5-Bromo-2-chloro-N-cyclopentyl-4-pyrimidinamine

To a solution of 5-bromo-2, 4- dichloropyrimidine (45.6 g, 200 mmol) in dioxane (400 mL) was added N-cyclopentylamine (20.4 g, 240 mmol) at room temperature. The mixture thus obtained was stirred at room temperature for 6 h. The reaction mixture was then diluted with ethyl acetate and washed with brine and dried over MgSOA solution of 5-bromo-2, 4-dichloropyrimidine(1) (5 g, 22 mmol) and N, N-diisopropylethylamine (5.7g, 44 mmol) in ethanol (30 mL) was cooled to 10°C under nitrogenatmosphere. Charged cyclopentylamine (2.1g, 24.1 mmol)and stirred for 5 hours at 40°C. Progress of the reaction wasmonitored by TLC and solvent was evaporated undervacuum. Resulting residue was stirred with hexane (20 mL)for 2 hours at 0°C. Precipitate was filtered and washed withhexane to obtain compound (2). Off-white crystalline solid, Yield: 90percent, mp. 95-97 °C. 1H NMR (400 MHz, DMSO-d6):1.57-1.62 (m, 4H, -CH2-CH2-), 1.64-1.69 (m, 2H, CH2), 1.87-1.93 (m, 2H, CH2), 4.27-4.33 (m, 1H, -NH-CH-), 7.35(d, 1H, J=7.44 Hz, -NH), 8.20 (s, 1H, Ar-H). 13C NMR(75.46 MHz, DMSO-d6): 159.4, 158.6, 157.1, 102.9, 53.0, 31.8, 24.0. ESI-HRMS (m/z): Calcd. for C9H11BrClN3:276.5614. Found: m/z 277.2618 [M+H]+.In a large sealed tube is added 5-bromo-2, 4-dichloropyrimidine (3g, 13.2 mmol) in 100 mL of EtOH. Then cyclopentyl amine (1.95 mL, 19.75 mmol) andN, N'-diisopropylethylamine (3.36 mL, 19.8 mmol) are added to the solution at rt. The solution is then stirred rt overnight. Solvent is evaporated and the crude is purified using silica gel chromatography (15percent ethyl acetate/85percenthexane) to give (5- bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine as a white solid (3.25g, 89percent). MS(ESI) m/z 278.4 (M+H)A nitrogen-flushed, suitably equipped 5 L 4-neck round bottom flask is charged with 250 g (1.097 mol, 140.4 mL, 1.0 eq.) of 5-bromo-2, 4-dichloropyrimidine (A1h) and 1127 g, (1250 mL) of ethyl acetate.Step i): synthesis of (5-Bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine (formula 13)Step i: A 4 L 3-necked RBF, equipped with a 500 ml addition funnel, was charged with 250.0 g of 5-Bromo-2, 4-dichloro-pyrimidine (1 .097 mol, 1 .00 eq.) and 880 ml absolute EtOH. The mixture was cooled to 10°C with an ice-bath A solution of 250 ml cyclopentylamine (130 mmol, 1 .18 eq.) in 250 ml absolute EtOH was added dropwise over 60 min while maintaining the temperature between 10-15°C After stirring for 1 h, the mixture was allowed to warm up to RT and further stirred for 1 h. The reaction was quenched with 1 .1 L water then seeding material was added. After stirring at RT for 2 h, the precipitated solid was collected by filtration, washed with 1 L water/EtOH (8/2) acetonitrile and left in air at RT to give crude wet (5-Bromo-2-chloro-pyrimidin-4-yl)- cyclopentyl-amine as white solid.HPLC (Method 1 ): 9.67 min (89.3percent) (254 nm).Crude product was suspended in 1 .5 L hexane and heated to reflux for 45 min. Resulting slurry was allowed to cool down slowly to RT with stirring. After 3 h, stirring was stopped and the mixture left at RT. Solid was collected by filtration, washed with hexane (350 ml), dried in air for 10 min then at 50^/35 mbar for 2 h to give 264.51 g of purified (5-Bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine (87.2percent yield) as white solid.HPLC (Method 1 ): 10.02 min (99.7percent) (254 nm).Preparation of 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2, 3-d]pyrimidin-7-one; Example 3A: Preparation of S-bromo^-chloro^-cyclopentyl-aminopyrimidineTo -1 -g (0.004 mol) of 5-bromo-2, 4-dichloropyrimidine in ethanol was added 1.5 kg (0.018 mol) cyclopentylamine under nitrogen. The