188416-35-5

Basic information

• Product Name: (2R,3S/2S,3R)-3-(4-Chloro-5-fluoro-6-pyrimidinyl)-2-(2,4-difluorophenyl)butan-2-ol hydrochloride
• Synonyms: 6-Chloro-α-(2,4-difluorophenyl)-5-fluoro-β-Methyl-α-(1H-1,2,4-triazol-1-ylMethyl)-4-pyriMidineethanol;4-PyriMidineethanol, 6-chloro-a-(2,4-difluorophenyl)-5-fluoro-b-Methyl-a-(1H-1,2,4-triazol-1-ylMethyl)-;(2R,3S/2S,3R)-3-(4-CHLORO-5-FLUORO PYRIMIDIN-6-YL)-2-(2,4-DIFLUOROPHENYL)-1-(1H-1,2,4-TRIAZOL-1-YL);Voriconazole (RR,SS)-6-Chloro IMpurity;(2S,3R)-3-(6-chloro-5-fluoropyriMidin-4-yl)-2-(2,4-difluorophenyl)butan-2-ol hydrochloride;6-Chloro Voriconazole;Voriconazole (RS,SR)-6-Chloro Impurity;N-2
• CAS NO: 188416-35-5
• Molecular Formula: C₁₆H₁₃ClF₃N₅O
• Molecular Weight: 383.76
• EINECS: 1806241-263-5
• Product Categories: INTERMEDIATESOFVORICONAZOLE;Heterocycles;Intermediates;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 188416-35-5.mol
• Article Data: 9

Chemical Properties

• Melting Point: 183-187°C
• Boiling Point: 550.9oC at 760 mmHg
• Flash Point: 287oC
• Appearance: /
• Density: 1.51
• Vapor Pressure: 5.69E-13mmHg at 25°C
• Storage Temp.: Refrigerator
• PKA: 11.44±0.29(Predicted)
• CAS DataBase Reference: (2R,3S/2S,3R)-3-(4-Chloro-5-fluoro-6-pyrimidinyl)-2-(2,4-difluorophenyl)butan-2-ol hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: (2R,3S/2S,3R)-3-(4-Chloro-5-fluoro-6-pyrimidinyl)-2-(2,4-difluorophenyl)butan-2-ol hydrochloride(188416-35-5)
• EPA Substance Registry System: (2R,3S/2S,3R)-3-(4-Chloro-5-fluoro-6-pyrimidinyl)-2-(2,4-difluorophenyl)butan-2-ol hydrochloride(188416-35-5)

Safety Data

• Hazardous Substances Data: 188416-35-5(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Uses

An achiral intermediate of Voriconazole (V760000).

InChI:InChI=1/C16H13ClF3N5O.ClH/c1-9(14-13(20)15(17)23-7-22-14)16(26,5-25-8-21-6-24-25)11-3-2-10(18)4-12(11)19;/h2-4,6-9,26H,5H2,1H3;1H/t9-,16+;/m1./s1

Synthetic route

1-(4-chloro-5-fluoropyrimidin-6-yl)bromoethane (188416-28-6) + 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone (86404-63-9) → 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5)

Conditions	Yield
With lead; samarium diiodide; 1-benzyl-3-(2-pyridylmethyl)-1H-benzimidazolium chloride; iodine; zinc In tetrahydrofuran at -5 - 40℃; for 1.33333h; Inert atmosphere;	87%
With zinc(II) chloride Reformatsky Reaction;
With hydrogenchloride; zinc In tetrahydrofuran; water

1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone (86404-63-9) + 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5)

Conditions	Yield
Stage #1: 4-chloro-6-ethyl-5-fluoropyrimidine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; n-heptane at -73 - 18℃; for 2.25h; Stage #2: 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone In tetrahydrofuran; hexane; n-heptane at -74 - 55℃; for 5h;	26.3%
Stage #1: 4-chloro-6-ethyl-5-fluoropyrimidine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; n-heptane at -80 - -70℃; for 0.25h; Inert atmosphere; Stage #2: 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone In tetrahydrofuran; hexane; n-heptane at -80 - -55℃; for 2h; Inert atmosphere;
Stage #1: 4-chloro-6-ethyl-5-fluoropyrimidine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane; n-heptane at -80 - -70℃; for 0.25h; Inert atmosphere; Stage #2: 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone In tetrahydrofuran; hexane; n-heptane at -80 - -55℃; for 2h; Stage #3: With acetic acid In tetrahydrofuran; hexane; n-heptane; water at -70 - -10℃;

1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone (86404-63-9) → 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5)

Conditions	Yield
With diisopropylamine In tetrahydrofuran; water; acetic acid

1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone + 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5)

Conditions	Yield
With lithium diisopropyl amide In tetrahydrofuran; n-heptane at -70 - -65℃; for 3 - 4h; pH=5 - 8;

6-ethyl-5-fluoro-4-hydroxypyrimidine (137234-87-8) → 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 5 - 10 °C 1.2: 8 h / 10 - 55 °C / Reflux 1.3: 0.5 h / 15 - 20 °C 2.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 2.2: 2 h / -80 - -55 °C 2.3: -70 - -10 °C View Scheme

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) → 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5)

Conditions	Yield
With sodium hydroxide In dichloromethane; water at 10℃; for 2h; pH=11;	25 g

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / dichloromethane / 16 h / 55 °C 2: hydrogenchloride; zinc / tetrahydrofuran; water View Scheme

3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5) → 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone (86404-63-9) + 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3)

Conditions	Yield
With hydrogenchloride In water at 60 - 70℃; Temperature; Reagent/catalyst; Solvent;	A 88.4% B n/a

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-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5) → voriconazole (137234-62-9)

Conditions	Yield
Stage #1: 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol With 5%-palladium/activated carbon; hydrogen; sodium acetate In methanol at 25℃; under 760.051 Torr; Stage #2: With [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid In methanol; acetone for 2h; Reflux;	35%
Multi-step reaction with 3 steps 1.1: sodium acetate / ethyl acetate; water / 0.5 h / 25 - 30 °C 1.2: 25 - 30 °C / 3677.86 Torr 1.3: 0.5 h / 20 - 25 °C 2.1: acetone; methanol / 15 h / -20 - 25 °C 3.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme
Multi-step reaction with 4 steps 1.1: hydrogen; sodium acetate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 1.2: 0.5 h / 20 - 25 °C 1.3: 12.5 h / 25 - 30 °C 2.1: sodium hydroxide / dichloromethane; water / 0.5 h / pH 9 - 12 3.1: acetone; methanol / 15 h / -20 - 25 °C 4.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme
Multi-step reaction with 4 steps 1.1: hydrogen; sodium acetate; sodium carbonate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 1.2: 0.5 h / 20 - 25 °C 1.3: 10 - 25 °C 2.1: potassium carbonate / dichloromethane; water / 0.5 h / pH 8 - 10 3.1: acetone; methanol / 15 h / -20 - 25 °C 4.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme

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-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol

Conditions	Yield
With hydrogen; sodium acetate; palladium 10% on activated carbon In water; ethyl acetate at 25 - 30℃; under 3677.86 Torr; Autoclave;

3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5) → (2RS,3SR)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride

Conditions	Yield
Stage #1: 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol With hydrogen; sodium acetate; palladium 10% on activated carbon In water; ethyl acetate at 25 - 30℃; under 3677.86 Torr; Autoclave; Stage #2: With hydrogenchloride In ethyl acetate; isopropyl alcohol at 10 - 25℃;

3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5) + camphor-10-sulfonic acid (76-26-6, 3144-16-9, 5872-08-2, 35963-20-3) → (2RS,3SR)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (+/-)-camphorsulfonate

Conditions	Yield
Stage #1: 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol With hydrogen; sodium acetate; palladium 10% on activated carbon In water; ethyl acetate at 25 - 30℃; under 3677.86 Torr; Autoclave; Stage #2: camphor-10-sulfonic acid In methanol; acetone at 25 - 30℃; for 12.5h;

