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CN116768879A - Synthesis method of antifungal drug - Google Patents

Synthesis method of antifungal drug Download PDF

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Publication number
CN116768879A
CN116768879A CN202310709905.5A CN202310709905A CN116768879A CN 116768879 A CN116768879 A CN 116768879A CN 202310709905 A CN202310709905 A CN 202310709905A CN 116768879 A CN116768879 A CN 116768879A
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compound
oxy
methyl
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俞雄
徐子安
张袁伟
宋明炜
傅永昌
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Shanghai Front Health Pharmaceutical Technology Co ltd
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Shanghai Front Health Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The application relates to a method for synthesizing antifungal drugs, which comprises the following steps: (1) Removing Boc from a compound of formula II in the presence of an acid in a reaction solvent to produce a compound of formula III; and (2) adding sulfuric acid to the compound of formula III obtained in the step (1) to convert the sulfuric acid into a sulfate compound of formula I, wherein the compound of formula II and the compound of formula III are described in the specification. The synthesis method of the application avoids the easy moisture absorption and degradation of the formula IV obtained by adopting HCl to remove Boc in the prior art, and reduces HCl and H in the prior art 2 SO 4 The generation of by-product formula V when TFA and other solvents are used for removing Boc can control the impurity below 0.10 percent without purification, the process operation is simple, the total purity can reach more than 99 percent, and all indexes are qualified.

Description

Synthesis method of antifungal drug
Technical Field
The application relates to the technical field of drug synthesis, in particular to a method for synthesizing an antifungal drug, in particular to a method for synthesizing 1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazole-2-yl ] -2- (2, 5-difluorophenyl) -2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl ] oxy } methyl) pyridin-2-yl ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazole-4-onium monosulfate.
Background
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 ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazol-4-ium monosulfate is a prodrug developed by An Si Talars (Astella) and Basilea in combination for the treatment of invasive Aspergillus infections and invasive Mucor infections, which was approved by the FDA for marketing in month 2015.
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 ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazol-4-ium monosulfate belongs to the azole antifungal drug, 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, has very strong water solubility compared to other triazole antibacterials, and therefore does not require the addition of β -cyclodextrin to its formulation to increase solubility, eliminating the potential for renal toxicity caused by cyclodextrin addition, while its absorption of oral formulation is not affected by food and has higher bioavailability. 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 ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazol-4-ium monosulfate has low metabolic toxicity, and the urinary solubility of the drug is negligible when administered orally, and urine concentration increases only slightly after intravenous administration, and it is normally used by patients with renal dysfunction. In addition, 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 ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazol-4-ium monosulfate has good safety and tolerability, common side effects are headache and mild gastrointestinal symptoms, and the drug causes liver toxicity to be reversible, and can be recovered upon discontinuation of the drug.
Since 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 ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazol-4-ium has thermal instability leading to difficulty in recrystallization purification, the structure contains multiple salt-forming sites leading to difficulty in controlling the number of sulfate groups, the conversion of halogen from the quaternary ammonium salt 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 ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazol-4-ium hydrochloride is a difficult technique to achieve the conversion of halogen from the quaternary ammonium salt of 1- { (2R, 3R) -3- [ 4-cyano-phenyl ] -2-hydroxy-methyl- } -4-ammonium salt, in the previously reported synthesis or purification processes 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 ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazol-4-ium monosulfate, the above problems are mostly optimized, for example, the purification method 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 ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazol-4-ium monosulfate, the method of CN106467534A is reported in China, and the number of the methods of CN106916152 are reported to be controlled by oxidation and reduction.
For deprotection of the protecting group Boc, the process reported in the original US7459561B2 for the removal of Boc from HCl to give the compound of formula IV is mainly followed as follows:
the original technology of US7459561B2 has two problems, namely, the compound of the formula IV is in the form of hydrochloride, is very easy to absorb moisture, needs to strictly control the moisture of the experimental environment, brings a plurality of inconveniences to the operation, and increases the cost of the control process; secondly, because of the strong acidity of HCl, the formation of the 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- (((methylglycino) oxy) methyl) pyridin-2-yl) carbamoyl) oxy) ethyl) -1H-1,2, 4-triazol-4-ium (compound of formula V) which is the formation of tert-butyl ion generated when the compound of formula II is debac with 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 ] carbamoyl) oxy) ethyl ] -1H-1,2, 4-triazol-4-ium is difficult to remove by simple purification or purification by column chromatography.
