4-AMINO-2-CHLOROPYRIMIDINE-5-CARBONITRILE

Chemical Properties

White to yellow to brown solid

Uses

4-Amino-2-chloropyrimidine-5-carbonitrile is a potential substituent in the synthesis of anti-anxiety, anti-depressant and anti-psychotic agents.

Synthesis Reference(s)

Journal of Heterocyclic Chemistry, 24, p. 1305, 1987 DOI: 10.1002/jhet.5570240514

Synthesis

2,4-Dichloropyrimidine-5-carbonitrile (E-1) (2.0 g, 11.5 mmol) was used as a feedstock and dissolved in 1,4-dioxane (20 mL) at 0 °C. Subsequently, ammonium hydroxide solution (28-30%, 4.4 mL, 34.5 mmol) was slowly added dropwise and the reaction mixture was kept at 0 °C during the dropwise addition. After the dropwise addition was completed, the reaction mixture was gradually warmed from 0 °C to room temperature with continuous stirring for 2 hours. Upon completion of the reaction, the mixture was transferred to a dispensing funnel and partitioned with ethyl acetate (200 mL) and water (50 mL). The organic layer was separated and washed with brine and subsequently dried over anhydrous sodium sulfate. The dried organic phase was filtered, mixed with silica gel and concentrated under vacuum. The residue was purified by silica gel column chromatography using a 0-100% ethyl acetate/hexane gradient elution to afford the target product 2-amino-4-chloropyrimidine-5-carbonitrile (E-2) (917 mg) and a mixture of (E-2) and 4-amino-2-chloropyrimidine-5-carbonitrile (E-3). Further purification by a second column chromatography allowed the isolation of additional (E-3) from the above mixture.

References

[1] Patent: US2013/53362, 2013, A1. Location in patent: Paragraph 0723; 0724; 0725
[2] Patent: WO2015/168079, 2015, A1. Location in patent: Paragraph 00607; 00608