241479-67-4

Usage

Uses

Used in Pharmaceutical Industry:
Isavuconazole is used as an antifungal agent for the treatment of invasive aspergillosis and invasive mucormycosis. It has shown in vitro activity against a large number of clinically important yeasts and molds, including Aspergillus spp., Fusarium spp., Scedosporium spp., Candida spp., the Zygomycetes, and Cryptococcus spp. This makes it a promising candidate for the treatment of various fungal infections, particularly those caused by drug-resistant strains.
Used in Clinical Trials:
Isavuconazole is currently undergoing phase III clinical trials, which are essential for evaluating its safety, efficacy, and optimal dosing regimens in treating invasive fungal infections. The results of these trials will help determine the potential role of isavuconazole in the management of these infections and its place in the antifungal drug market.
Used in Drug Resistance Management:
Due to its broad-spectrum activity and unique mechanism of action, isavuconazole has the potential to be used in the management of drug-resistant fungal infections. This could be particularly beneficial in cases where traditional antifungal agents have failed or are contraindicated.
Used in Combination Therapy:
Isavuconazole may also be used in combination with other antifungal agents to enhance the treatment of invasive fungal infections. This could help improve the overall efficacy of the treatment and reduce the likelihood of drug resistance development.

Antimicrobial activity

Isavuconazole is a new broad-spectrum triazole with activity against Candida, Cryptococcus, Aspergillus, Zygomycetes, Rhizopus, and Rhizomucor spp. and dimorphic fungi including Histoplasma capsulatum and Blastomyces dermatitidis and a range of dermatophytes. In animal models, isavuconazole is highly effective against systemic candidiasis and disseminated Aspergillus fumigatus and flavus infections.

Biochem/physiol Actions

Maximum plasma concentrations of BAL 4815 are observed 1.5–3 hours after oral doses or at the end of the 1-hour intravenous infusion. Mean elimination half-lives are remarkably long more than 50 and 70 hours after oral and intravenous doses, respectively, allowing for once-daily (or less frequent) dosing. The volume of distribution is large and systemic clearance low. The protein binding is 98%. Escalation in multiple dosing regimens results in a proportional increase in maximum plasma drug concentration.

Clinical Use

Three regimens of isavuconazonium (BAL 8557) – single 200 mg dose followed by 50 mg daily, single 400 mg followed by 100 mg daily and single 400 mg followed by 400 mg weekly –were demonstrated to be as efficacious as fluconazole in a phase II study conducted on patients with uncomplicated esophageal candidiasis. The results of a phase II open-label dose-escalating trial of intravenous isavuconazonium as prophylaxis in AML (NCT00413439) are pending (NIH, 2008). Two phase III randomized double-blind studies to evaluate the safety and efficacy of isavuconazole are currently under way, versus caspofungin followed by voriconazole in the treatment of candidaemia and invasive candidiasis and versus voriconazole in primary treatment of invasive filamentous fungal infection . A phase III open-label study using isavuconazole in patients with aspergillosis and renal impairment and those with rare fungi is being planned NCT00634049.

Toxicology

In animals, isavuconazole has revealed no mutagenic, allergenic, phototoxic, or irritant potential. In 15 healthy volunteers, single doses of isavuconazole (up to 200 mg) were well tolerated, and no severe or serious adverse events occurred. In a multiple-dose pharmacokinetic study, 24 healthy males received isavuconazole for 21 days of oral or 14 days of intravenous dosing. The most frequent adverse events were headache, nasopharyngitis, and rhinitis, and all were mild or moderate; however one subject on oral high-dose BAL 8557 had mild transient abnormal liver function on day 14 of therapy, which resolved despite continuing the drug. No clinically relevant changes in vital signs or electrocardiogram were observed. In a double-blind randomized phase II trial for the treatment of esophageal candidiasis, BAL 8557 was safe and well tolerated, with an adverse event profile similar to that of fluconazole, the comparator drug.

Drug interactions

Rifampicin, a potent CYP3A4 inducer, decreases the Cmax and AUC of isavuconazole . Ketoconazole increases exposure to isavuconazole. Neither ciclosporin nor warfarin is affected by isavuconazole co-administration. Isavuconazole increases tacrolimus levels.

Metabolism

Molecular weight (daltons) 814.8 (as isavuconazonium sulphate) % Protein binding >99 % Excreted unchanged in urine <1 Volume of distribution (L/kg) 450 Litres Half-life - normal/ESRF (hrs) 2-4 (as isavuconazole); 80-130 (as isavuconazonium) / Unchanged

Synthetic route

isavuconazole hydrobromide → Isavuconazole (241479-67-4)

Conditions	Yield
With sodium hydrogencarbonate In ethyl acetate	92.6%

(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanethioamide + 4-Cyanophenacyl bromide (20099-89-2) → Isavuconazole (241479-67-4)

Conditions	Yield
With sodium hydrogencarbonate In ethanol	86%
In ethanol at 60 - 65℃; for 15h;	81.6%
In ethanol at 78℃; for 3h;	77.4%
In ethanol at 70℃;

4-Cyanophenacyl bromide (20099-89-2) + C13H19FN4OS → Isavuconazole (241479-67-4)

Conditions	Yield
In ethanol at 60℃; for 2h;	70%

(2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butyronitrile (241479-74-3) → Isavuconazole (241479-67-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogen sulfide; sulfuric acid / ethanol / 5 h / Autoclave; Heating 2.1: ethanol / 8 h / 60 - 70 °C 2.2: 5 h / 20 - 70 °C / pH 4 - 5 View Scheme
Multi-step reaction with 2 steps 1: O,O-Diethyl hydrogen phosphorodithioate / water / 6 h / 78 °C 2: ethanol / 3 h / 78 °C View Scheme
Multi-step reaction with 2 steps 1: diammonium sulfide / tetrahydrofuran / 96 h / 27 - 30 °C / Reflux 2: ethanol / 15 h / 60 - 65 °C View Scheme

(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)thiobutyramide hydrogensulphate + 4-(2-chloroacetyl)benzenecarbonitrile (40805-50-3) → Isavuconazole (241479-67-4)

Conditions	Yield
Stage #1: (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)thiobutyramide hydrogensulphate; 4-(2-chloroacetyl)benzenecarbonitrile In ethanol at 60 - 70℃; for 8h; Stage #2: With triethylamine In ethanol; water at 20 - 70℃; for 5h; pH=4 - 5;

3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol → Isavuconazole (241479-67-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid / toluene / 20 - 70 °C 2: sodium hydrogencarbonate / dichloromethane; water View Scheme

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol (1R)-10-camphorsulfonate → Isavuconazole (241479-67-4)

Conditions	Yield
With sodium hydrogencarbonate In dichloromethane; water

3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile → Isavuconazole (241479-67-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: acetone; methanol / 20 °C / Reflux 2.1: sodium hydroxide / dichloromethane; water 3.1: hydrogen sulfide; sulfuric acid / ethanol / 5 h / Autoclave; Heating 4.1: ethanol / 8 h / 60 - 70 °C 4.2: 5 h / 20 - 70 °C / pH 4 - 5 View Scheme

(2S,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile-(1R)-10-camphorsulfonate → Isavuconazole (241479-67-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / dichloromethane; water 2.1: hydrogen sulfide; sulfuric acid / ethanol / 5 h / Autoclave; Heating 3.1: ethanol / 8 h / 60 - 70 °C 3.2: 5 h / 20 - 70 °C / pH 4 - 5 View Scheme

(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5-difluorophenyl)-butan-2-ol hydrobromide → Isavuconazole (241479-67-4)

Conditions	Yield
With sodium hydrogencarbonate In dichloromethane; water	18.5 g

α-chloro-2',5'-difluoroacetophenone (60468-36-2) → Isavuconazole (241479-67-4)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: triphenylphosphine; dichloro bis(acetonitrile) palladium(II) / tetrahydrofuran / 0.17 h / -20 °C / Inert atmosphere 1.2: 3 h / -10 °C 2.1: sodium carbonate / dimethyl sulfoxide / 4 h / 70 °C 3.1: [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid / toluene; tert-butyl methyl ether; methanol / 1 h / 60 °C 4.1: O,O-Diethyl hydrogen phosphorodithioate / water / 6 h / 78 °C 5.1: ethanol / 3 h / 78 °C View Scheme

C11H10ClF2NO → Isavuconazole (241479-67-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium carbonate / dimethyl sulfoxide / 4 h / 70 °C 2: [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid / toluene; tert-butyl methyl ether; methanol / 1 h / 60 °C 3: O,O-Diethyl hydrogen phosphorodithioate / water / 6 h / 78 °C 4: ethanol / 3 h / 78 °C View Scheme

