Method for producing fosravuconazole L-lysine ethanol adduct

Abstract

This invention provides a method for producing fosravuconazole L-lysine ethanol adducts in high yield. [Solution] In one aspect, a method for producing fosravuconazole L-lysine ethanol adduct is provided. This production method includes contacting an acid catalyst having an acid dissociation constant pKa of 2.0 or more and 4.0 or less with di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate to obtain fosravuconazole, and contacting fosravuconazole with L-lysine and ethanol to obtain fosravuconazole L-lysine ethanol adduct.

Description

Technical Field

[0001] The present invention relates to a method for producing fostrabucol L-lysine ethanol adduct.

Background Art

[0002] Fostrabucol lysine ethanol adduct is useful as a therapeutic agent for onychomycosis. Fostrabucol lysine ethanol adduct is represented by the following formula.

[0003]

Chemical Formula

Prior Art Documents

Patent Documents

[0004]

Patent Document No. 1

Patent Document No. 2

Patent Document No. 3

Non-Patent Documents

[0005]

Non-Patent Document No. 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] The object of the present invention is to provide a method for producing fosravuconazole L-lysine ethanol adducts in high yield. [Means for solving the problem]

[0007] In one aspect, a method for producing fosravuconazole L-lysine ethanol adduct is provided. This method comprises contacting an acid catalyst having an acid dissociation constant pKa of 2.0 or more and 4.0 or less with di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate to obtain fosravuconazole, and contacting fosravuconazole with L-lysine and ethanol to obtain fosravuconazole L-lysine ethanol adduct. [Effects of the Invention]

[0008] The present invention provides a method for producing fosravuconazole L-lysine ethanol adducts in high yield. [Modes for carrying out the invention]

[0009] The manufacturing method according to the embodiment includes contacting an acid catalyst having an acid dissociation constant pKa of 2.0 or more and 4.0 or less with di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate to obtain fosravuconazole, and contacting fosravuconazole with L-lysine and ethanol to obtain a fosravuconazole-L-lysine-ethanol adduct.

[0010] Di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate can be an intermediate for the synthesis of fosravuconazole lysine ethanol adducts. Hereinafter, di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate will also be referred to as FS-12. FS-12 is represented by the following formula. In the following formula, t BU stands for tert-butyl group.

[0011] [ka]

[0012] Fosravuconazole is obtained by contacting FS-12 with an acid catalyst and removing the two tert-butyl groups of FS-12. The inventors have found that in this deprotection reaction, using an acid catalyst with an acid dissociation constant pKa in the range of 2.0 to 4.0 increases the purity of fosravuconazole. That is, compared to using trifluoroacetic acid with an acid dissociation constant pKa of -0.3, hydrochloric acid with an acid dissociation constant pKa of -8, or acetic acid with an acid dissociation constant pKa of 4.8, using an acid catalyst with an acid dissociation constant pKa in the range of 2.0 to 4.0 results in less impurity generation and yields high-purity fosravuconazole. By using this high-purity fosravuconazole, fosravuconazole L-lysine ethanol adduct can be obtained in high yield.

[0013] The manufacturing method according to the embodiment will be described in detail below.

[0014] (Method for manufacturing fosravuconazole) Hosulabconazole is obtained by subjecting an acid catalyst having an acid dissociation constant pKa of 2.0 or more and 4.0 or less to a deprotection reaction by contacting it with FS-12.

[0015] FS-12 can be produced, for example, by the methods described in Patent Documents 1 to 3.

[0016] As the acid catalyst having an acid dissociation constant pKa of 2.0 or more and 4.0 or less, for example, at least one selected from the group consisting of formic acid having an acid dissociation constant pKa of 3.8, phosphoric acid having an acid dissociation constant pKa of 2.1, and monofluoroacetic acid having an acid dissociation constant pKa of 2.7 is used. As the acid catalyst, it is preferable to use at least one of formic acid and phosphoric acid, and it is more preferable to use formic acid.