mixture was stirred at 25°C for 2hrs. Water was added to precipitate the product, and the solid was recrystallized using hexane 4:1 to give a white crystalline product (3A).To a vessel was added absolute ethanol (3000 mL, 3.0 vol) followed by 5-bromo-2, 4- dichloropyrimidine (mw 227.87; 1000 g, 1.0 equiv.). Triethylamine (612 mL, 1.0 equiv.) was added, and then cyclopentylamine (mw 85.15; 520 mL, 1.2 equiv.) was added slowly over 2 hours to control the mild exotherm. After completion of cyclopentylamine addition, the reaction was seeded with 5-bromo-2-chloro-6-cyclopentylamino-pyrimidine (5 g, 0.5 wtpercent) to induce crystallization, if needed. The reaction was stirred at 25°C for 2 hours.Water (2500 mL, 2.5 vol) was added to the vessel at 20-25 °C at a rate of 30 mL/min. The mixture was cooled to 8-12°C at 2°C/min. The slurry was kept at 8-12°C for 1 hour and then filtered onto a 2 Whatman™ paper filter. The cake was rinsed with n-heptane (2000 mL). The cake was reslurried with n-heptane on the filter drier (2000 mL). The material was dried overnight in the vacuum oven at 50-55°C to give 5-bromo-2-chloro-6-cyclopentylamino- pyrimidine (1020 g; 84percent) as a white solid.Add 5-bromo-2, 4-dichloropyrimidine (IV-1) (11.4 g, 50 mmol) to the reaction flask.Triethylamine (2.24 g, 20 mmol) and methylene chloride (150 mL) were stirred and cooled to 0-5 °C.Cyclopentylamine (V) (4.257 g, 50 mmol) was slowly added dropwise. After the addition was complete, the reaction was heated to 45° C. for 6 hours.TLC detection reaction is complete. At the end of the reaction, 150 mL of quenched water was added.The organic phase is washed twice with saturated saline solution.The aqueous phase is extracted twice with ethyl acetate, Combine the organic phase, Drying with anhydrous sodium sulfate, Distillation under reduced pressure to recover the solventThe resulting concentrate was purified by column chromatography using a mixture of petroleum ether and ethyl acetate to give 2-chloro-4-cyclopentylamino-5-bromopyrimidine (VI-1) (11.0 g).Yield 80percent; Purity 99.8percentTo the reaction flask was added 5-bromo-2, 4-dichloropyrimidine (I) (11.4 g, 50 mmol), triethylamine (2.24 g, 20 mmol)Dichloromethane (150 mL) was added and the mixture was stirred and cooled to 0-5°C. Cyclopentylamine (II) (4.257 g, 50 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 45° C. for 6 hours. TLC reaction was completed. . At the end of the reaction, 150 mL of water was quenched, the organic phase was washed twice with saturated brine, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting concentrate was used with petroleum ether and The compound 2-chloro-4-cyclopentylamino-5-bromopyrimidine (III-1) was isolated by column chromatography of ethyl acetate mixed solvent to give 11.0 g; the yield was 80percent; the purity was 99.8percent (HPLC area normalization method).5-BROMO-2, 4-dichloro-pyrimidine (18.21 g, 79.9 mmol) was dissolved in THE and place in a 0°C ice bath. Triethylamine (23.77 g, 235 mmol) was added. Reaction became light yellow. Following this, cyclopentyl amine (3.67 g, 78.31 mmol) was added. The ice bath was removed and the reaction was stirred overnight. Reaction was filtered and concentrated. Purified on silica gel using 20: 1 Hexane/EtOAc to afford 16.09 g (74percent) of (5-BROMO-2-CHLORO-PYRIMIDIN-4- yl) -cyclopentyl-amine.7gcyclopentaneamine (Compound 5b) was dissolved in 100ml of absolute ethanol.16ml of Et

Molecular Weight:276.56
XLogP3:3.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:274.98249
Monoisotopic Mass:274.98249
Topological Polar Surface Area:37.8
Heavy Atom Count:14
Complexity:187
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes