182230-43-9

Basic information

• Product Name: (2R,3S/2S,3R)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol
• Synonyms: (2r,3s/2s,3r)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl)butan-2-ol;(2r,3s/2s,3r)-3-(5-Fluoro-6-Pyrimidinyl)-2-(2,4-Difluorophenyl)-1-(1h-1,2,4-Triazol- 1-Yl)-2- Butanol Hydrochloride;( 2R.3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyriMidinyl)-1-(1H-1,2,4-triazol-yl)-2-butanol;(2RS,3RS)-α-(2,4-Difluorophenyl)-5-fluoro-β-Methyl-α-(1H-1,2,4-triazol-1-ylMethyl)-4-pyriMidineethanol;Voriconazole Impurity 1;Voriconazole USP Related Compound A
• CAS NO: 182230-43-9
• Molecular Formula: C₁₆H₁₄F₃N₅O
• Molecular Weight: 349.31
• EINECS: 1806241-263-5
• Mol File: 182230-43-9.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 508.578 °C at 760 mmHg
• Flash Point: 261.379 °C
• Appearance: /
• Density: 1.427 g/cm³
• Refractive Index: 1.617
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 11.54±0.29(Predicted)
• CAS DataBase Reference: (2R,3S/2S,3R)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol(CAS DataBase Reference)
• NIST Chemistry Reference: (2R,3S/2S,3R)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol(182230-43-9)
• EPA Substance Registry System: (2R,3S/2S,3R)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol(182230-43-9)

Safety Data

• Hazardous Substances Data: 182230-43-9(Hazardous Substances Data)

Usage

Uses

(2RS,3RS)α-(2,4-Difluorophenyl)-5-fluoro-β-methyl-α-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol (Voriconazole USP Related Compound A), is a derivative of Voriconazole (V760000), which is a triazole antifungal medication that is generally used to treat serious fungal infections.

InChI:InChI=1/C16H14F3N5O/c1-10(15-14(19)5-20-7-22-15)16(25,6-24-9-21-8-23-24)12-3-2-11(17)4-13(12)18/h2-5,7-10,25H,6H2,1H3/t10-,16+/m1/s1

Synthetic route

(2R,3S/2S,3R)-6-[4-(3,5-dibromo-1H-1,2,4-triazol-1-yl)-3-(2,4-difluorophenyl)-3-hydroxybutan-2-yl]-5-fluoropyrimidin-4-yl methanesulfonate → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
With ammonium formate; palladium on carbon In toluene at 80℃; for 3h;	92.5%

3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
With 5% Pd/C; hydrogen; sodium acetate In methanol at 25 - 30℃; under 1500.15 - 3000.3 Torr; for 0.0833333h;	85%
With hydrogen; sodium acetate; Raney nickel In methanol at 54 - 56℃; under 2206.72 - 3677.86 Torr; for 5h;	66.4%

3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol hydrochloride salt (188416-20-8) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
Stage #1: 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol hydrochloride salt With palladium 10% on activated carbon; hydrogen; sodium acetate In methanol at 35 - 45℃; under 1500.15 - 3000.3 Torr; Large scale; Stage #2: With sodium hydroxide In water at 0 - 10℃; for 1h; Inert atmosphere; Large scale;	76%

1-(5-fluoropyrimidin-4-yl)ethyl-4-methyl benzenesulfonate (1289559-67-6) + 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone (86404-63-9) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
With zinc(II) chloride; zinc In tetrahydrofuran at 0 - 30℃; Product distribution / selectivity;

C6H5FN2O (1289559-75-6) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tetrahydroborate / ethanol / 5 h 2: triethylamine / dmap / dichloromethane / 20 - 30 °C 3: zinc; zinc(II) chloride / tetrahydrofuran / 0 - 30 °C View Scheme

1-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethanone (1289559-65-4) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen; sodium acetate / palladium on activated carbon / ethanol / 25 °C 2: sodium tetrahydroborate / ethanol / 5 h 3: triethylamine / dmap / dichloromethane / 20 - 30 °C 4: zinc; zinc(II) chloride / tetrahydrofuran / 0 - 30 °C View Scheme

1-(5-fluoropyrimidin-4-yl)ethanol (1289559-66-5) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / dmap / dichloromethane / 20 - 30 °C 2: zinc; zinc(II) chloride / tetrahydrofuran / 0 - 30 °C View Scheme

2-chloro-1-(2,4-dichlorophenyl)ethanone (51336-94-8) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / tetrahydrofuran / 7 h / 20 °C 2: lead; zinc; iodine / tetrahydrofuran / -15 - 20 °C / Inert atmosphere 3: ammonium formate / palladium on carbon / toluene / 3 h / 80 °C View Scheme

6-ethyl-5-fluoro-4-hydroxypyrimidine (137234-87-8) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 5 h / 20 °C 2: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / dichloromethane / 12 h / 45 - 50 °C 3: lead; zinc; iodine / tetrahydrofuran / -15 - 20 °C / Inert atmosphere 4: ammonium formate / palladium on carbon / toluene / 3 h / 80 °C View Scheme

6-ethyl-5-fluoropyrimidin-4-yl methanesulfonate (1237496-99-9) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / dichloromethane / 12 h / 45 - 50 °C 2: lead; zinc; iodine / tetrahydrofuran / -15 - 20 °C / Inert atmosphere 3: ammonium formate / palladium on carbon / toluene / 3 h / 80 °C View Scheme

6-(1-bromoethyl)-5-fluoropyrimidin-4-yl methanesulfonate (1237497-00-5) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: lead; zinc; iodine / tetrahydrofuran / -15 - 20 °C / Inert atmosphere 2: ammonium formate / palladium on carbon / toluene / 3 h / 80 °C View Scheme

1-(2,4-difluorophenyl)-2-(3,5-dibromo-1H-1,2,4-triazol-1-yl)ethanone (906451-64-7) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: lead; zinc; iodine / tetrahydrofuran / -15 - 20 °C / Inert atmosphere 2: ammonium formate / palladium on carbon / toluene / 3 h / 80 °C View Scheme

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / dichloromethane / 16 h / 55 °C 2: hydrogenchloride; zinc / tetrahydrofuran; water 3: 5%-palladium/activated carbon; methanol; potassium formate / 45 °C / Inert atmosphere View Scheme

(R)-10-camphorsulfonic acid (35963-20-3) + 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9) → (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1R)-10-camphorsulfonate (188416-34-4, 137234-71-0)

Conditions	Yield
In methanol at 0 - 2℃; Product distribution / selectivity;	81.52%
In acetone at 45 - 55℃; for 2h; Large scale;	70%
In methanol; acetone for 1h; Reflux;	40%

(R)-10-camphorsulfonic acid (35963-20-3) + 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9) → voriconazole L-camphorsulfate

Conditions	Yield
In water; acetone at 20 - 50℃; for 2h; Temperature;	40.4%

(1S)-10-camphorsulfonic acid (3144-16-9) + 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9) → 2-(2,4difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol-R(-)-10-camphor sulphonate (321589-01-9)

Conditions	Yield
In methanol; acetone at 15 - 65℃; for 3.25h;

2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9) → voriconazole (137234-62-9)

Conditions	Yield
Stage #1: 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol With (R)-10-camphorsulfonic acid In methanol; acetone at 25 - 60℃; for 2h; Stage #2: With sodium hydroxide In dichloromethane; water; isopropyl alcohol at 20 - 30℃; pH=12 - 13; Product distribution / selectivity;
With (1S)-10-camphorsulfonic acid In methanol; acetone at 20 - 30℃; for 3.5h; Reflux;
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 3 h / 45 °C 2: camphor-10-sulfonic acid / methanol; acetone View Scheme

2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9) → (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol + voriconazole (137234-62-9)

Conditions	Yield
With 3-aminopropyl silica-supported chitosan bis(3,4-dichlorophenylcarbamate)(n-octylurea) In hexane; isopropyl alcohol Resolution of racemate;

2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9) → C6H7FN2 + 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone (86404-63-9)

Conditions	Yield
With sodium hydroxide In water at 45℃; for 3h;

Rose-Bengale (152-74-9) + 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9) → C20H4Cl4I4O5*C16H14F3N5O

Conditions	Yield
In aq. buffer pH=2;

Upstream product

• 188416-35-5 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol 
• 1289559-67-6 1-(5-fluoropyrimidin-4-yl)ethyl-4-methyl benzenesulfonate 
• 86404-63-9 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone 
• 1289559-75-6 C₆H₅FN₂O 
• 1289559-65-4 1-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethanone 
• 1289559-66-5 1-(5-fluoropyrimidin-4-yl)ethanol 
• 51336-94-8 2-chloro-1-(2,4-dichlorophenyl)ethanone 
• 137234-87-8 6-ethyl-5-fluoro-4-hydroxypyrimidine 
• 1237496-99-9 6-ethyl-5-fluoropyrimidin-4-yl methanesulfonate 
• 1237497-00-5 6-(1-bromoethyl)-5-fluoropyrimidin-4-yl methanesulfonate 
• 906451-64-7 1-(2,4-difluorophenyl)-2-(3,5-dibromo-1H-1,2,4-triazol-1-yl)ethanone 
• 188416-20-8 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol hydrochloride salt 
• 137234-74-3 4-chloro-6-ethyl-5-fluoropyrimidine 

Downstream Products

• 321589-01-9 2-(2,4difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol-R(-)-10-camphor sulphonate 
• 188416-34-4 (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1R)-10-camphorsulfonate 
• 137234-62-9 voriconazole 
• 137234-63-0 (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 
• 86404-63-9 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone 

Relevant articles and documents

Preparation method of voriconazole intermediate

The invention is suitable for the technical field of chemical synthesis and medicine, and provides a preparation method of voriconazole intermediate, which comprises steps of: carrying out a bromination reaction on 4-chloro-6-ethyl-fluoropyrimidine, N-bromosuccinimide, azodiisobutyronitrile and a first solvent to obtain a first intermediate; carrying out condensation reaction on the first intermediate, 2',4'-difluoro-2-[1-(1H-1,2,4-triazolyl)]acetophenone, zinc powder subjected to acid treatment and a second solvent to obtain a second intermediate; mixing the second intermediate, a third solvent and potassium formate to obtain a mixed solution; and adding palladium carbon into the mixed solution, and carrying out reflux reaction in a protective atmosphere to obtain the voriconazole intermediate. According to the preparation method disclosed by the invention, the voriconazole intermediate with high yield and high purity can be prepared.

Voriconazole and intermediate preparation method

The present invention discloses a Voriconazole condensate isomer as raw materials for recovery under acidic conditions to obtain 4 - chloro - 6 - ethyl - 5 - fluoro pyrimidine and 2 '4' - difluoro - 2 - [1 - (1 H - 1, 2, 4 - triazolyl)] acetophenone, and can further be used for the preparation of Voriconazole. The method can greatly improve the prior art for preparing the utilization rate of the fu likang zuozuo original auxiliary materials, the cost is reduced.

A NOVEL PROCESS TO MANUFACTURE (2R,3S)-2-(2,4-DIFLUOROPHENYL)-3-(5-FLUOROPYRIMIDIN-4-YL)-1-(1H-1,2,4-TRIAZOL-1-YL)BUTAN-2-OL

The present invention relates to a novel industrially viable, cost effective process to manufacture substantially pure form of (2R,3S)-2-(2,4-difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol (Voriconazole) with a chiral purity level of greater than 99.9 % and impurity level of less than 0.1 %.