[0017] The acid dissociation constant pKa means the acid dissociation constant in water at 25°C. In an acid in which the dissociation of hydrogen ions occurs stepwise, it means the first-stage acid dissociation constant pKa1. The acid dissociation constant pKa of the acid catalyst is, for example, the value described in Non-Patent Document 1.

[0018] The contact temperature between the acid catalyst having an acid dissociation constant pKa of 2.0 or more and 4.0 or less and FS-12 is, for example, -10°C or more and 50°C or less. This contact temperature is preferably 0°C or more and 40°C or less, and more preferably 10°C or more and 30°C or less. According to the method according to the embodiment, since an acid catalyst having an acid dissociation constant pKa of 2.0 or more and 4.0 or less is used, the deprotection reaction can be carried out at room temperature.

[0019] The contact time between the acid catalyst having an acid dissociation constant pKa of 2.0 or more and 4.0 or less and FS-12 is, for example, 0.5 hours or more and 24 hours or less. This contact time is preferably 1 hour or more and 6 hours or less.

[0020] The contact between an acid catalyst having an acid dissociation constant pKa of 2.0 to 4.0 and FS-12 may be carried out in the presence of a reaction solvent or in the absence of a solvent. Examples of reaction solvents include at least one selected from the group consisting of dichloromethane, methanol, ethyl acetate, tetrahydrofuran, t-butyl methyl ether, and toluene. The amount of reaction solvent per 1 g of FS-12 is, for example, 1 mL to 10 mL.

[0021] Contact between an acid catalyst with an acid dissociation constant pKa of 2.0 to 4.0 and FS-12 is preferably carried out in a solvent-free environment. Here, "solvent-free environment" means that no other solvents are present except for the acid catalyst and FS-12. In other words, it is preferable that the acid catalyst with an acid dissociation constant pKa of 2.0 to 4.0 also serves as the reaction solvent. If no reaction solvent other than the acid catalyst is present, the amount of impurities generated tends to decrease.

[0022] For contact between an acid catalyst having an acid dissociation constant pKa of 2.0 or more and 4.0 or less and FS-12, it is preferable, for example, to dropwise add FS-12 to an acid catalyst at a temperature of 0°C to 20°C and allow the reaction to proceed at a temperature within the range of 10°C to 30°C.

[0023] The amount of acid catalyst with an acid dissociation constant pKa of 2.0 to 4.0 relative to 1 mole of FS-12 is, for example, 1 mole to 100 moles. In the case of formic acid, the amount of acid catalyst is preferably 60 moles to 350 moles, and more preferably 80 moles to 300 moles. In the case of monofluoroacetic acid and phosphoric acid, the amount is preferably 10 moles to 50 moles, and more preferably 20 moles to 40 moles.

[0024] Fosravuconazole can be isolated from the reaction solution obtained by contacting an acid catalyst with an acid dissociation constant pKa of 2.0 to 4.0 with FS-12, for example, by post-treatment or liquid-liquid separation. In post-treatment, it is preferable to neutralize the acid catalyst by contacting the reaction solution with a basic solution containing a solvent such as ethyl acetate or a base. As the base, at least one compound selected from the group consisting of dipotassium hydrogen phosphate and disodium hydrogen phosphate is used.

[0025] In this reaction solution, the purity of fosravuconazole is, for example, 80% or more, preferably 85% or more, and more preferably 90% or more. In this reaction solution, the amount of impurities is, for example, 20% or less, preferably 15% or less, and more preferably 10% or less. This purity and concentration are obtained by high-performance liquid chromatography (HPLC) measurement as described in the examples. Examples of impurities include amide compounds represented by the following formula.

[0026] [ka]

[0027] (Method for producing fosravuconazole L-lysine ethanol adduct) The fosravuconazole L-lysine ethanol adduct is obtained by contacting fosravuconazole with L-lysine and ethanol. Fosravuconazole is obtained by the above method. As fosravuconazole, for example, the reaction solution obtained by the above method may be used, or the liquid obtained by post-treatment and liquid-liquid treatment of the reaction solution may be used.

[0028] The amount of L-lysine per mole of fosravuconazole is, for example, 0.8 moles to 2.0 moles, preferably 1.0 mole to 1.4 moles.

[0029] The amount of ethanol per 1 g of fosravuconazole is, for example, 3 mL to 100 mL, preferably 5 mL to 30 mL.

[0030] It is preferable to use purified fosravuconazole as the fosravuconazole. Purified fosravuconazole can be obtained, for example, by contacting the fosravuconazole obtained by the above method with tert-butylamine to obtain fosravuconazole di-tert-butylamine salt, and then contacting this fosravuconazole di-tert-butylamine salt with an acid.

[0031] Specifically, for example, after post-treatment and liquid-liquid separation of the reaction solution obtained by the above method, tert-butylamine is added to the resulting separatory to precipitate fosravuconazole di-tert-butylamine salt. The amount of tert-butylamine per mole of fosravuconazole is, for example, 1.7 moles or more and 5.0 moles or less, preferably 2.0 moles or more and 3.0 moles or less.

[0032] The precipitated fosravuconazole di-tert-butylamine salt is removed by filtration and dried. The dried fosravuconazole di-tert-butylamine salt is dissolved in a solvent, for example, water and ethyl acetate, and then an acid is added to this solution. This yields purified fosravuconazole.

[0033] As the acid, at least one compound selected from the group consisting of hydrochloric acid, phosphoric acid, formic acid, and sulfuric acid is used. The acid is used to adjust the pH of the aqueous layer. The pH of the aqueous layer is, for example, 1.0 to 3.5, preferably 2.0 to 3.0.

[0034] A fosravuconazole-L-lysine-ethanol adduct can be obtained by contacting purified fosravuconazole with L-lysine and ethanol.

[0035] According to the method of the embodiment, the amount of impurities can be reduced, so that, for example, a fosravuconazole L-lysine ethanol adduct with a purity of 90% or more by HPLC can be obtained. This purity is preferably 94.0% or more, more preferably 95.0% or more, and even more preferably 96.0% or more. There is no particular upper limit to this purity, but in one example it is 99.9% or less, and in another example it is 98.0% or less. Furthermore, the HPLC content of the above amide in the fosravuconazole L-lysine ethanol adduct is preferably 1.00% or less, more preferably 0.50% or less, and even more preferably 0.30% or less. There is no particular lower limit to this content, but in one example it is 0.001% or more, and in another example it is 0.01% or more. [Examples]

[0036] The present invention will be described in detail below with reference to examples, but the present invention can be controlled by these examples. It is not limited. <Evaluation Test> The purity of the fosravuconazole obtained in the examples was measured under the following conditions. Equipment: High-performance liquid chromatography (HPLC) Column: YMC-Triart C18, 4.6 × 150 mm, 3 μm Solution A: 20 mM KH2PO4 aqueous solution (adjusted to pH 5.0) Solution B: Acetonitrile Gradient:

[0037] [Table 1]

[0038] Flow rate: 1mL / min Injection volume: 10μL Detection wavelength: 287nm Column temperature: 25℃ Under the above conditions, the peak positions obtained by high-performance liquid chromatography were as follows. Fosravuconazole: 13.8 minutes Amide form: 14.3 min FS-12:31.4 minutes <Example 1> 12.2 g (175 eq.) of formic acid was cooled to 10°C, and 1.0 g (1.5 mmol) of FS-12 was added dropwise. After reacting at 15°C for 2 hours, this solution was added dropwise to a mixture of 2.6 g of dipotassium hydrogen phosphate and 5.4 g of disodium hydrogen phosphate dodecahydrate dissolved in 15 mL of water, and 7 mL of ethyl acetate. The aqueous layer was removed, and the organic layer was washed with 6 mL of 5% saline solution. The organic layer was extracted twice with 10 mL of 10% tripotassium phosphate aqueous solution. 6 mL of butyl acetate was added to this solution, and the pH was adjusted to 2.5 with 5 M hydrochloric acid. The aqueous layer was removed, and the organic layer was washed with 6 mL of 5% saline solution. 1.1 mL of 2 M L-lysine aqueous solution (1.4 eq.) was added to this solution, and the organic layer was removed. 0.4 mL of water and 0.6 mL of acetic acid were added to this solution and stirred. 18 mL of ethanol was added to this solution and stirred at 40°C for 6 hours and then at 25°C for 60 hours to obtain 0.97 g of fosravuconazole L-lysine ethanol adduct in a yield of 86.2%. <Example 2> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Example 1, except that 5 mL of dichloromethane was used as the reaction solvent. <Examples 3 and 4> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Example 1, except that the equivalent amount of formic acid was changed to 80 eq. or 300 eq. <Examples 5 and 6> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Example 1, except that the reaction temperature was changed to 10°C or 40°C. <Examples 7 and 8> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Example 1, except that 3.5 g (30 eq.) of monofluoroacetic acid or 4.5 g (30 eq.) of phosphoric acid was used as the acid catalyst. <Example 9> 12.2 g (175 eq.) of formic acid was cooled to 10°C, and 1.0 g (1.5 mmol) of FS-12 was added dropwise. After reacting at 15°C for 2 hours, this solution was added dropwise to a mixture of 2.6 g of dipotassium hydrogen phosphate and 5.4 g of disodium hydrogen phosphate dodecahydrate dissolved in 15 mL of water, and 7 mL of ethyl acetate. The aqueous layer was removed, and the organic layer was washed with 6 mL of 10% saline solution. The organic layer was extracted twice with 10 mL of 10% tripotassium phosphate aqueous solution. 6 mL of ethyl acetate was added to this solution, and the pH was adjusted to 2.5 with 10% hydrochloric acid. The aqueous layer was removed, and the organic layer was washed with 6 mL of 5% saline solution. 0.33 g of tert-butylamine (3.0 eq.) was added dropwise to this solution, and the mixture was stirred at 25°C for 8 hours. The precipitated solid was filtered and washed with 2 mL of ethyl acetate. The solid was mixed with 4 mL of acetonitrile and 0.3 mL of water, and stirred at 70°C for 1 hour, then stirred at below 10°C for 1 hour. The solid was filtered, washed sequentially with 2 mL of acetonitrile and 4 mL of ethyl acetate, and dried to obtain fosravuconazole di-tert-butylamine salt. Fosravuconazole di-tert-butylamine salt was dissolved in 4 mL of ethyl acetate and 4 mL of 10% saline solution. The pH of this solution was adjusted to 2.5 by adding 10% hydrochloric acid. The aqueous layer was removed, and the organic layer was washed sequentially with 4 mL of 10% saline solution and 4 mL of water. 1.1 mL of 2 M L-lysine aqueous solution (1.4 eq.) was added to this solution, and the organic layer was removed. The pH of the aqueous layer was adjusted to 4.5 with acetic acid, and 20 mL of ethanol was added. The solution was filtered, seed crystals were added, and the mixture was stirred for 12 hours to obtain 0.91 g of fosravuconazole L-lysine ethanol adduct in 81.1% yield. <Comparative Examples 1 and 2> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Example 1, except that 6.9 g (40 eq.) of trifluoroacetic acid or 15.9 g (175 eq.) of acetic acid was used as the acid catalyst. <Comparative Example 3> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Example 1, except that 15.9 g (175 eq.) of acetic acid was used as the acid catalyst and the reaction temperature was set to 80°C. <Comparative Example 4> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Example 1, except that 0.80 g (4.6 eq.) of trifluoroacetic acid was used as the acid catalyst and 1 mL of dichloromethane was used as the solvent. <Comparative Example 5> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Example 1, except that 6.4 g (30 eq.) of 8 M hydrochloric acid was used as the acid catalyst and 1.6 mL of methanol was used as the solvent. <Comparative Example 6> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Example 1, except that 5.2 g (30 eq.) of trifluoroacetic acid was used as the acid catalyst, 5 mL of dichloromethane was used as the solvent, and 2.3 g (14.1 eq.) of anisole was used as the additive. <Comparative Example 7> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Comparative Example 6, except that 2.4 g (13 eq.) of thioanisole was used as an additive. <Comparative Example 8> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Comparative Example 6, except that 1.8 g (29.4 eq.) of acetonitrile was used as an additive. <Comparative Example 9> Fosravuconazole L-lysine ethanol adduct was obtained in the same manner as in Comparative Example 6, except that 2.3 g (15 eq.) of benzonitrile was used as an additive.

