2-Chloro-5-pyrimidinamine

Light yellow solid

4.2.6. Synthesis of 2-chloropyrimidin-5-amine (8). A mixture of 2-chloro-5-nitropyrimidine (0.160 g, 1 mmol), iron powder (0.200 g, 3.6 mmol), dried ethanol (2.5 mL), and acetic acid (0.4 mL) wasrefluxed for 6 h, which was then diluted with ethyl acetate, andneutralized with aqueous NaHCO3 before it was filtered with Celite.The filtrate was extracted with ethyl acetate (20 mL3), washedwith brine, and dried over MgSO4. Evaporation of the solvents givesa yellow solid of 8. Yield: 0.127 g, 98percent. 1H NMR (600 MHz, DMSOd6):8.03 (s, 2H), 5.76 (br s, 2H). 13C NMR (150 MHz, DMSO-d6):146.0, 144.2, 142.3. FTIR (KBr, cm1): 3394, 3332, 3212, 1649, 1585, 1545, 1412, 1163, 644. MS (EI, m/z): calcd: 129.0; found: 129 (M).To a solution of 36 (400 mg, 2.5 mmol) in HOAc (5 mL) is added Fe (700 mg.12.5 mmoi). After stirring at 75 °C for 2 hours, the mixture is cooled to room temperature, filtered, concentrated, and purified by silica gel column chromatography (F:A:PE == 1:5) to give 37 as as an oil (320 mg. 98percent yield). (MS: [M+Hj 1300)Example 7 Example 41Synthesis of N-(2-chloro-5-pyrimidinyl)-4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1, 3, 5-triazin-2-amineThe compound was synthesized according to Method A.A suspension of 3.5 g (63 mmol) of iron dust in 10 mL of 1.5percent aq. AcOH and 35 mL of 65percent EtOH was heated to 80° C., and 1.005 g (6.28 mmol) of 2-chloro-5-nitropyrimidine was added. The reaction mixture was then heated at 90° C. for 1 hr. After cooling to room temperature, the reaction mixture was neutralized with aq. NHAcetic acid (15 mL, 261 mmol, 8 equiv) was slowly added to a stirred mixture of iron powder (11 g, 196 mmol, 6 equiv), 2-chloro-5-nitro-pyrimidine (5.3 g, 3 3. 33 m mol, 1 e quiv), a nd m ethanol (75 mL). Note: the reaction will exotherm if the acetic acid is added rapidly. After three hours, the reaction mixture was diluted with EtOAc (300 mL), filtered through celite, and neutralized with aqueous K2CO3 (200 mL). The organic layer was separated, washed with H20 (200 mL) and brine (200 mL), dried (NA2SO4), filtered, and concentrated to give 2 as a yellow solid (2.5 g, 58percent, m/z+ = 130. 1).[0091] Acetic acid (15 mL, 261 mmol, 8 equivalents) is slowly dripped into a mixture containing iron powder (11 g, 196mmol, 6 equivalents) and 2-chloro-5-nitro-pyrimidine (5.3 g, 33.33 mmol, 1 equivalent) and methanol (75 mL). After 3hours, the reaction mixture is diluted with ethyl acetate (300 mL) and filtrated through celite. The organic phase is washedsuccessively with saturated aqueous potassium carbonate solution (200 mL) and brine (200 mL), dried through anhydroussodium sulfate, and concentrated to give compound (1-2) (2.0 g, 46.4percent) as a yellow solid.[0099] Acetic acid (15 ml., 261 mmol, 8 equivalents) is slowly dripped into a mixture containing iron powder (11 g, 196 mmol, 6 equivalents) and 2-chloro-5-nitro-pyrimidine (5.3 g, 33.33 mmol, 1 equivalent) and methanol (75 mL). After 3 hours, the reaction mixture is diluted with ethyl acetate (300 mL) and filtrated through celite. The organic phase is washed successively with saturated aqueous potassium carbonate solution (200 mL) and brine (200 mL), dried through anhydrous sodium sulfate, and concentrated to give compound (1-2) (2.0 g, 46.4percent) as a yellow solidPreparation of 2-chloro-pyrimidin-5-ylamine To a solution of 2-chloro-5-nitropyrimidine (5 g 31.3 mmol) and zinc (20.49 g 313 mmol) in Methanol (150 mL) was added ammonium chloride (16.77 g 313 mmol) at 0 . The resulting mixture was stirred at 25 for 16 hr. After LCMS analysis showed the starting material disappeared the mixture was filtered. The filtrate was concentrated to give the crude product which was purified by column chromatography (PE/EA3/1 to 1/1) . All fractions found to contain product by TLC (PE/EA1/1 R2-Chloropyrimidin-5-amine (500 