6-Chloropyrimidin-4(3H)-one

Off-White to Pale Yellowish Solid

Intermediate 1: 6-Chloro-3H-pyrimidin-4-one A solution of 4, 6-dichloropyrimidine (2 g, 13.42 mmol) in a mixture of 4N HC1 (10.49 mL, 121 mmol)- 1, 4-dioxane (10 mL)-water (10 mL) was heated to 70 CC for 6 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a pink solid. Ethanol (25 mL) was added to thesolid and the mixture was heated at 50 °C until the solid dissolved. The resulting pink solution was left overnight at room temperature and the precipitation formed was filtered and dried under vacuum to afford 6-chloropyrimidin-4(3B)-one (1 g, 7.51 mmol, 56percent yield) as an off-white solid. LCMS (ESI)m/e 130.8 [(M+H), calcd for C4H4C1N2O, 130.91; LC/MS retention time (Method C): tR = 0.51 mm.General procedure: The appropriate nucleophile (1 equiv.), the epoxide (1-3 equiv.) and a base (1-5 equiv.) were suspended in a solvent and the reaction mixture was heated under the stated conditions. (0735) The reaction was allowed to cool to rt, saturated NH4CI(aq) or water was added and the resulting mixture was extracted using DCM or EtOAc (x 3). The combined organic extracts were dried (phase separator or MgS04), concentrated under reduced pressure and the remaining residue was purified by flash chromatography to give the product.General procedure: The appropriate nucleophile (1 equiv.), the epoxide (1-3 equiv.) and a base (1-5 equiv.) were suspended in a solvent and the reaction mixture was heated under the stated conditions. (0735) The reaction was allowed to cool to rt, saturated NH4CI(aq) or water was added and the resulting mixture was extracted using DCM or EtOAc (x 3). The combined organic extracts were dried (phase separator or MgS04), concentrated under reduced pressure and the remaining residue was purified by flash chromatography to give the product.To A suspension of 6-chloropyrimidin-4(3/-/)-one (U.S. Pat. Appl. Publ., 20090149466, 1 1 Jun 2009) (200 mg, 1.53 mmol), Epoxide 2 (397 mg, 1.53 mmol) and DIPEA (401 muIota, 2.30 mmol) in DMF (3 mL) was heated at 80 C for 16 h. The reaction mixture was then allowed to cool to RT and was quenched by the addition of saturated NH4CI(aq) (20 mL).The mixture was extracted with EtOAc (3 x 20 mL), the combined organic extracts were dried over Na2S04, concentrated, and the residue was purified by flash chromatography (Biotage 25 g KP-Sil, 0- 100% EtOAc in PE then 0-30% MeOH in EtOAc) to give the title compound (350 mg, 59%) as a pale yellow solid. LCMS (Method A): RT = 1.11 min, m/z = 390, 392 [M+H]+. 1H NMR (300 MHz, methanol-d4, this molecule appears as two conformers A and B in a 2:3 ratio respectively): delta 8.28 (s, 0.4H (conformer A)), 8.24 (s, 0.6H (conformer B)), 7.38-7.13 (m, 5H), 6.58 (s, 1 H), 4.27-4.09 (m, 1 H), 4.00 (dd, 0.8H (conformer A)), 3.84 (dd, 1.2H (0604) (conformer B)), 3.74-3.57 (m, 1 H), 3.39-2.86 (m, 3H), 2.86-2.67 (m, 1 H), 2.66-2.43 (m, 1 H), 1.66-1.20 (m, 7H), 0.93-0.79 (m, 0.6H (conformer B only)).General procedure: The appropriate nucleophile (1 equiv.), the epoxide (1-3 equiv.) and a base, either Cs2C03 (1-3 equiv.) or DIPEA (1.5 equiv.), were suspended in DMF and the mixture was heated at 80 C for 10-24 h or as indicated. The reaction was cooled to RT. Saturated aqueous ammonium chloride solution or water was added and the mixture was extracted with DCM or EtOAc (*3). The combined organic extracts were dried (Biotage phase separator or MgS04), concentrated and the residue was purified by flash chromatography (Biotage KP-Sil and/or KP-NH, 0-100% EtOAc in cyclohexane; then 0-30% MeOH in EtOAc) to give the product.A solution of 6-chloropyrimidin-4(3/-/)-one (3.72 g, 28.5 mmol), Epoxide 1 (6.08 g, 28.5 mmol) and DIPEA (7.47 mL, 42.7 mmol) in DMF (35 mL) was heated at 80 C for 16 h. The reaction mixture was allowed to cool to RT before it was quenched by the addition of saturated NH4CI(aq) (20 mL) and the resulting mixture was extracted with EtOAc. The combined organic extracts were dried over MgS04, concentrated and the residue was purified by chromatography (Grace 120 g Resolv, 0-100% EtOAc in cyclohexane) to give tert-butyl 4-((4-chloro-6-oxopyrimidin-1 (6/-/)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (5.87 g, 60%) as an off-white solid. LCMS (Method B): RT = 0.99 min, m/z = 342 [M+H]+.General procedure: The appropriate nucleophile (1 equiv.), the epoxide (1-3 equiv.) and a base, either Cs2C03 (1-3 equiv.) or DIPEA (1.5 equiv.), were suspended in DMF and the mixture was heated at 80 C for 10-24 h or as indicated. The reaction was cooled to RT. Saturated aqueous ammonium chloride solution or water was added and the mixture was extracted with DCM or EtOAc (*3). The combined organic extracts were dried (Biotage phase separator or MgS04), concentrated and the residue was purified by flash chromatography (Biotage KP-Sil and/or KP-NH, 0-100% EtOAc in cyclohexane; then 0-30% MeOH in EtOAc) to give the product.General procedure: The appropriate nucleophile (1 equiv.), the epoxide (1-3 equiv.) and a base (1-5 equiv.) were suspended in a solvent and the reaction mixture was heated under the stated conditions. (0735) The reaction was allowed to cool to rt, saturated NH4CI(aq) or water was added and the resulting mixture was extracted using DCM or EtOAc (x 3). The combined organic extracts were dried (phase separator or MgS04), concentrated under reduced pressure and the remaining residue was purified by flash chromatography to give the product.General procedure: The appropriate nucleophile (1 equiv.), the epoxide (1-3 equiv.) and a base, either Cs2C03 (1-3 equiv.) or DIPEA (1.5 equiv.), were suspended in DMF and the mixture was heated at 80 C for 10-24 h or as indicated. The reaction was cooled to RT. Saturated aqueous ammonium chloride solution or water was added and the mixture was extracted with DCM or EtOAc (*3). The combined organic extracts were dried (Biotage phase separator or MgS04), concentrated and the residue was purified by flash chromatography (Biotage KP-Sil and/or KP-NH, 0-100% EtOAc in cyclohexane; then 0-30% MeOH in EtOAc) to give the product.

Molecular Weight:130.53
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:129.9933904
Monoisotopic Mass:129.9933904
Topological Polar Surface Area:41.5
Heavy Atom Count:8
Complexity:173
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes