N-[3-[[2-[[4-(4-Acetyl-1-piperazinyl)-2-Methoxyphe

On May 20, 2014, Clovis Oncology announced that the US FDA had granted its test drug CO-1686 for breakthrough treatment drug qualification, as a second line, single administrated drug for the treatment of EFGR mutation non-small cell lung cancer (NSCLC) of the T790M mutation patients. The awarding for this breakthrough therapeutic drug eligibility was based on the efficacy and safety results of Co-1686 in an ongoing Phase 1/2 study. Data of related study have shown that CO-1686 is a third-gener

Rociletinib has been used in trials studying the treatment and prevention of Nonsmall Cell Lung Cancer, Non-small Cell Lung Cancer, and Locally Advanced or Metastatic Non-small Cell Lung Cancer.|Rociletinib is an orally available small molecule, irreversible inhibitor of epidermal growth factor receptor (EGFR) with potential antineoplastic activity. Rociletinib binds to and inhibits mutant forms of EGFR, including T790M, thereby leading to cell death of resistant tumor cells. Compared to other EGFR inhibitors, CO-1686 inhibits T790M, a secondary acquired resistance mutation, as well as other mutant EGFRs and may have therapeutic benefits in tumors with T790M-mediated resistance to other EGFR tyrosine kinase inhibitors. This agent shows minimal activity against wild-type EGFR, hence does not cause certain dose-limiting toxicities.