In view of the foregoing, there is a great need to develop a novel synthetic method for 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 ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazol-4-ium monosulfate that avoids the hygroscopic intermediate compound of formula IV and controls the formation of the by-product compound of formula V when the compound of formula II is debac.
Disclosure of Invention
The object of the present application is to provide a 1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl group]-2- (2, 5-difluorophenyl) -2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl)]Oxy } methyl) pyridin-2-yl]Carbamoyl } oxy) ethyl]-1H-1,2, 4-triazol-4-ium monosulfate synthesis process comprising the removal of Boc from a compound of formula II in trifluoroacetic acid and hexafluoroisopropanol to give a compound of formula III, and the trans-salt of the compound of formula III to give a compound of formula I. The synthesis method of the application avoids the easy moisture absorption and degradation of the formula IV obtained by adopting HCl to remove Boc in the prior art, and reduces the adoption of HCl and H in the prior art 2 SO 4 The generation of by-product formula V when TFA and other solvents are used for removing Boc can control the impurity below 0.10 percent without purification, the process operation is simple, the total purity can reach more than 99 percent, and all indexes are qualified.
The technical scheme of the application is as follows:
a method of synthesizing 1- { (2 r,3 r) -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 ] carbamoyl } oxy) ethyl ] -1H-1,2, 4-triazol-4-ium monosulfate, 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 produce a compound of formula III:
and
(2) Adding sulfuric acid to the compound of formula III obtained in step (1) to convert to a sulfate compound of formula I:
wherein X represents halogen or TFA.
According to the application, the compound of formula II is selected from the following:
according to the application, the starting compounds of formula II used in step (1) are purchased directly or synthesized according to prior art reports.
According to the application, in step (1), the reaction solvent is a reaction solvent other than t-butyl ion, for example hexafluoroisopropanol.
According to the application, in step (1), the reaction temperature is from 0 to 60℃and preferably from 40 to 45 ℃.
According to the application, in step (1), the molar feed ratio between the compound of formula II and the trifluoroacetic acid is from 1:0.8 to 1:40, preferably from 1:3 to 1:5 (for example from 1mmol to 40mmol, preferably from 1mmol to 3mmol to 1mmol to 5 mmol).
According to the application, in step (1), the mass to volume ratio of the compound of formula II to the reaction solvent is 1:1 to 1:100, preferably 1:5 to 1:15 (for example 1g:1mL to 1g:100mL, preferably 1g:5mL to 1g:15 mL).
According to the 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 the excess sulfuric acid, filtered, and the aqueous phase is lyophilized to obtain the sulfate compound of formula I.
Advantages of the present application compared to the prior art include at least the following:
the application adopts the special solvent to match with trifluoroacetic acid, the by-product formula V compound is below 0.10%, and the impurities are removed without column chromatography or preparation and purification, thus being suitable for industrial scale-up production.
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 separated out by sulfuric acid is added, so that moisture absorption is not easy, the stability is better than that 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 hydrochloride, and the filtration in a nitrogen environment is not needed, and the operation is simple.
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials and reagent materials used in the examples below are all commercially available products unless otherwise specified.
The instrument used is as follows: nuclear magnetic resonance (Bruker AVANCE III HD 500); mass spectrometry (LTQ Orbitrap Elite); liquid chromatography (Agilent 1260).
Analytical methods the liquid phase assays in the examples below were all performed as follows
Example 1:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.000g (1.172 mmol) of the compound of the formula II-a, 5mL of hexafluoroisopropanol and 0.114g (1 mmol) of trifluoroacetic acid are added into a reaction bottle, after the reaction is carried out for 48 hours at the temperature of between 0 and 5 ℃, the compound of the formula II-a is completely converted into the compound of the formula III, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that 0.924g of the compound of the formula I is obtained, the yield is 96.8%, the HPLC purity is 99.52%, and the impurity compound of the formula V is 0.03%.
Nuclear magnetic resonance hydrogen spectrum and mass spectrum data of formula I:
1 H NMR(500MHz,CDCl 3 )δ10.40(m,1H),9.44(s,2H),9.23(m,1H),8.47(m,2H),8.22(d,J＝7.6Hz,2H),8.03(d,J＝7.4Hz,1H),7.92(d,J＝7.6Hz,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＝12.2Hz,2H),3.23(d,J＝16.4Hz,3H),2.60(s,3H),1.56(m,3H),1.26(d,J＝7.4Hz,3H).
ES-MS M/Z＝716.91(M + )
nuclear magnetic resonance hydrogen spectrum and mass spectrum data of formula V:
1 H NMR(500MHz,CDCl 3 )δ10.41(m,1H),9.42(s,2H),9.20(m,1H),8.46(m,2H),8.21(d,J＝7.5Hz,2H),8.05(d,J＝7.5Hz,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＝16.1Hz,3H),2.63(s,3H),1.56(m,3H),1.46(m,9H),1.25(d,J＝7.4Hz,3H).
ES-MS M/Z＝791.52(M + )
example 2:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.052g (1.172 mmol) of the compound of the formula II-b, 10mL of hexafluoroisopropanol and 0.228g (2 mmol) of trifluoroacetic acid are added into a reaction bottle, after the reaction is carried out for 24 hours at the temperature of 20-25 ℃, the compound of the formula II-b is completely converted into the compound of the formula III, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that the compound of the formula I, 0.938g, the yield is 98.2%, the HPLC purity is 99.66%, and the impurity compound of the formula V is 0.05%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Example 3:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.107g (1.172 mmol) of the compound of the formula II-c, 15mL of hexafluoroisopropanol and 0.342g (3 mmol) of trifluoroacetic acid are added into a reaction bottle, after the reaction is carried out for 6 hours at the temperature of 40-45 ℃, the compound of the formula II-c is completely converted into the compound of the formula III, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that the compound of the formula I is obtained, 0.912g, the yield is 95.5%, the HPLC purity is 99.79%, and the impurity compound of the formula V is 0.04%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Implementation of the embodimentsExample 4:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.073g (1.172 mmol) of the compound of the formula II-d, 20mL of hexafluoroisopropanol, 0.456g (4 mmol) of trifluoroacetic acid are added into a reaction bottle, the reaction is carried out at 55-60 ℃ for 1h, the compound of the formula II-d is completely converted into the compound of the formula III, 1mL of sulfuric acid is dropwise added into the reaction solution, stirring and crystallization are carried out for 1h, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that 0.918g of the compound of the formula I is obtained, the yield is 96.1%, the HPLC purity is 99.65%, and the impurity compound of the formula V is 0.06%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Example 5:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
0.250g (0.293 mmol) of the compound of formula II-a, 0.263g (0.293 mmol) of the compound of formula II-b, 0.277g (0.293 mmol) of the compound of formula II-c, 0.268g (0.293 mmol) of the compound of formula II-d, 5mL of hexafluoroisopropanol, 0.114g (1 mmol) of trifluoroacetic acid are added to a reaction flask, after 48h of reaction at 0-5 ℃ the compound of formula II-a, formula II-b, formula II-c, formula II-d is completely converted to the compound of formula III, 1mL of sulfuric acid is added dropwise to the reaction solution, stirred for crystallization for 1h, filtered, the filter cake is dissolved with 5mL of water, 0.402g (2.344 mmol) of barium hydroxide and excess sulfuric acid are added, filtered, and the aqueous phase is lyophilized to give the compound of formula I, 0.925g, yield 96.9%, HPLC purity 99.57%, and the compound of impurity formula V is 0.03%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Example 6:1- { (2R)3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.052g (1.172 mmol) of the compound of the formula II-b, 2mL of hexafluoroisopropanol and 0.228g (2 mmol) of trifluoroacetic acid are added into a reaction bottle, after the reaction is carried out for 24 hours at the temperature of 20-25 ℃, the compound of the formula II-b is completely converted into the compound of the formula III, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that the compound of the formula I, 0.878g, the yield of 91.9%, the HPLC purity of 99.56% and the impurity compound of the formula V are obtained. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Example 7:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.052g (1.172 mmol) of the compound of the formula II-b, 5mL of hexafluoroisopropanol and 0.228g (2 mmol) of trifluoroacetic acid are added into a reaction bottle, after the reaction is carried out for 24 hours at the temperature of 20-25 ℃, the compound of the formula II-b is completely converted into the compound of the formula III, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that the compound of the formula I, 0.930g, the yield is 97.4%, the HPLC purity is 99.62%, and the impurity compound of the formula V is 0.05%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Example 8:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) ethyl)Acyl group]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.052g (1.172 mmol) of the compound of the formula II-b, 15mL of hexafluoroisopropanol and 0.228g (2 mmol) of trifluoroacetic acid are added into a reaction bottle, after the reaction is carried out for 24 hours at the temperature of 20-25 ℃, the compound of the formula II-b is completely converted into the compound of the formula III, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that the compound of the formula I, 0.936g, the yield of 98.0%, the HPLC purity of 99.59% and the impurity compound of the formula V are obtained. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Example 9:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.052g (1.172 mmol) of the compound of the formula II-b, 30mL of hexafluoroisopropanol and 0.228g (2 mmol) of trifluoroacetic acid are added into a reaction bottle, after the reaction is carried out for 24 hours at the temperature of 20-25 ℃, the compound of the formula II-b is completely converted into the compound of the formula III, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that 0.898g of the compound of the formula I is obtained, the yield is 94.0%, the HPLC purity is 99.63%, and the impurity compound of the formula V is 0.04%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Example 10:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]-2- (2, 5-difluorobenzene) Phenyl) -2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl)]Oxy } methyl) pyridin-2-yl] Carbamoyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.052g (1.172 mmol) of the compound of the formula II-b, 50mL of hexafluoroisopropanol and 0.228g (2 mmol) of trifluoroacetic acid are added into a reaction bottle, after the reaction is carried out for 24 hours at the temperature of 20-25 ℃, the compound of the formula II-b is completely converted into the compound of the formula III, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that the compound of the formula I, 0.811g, the yield of 84.9%, the HPLC purity of 99.68% and the impurity compound of the formula V are obtained. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Comparative example 1:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.107g (1.172 mmol) of the compound of the formula II-c and 10mL of ethyl acetate are added into a reaction bottle, 1mL of 4M HCl ethyl acetate solution is dropwise added at the temperature of 0-5 ℃ in an ice bath, the temperature is kept at 0-5 ℃ for 4 hours, the compound of the formula II-c is completely converted into the compound of the formula III after reaction, filtering is carried out under the protection of nitrogen, the filter cake is dried in vacuum for 4 hours at 40-45 ℃ and then is dissolved by 5mL of water, 5g of styrene-based hydrogen sulfate anion exchange resin is added, stirring is carried out for 4 hours, filtering and water phase freeze-drying are carried out, so that the compound of the formula I is obtained, 0.782g, the yield is 81.9%, the HPLC purity is 98.35%, and the compound of the impurity formula V is 0.86%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Comparative example 2:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.107g (1.172 mmol) of the compound of the formula II-c and 10mL of ethyl acetate are added into a reaction bottle, 1mL of 4M ethyl sulfate acetate solution is dropwise added at the temperature of 0-5 ℃ in an ice bath, the temperature is kept at 0-5 ℃ for 4 hours, the compound of the formula II-c is completely converted into the compound of the formula III, the compound is filtered, 5mL of water is used for dissolving filter cakes, 0.402g (2.34 mmol) of barium hydroxide is added for neutralizing excessive sulfuric acid, the filtration and water phase freeze-drying are carried out, so that the compound of the formula I is obtained, 0.773g, the yield is 80.9%, the HPLC purity is 95.42%, and the impurity compound of the formula V is 3.77%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Comparative example 3:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.107g (1.172 mmol) of the compound of the formula II-c and 10mL of hexafluoroisopropanol are added into a reaction bottle, 1mL of 4M ethyl acetate solution of HCl is dropwise added in ice bath at the temperature of 0-5 ℃, the compound of the formula II-c is completely converted into the compound of the formula III after the reaction is carried out for 4 hours at the temperature of 0-5 ℃, the compound is filtered under the protection of nitrogen, a filter cake is dried in vacuum for 4 hours at the temperature of 40-45 ℃ and then is dissolved by 5mL of water, 5g of styrene-based hydrogen sulfate anion exchange resin is added, the mixture is stirred for 4 hours, the filtration and the water phase freeze-drying are carried out, so that the compound of the formula I is obtained, the yield is 0.792g, the yield is 82.9%, the HPLC purity is 98.25%, and the compound of the impurity formula V is 0.68%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Comparative example 4:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.107g (1.172 mmol) of the compound of the formula II-c and 10mL of hexafluoroisopropanol are added into a reaction bottle, 1mL of 4M ethyl sulfate acetate solution is dropwise added in ice bath at the temperature of 0-5 ℃, the temperature is kept at 0-5 ℃ for reaction for 4 hours, the compound of the formula II-c is completely converted into the compound of the formula III, the compound is filtered, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, the filtration and the water phase freeze-drying are carried out, so that the compound of the formula I is obtained, 0.803g, the yield is 84.1%, the HPLC purity is 95.72%, and the impurity compound of the formula V is 3.28%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Comparative example 5:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.107g (1.172 mmol) of the compound of the formula II-c and 10mL of hexafluoroisopropanol were put into a reaction flask, and the reaction was carried out at 55 to 60℃for 24 hours with almost no compound of the formula I.
Comparative example 6:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.107g (1.172 mmol) of the compound of the formula II-c and 10mL of trifluoroacetic acid are added into a reaction bottle, the reaction is carried out at 25-30 ℃ for 6 hours, the compound of the formula II-d is completely converted into the compound of the formula III, the reaction solution is concentrated to dryness under reduced pressure at 30 ℃, the residue is dissolved by 10mL of ethyl acetate, 1mL of sulfuric acid is added dropwise, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that the compound of the formula I, 0.732g, the yield 76.6%, the HPLC purity 92.65% and the impurity compound of the formula V are obtained. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Comparative example 7:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ A)A radical [3- ({ [ (methylamino) acetyl)]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.107g (1.172 mmol) of the compound of the formula II-c, 10mL of dichloromethane and 0.342g (3 mmol) of trifluoroacetic acid are added into a reaction bottle, the compound of the formula II-c is completely converted into the compound of the formula III after the reaction is carried out for 12 hours at the temperature of 30-35 ℃, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that 0.825g of the compound of the formula I is obtained, the yield is 86.4%, the HPLC purity is 98.75%, and the impurity compound of the formula V is 0.48%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Comparative example 8:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.107g (1.172 mmol) of the compound of the formula II-c, 10mL of acetonitrile and 0.342g (3 mmol) of trifluoroacetic acid are added into a reaction bottle, the compound of the formula II-c is completely converted into the compound of the formula III after the reaction is carried out for 6 hours at the temperature of 40-45 ℃, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that 0.847g of the compound of the formula I is obtained, the yield is 88.7%, the HPLC purity is 98.05%, and the impurity compound of the formula V is 0.52%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Comparative example 9:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]2- (2, 5-difluorophenyl) propanoic acid 2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl) yl]Oxy } methyl) pyridin-2-yl]Amino group Formyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.107g (1.172 mmol) of the compound of the formula II-c, 10mL of propionitrile and 0.342g (3 mmol) of trifluoroacetic acid are added into a reaction bottle, the compound of the formula II-c is completely converted into the compound of the formula III after the reaction is carried out for 6 hours at the temperature of 40-45 ℃, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that 0.873g of the compound of the formula I is obtained, the yield is 91.4%, the HPLC purity is 98.37%, and the impurity compound of the formula V is 0.67%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Comparative example 10:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]-2- (2, 5-difluorobenzene) Phenyl) -2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl)]Oxy } methyl) pyridin-2-yl] Carbamoyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.052g (1.172 mmol) of the compound of the formula II-b, 10mL of dichloromethane and 0.228g (2 mmol) of trifluoroacetic acid are added into a reaction bottle, after the reaction is carried out for 24 hours at the temperature of 20-25 ℃, the compound of the formula II-b is completely converted into the compound of the formula III, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, a filter cake is dissolved by 5mL of water, 0.402g (2.344 mmol) of barium hydroxide is added to neutralize excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that 0.864g of the compound of the formula I is obtained, the yield is 90.5%, the HPLC purity is 98.43%, and the impurity compound of the formula V is 0.65%. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.
Comparative example 11:1- { (2R, 3R) -3- [4- (4-cyanophenyl) -1, 3-thiazol-2-yl]-2- (2, 5-difluorobenzene) Phenyl) -2-hydroxybutyl } -4- [ (1 RS) -1- ({ methyl [3- ({ [ (methylamino) acetyl)]Oxy } methyl) pyridin-2-yl] Carbamoyl } oxy) ethyl]Preparation of 1H-1,2, 4-triazol-4-ium monosulfate (formula I)
1.052g (1.172 mmol) of the compound of the formula II-b, 10mL of hexafluoroisopropanol, 0.5mL (2 mmol) of 4M HCl hexafluoroisopropanol solution are added into a reaction bottle, after the reaction is carried out for 24 hours at a temperature of 20-25 ℃, the compound of the formula II-b is completely converted into the compound of the formula III, 1mL of sulfuric acid is added dropwise into the reaction solution, stirring and crystallization are carried out for 1 hour, filtration is carried out, 5mL of water is used for dissolving a filter cake, 0.402g (2.344 mmol) of barium hydroxide is added for neutralizing excessive sulfuric acid, filtration and water phase freeze-drying are carried out, so that the compound of the formula I, 0.795g, the yield of 83.2%, the HPLC purity of 98.19% and the compound of the impurity formula V are obtained. The nmr hydrogen spectra and mass spectrum data of the compounds of formula I and formula V are shown in example 1.

Claims (10)

1. A method for synthesizing an antifungal drug, comprising the steps of:
(1) Removing Boc from a compound of formula II in the presence of trifluoroacetic acid in a reaction solvent to produce a compound of formula III:
and
(2) Adding sulfuric acid to the compound of formula III obtained in step (1) to convert to a sulfate compound of formula I:
wherein X represents halogen or TFA.
2. The synthetic method of claim 1, wherein the compound of formula II is selected from the group consisting of:
3. the synthetic method according to claim 1 or 2, wherein in step (1), the reaction solvent is hexafluoroisopropanol.
4. A synthetic method according to any one of claims 1 to 3, wherein in step (1), the reaction temperature is 0 to 60 ℃.
5. The synthetic method according to claim 4, wherein in the step (1), the reaction temperature is 40 to 45 ℃.
6. The synthetic method according to any one of claims 1 to 5, wherein in step (1), the molar feed ratio between the compound of formula II and the trifluoroacetic acid is 1:0.8 to 1:40.
7. The synthetic method of claim 6, wherein in step (1), the molar feed ratio between the compound of formula II and the trifluoroacetic acid is 1:3 to 1:5.
8. The synthetic method according to any one of claims 1 to 7, wherein in step (1), the mass-to-volume ratio of the compound of formula II to the reaction solvent is 1:1 to 1:100.
9. The synthetic method according to claim 8, wherein in step (1), the mass-to-volume ratio of the compound of formula II to the reaction solvent is 1:5 to 1:15.
10. The synthesis method according to any one of claims 1 to 9, wherein in step (2), sulfuric acid is added to the compound of formula III obtained in step (1), solids are 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.
CN202310709905.5A 2023-06-15 2023-06-15 Synthesis method of antifungal drug Pending CN116768879A (en)

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