mg, 3.86 mmol) was added to a suspension of an aqueous Na2CO3 solution (2.0 M, 3.9 ml_, 7.72 mmol), (0525) Pd(dppf)CI2.CH2Cl2 (252 mg, 0.308 mmol ) and 4-fluorophenyl boronic acid (801 mg, 5.78 mmol ) in 1 , 4- dioxane (15 ml_). The reaction mixture was refluxed for 5 h and allowed to reach rt, poured into water (20 ml_) and extracted with EtOAc. The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. The crude product thus obtained was purified by flash chromatography on silica gel, gradient acetone/hexane (40:0) to give the title compound as yellow oil (765 mg, 94% yield). (0526) 1H-NMR (CDCIs, 250 MHz, delta): 8.27 (m, 4H, ArH); 7.1 1 (m, 2H, ArH); 3.77 (bs 2H, NH2). (0527) HPLC-MS (Method C): Ret, 7.84 min; ESI+-MS m/z, 190.2 (M+1 ).To a suspension of NaH (6.17 g, 154 mmol) in THF (100 ml) was added (S)-(2, 2- dimethyl-l, 3-dioxolan-4-yl)methanol (13.26 g, 100 mmol) in THF (50 ml) was added to the reaction mixture at 0 C, and the reaction mixture was stirred for lh at 25C.to this 2- chloropyrimidin-5-amine (10 g, 77 mmol) in THF (50 ml) and was added at 0C and slowly heated to 80 C and stirred for 16 hr at 80 C. After completion of the reaction, reaction mixture was quenched with the ammonium chloride (10 ml) and extracted with the ethyl acetate (3x20 ml). The organic layer was separated and washed with the brine and dried over Na2S04, filtered it and concentrated under reduced pressure to get the crude. This crude was triturated with the diethyl ether to get (S)-2-((2, 2-dimethyl-l, 3-dioxolan-4- yl)methoxy)pyrimidin-5 -amine (5.0 g, 19.77 mmol, 25.6 % yield) as a brown solid, LCMS (/// r): 226.1 [M+H]+.Tetrahydrofuran (75 mL) was added to NaH (5.56 g, 232 mmol) at 0 C, (R)-(2, 2- dimethyl-l, 3-dioxolan-4-yl)methanol (12.46 mL, 100 mmol) in Tetrahydrofuran (50 mL was added to the reaction mixture at 0 C, and the reaction mixture was stirred for lh at 28C. [0125] 5-Chlorosalicyclic acid (253.4 mg, 1.468 mmol) was dissolved in THF (10.0 mL), followed by the addition of catalytic amount of DMF (10 .iL) and oxalyl chloride (0.15 mL, 1.762 mmol) respectively. The reaction was allowed to stir at rt for 30 mm and then concentrated in vacuo. The residue was re-dissolved in xylene (7.0 mL) followed by the addition of 4- chloropyrimidin-5-amine (152.0 mg, 1.174 mmol). The mixture was heated to 132 C and stirred for 20 minutes before it was brought back to it The solvent was removed in vacuo and the resulting residue was purified via silica gel column chromatography to yield 5-Chloro-N-(2- chloropyrimidin-5-yl)-2-hydroxybenzamide 7 (174.6 mg, 52% yield). 'H NMR (300 MHz, DMSO-d6) 6 11.54 (s, 1H), 10.77 (s, 1H), 9.01 (s, 2H), 7.86 (d, J= 2.7 Hz, 1H), 7.56-7.42 (m, 1H), 7.06 (d, J = 8.8 Hz, 1H). MS (ESI) exact mass calculated for [M+H] (Cl 1H8C12N302) requires m/z 284.0, found m/z 283.9.To a solution of General procedure: To a 5 mL vial containing a stir bar, 3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol (88 mg, 0.34 mmol) and 4-amino-6-chloropyrimidine (46 mg, 0.36 mmol) were added K2CO3 (70 mg, mg, 0.51 mmol), 18-crown-6 (9 mg, 0.03 mmol) and DMA (0.68 mL). The resultant mixture was stirred at 120 Celsius for approximately 3 hours before cooling to room temperature and passing it through a syringe filter and subjecting the filtrate to FCC to afford the title compound (42 mg, 35%). The title compound was prepared using conditions similar to those described in Example 164 heating for 18 hours at 140 Celsius using Intermediate B and The title compound was prepared using conditions similar to those described in Example 164 heating for 18 hours at 140 Celius using Intermediate B and

Molecular Weight:129.55
XLogP3:0.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:129.0093748
Monoisotopic Mass:129.0093748
Topological Polar Surface Area:51.8
Heavy Atom Count:8
Complexity:69.7
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes