4-Chloro-5H-pyrrolo[3,2-d] pyrimidine

Description

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine is a purine analog that inhibits the growth of bacteria by binding to the enzyme DNA gyrase. It has been shown to be effective against staphylococcus and Mycobacterium tuberculosis.

Uses

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine is a chlorinated pyrrolopyrimidine used in the preparation of compounds with antibacterial and antitumor activities.

Application

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine binds to the enzyme DNA gyrase and prevents it from breaking down the bacterial DNA. This drug also has antimycobacterial activity due to its ability to bind to the enzyme RNA polymerase.

Synthesis

Step 4: Preparation of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (32e). 3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (32d) (31.08 g, 230 mmol) was placed under a nitrogen atmosphere and phosphoryl chloride (60 mL, 644 mmol) was added. The reaction mixture was heated to reflux for 1 h, during which the mixture was observed to transform into a black homogeneous solution. Upon completion of the reaction, the mixture was cooled in an ice-water bath and subsequently slowly poured into crushed ice (775 mL) under stirring. The pH of the aqueous solution was slowly adjusted to about 8 with concentrated ammonia (225 mL) while keeping the mixture cool. The resulting precipitate was collected by vacuum filtration and washed with cold water. The solid was transferred to a drying tray and dried under vacuum at 110 °C to afford 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (32e) (31.48 g, 89% yield) as a dark gray solid. To obtain an analytically pure sample, it was purified by silica gel column chromatography (eluent: EtOAc-hexane, 35:65) and the relevant fractions were collected and concentrated. Grinding of the solid with EtOAc-MeOH mixed solvent afforded an off-white solid 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (32e) with a melting point >150 °C (decomposition).1H NMR (DMSO-d6) δ 12.43 (s, D2O exchangeable, 1H), 8.61 (s, 1H), 7.97 (dd, J = 2.8, 2.8 Hz; D2O-exchangeable to d, 1H), 6.72 (dd, J = 1.7, 3.5 Hz; D2O-exchangeable to d, 1H).13C NMR (DMSO-d6) δ 151.30, 149.58, 142.12, 134.83, 124.32, 102.70.IR (pure sample) 3128, 3078, 2979, 1621 cm-1. MS (ES+) m/z 154.01 (100%, [M+H]+), 156.01 (33%). Elemental analysis (C6H4N3Cl) Calculated values: C, 46.93; H, 2.63; N, 27.36; Cl, 23.09. Measured values: C, 47.10; H, 2.79; N, 27.15; Cl, 22.93.

References

[1] Organic Process Research and Development, 2009, vol. 13, # 5, p. 928 - 932
[2] Patent: WO2014/78778, 2014, A2. Location in patent: Page/Page column 105
[3] Journal of Organic Chemistry, 2011, vol. 76, # 21, p. 8658 - 8669
[4] Patent: WO2008/70507, 2008, A2. Location in patent: Page/Page column 150-151
[5] Patent: US2012/202785, 2012, A1. Location in patent: Page/Page column 129