1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (1157938-97-0) → Isavuconazole (241479-67-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.17 h / -78 °C / Inert atmosphere 1.2: 0.33 h 1.3: 2 h / -50 °C 2.1: [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid / toluene; tert-butyl methyl ether; methanol / 1 h / 60 °C 3.1: O,O-Diethyl hydrogen phosphorodithioate / water / 6 h / 78 °C 4.1: ethanol / 3 h / 78 °C View Scheme
Multi-step reaction with 4 steps 1.1: indium / tetrahydrofuran / 0.5 h / 0 °C / Inert atmosphere 1.2: 10 h / -10 °C 2.1: [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid / toluene; tert-butyl methyl ether; methanol / 1 h / 60 °C 3.1: O,O-Diethyl hydrogen phosphorodithioate / water / 6 h / 78 °C 4.1: ethanol / 3 h / 78 °C View Scheme

3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl) butyronitrile → Isavuconazole (241479-67-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid / toluene; tert-butyl methyl ether; methanol / 1 h / 60 °C 2: O,O-Diethyl hydrogen phosphorodithioate / water / 6 h / 78 °C 3: ethanol / 3 h / 78 °C View Scheme

N-methyl N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy)methyl]pyridin-2-yl)carbamic acid (1-chloroethyl) ester (338990-31-1) + Isavuconazole (241479-67-4) → 1-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino)acetoxymethyl]pyridin-2-yl]carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]-triazo-4-ium iodide

Conditions	Yield
With sodium iodide In acetonitrile at 70℃; for 3h; Inert atmosphere;	98%
With sodium iodide In acetonitrile at 45 - 50℃; for 15h;	88.4%
With sodium iodide In acetonitrile at 50 - 60℃; for 12h; Reagent/catalyst; Temperature; Inert atmosphere;	83%

2(S)-[acetoxymethyl]-1-[chloromethyloxycarbonyl]pyrrolidine (338990-23-1) + Isavuconazole (241479-67-4) → [[2(S)-(acetoxymethyl)pyrrolidin-1-yl]carbonyloxy]methyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium iodide

Conditions	Yield
With sodium iodide In acetonitrile at 50℃;	92%

N-methyl N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy)methyl]pyridin-2-yl)carbamic acid (1-chloroethyl) ester (338990-31-1) + Isavuconazole (241479-67-4) → C40H43F2N8O7S(1+)*Br(1-)

Conditions	Yield
With tetrabutylammomium bromide; sodium bromide In acetonitrile at 25 - 30℃; for 48h; Reagent/catalyst; Temperature;	89.2%

[N-ethyl-N-(tert-butoxycarbonylethylamino)ethyl]carbamic acid 1-chloroethyl ester (338990-56-0) + Isavuconazole (241479-67-4) → 1-[[N-ethyl-N-2-(t-butoxycarbonylethylamino)ethyl]carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride

Conditions	Yield
sodium iodide In acetonitrile at 60℃;	86%

4-tert-butoxycarbonyl-methyl-aminoacetoxy-3,5-dimethyl-benzyl bromide + Isavuconazole (241479-67-4) → 4-{4-[(tert-Butoxycarbonyl-methyl-amino)-acetoxy]-3,5-dimethyl-benzyl}-1-[(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-1H-[1,2,4]triazol-4-ium bromide

Conditions	Yield
In acetonitrile	84%

[N-methyl-N-3-(acetoxy)propyl]carbamic acid chloromethyl ester + Isavuconazole (241479-67-4) → [[N-methyl-N-3-(acetoxy)propyl]carbamoyloxy]methyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium iodide

Conditions	Yield
With sodium iodide In acetonitrile at 50℃;	82%

[N-methyl-N-2-[(tert-butoxycarbonylmethylamino)acetoxymethyl]-4-fluoro-phenyl]carbamic acid 1-chloroethyl ester (338990-35-5) + Isavuconazole (241479-67-4) → 4-[1-({2-[(tert-butoxycarbonyl-methyl-amino)-acetoxymethyl]-4-fluoro-phenyl}-methyl-carbamoyloxy)-ethyl]-1-[3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-1H-[1,2,4]triazol-4-ium; chloride

Conditions	Yield
With sodium iodide In acetonitrile at 70℃;	72%

N-methyl N-(3-[((N-tert-butoxycarbonyl-N-methylamino)acetoxy)methyl]pyridin-2-yl)carbamic acid (1-chloroethyl) ester (338990-31-1) + Isavuconazole (241479-67-4) → 1-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino)acetoxymethyl]pyridin-2-yl]carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride

Conditions	Yield
With sodium iodide In acetonitrile at 50℃;	65%

[N-methyl-N-2-(acetoxymethyl)phenyl]carbamic acid chloromethyl ester (338990-20-8) + Isavuconazole (241479-67-4) → [[N-methyl-N-2-(acetoxymethyl)phenyl]carbamoyloxy]methyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride

Conditions	Yield
With sodium iodide In acetonitrile Heating;	63%
sodium iodide In acetonitrile at 20 - 80℃; for 9h;	63%

[N-methyl-N-phenyl]carbamic acid chloromethyl ester (186353-05-9) + Isavuconazole (241479-67-4) → [[N-methyl-N-phenyl]carbamoyloxy]methyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride

Conditions	Yield
In acetonitrile at 80℃;	60%

[N-methyl-N-2-((tert-butoxycarbonylisopropylamino)methyl)phenyl]carbamic acid 1-chloroethyl ester (338990-27-5) + Isavuconazole (241479-67-4) → 1-[[N-methyl-N-2-(t-butoxycarbonyl-isopropylaminomethyl)phenyl]carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride (338990-62-8)

Conditions	Yield
sodium iodide In acetonitrile at 70℃;	51%

[N-methyl-N-2-[(tert-butoxycarbonylmethylamino)acetoxymethyl]-4,5-difluoro-phenyl]carbamic acid 1-chloroethyl ester (338990-34-4) + Isavuconazole (241479-67-4) → 4-[1-({2-[(tert-butoxycarbonyl-methyl-amino)-acetoxymethyl]-4,5-difluoro-phenyl}-methyl-carbamoyloxy)-ethyl]-1-[3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-1H-[1,2,4]triazol-4-ium; chloride

Conditions	Yield
With sodium iodide In acetonitrile at 80℃;	50%

acetic acid 2-(iodomethoxycarbonyl-methyl-amino)-ethyl ester + Isavuconazole (241479-67-4) → [[N-methyl-N-2-(acetoxy)ethyl]carbamoyloxy]methyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium iodide

Conditions	Yield
In acetonitrile at 50℃;

[N-methyl-N-2-[(tert-butoxycarbonylmethylamino)acetoxymethyl]-5-chlorophenyl]carbamic acid 1-chloroethyl ester (338990-41-3) + Isavuconazole (241479-67-4) → 4-[1-({2-[(tert-butoxycarbonyl-methyl-amino)-acetoxymethyl]-5-chloro-phenyl}-methyl-carbamoyloxy)-ethyl]-1-[3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-1H-[1,2,4]triazol-4-ium; chloride

Conditions	Yield
In acetonitrile at 65℃;

[N-methyl-N-2-[(tert-butoxycarbonylmethylamino)acetoxymethyl]-3-fluorophenyl]carbamic acid 1-chloroethyl ester (338990-44-6) + Isavuconazole (241479-67-4) → 4-[1-({2-[(tert-butoxycarbonyl-methyl-amino)-acetoxymethyl]-3-fluoro-phenyl}-methyl-carbamoyloxy)-ethyl]-1-[3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-1H-[1,2,4]triazol-4-ium; chloride

Conditions	Yield
With sodium iodide In acetonitrile Heating;

Isavuconazole (241479-67-4) → C35H35F2N8O5S(1+)*I(1-)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium iodide / acetonitrile / 12 h / 50 - 60 °C / Inert atmosphere 2: sulfuric acid / ethyl acetate; ethanol / 1 h / 30 °C / Reflux; Large scale View Scheme

Upstream product

• 20099-89-2 4-Cyanophenacyl bromide 
• 241479-75-4 (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanamide 
• 483340-19-8 (2R,3R)-3-[3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-3-(1H-1,2,4-triazol-1-yl)]butanoic acid 
• 483340-19-8 3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanoic acid 
• 241479-73-2 (2R,3S)-2-(2,5-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)-methyl]-oxirane 
• 241479-72-1 (2R,3R)-2-(2,5-difluoro-phenyl)-1-(1H-1,2,4-triazole-1-yl)butan-2,3-diol 
• 367-30-6 2,5-difluoroaniline 
• 1157938-97-0 1-(2,5-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone 
• 60468-36-2 α-chloro-2',5'-difluoroacetophenone 

Downstream Products

• 338990-63-9 1-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino)acetoxymethyl]pyridin-2-yl]carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride 
• 338990-62-8 1-[[N-methyl-N-2-(t-butoxycarbonyl-isopropylaminomethyl)phenyl]carbamoyloxy]ethyl-1-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-1H-[1,2,4]triazol-4-ium chloride 
• 946075-13-4 1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4-[1-({methyl[3-({[2-(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium hydrogensulfate 

Relevant academic research and scientific papers

Asymmetric Catalytic Epoxidation of Terminal Enones for the Synthesis of Triazole Antifungal Agents

An enantioselective epoxidation of α-substituted vinyl ketones was realized to construct the key epoxide intermediates for the synthesis of various triazole antifungal agents. The reaction proceeded efficiently in high yields with good enantioselectivities by employing a chiral N,N′-dioxide/ScIII complex as the chiral catalyst and 35% aq. H2O2 as the oxidant. It enabled the facile transformation for optically active isavuconazole, efinaconazole, and other potential antifungal agents.

