5-[(4-Nitrobenzoyl)oxy]-2-[(2-pyrimidinylthio)methyl]-4H-pyran-4-one Chemical Properties

Boiling point:

624.1±55.0 °C(Predicted)

Density 

1.54±0.1 g/cm3(Predicted)

storage temp. 

Sealed in dry,2-8°C

solubility 

DMSO: soluble5mg/mL, clear (warmed)

pka

0.30±0.33(Predicted)

form 

powder

color 

white to beige

Safety Information

WGK Germany 

3

5-[(4-Nitrobenzoyl)oxy]-2-[(2-pyrimidinylthio)methyl]-4H-pyran-4-one Usage And Synthesis

Description

ML-221 is an antagonist of the G protein-coupled receptor (GPCR) APJ (IC₅₀ = 4.8 μM). It is selective for APJ over the angiotensin II type 1 (AT₁) receptor (IC₅₀ = >78 μM). ML-221 antagonizes apelin 13-induced activation of APJ in cAMP and β-arrestin recruitment assays (IC₅₀s = 0.7 and 1.75 μM, respectively). It inhibits proliferation and angiogenesis in Mz-ChA-1 cholangiocarcinoma cells when used at concentrations ranging from 5 to 15 μM. In vivo, ML-221 (150 μg/kg) reduces tumor growth in a Mz-ChA-1 mouse xenograft model. Intrathecal injection of ML-221 (10 μg per animal) reduces mechanical allodynia and heat hyperalgesia induced by chronic constriction injury (CCI) of the sciatic nerve in rats. ML-221 also inhibits pathological angiogenesis and enhances normal vessel recovery in retinal ischemic regions in a mouse model of oxygen-induced retinopathy.

Uses

ML 221 is a functional antagonist of the apelin (APJ) receptor which is shown to treat or mediate the homeostasis of the cardiovascular system.

Definition

ChEBI: 4-nitrobenzoic acid [4-oxo-6-[(2-pyrimidinylthio)methyl]-3-pyranyl] ester is a nitrobenzoic acid.

Synthesis

5-Hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (tricarboxylic acid) (0.55 g, 3.87 mmol) was used as starting material, which was dissolved in thionyl chloride (5 mL, 68.5 mmol), and stirred for 3 hours at room temperature. After completion of the reaction, the excess thionyl chloride was removed by distillation under reduced pressure to afford 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (0.61 g, 98% yield), the product was an off-white solid.1H NMR (500 MHz, DMSO-d6) δ: 8.13 (s, 1H), 6.57 (s, 1H), 4.66 (s, 2H). Step 2: Pyrimidine-2-thiol (161 mg, 1.433 mmol) was dissolved in 2 mL of methanol, sodium methanol solution (310 mg, 1.433 mmol) was added and stirred until completely dissolved. Acetonitrile (10 mL) and 2-(chloromethyl)-5-hydroxy-4H-pyran-4-one (230 mg, 1.433 mmol) were then added and stirred for 3 h at room temperature. The completion of the reaction was confirmed by LC/MS analysis. The solvent was removed under reduced pressure to afford the crude product 5-hydroxy-2-((pyrimidin-2-ylthio)methyl)-4H-pyran-4-one (406 mg, 96% yield) and an equimolar amount of NaCl, the product was a yellow solid, which could be used in the next reaction without further purification.1H NMR (500 MHz, CDCl3) δ: 8.52 (d, 2H, J=4.9 Hz) , 7.80 (s, 1H), 7.02 (t, 1H, J=4.8Hz), 6.63 (s, 1H), 4.23 (s, 2H). Step 3: 5-Hydroxy-2-((pyrimidin-2-ylthio)methyl)-4H-pyran-4-one (200 mg, 0.847 mmol), cesium carbonate (276 mg, 0.847 mmol), and 4-nitrobenzoyl chloride (220 mg, 1.185 mmol) were dissolved in acetonitrile (8 mL) and stirred overnight at room temperature. After the reaction was complete, the solvent was removed under reduced pressure to give a light yellow solid. The solid was partitioned with about 20 mL of 1:1 ethyl acetate and water. The target product, 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate, was insoluble in both phases and was collected by filtration. The solid was dried in vacuum to afford the target product (202 mg, 62% yield) as a brown solid.1H NMR (500 MHz, DMSO-d6) δ: 8.69 (d, 2H, J=4.8 Hz), 8.68 (s, 1H), 8.40 (d, 2H, J=8.8 Hz), 8.29 (d, 2H, J=8.8 Hz), 7.29 ( t, 1H, J=4.9Hz), 6.65 (s, 1H), 4.45 (s, 2H).13C NMR (125 MHz, DMSO-d6) δ: 171.2, 168.8, 165.9, 161.7, 158.1, 150.8, 149.9, 140.3, 133.0, 131.4, 124.2 118.0, 114.6, 31.2.

storage

Store at +4°C

References

[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 21, p. 6656 - 6660,5
[2] Patent: US2014/5181, 2014, A1. Location in patent: Paragraph 0155

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