of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate, comprising the following steps:

[0013] (1) deprotecting Boc of a compound of formula II in a reaction solvent in the presence of trifluoroacetic acid to obtain a compound of formula III:

[0014] and

[0015] (2) converting the compound of formula III obtained in step (1) into a sulfate compound of formula I by adding sulfuric acid:

[0016]

[0017] wherein X represents halogen or TFA.

[0018] According to the present application, the compound of formula II is selected from the following:

[0019]

[0020] According to the present application, the raw material compound of formula II used in step (1) is directly purchased or synthesized according to the existing literature.

[0021] According to the present application, in step (1), the reaction solvent is a non-tert-butyl ion reaction solvent, for example, hexafluoroisopropanol.

[0022] According to the present application, in step (1), the reaction temperature is 0-60°C, preferably 40-45°C.

[0023] According to the present application, in step (1), the molar ratio of the compound of formula II to the trifluoroacetic acid is 1:0.8-1:40, preferably 1:3-1:5 (for example, 1 mmol:0.8 mmol-1 mmol:40 mmol, preferably 1 mmol:3 mmol-1 mmol:5 mmol).

[0024] According to the present application, in step (1), the mass-volume ratio of the compound of formula II to the reaction solvent is 1:1-1:100, preferably 1:5-1:15 (for example, 1 g:1 mL-1 g:100 mL, preferably 1 g:5 mL-1 g:15 mL).

[0025] According to the present application, in step (2), sulfuric acid is added to the compound of formula III obtained in step (1), a solid is precipitated, filtered, the filter cake is dissolved with water, barium hydroxide is added to neutralize excess sulfuric acid, filtered, and the aqueous phase is lyophilized to obtain the sulfate compound of formula I.

[0026] Compared with the prior art, the present application has at least the following advantages:

[0027] The present application uses a special solvent in combination with trifluoroacetic acid, the by-product compound of formula V is less than 0.10%, and there is no need to remove the impurity by column chromatography or preparative purification, which is suitable for industrial scale-up production.

[0028] After the reaction is completed, the 4-(2-((2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)thiazol-4-yl)benzonitrile polysulfate precipitated by adding sulfuric acid is not easy to absorb moisture, and has better stability than 4-(2-((2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)thiazol-4-yl)benzonitrile hydrochloride, and there is no need to filter in a nitrogen environment, and the operation is simple. DETAILED DESCRIPTION

[0029] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. Furthermore, it should be understood that after reading the content taught by the present application, those skilled in the art can make various modifications or changes to the present application, and these equivalent forms also fall within the scope defined by the claims attached hereto.

[0030] The experimental methods in the following examples are all conventional methods unless otherwise specified. The medicinal material raw materials, reagent materials, etc. used in the following examples are all commercially purchased products unless otherwise specified.

[0031] Instruments used: nuclear magnetic resonance (Bruker AVANCE III HD 500); mass spectrometry (LTQ Orbitrap Elite); liquid chromatography (Agilent 1260).

[0032] Analysis method: The liquid phase detection in the following examples is carried out by the following method

[0033]

[0034]

[0035] Example 1 : Preparation of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5- difluorophenyl)-2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin- 2-yl]amino}formyl)oxy]ethyl]-1 H-1,2,4-triazol-4-ium monosulfate (Formula I) Example 2: Preparation of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5- difluorophenyl)-2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin- 2-yl]amino}formyl)oxy]ethyl]-1 H-1,2,4-triazol-4-ium monosulfate (Formula I) Example 3: Preparation of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5- difluorophenyl)-2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin- 2-yl]amino}formyl)oxy]ethyl]-1 H-1,2,4-triazol-4-ium monosulfate (Formula I)

[0036] Compound 1.000 g (1.172 mmol) of formula II-a, hexafluoroisopropanol 5 mL, trifluoroacetic acid 0.114 g (1 mmol) were added to the reaction bottle, and after incubation at 0-5°C for 48 h, the compound of formula II-a was completely converted into the compound of formula III. The reaction liquid was added dropwise with sulfuric acid 1 mL, and stirred for crystallization for 1 h, filtered, and the filter cake was dissolved with water 5 mL, and barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, and filtered, and the aqueous phase was freeze-dried to obtain the compound of formula I, 0.924 g, yield 96.8%, HPLC purity 99.52%, impurity compound V 0.03%.

[0037] NMR hydrogen spectrum and mass spectrum data of formula I:

[0038] 1 H NMR (500 MHz, CDCl3) δ 10.40 (m, 1H), 9.44 (s, 2H), 9.23 (m, 1H), 8.47 (m, 2H), 8.22 (d, J = 7.6 Hz, 2H), 8.03 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 2H), 7.47 (s, 1H), 7.33 (m, 1H), 7.26 (m, 1H), 7.12 (m, 1H), 6.83 (m, 1H), 6.81 (s, 1H), 4.95 (m, 4H), 4.16 (m, 1H), 4.05 (d, J = 12.2 Hz, 2H), 3.23 (d, J = 16.4 Hz, 3H), 2.60 (s, 3H), 1.56 (m, 3H), 1.26 (d, J = 7.4 Hz, 3H).

[0039] ES-MS M / Z = 716.91 (M + )

[0040] NMR and mass spectral data of the compound of formula V:

[0041] 1 H NMR (500 MHz, CDC13) δ 10.41 (m, 1H), 9.42 (s, 2H), 9.20 (m, 1H), 8.46 (m, 2H), 8.21 (d, J = 7.5 Hz, 2H), 8.05 (d, J = 7.5 Hz, 1H), 7.90 (m, 2H), 7.46 (s, 1H), 7.40 (s, 1H), 7.35 (m, 1H), 7.28 (m, 1H), 7.11 (m, 1H), 6.85 (m, 1H), 6.82 (s, 1H), 4.96 (m, 4H), 4.15 (m, 1H), 4.04 (m, 2H), 3.22 (d, J = 16.1 Hz, 3H), 2.63 (s, 3H), 1.56 (m, 3H), 1.46 (m, 9H), 1.25 (d, J = 7.4 Hz, 3H).

[0042] ES-MS M / Z = 791.52 (M + )

[0043] Example 4: Preparation of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5- difluorophenyl)-2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin- 2-yl]amino}formyl)oxy]ethyl]-1 H-1,2,4-triazol-4-ium monosulfate (Formula I) Example 5: Preparation of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5- difluorophenyl)-2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin- 2-yl]amino}formyl)oxy]ethyl]-1 H-1,2,4-triazol-4-ium monosulfate (Formula I) Example 6: Preparation of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5- difluorophenyl)-2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin- 2-yl]amino}formyl)oxy]ethyl]-1 H-1,2,4-triazol-4-ium monosulfate (Formula I)

[0044] The compound of formula II-b 1.052 g (1.172 mmol), hexafluoroisopropanol 10 mL, trifluoroacetic acid 0.228 g (2 mmol) were added into the reaction bottle, and the reaction was carried out at 20-25°C for 24 h. The compound of formula II-b was completely converted into the compound of formula III. Sulfuric acid 1 mL was added dropwise into the reaction solution, and the reaction was carried out at 20-25°C for 1 h. The reaction solution was filtered, and the filter cake was dissolved in water 5 mL. Barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid. The reaction solution was filtered, and the water phase was freeze-dried to obtain the compound of formula I, 0.938 g, with a yield of 98.2%, HPLC purity 99.66%, and impurity of the compound of formula V 0.05%. The NMR and mass spectral data of the compound of formula I and the compound of formula V are shown in Example 1.

[0045] Example 7: Preparation of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5- difluorophenyl)-2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin- 2-yl]amino}formyl)oxy]ethyl]-1 H-1,2,4-triazol-4-ium monosulfate (Formula I) ​ ​

[0046] Compound of formula II-c 1.107 g (1.172 mmol), hexafluoroisopropanol 15 mL, trifluoroacetic acid 0.342 g (3 mmol) were added to the reaction flask and kept at 40-45 °C for 6 h. Compound of formula II-c was completely converted to compound of formula III. To the reaction mixture, sulfuric acid 1 mL was added drop wise and stirred for 1 h. The reaction mixture was filtered and the filter cake was dissolved in water 5 mL. Barium hydroxide 0.402 g (2.344 mmol) was added to neutralize excess sulfuric acid. The reaction mixture was filtered and the aqueous phase was lyophilized to obtain compound of formula I, 0.912 g, 95.5% yield, 99.79% HPLC purity, 0.04% impurity compound of formula V. The1H NMR and mass spectral data of compound of formula I and compound of formula V are as shown in example 1.

[0047] ​ ​ ​

[0048] Compound of formula II-d 1.073 g (1.172 mmol), hexafluoroisopropanol 20 mL, trifluoroacetic acid 0.456 g (4 mmol) were added to the reaction flask and kept at 55-60 °C for 1 h. Compound of formula II-d was completely converted to compound of formula III. To the reaction mixture, sulfuric acid 1 mL was added drop wise and stirred for 1 h. The reaction mixture was filtered and the filter cake was dissolved in water 5 mL. Barium hydroxide 0.402 g (2.344 mmol) was added to neutralize excess sulfuric acid. The reaction mixture was filtered and the aqueous phase was lyophilized to obtain compound of formula I, 0.918 g, 96.1% yield, 99.65% HPLC purity, 0.06% impurity compound of formula V. The1H NMR and mass spectral data of compound of formula I and compound of formula V are as shown in example 1.

[0049] ​ ​ ​

[0050] The compound of formula II-a 0.250 g (0.293 mmol), compound of formula II-b 0.263 g (0.293 mmol), compound of formula II-c 0.277 g (0.293 mmol), compound of formula II-d 0.268 g (0.293 mmol), hexafluoroisopropanol 5 mL, trifluoroacetic acid 0.114 g (1 mmol) were taken in a reaction flask, kept at 0-5 °C for 48 h after the complete conversion of the compound of formula II-a, compound of formula II-b, compound of formula II-c, compound of formula II-d to the compound of formula III, to the reaction mixture dropwise sulfuric acid 1 mL was added and stirred for crystallization for 1 h, filtered, the filter cake was dissolved in water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the aqueous phase was lyophilized to obtain the compound of formula I, 0.925 g, yield 96.9%, HPLC purity 99.57%, impurity compound of formula V 0.03%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of the compound of formula I and the compound of formula V are shown in Example 1.

[0051] ​ ​ ​

[0052] The compound of formula II-b 1.052 g (1.172 mmol), hexafluoroisopropanol 2 mL, trifluoroacetic acid 0.228 g (2 mmol) were taken in a reaction flask, kept at 20-25 °C for 24 h after the complete conversion of the compound of formula II-b to the compound of formula III, to the reaction mixture dropwise sulfuric acid 1 mL was added and stirred for crystallization for 1 h, filtered, the filter cake was dissolved in water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the aqueous phase was lyophilized to obtain the compound of formula I, 0.878 g, yield 91.9%, HPLC purity 99.56%, impurity compound of formula V 0.08%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of the compound of formula I and the compound of formula V are shown in Example 1.

[0053] ​ ​ Preparation of formyloxyethyl]-1H-1,2,4-triazol-4-onium monosulfate (Formula I)

[0054] Compound of formula II-b 1.052 g (1.172 mmol), hexafluoroisopropanol 5 mL, trifluoroacetic acid 0.228 g (2 mmol) were added to the reaction flask, after incubation at 20-25 °C for 24 h, compound of formula II-b was completely converted to compound of formula III, sulfuric acid 1 mL was added dropwise to the reaction liquid, stirred for crystallization for 1 h, filtered, the filter cake was dissolved with water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the aqueous phase was freeze-dried to obtain compound of formula I, 0.930 g, yield 97.4%, HPLC purity 99.62%, impurity compound of formula V 0.05%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

[0055] Example 8: 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazolyl-2-yl]-2-(2,5-difluorophenyl)- 2-Hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino] Preparation of formyloxyethyl]-1H-1,2,4-triazol-4-onium monosulfate (Formula I)

[0056] Compound of formula II-b 1.052 g (1.172 mmol), hexafluoroisopropanol 5 mL, trifluoroacetic acid 0.228 g (2 mmol) were added to the reaction flask, after incubation at 20-25 °C for 24 h, compound of formula II-b was completely converted to compound of formula III, sulfuric acid 1 mL was added dropwise to the reaction liquid, stirred for crystallization for 1 h, filtered, the filter cake was dissolved with water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the aqueous phase was freeze-dried to obtain compound of formula I, 0.930 g, yield 97.4%, HPLC purity 99.62%, impurity compound of formula V 0.05%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

[0057] Example 9: 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazolyl-2-yl]-2-(2,5-difluorophenyl)- 2-Hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino] Preparation of formyloxyethyl]-1H-1,2,4-triazol-4-onium monosulfate (Formula I)

[0058] Compound of formula II-b 1.052 g (1.172 mmol), hexafluoroisopropanol 5 mL, trifluoroacetic acid 0.228 g (2 mmol) were added to the reaction flask, after incubation at 20-25 °C for 24 h, compound of formula II-b was completely converted to compound of formula III, sulfuric acid 1 mL was added dropwise to the reaction liquid, stirred for crystallization for 1 h, filtered, the filter cake was dissolved with water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the aqueous phase was freeze-dried to obtain compound of formula I, 0.930 g, yield 97.4%, HPLC purity 99.62%, impurity compound of formula V 0.05%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

[0059] Example 10: 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazolyl-2-yl]-2-(2,5-difluorobenzene) {(1RS)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl] Preparation of carbamoyloxyethyl]-1H-1,2,4-triazol-4-onium monosulfate (Formula I)

[0060] Compound of formula II-b 1.052 g (1.172 mmol), hexafluoroisopropanol 50 mL, trifluoroacetic acid 0.228 g (2 mmol) were added into the reaction flask, after incubation at 20-25 °C for 24 h, compound of formula II-b was completely converted to compound of formula III, 1 mL of sulfuric acid was added dropwise into the reaction solution, and the reaction solution was stirred for crystallization for 1 h, then filtered, the filter cake was dissolved in 5 mL of water, 0.402 g of barium hydroxide (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, and the water phase was freeze-dried to obtain the compound of formula I, 0.811 g, yield 84.9%, HPLC purity 99.68%, impurity compound of formula V 0.04%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of the compound of formula I and the compound of formula V are shown in Example 1.

[0061] Comparative Example 1: 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazolyl-2-yl]-2-(2,5-difluorophenyl)- 2-Hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino] Preparation of formyloxyethyl]-1H-1,2,4-triazol-4-onium monosulfate (Formula I)

[0062] Compound of formula II-c 1.107 g (1.172 mmol), ethyl acetate 10 mL were added into the reaction flask, 1 mL of 4M HCl ethyl acetate solution was added dropwise under ice bath cooling at 0-5 °C, after incubation at 0-5 °C for 4 h, compound of formula II-c was completely converted to compound of formula III, filtered under nitrogen protection, the filter cake was vacuum dried at 40-45 °C for 4 h, then dissolved in 5 mL of water, 5 g of styrene sulfonate anion exchange resin was added, stirred for 4 h, filtered, and the water phase was freeze-dried to obtain the compound of formula I, 0.782 g, yield 81.9%, HPLC purity 98.35%, impurity compound of formula V 0.86%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of the compound of formula I and the compound of formula V are shown in Example 1.

[0063] Comparative Example 2: 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazolyl-2-yl]-2-(2,5-difluorophenyl)- 2-Hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino] Preparation of formyloxyethyl]-1H-1,2,4-triazol-4-onium monosulfate (Formula I)

[0064] Compound of formula II-c 1.107 g (1.172 mmol), ethyl acetate 10 mL were added into the reaction flask, 1 mL of 4M HCl ethyl acetate solution was added dropwise under ice bath cooling at 0-5 °C, after incubation at 0-5 °C for 4 h, compound of formula II-c was completely converted to compound of formula III, filtered, the filter cake was dissolved in 5 mL of water, 0.402 g of barium hydroxide (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, and the water phase was freeze-dried to obtain the compound of formula I, 0.773 g, yield 80.9%, HPLC purity 95.42%, impurity compound of formula V 3.77%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of the compound of formula I and the compound of formula V are shown in Example 1.

[0065] Comparative Example 3: 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazolyl-2-yl]-2-(2,5-difluorophenyl)- 2-Hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino] Preparation of formyloxyethyl]-1H-1,2,4-triazol-4-onium monosulfate (Formula I)

[0066] Compound of formula II-c 1.107 g (1.172 mmol), hexafluoroisopropanol 10 mL was taken in a reaction flask, 4M HCl in ethyl acetate 1 mL was added drop wise at 0-5°C under ice bath cooling, compound of formula II-c was completely converted to compound of formula III after 4h of reaction at 0-5°C, filtered under nitrogen protection, the filter cake was dried under vacuum at 40-45°C for 4h, dissolved in water 5 mL, styrene sulfonate anion exchange resin 5 g was added, stirred for 4h, filtered, the water phase was lyophilized to obtain compound of formula I, 0.792 g, yield 82.9%, HPLC purity 98.25%, impurity compound of formula V 0.68%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

[0067] Comparative Example 4: 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazolyl-2-yl]-2-(2,5-difluorophenyl)- 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino

[0068] Compound of formula II-c 1.107 g (1.172 mmol), hexafluoroisopropanol 10 mL was taken in a reaction flask, 4M HCl in ethyl acetate 1 mL was added drop wise at 0-5°C under ice bath cooling, compound of formula II-c was completely converted to compound of formula III after 4h of reaction at 0-5°C, filtered, the filter cake was dissolved in water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize excess sulfuric acid, filtered, the water phase was lyophilized to obtain compound of formula I, 0.803 g, yield 84.1%, HPLC purity 95.72%, impurity compound of formula V 3.28%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

[0069] Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino

[0070] Compound of formula II-c 1.107 g (1.172 mmol), hexafluoroisopropanol 10 mL was taken in a reaction flask, heated to 55-60°C for 24h, almost no compound of formula I was generated.

[0071] Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino

[0072] Compound of formula II-c 1.107 g (1.172 mmol), dichloromethane 10 mL, trifluoroacetic acid 0.342 g (3 mmol) were added to the reaction flask, after keeping at 30-35 °C for 12 h, compound of formula II-c was completely converted to compound of formula III, sulfuric acid 1 mL was added dropwise to the reaction liquid, stirred for 1 h, filtered, the filter cake was dissolved with water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the aqueous phase was freeze-dried to obtain compound of formula I, 0.825 g, yield 86.4%, HPLC purity 98.75%, compound of formula V impurity 0.48%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

[0073] Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino

[0074] Compound of formula II-c 1.107 g (1.172 mmol), dichloromethane 10 mL, trifluoroacetic acid 0.342 g (3 mmol) were added to the reaction flask, after keeping at 30-35 °C for 12 h, compound of formula II-c was completely converted to compound of formula III, sulfuric acid 1 mL was added dropwise to the reaction liquid, stirred for 1 h, filtered, the filter cake was dissolved with water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the aqueous phase was freeze-dried to obtain compound of formula I, 0.825 g, yield 86.4%, HPLC purity 98.75%, compound of formula V impurity 0.48%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

[0075] Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino

[0076] Compound of formula II-c 1.107 g (1.172 mmol), dichloromethane 10 mL, trifluoroacetic acid 0.342 g (3 mmol) were added to the reaction flask, after keeping at 30-35 °C for 12 h, compound of formula II-c was completely converted to compound of formula III, sulfuric acid 1 mL was added dropwise to the reaction liquid, stirred for 1 h, filtered, the filter cake was dissolved with water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the aqueous phase was freeze-dried to obtain compound of formula I, 0.825 g, yield 86.4%, HPLC purity 98.75%, compound of formula V impurity 0.48%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

[0077] Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino Preparation of 2-hydroxybutyl}-4-[(1 RS)-1 -({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino

[0078] Compound of formula II-c 1.107 g (1.172 mmol), propionitrile 10 mL, trifluoroacetic acid 0.342 g (3 mmol) were added into the reaction flask, after incubation at 40-45 °C for 6 h, compound of formula II-c was completely converted to compound of formula III, sulfuric acid 1 mL was added into the reaction mixture dropwise, and stirred for crystallization for 1 h, filtered, the filter cake was dissolved in water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the water phase was freeze-dried to obtain compound of formula I, 0.873 g, yield 91.4%, HPLC purity 98.37%, impurity compound of formula V 0.67%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

[0079] ​ ​ ​

[0080] Compound of formula II-b 1.052 g (1.172 mmol), dichloromethane 10 mL, trifluoroacetic acid 0.228 g (2 mmol) were added into the reaction flask, after incubation at 20-25 °C for 24 h, compound of formula II-b was completely converted to compound of formula III, sulfuric acid 1 mL was added into the reaction mixture dropwise, and stirred for crystallization for 1 h, filtered, the filter cake was dissolved in water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the water phase was freeze-dried to obtain compound of formula I, 0.864 g, yield 90.5%, HPLC purity 98.43%, impurity compound of formula V 0.65%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

[0081] Comparative Example 11 : Preparation of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3- thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino- carbonyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate (Formula I) Comparative Example 11 : Preparation of 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3- thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]amino- carbonyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate (Formula I) ​

[0082] Compound of formula II-b 1.052 g (1.172 mmol), hexafluoroisopropanol 10 mL, 4M HCl hexafluoroisopropanol solution 0.5 mL (2 mmol) were added into the reaction flask, after incubation at 20-25 °C for 24 h, compound of formula II-b was completely converted to compound of formula III, sulfuric acid 1 mL was added into the reaction mixture dropwise, and stirred for crystallization for 1 h, filtered, the filter cake was dissolved in water 5 mL, barium hydroxide 0.402 g (2.344 mmol) was added to neutralize the excess sulfuric acid, filtered, the water phase was freeze-dried to obtain compound of formula I, 0.795 g, yield 83.2%, HPLC purity 98.19%, impurity compound of formula V 0.89%. The nuclear magnetic resonance hydrogen spectrum and mass spectrum data of compound of formula I and compound of formula V are shown in Example 1.

Claims

1. A method for synthesizing an antifungal drug, the method comprising the steps of: (1) removing Boc from a compound of formula II in the presence of trifluoroacetic acid in a reaction solvent to generate a compound of formula III: ; and (2) adding sulfuric acid to the compound of formula III obtained in step (1) to convert it into a sulfate compound of formula I: ； wherein X represents halogen or TFA; in step (1), the reaction solvent is hexafluoroisopropanol; in step (1), the molar feeding ratio between the compound of formula II and the trifluoroacetic acid is 1:0.8-1:

5. 2.The method according to claim 1, wherein the compound of formula II is selected from: 。 3. The method of synthesis of claim 1, wherein, in step (1), the reaction temperature is 0-60 ℃.

4. The method of synthesis according to claim 3, wherein, in step (1), the reaction temperature is 40-45 ℃.

5. The method of synthesis of claim 1, wherein, in step (1), the molar feeding ratio between the compound of formula II and the trifluoroacetic acid is 1:3-1:

5.

6. The method of synthesis of claim 1, wherein, in step (1), the mass-volume ratio of the compound of formula II to the reaction solvent is 1 g:1 mL-1 g:100 mL.

7. The method of synthesis according to claim 6, wherein, in step (1), the mass-volume ratio of the compound of formula II to the reaction solvent is 1 g:5 mL-1 g:15 mL.

8. The method of synthesis according to any one of claims 1 to 7, wherein, in step (2), sulfuric acid is added to the compound of formula III obtained in step (1), solid is precipitated, filtered, the filter cake is dissolved in water, barium hydroxide is added to neutralize the excess sulfuric acid, filtered, the aqueous phase is freeze-dried to obtain the sulfate compound of formula I.

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