5-Bromo-2-chloropyrimidine Chemical Properties

Melting point:

73-79 °C (lit.)

Boiling point:

95°C 15mm

Density 

1.859±0.06 g/cm3(Predicted)

Flash point:

95°C/15mm

storage temp. 

Keep in dark place,Sealed in dry,Room Temperature

solubility 

soluble in Methanol

pka

-2.84±0.22(Predicted)

form 

Crystalline Powder

color 

Off-white to beige

Water Solubility 

insoluble

BRN 

507955

Stability:

Hygroscopic

InChI

InChI=1S/C4H2BrClN2/c5-3-1-7-4(6)8-2-3/h1-2H

InChIKey

XPGIBDJXEVAVTO-UHFFFAOYSA-N

SMILES

C1(Cl)=NC=C(Br)C=N1

CAS DataBase Reference

32779-36-5(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38

Safety Statements 

26-36/39-37/39-36

RIDADR 

UN 3335

WGK Germany 

3

HazardClass 

IRRITANT

HS Code 

29335990

MSDS

• Language:English Provider:ACROS
• Language:English Provider:SigmaAldrich
• Language:English Provider:ALFA

5-Bromo-2-chloropyrimidine Usage And Synthesis

Description

5-Bromo-2-chloropyrimidine is a halogenated pyrimidine analogue containing chloro and bromo substituents at positions 2 and 5 of the benzene ring structure. The compound is used as a pharmaceutical intermediate in the preparation of macitentan, an endothelin receptor antagonist drug for the treatment of pulmonary hypertension.

Chemical Properties

Off-white to beige crystalline powder

Uses

5-Bromo-2-chloropyrimidine is applied as a pharmaceutical intermediate, in the synthesis of pharmaceutical goods such as inhibitors. It is also employed in the cross-coupling reactions of indium organometallics with 2,5-dihalopyrimidines.

Uses

5-Bromo-2-chloropyrimidine is a intermediate in the synthesis of pharmaceutical goods such as inhibitors.

Preparation

Under nitrogen protection, 35 g (0.2 mol) of 2-hydroxy-5-bromopyrimidine, 61.3 g (0.4 mol) of phosphorus oxychloride, and 200 mL of toluene were added into the reaction flask. At 35 ℃, triethylamine 40.5g was added and then heated up at 80-85 ℃. Stir the reaction for 6 hours, sampling HPLC to detect the raw material (less than 2%), and lower the temperature. After concentrating the mixture under reduced pressure to remove most of the toluene and Phosphorus oxychloride, put the reaction solution into 10°C water, and adjust pH=8-9 with 20% sodium carbonate aqueous solution. Finally, 5-Bromo-2-chloropyrimidine was obtained after purification.

Reactivity Profile

5-Bromo-2-chloropyrimidine, a 2,5-dihalopyrimidine, is a useful organic electrophiles. It could react with tri(3-indolyl)indium reagent through cross-coupling reaction. Other aryl- and heteroarylindium reagents, such as thiophenyl-, pyridyl-, naphthyl-, and alkynylindium reagents, also reacted with 5-bromo-2- chloropyrimidine to afford the corresponding 2-chloro-5-substituted pyrimidines[1].

Synthesis

General procedure for the synthesis of 5-bromo-2-chloropyrimidine from 5-bromopyrimidin-2(1H)-one: Phosphoryl chloride (225 mL, 2.4 mol, 1.4 eq.) was slowly added to a reaction flask containing a mixture of 5-bromo-2-hydroxypyrimidine (30 g, 0.17 mol) and dimethylaniline (7.5 mL). The reaction mixture was heated to reflux under nitrogen protection for 4 hours. Upon completion of the reaction, the dark brown reaction mixture was cooled to room temperature and then carefully poured into ice water. The mixture was extracted with ether to separate the organic phase. The organic phase was subsequently washed with sodium bicarbonate solution to remove acidic impurities. The washed organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the target product 5-bromo-2-chloropyrimidine (25 g, 75% yield). [Ref: Goodby, J.W.; Hird, M.; Lewis, R.A.; Toyne, K.J. J. Chem. Soc., Chem. Commun. 1996, 2719.]

References

[1] Mosquera A, et al. Cross-Coupling Reactions of Indium Organometallics with 2,5-Dihalopyrimidines: Synthesis of Hyrtinadine A?. Organic Letters, 2008; 10: 3745–3748.

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