137234-74-3

Basic information

• Product Name: 4-Chloro-6-ethyl-5-fluoropyrimidine
• Synonyms: 4-chloro-6-ethyl-5-fluoropyiMidine;4-CHLORO-6-ETHYL-5-FLUOROPYRIMIDINE;6-CHLORO-4-ETHYL-5-FLUORO-1,6-DIHYDROPYRIMIDINE;4-chloro-6-ethyl-5-flouropyrimidine;4-Chloro-5-fluoro-6-ethylpyriMidine;PyriMidine, 4-chloro-6-ethyl-5-fluoro-
• CAS NO: 137234-74-3
• Molecular Formula: C₆H₆ClFN₂
• Molecular Weight: 160.58
• EINECS: 1308068-626-2
• Product Categories: APIs & Intermediate;Pyrimidine;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Fluorine series
• Mol File: 137234-74-3.mol
• Article Data: 13

Chemical Properties

• Boiling Point: 211°C
• Flash Point: 81°C
• Appearance: /
• Density: 1.286
• Vapor Pressure: 0.272mmHg at 25°C
• Refractive Index: 1.496
• Storage Temp.: Room temperature.
• Solubility: Chloroform, Ethyl Acetate
• PKA: -0.45±0.26(Predicted)
• CAS DataBase Reference: 4-Chloro-6-ethyl-5-fluoropyrimidine(CAS DataBase Reference)
• NIST Chemistry Reference: 4-Chloro-6-ethyl-5-fluoropyrimidine(137234-74-3)
• EPA Substance Registry System: 4-Chloro-6-ethyl-5-fluoropyrimidine(137234-74-3)

Safety Data

• Statements: 20/21/22-36/37/38-41
• Safety Statements: 22-36/37/39-45-39-26
• RIDADR: UN3267
• HazardClass: 8
• Hazardous Substances Data: 137234-74-3(Hazardous Substances Data)

Usage

Chemical Properties

4-Chloro-6-ethyl-5-fluoropyrimidine is Yellow Liquid

Uses

Different sources of media describe the Uses of 137234-74-3 differently. You can refer to the following data:
1. 4-Chloro-6-ethyl-5-fluoropyrimidine is a pyrimidine derivative used as a building block in the preparation of bio-active compounds such as broad-spectrum triazole antifungal agents.
2. A pyrimidine derivative used as a building block in the preparation of bio-active compounds such as broad-spectrum triazole antifungal agents.

InChI:InChI=1/C6H6ClFN2/c1-2-4-5(8)6(7)10-3-9-4/h3H,2H2,1H3

Synthetic route

6-ethyl-5-fluoropyrimidin-4(1H)-one (137234-87-8) → 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3)

Conditions	Yield
With triethylamine; trichlorophosphate In dichloromethane at 48℃; for 6h; Product distribution / selectivity; Industry scale; Heating / reflux;	99%
With triethylamine; trichlorophosphate In dichloromethane for 5h; Product distribution / selectivity; Heating / reflux;	90%
With triethylamine; trichlorophosphate In dichloromethane at 40℃; for 5.16667h; Reflux;

6-ethyl-5-fluoro-4-hydroxypyrimidine (137234-87-8) → 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3)

Conditions	Yield
Stage #1: 6-ethyl-5-fluoro-4-hydroxypyrimidine With triethylamine; trichlorophosphate In dichloromethane for 5.5h; Heating / reflux; Stage #2: With hydrogenchloride; water In dichloromethane at 20℃;	95%
With triethylamine; trichlorophosphate In dichloromethane at 40℃; for 8h; Reflux;	90%
With trichlorophosphate In N,N-dimethyl-formamide at 90℃; for 5h;	90.2%

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

6-Ethyl-5-fluoropyrimidin-4(3H)-one (137234-87-8) → 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3)

Conditions	Yield
With trichlorophosphate Heating;

2-fluoro-3-oxopentanoic acid ethyl ester (759-67-1) → 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1) MeONa, MeOH 2: POCl3 / Heating View Scheme
Multi-step reaction with 2 steps 1: sodium methylate / methanol / 20 h / 15 °C 2: trichlorophosphate / 3 h / 60 °C View Scheme

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → 1-(4-chloro-5-fluoropyrimidin-6-yl)bromoethane (188416-28-6)

Conditions	Yield
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In dichloromethane at 55℃; for 16h; Temperature;	98%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In dichloromethane for 12h; Reflux;	95.1%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In dichloromethane for 12h; Reflux;	95.1%

p-Chlorothiophenol (106-54-7) + 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → 4-(4-chloro-phenylsulfanyl)-6-ethyl-5-fluoropyrimidine (1112937-23-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 10 - 20℃; for 2h;	96%

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) + Methyl thiosalicylate (4892-02-8) → methyl 2-(6-ethyl-5-fluoropyrimidin-4-yl-sulfanyl)benzoate (1258386-27-4)

Conditions	Yield
Stage #1: Methyl thiosalicylate With sodium hydride In tetrahydrofuran at 5℃; for 0.666667h; Stage #2: 4-chloro-6-ethyl-5-fluoropyrimidine In tetrahydrofuran at 20 - 25℃;	96%

thiophenol (108-98-5) + 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → 4-(phenylsulfanyl)-6-ethyl-5-fluoropyrimidine (1112937-27-5)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In acetonitrile at 10℃; for 2h;	95%

(3-(3-phenylpropyl)piperidin-3-yl)methanol + 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → (1-(6-ethyl-5-fluoropyrimidin-4-yl)-3-(3-phenylpropyl)piperidin-3-yl)methanol

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide at 120℃; for 17.3h; Sealed tube;	81%

(4-(3-phenylpropyl)piperidin-4-yl)methanol hydrochloride + 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → (1-(6-ethyl-5-fluoropyrimidin-4-yl)-4-(3-phenylpropyl)piperidin-4-yl)methanol

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide at 120℃; for 18h; Sealed tube;	74%

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → 6-ethyl-5-fluoropyrimidine-4-thiol (1119241-48-3)

Conditions	Yield
With sodium hydrogensulfide In acetonitrile at 48 - 52℃; for 8.75h; Product distribution / selectivity; Industry scale;	73%
With sodium hydrogensulfide In methanol at 50℃; for 4.25h; Product distribution / selectivity;

1-methyl-5-mercaptotetrazole (13183-79-4) + 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → 4-ethyl-5-fluoro-6-(1-methyl-1H-tetrazol-5-yl-sulfanyl)pyrimidine

Conditions	Yield
Stage #1: 1-methyl-5-mercaptotetrazole With sodium hydride In tetrahydrofuran at 5 - 25℃; Stage #2: 4-chloro-6-ethyl-5-fluoropyrimidine In tetrahydrofuran at 5 - 25℃;	63.4%

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) + dl-α-methyl-4-pentafluorophenoxybenzylamine (130339-49-0) → 6-ethyl-5-fluoro-4-(α-methyl-4-pentafluorophenoxybenzylamino)pyrimidine

Conditions	Yield
With triethylamine; dmap In N,N-dimethyl-formamide for 8h; Substitution; Heating;

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) + dl-α-methyl-4-difluoromethoxybenzylamine (136123-72-3) → 6-ethyl-5fluoro-4-(α-methyl-4-difluoromethoxybenzylamino)pyrimidine

Conditions	Yield
With triethylamine at 20℃; Substitution;

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Conditions	Yield
Multi-step reaction with 2 steps 1: LDA / tetrahydrofuran 2: H2, AcONa / Pd/C / ethanol / 20 °C View Scheme

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → voriconazole (137234-62-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: LDA / tetrahydrofuran 2: H2, AcONa / Pd/C / ethanol / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: sodium acetate / ethyl acetate; water / 0.5 h / 25 - 30 °C 2.2: 25 - 30 °C / 3677.86 Torr 2.3: 0.5 h / 20 - 25 °C 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 5 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: hydrogen; sodium acetate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 2.2: 0.5 h / 20 - 25 °C 2.3: 12.5 h / 25 - 30 °C 3.1: sodium hydroxide / dichloromethane; water / 0.5 h / pH 9 - 12 4.1: acetone; methanol / 15 h / -20 - 25 °C 5.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme

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;

1-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]methanamine (1289106-56-4) + 4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → 6-ethyl-5-fluoro-N-{[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}-4-pyrimidinamine hydrochloride

Conditions	Yield
Stage #1: 1-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]methanamine; 4-chloro-6-ethyl-5-fluoropyrimidine With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 0℃; Stage #2: With hydrogenchloride In 1,4-dioxane; methanol

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)butane-2-ol

Conditions	Yield
Multi-step reaction with 2 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: sodium acetate / ethyl acetate; water / 0.5 h / 25 - 30 °C 2.2: 25 - 30 °C / 3677.86 Torr 2.3: 0.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: hydrogen; sodium acetate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 2.2: 0.5 h / 20 - 25 °C 2.3: 12.5 h / 25 - 30 °C 3.1: sodium hydroxide / dichloromethane; water / 0.5 h / pH 9 - 12 View Scheme
Multi-step reaction with 3 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: hydrogen; sodium acetate; sodium carbonate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 2.2: 0.5 h / 20 - 25 °C 2.3: 10 - 25 °C 3.1: potassium carbonate / dichloromethane; water / 0.5 h / pH 8 - 10 View Scheme