AN IMPROVED PROCESS FOR THE PREPARATION OF TRIAZOLE DERIVATIVES

The present invention relates to an improved process for the preparation of triazole derivatives such as ravuconazole and isavuconazole.

Preparation method of liconazole sulfate and intermediate thereof (by machine translation)

The preparation method disclosed by the invention has, the advantages that the preparation process efficiency of the idazooconazole sulfate and the. intermediate thereof is higher by no need C2 for column A4 chromatography and purification . and the method disclosed by, the invention only needs. to be subjected to deprotecting A4 and ion exchange by simple purification. (by machine translation)

Crystal form of isavuconazole and preparation method thereof

The invention relates to a crystal form I of isavuconazole, a preparation method and application thereof. X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, hygroscopicity analysis and other means are employed for comprehensive characterization of the crystal form I of isavuconazole, and the invention finds that the crystal form I has more excellent stability than amorphism. The preparation method of the crystal form I of isavuconazole has the characteristics of simple operation, easy control and good reproducibility.

Method for manufacturing isavuconazole or ravuconazole

The invention provides a method for manufacturing a triazole compound isavuconazole or ravuconazole which is enriched by a diastereoisomer and enantiomer. The method comprises the following steps: a Reformatsky reaction is carried out between ketone and dihalogeno metal propionitrile; an enantiomer mixture is generated, and separation is carried out. The method can obviously reduce steps for synthesis of isavuconazole or ravuconazole, yield of products is improved, and production cost is reduced.

NOVEL STABLE POLYMORPHS OF ISAVUCONAZOLE OR ITS SALT THEREOF

The present invention relates to novel stable novel stable polymorphs of Isavuconazole or its salt thereof, having purity more than 90 % when measured by HPLC. In particular the present invention directs process for the preparation of solid amorphous and crystalline form of Isavuconazole base. In a further embodiment present invention directs to crystalline form Isavuconazole Hydrobromide salt and oxalate salt of 2-(2,5-difluoro- phenyl)-1-[1,2,4]triazol-1-yl-butane-2,3-diol.

Preparation method of isavuconazole and isavuconazole prepared through method

The invention relates to a preparation method of isavuconazole and isavuconazole prepared through the method.The preparation method comprises the following steps that 1, diflurophenyl acetylchloride, triazole, CuI, potassium carbonate and first organic solvent are sequentially added into a reaction kettle, reacting under stirring is performed at the temperature of 80 DEG C-100 DEG C, and then purifying is performed to obtain a first product; 2, propionitrile, a catalyst and second organic solvent are added into a reaction container, the temperature is lowered to minus 20 DEG C-minus 5 DEG C, the second organic solvent containing the first product is dropwise added, reacting and purifying are performed to obtain a second product, and a mixture composed of C-9 primary amine quinine and copper pigment alkali is adopted as the catalyst; 3, the second product is added into another reaction container, diethylphosphorodithioate, water and mixed isopropanol solvent are added into the reaction container, heating is performed until the temperature is increased to 80 DEG C-90 DEG C, reacting under stirring and purifying are sequentially performed, and a third product is obtained; 4, the third product, 2-bromo-4'-acetylbenzonitrile and third organic solvent are mixed, react under stirring at the temperature of 60 DEG C-70 DEG C and then purified, and the isavuconazole is obtained.Accordingly, a novel synthetic route is redesigned, and the reaction steps are reduced.

Process for the manufacture of enantiomerically pure antifungal azoles as ravuconazole and isavuconazole

A new technical process for preparation of enantiomerically pure antifungal compounds of formula I by resolution of the racemates has been disclosed.

Azoles for treatment of fungal infections

Azole derivatives of the formula I wherein R14, R15are each independently hydrogen or fluorine, T is a group of the formula: wherein R9is pyrrolidinyl or a group A—NH—B—, A is hydrogen or straight-chain or branched C1-C5alkyl; B is straight-chain or branched C1-C4alkylene, —CH2—CONH—CH2or —CH2CH2CH2—CH(NH2); and X?is a pharmaceutically acceptable anion; and pharmaceutically acceptable salts of said compounds, and hydrates and solvates of the compounds of formula I and the salts thereof can be used in the production of medicaments for treating fungal infections and mycoses.