[0039] [Table 2]

[0040] The following are some of the favorable aspects of the invention. [1] The method involves contacting an acid catalyst with an acid dissociation constant pKa of 2.0 to 4.0 with di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate to obtain fosravuconazole, The fosravuconazole is brought into contact with L-lysine and ethanol to obtain a fosravuconazole-L-lysine-ethanol adduct. A method for producing a fosravuconazole L-lysine ethanol adduct, which includes the fosravuconazole L-lysine ethanol adduct. [2] The production method according to [1], wherein the acid catalyst comprises at least one acid selected from the group consisting of formic acid, phosphoric acid, and monofluoroacetic acid. [3] The method for producing the product according to [1] or [2], wherein the amount of the acid catalyst relative to 1 mole of the di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate is 60 moles or more and 350 moles or less. [4] The production method according to any one of [1] to [3], wherein the contact between the acid catalyst and the di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate is carried out without a solvent. [5] The production method according to any one of [1] to [4], wherein the contact between the acid catalyst and the di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate is carried out in a range of 0°C to 40°C. [6] The fosravuconazole and tert-butylamine salt are brought into contact to obtain the fosravuconazole di-tert-butylamine salt. The fosravuconazole di-tert-butylamine salt is brought into contact with an acid to obtain purified fosravuconazole. The purified fosravuconazole is brought into contact with L-lysine and ethanol to obtain the fosravuconazole-L-lysine-ethanol adduct. A manufacturing method according to any one of [1] to [5], including the above.

Claims

1. The method involves contacting an acid catalyst with an acid dissociation constant pKa of 2.0 or higher and 4.0 or lower with di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate to obtain fosravuconazole, The fosravuconazole is brought into contact with L-lysine and ethanol to obtain a fosravuconazole-L-lysine-ethanol adduct. A method for producing a fosravuconazole L-lysine ethanol adduct, which contains the fosravuconazole L-lysine ethanol adduct.

2. The production method according to claim 1, wherein the acid catalyst comprises at least one acid selected from the group consisting of formic acid, phosphoric acid, and monofluoroacetic acid.

3. The production method according to claim 1, wherein the amount of the acid catalyst relative to 1 mole of the di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate is 60 moles or more and 350 moles or less.

4. The production method according to claim 1, wherein the contact between the acid catalyst and the di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate is carried out without a solvent.

5. The production method according to claim 1, wherein the contact between the acid catalyst and the di-tert-butyl[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazole-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-ylmethyl)propyl}-oxy]methyl phosphate is carried out in a range of 0°C to 40°C.

6. The fosravuconazole di-tert-butylamine salt is obtained by contacting the fosravuconazole with tert-butylamine. The fosravuconazole di-tert-butylamine salt is brought into contact with an acid to obtain purified fosravuconazole. The purified fosravuconazole is brought into contact with L-lysine and ethanol to obtain the fosravuconazole-L-lysine-ethanol adduct. The manufacturing method according to claim 1, including

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