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → (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 3 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: sodium acetate / ethyl acetate; water / 0.5 h / 25 - 30 °C 2.2: 25 - 30 °C / 3677.86 Torr 2.3: 0.5 h / 20 - 25 °C 3.1: acetone; methanol / 15 h / -20 - 25 °C View Scheme
Multi-step reaction with 4 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: hydrogen; sodium acetate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 2.2: 0.5 h / 20 - 25 °C 2.3: 12.5 h / 25 - 30 °C 3.1: sodium hydroxide / dichloromethane; water / 0.5 h / pH 9 - 12 4.1: acetone; methanol / 15 h / -20 - 25 °C View Scheme
Multi-step reaction with 4 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: hydrogen; sodium acetate; sodium carbonate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 2.2: 0.5 h / 20 - 25 °C 2.3: 10 - 25 °C 3.1: potassium carbonate / dichloromethane; water / 0.5 h / pH 8 - 10 4.1: acetone; methanol / 15 h / -20 - 25 °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)-2-butanol hydrochloride salt

Conditions	Yield
Multi-step reaction with 2 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: hydrogen; sodium acetate; sodium carbonate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 2.2: 0.5 h / 20 - 25 °C 2.3: 10 - 25 °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)-2-butanol (+/-)-camphorsulphonate salt

Conditions	Yield
Multi-step reaction with 2 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: hydrogen; sodium acetate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 2.2: 0.5 h / 20 - 25 °C 2.3: 12.5 h / 25 - 30 °C View Scheme

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / dichloromethane / 16 h / Inert atmosphere; Reflux 2.1: lead; zinc; bromine / dichloromethane; tetrahydrofuran / 30 - 50 °C 2.2: 4 h / 20 - 25 °C View Scheme

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → voriconazole L-camphorsulfate

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / dichloromethane / 16 h / Inert atmosphere; Reflux 2.1: lead; zinc; bromine / dichloromethane; tetrahydrofuran / 30 - 50 °C 2.2: 4 h / 20 - 25 °C 3.1: sodium hydroxide / water; methanol / 20 - 25 °C / pH 8 - 9 3.2: 55 - 60 °C 3.3: 1 h / 40 - 45 °C View Scheme

Upstream product

• 24045-73-6 ethyl 2-chloro-3-oxopentanoate 
• 137234-87-8 6-ethyl-5-fluoropyrimidin-4(1H)-one 
• 759-67-1 2-fluoro-3-oxopentanoic acid ethyl ester 
• 137234-87-8 6-Ethyl-5-fluoropyrimidin-4(3H)-one 
• 137234-87-8 6-ethyl-5-fluoro-4-hydroxypyrimidine 
• 14989-30-1 hypochloric acid 
• 188416-35-5 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol 
• 137234-85-6 2,4-dichloro-6-ethyl-5-fluoropyrimidine 

Downstream Products

• 188416-35-5 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol 
• 182230-43-9 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 
• 1258386-27-4 methyl 2-(6-ethyl-5-fluoropyrimidin-4-yl-sulfanyl)benzoate 
• 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 
• 137234-63-0 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol 
• 1112937-23-1 4-(4-chloro-phenylsulfanyl)-6-ethyl-5-fluoropyrimidine 
• 1112937-27-5 4-(phenylsulfanyl)-6-ethyl-5-fluoropyrimidine 
• 188416-28-6 1-(4-chloro-5-fluoropyrimidin-6-yl)bromoethane 
• 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 

Relevant articles and documents

Preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine

The invention provides a preparation method of 6-ethyl-5-fluoro-4-chloropyrimidine. The preparation method comprises the following steps of: preparation of 6-ethyl-5-chloro-4-hydroxypyrimidine; preparation of 6-ethyl-5-fluoro-4-hydroxypyrimidine; and finally, acquisition of 6-ethyl-5-fluoro-4-chloropyrimidine. According to the invention, cheap alpha-chloropropionyl ethyl acetate or alpha-chloropropionyl methyl acetate is used as the raw material, after ring closing, potassium fluoride is used for fluorination, and finally thionyl chloride is used for chlorination so as to obtain the high yield6-ethyl-5-fluoro-4-chloropyrimidine, and the reaction steps are simple and easy to control, the method is suitable for industrial production, such that a more valuable synthesis route is provided forpreparation of aprepitant, good social benefits and economic benefits can be brought about, and the economic value potential is great.

A 4 - (1-bromo-ethyl) - 5-fluoro-6-chloro-pyrimidine synthesis method

The invention discloses a method for synthesizing 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine. The synthesis method comprises the steps of reacting 2-fluoro-ethyl acetate which is inexpensive and readily available and is used as an initial material with propionyl chloride under basic conditions in a solvent to synthesize an intermediate product 2-fluoro propionyl ethyl acetate; then carrying out cyclization on 2-fluoro propionyl ethyl acetate and formamidine acetate as well as a base in a solvent to obtain a cyclized product; then chlorinating the cyclized product with a chlorinating reagent; and finally adding a brominating reagent and brominating the chlorinated product in the presence of an initiator to obtain 4-(1-bromoethyl) -5-fluoro-6-chloropyrimidine. The synthesis method disclosed by the invention has the advantages of simple process, available raw materials, high yield, safety and environmental protection, and is convenient to industrialize.

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.