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)butane-2-ol

Conditions	Yield
Stage #1: 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol With sodium acetate In water; ethyl acetate at 25 - 30℃; for 0.5h; Stage #2: With hydrogen; sodium acetate; palladium 10% on activated carbon In water; ethyl acetate at 25 - 30℃; under 3677.86 Torr; Stage #3: With sodium carbonate In water; ethyl acetate at 20 - 25℃; for 0.5h;
Multi-step reaction with 2 steps 1.1: hydrogen; sodium acetate; sodium carbonate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 1.2: 0.5 h / 20 - 25 °C 1.3: 10 - 25 °C 2.1: potassium carbonate / dichloromethane; water / 0.5 h / pH 8 - 10 View Scheme

3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5) → (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
Multi-step reaction with 2 steps 1.1: sodium acetate / ethyl acetate; water / 0.5 h / 25 - 30 °C 1.2: 25 - 30 °C / 3677.86 Torr 1.3: 0.5 h / 20 - 25 °C 2.1: acetone; methanol / 15 h / -20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: hydrogen; sodium acetate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 1.2: 0.5 h / 20 - 25 °C 1.3: 12.5 h / 25 - 30 °C 2.1: sodium hydroxide / dichloromethane; water / 0.5 h / pH 9 - 12 3.1: acetone; methanol / 15 h / -20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: hydrogen; sodium acetate; sodium carbonate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 1.2: 0.5 h / 20 - 25 °C 1.3: 10 - 25 °C 2.1: potassium carbonate / dichloromethane; water / 0.5 h / pH 8 - 10 3.1: acetone; methanol / 15 h / -20 - 25 °C View Scheme

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)-2-butanol hydrochloride salt

Conditions

Yield

Stage #1: 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol With hydrogen; sodium acetate; sodium carbonate; palladium 10% on activated carbon In water; ethyl acetate at 25 - 30℃; under 3677.86 Torr; Stage #2: With sodium carbonate In water; ethyl acetate at 20 - 25℃; for 0.5h; Stage #3: With hydrogenchloride In ethyl acetate; isopropyl alcohol at 10 - 25℃;

3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5) + (1S)-10-camphorsulfonic acid (3144-16-9) + (R)-10-camphorsulfonic acid (35963-20-3) → 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (+/-)-camphorsulphonate salt

Conditions

Yield

Stage #1: 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol With hydrogen; sodium acetate; palladium 10% on activated carbon In water; ethyl acetate at 25 - 30℃; under 3677.86 Torr; Stage #2: With sodium carbonate In water; ethyl acetate at 20 - 25℃; for 0.5h; Stage #3: (1S)-10-camphorsulfonic acid; (R)-10-camphorsulfonic acid In methanol; acetone at 25 - 30℃; for 12.5h;

Upstream product

• 137234-74-3 4-chloro-6-ethyl-5-fluoropyrimidine 
• 188416-28-6 1-(4-chloro-5-fluoropyrimidin-6-yl)bromoethane 
• 86404-63-9 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)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 
• 137234-87-8 6-ethyl-5-fluoro-4-hydroxypyrimidine 

Downstream Products

• 182230-43-9 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 
• 137234-63-0 2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol 
• 137234-62-9 voriconazole 
• 137234-63-0 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol 
• 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 
• 86404-63-9 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone 
• 137234-74-3 4-chloro-6-ethyl-5-fluoropyrimidine 

Relevant articles and documents

Synthesis method of voriconazole and intermediate of voriconazole

The invention relates to a synthesis method of voriconazole and an intermediate of voriconazole. The synthesis method comprises the following step: in a protective gas atmosphere, reacting a compoundshown in formula I and a compound shown in formula II in an organic solvent under the action of a metal catalyst, N-heterocyclic carbene, samarium diiodide and elemental iodine to obtain the voriconazole intermediate shown in formula III. According to the synthesis method of the voriconazole intermediate, under the action of the metal catalyst and SmI2, N-heterocyclic carbene is simultaneously added as a ligand, and elemental iodine is used as an initiator to initiate a reformask coupling reaction between the compound shown in formula I and the compound shown in formula II, so that the defectsof low yield, more byproducts and the like of the traditional reaction are overcome, and the yield and the purity are further improved.

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.

PROCESS FOR THE PREPARATION OF VORICONAZOLE

The present invention provides a process for preparation of racemic voriconazole in a single reaction vessel. The present invention also provides a process for preparation of voriconazole using racemic voriconazole and the process of making it therewith.