Compound (X) 40.12g (0.08mol) dissolved in 280 ml methylene chloride, then adding 16.2g (0.16mol) triethylamine, acryloyl chloride dropwise under ice bath 9.05g (0.10mol), and then room temperature reaction 4-5h. Remove the solvent under reduced pressure, to residue 200 ml water, stirring after-filtration, to obtain a kind of white solid, dichloromethane/methanol is recrystallized to get kind of white powder 41.0g, purity 99.6percent, yield 92percent.5g of intermediate V with 150mlTHF dissolved, then 75ml of water was dissolved 2.3g of sodium bicarbonate and water was added to the reaction mixture a solvent, 0 placed in the reaction, the reaction liquid at this time as a red supernatant, the chloropropionyl chloride with 1.3g 75mlTHF dilution, was slowly added dropwise to the reaction mixture.TLC analysis after the addition was complete the reaction was complete feed.The reaction solution was spin to most of the tetrahydrofuran, was added 100ml of saturated aqueous sodium bicarbonate, 3 × 100ml extracted three times with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation 2/3.Was added to the rotovap 7gDBU, 60 stirred for 12h, TLC detection starting material the reaction was complete, the aqueous solution was washed with 100ml × 3 was added, the organic phase is retained, dried over anhydrous sodium sulfate, filtered, spin-dries off-white solid, ethyl acetate was added heavy crystallized 4.7g, HPLC purity 99.6percent detection productsAdding 2-[[4-(4-acetyl-1 -piperazinyl)-2-methoxy- phenyl]amino]-5-(trifluoromethyl)-pyrimidin-4-one (IV) (2.06 g, 5 mmol) and phosphorus oxychloride (7.5 mL) into a reaction flask, starting stirring, cooling to 0° C. or below, and dropwisely adding 3.5 mL of 2, 6-dimethylpyridine. Slowly heating to 50-70° C., and stirring to react for 9 hours while maintaining the temperature. Reducing the pressure to recover the phosphorus oxychloride, cooling the residue to room temperature, and quenching the reaction with ice watet Extracting with dichloromethane for 3 times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, reducing the pressure to recover the solvent, dissolving an obtained oily matter 2-[[4-(4- acetyl- 1 -piperazinyl)-2-methoxyphenyl]amino] -5-(trifluo- romethyl)-4-chloro-pyrimidine (V) with 25 mL of N, Ndimethylformamide, transferring into the reaction flask, and adding N-(3-aminophenyl)-2-acrylamide (1.0 g, 6 mmol) and a catalyst cesium carbonate (0.3 g). Stirring to react for 12 hours while maintaining the temperature at 90-110° C., and performing TLC detection until the reaction is finished. Filtering, concentrating under reduced pressure, adding ethyl acetate and water into the residue, and regulating pH to 5-6 with dilute acid. Separating out the organic phases, and extracting a water phase with ethyl acetate for 3 times. Combining the organic phases, washing the organic phases sequentially with pure water and brine, drying, performing reduced pressure distillation to recover the solvent, and washing with ethanol to obtain 2.15 g of an off-white solid rociletinib, wherein the yield is 77.5percent. Mass spec (El):El-MS mlz: 556 [M+H], ‘H NMR (DMSO-d5): ö 2.05 (s, 3H), 3.01 (m, 4H), 3.55 (m, 4H), 3.77 (m, 3H), 5.78 (d, 1H), 6.25 (d, 2H), 6.44 (m, 1H), 6.61 (s, 1H), 7.17 (s, 1H), 7.28 (m, 1H), 7.52 (m, 2H), 7.76 (s, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.63 (s, 1H), 10.21 (s, 1H).Compound (X) 40.12g (0.08mol) dissolved in 280 ml methylene chloride, then adding 16.2g (0.16mol) triethylamine, acryloyl chloride dropwise under ice bath 9.05g (0.10mol), and then room temperature reaction 4-5h. Remove the solvent under reduced pressure, to residue 200 ml water, stirring after-filtration, to obtain a kind of white solid, dichloromethane/methanol is recrystallized to get kind of white powder 41.0g, purity 99.6percent, yield 92percent.5g of intermediate V with 150mlTHF dissolved, then 75ml of water was dissolved 2.3g of sodium bicarbonate and water was added to the reaction mixture a solvent, 0 placed in the reaction, the reaction liquid at this time as a red supernatant, the chloropropionyl chloride with 1.3g 75mlTHF dilution, was slowly added dropwise to the reaction mixture.TLC analysis after the addition was complete the reaction was complete feed.The reaction solution was spin to most of the tetrahydrofuran, was added 100ml of saturated aqueous sodium bicarbonate, 3 × 100ml extracted three times with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation 2/3.Was added to the rotovap 7gDBU, 60 stirred for 12h, TLC detection starting material the reaction was complete, the aqueous solution was washed with 100ml × 3 was added, the organic phase is retained, dried over anhydrous sodium sulfate, filtered, spin-dries off-white solid, ethyl acetate was added heavy crystallized 4.7g, HPLC purity 99.6percent detection productsAdding 2-[[4-(4-acetyl-1 -piperazinyl)-2-methoxy- phenyl]amino]-5-(trifluoromethyl)-pyrimidin-4-one (IV) (2.06 g, 5 mmol) and phosphorus oxychloride (7.5 mL) into a reaction flask, starting stirring, cooling to 0° C. or below, and dropwisely adding 3.5 mL of 2, 6-dimethylpyridine. Slowly heating to 50-70° C., and stirring to react for 9 hours while maintaining the temperature. Reducing the pressure to recover the phosphorus oxychloride, cooling the residue to room temperature, and quenching the reaction with ice watet Extracting with dichloromethane for 3 times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, reducing the pressure to recover the solvent, dissolving an obtained oily matter 2-[[4-(4- acetyl- 1 -piperazinyl)-2-methoxyphenyl]amino] -5-(trifluo- romethyl)-4-chloro-pyrimidine (V) with 25 mL of N, Ndimethylformamide, transferring into the reaction flask, and adding N-(3-aminophenyl)-2-acrylamide (1.0 g, 6 mmol) and a catalyst cesium carbonate (0.3 g). Stirring to react for 12 hours while maintaining the temperature at 90-110° C., and performing TLC detection until the reaction is finished. Filtering, concentrating under reduced pressure, adding ethyl acetate and water into the residue, and regulating pH to 5-6 with dilute acid. Separating out the organic phases, and extracting a water phase with ethyl acetate for 3 times. Combining the organic phases, washing the organic phases sequentially with pure water and brine, drying, performing reduced pressure distillation to recover the solvent, and washing with ethanol to obtain 2.15 g of an off-white solid rociletinib, wherein the yield is 77.5percent. Mass spec (El):El-MS mlz: 556 [M+H], ‘H NMR (DMSO-d5): ö 2.05 (s, 3H), 3.01 (m, 4H), 3.55 (m, 4H), 3.77 (m, 3H), 5.78 (d, 1H), 6.25 (d, 2H), 6.44 (m, 1H), 6.61 (s, 1H), 7.17 (s, 1H), 7.28 (m, 1H), 7.52 (m, 2H), 7.76 (s, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.63 (s, 1H), 10.21 (s, 1H).Adding 2-[[4-(4-acetyl-1 -piperazinyl)-2-methoxy- phenyl]amino]-5-(trifluoromethyl)-pyrimidin-4-one (IV) (2.06 g, 5 mmol), phosphorus tribromide (2.7 g, 10 mmol) and dichloromethane (50 mE) into a reaction flask, starting stirring, cooling to 00 C. or below, and dropwisely adding 3.0 mE of diisopropylethylamine. Slowly heating for reflux, and stirring to react for 8 hours while maintaining the temperature. Afier cooling to room temperature, quenching the reaction with ice watet Extracting with dichloromethane for 2 times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, reducing the pressure to recover the solvent, dissolving an obtained oily matter 2-[[4-(4-acetyl- 1 -piperazinyl)-2-methoxyphenyl]amino] -5- (trifluoromethyl)-4-bromo-pyrimidine (V) with 25 mE of dimethyl sulfoxide, transferring into the reaction flask, and adding N-(3-aminophenyl)-2-acrylamide (1.0 g, 6 mmol) and a catalyst potassium tert-butoxide (0.5 g). Stirring to react for 12 hours while maintaining the temperature at 90-110 C., and performing TEC detection until the reaction is finished. Filtering, concentrating under reduced pressure, adding ethyl acetate and water into the residue, and regulating pH to 5-6 with dilute acid. Separating out the organic phases, and extracting a water phase with ethyl acetate for 3 times. Combining the organic phases, washing the organic phases sequentially with pure water and brine, drying, performing reduced pressure distillation to recover the solvent, and washing with ethanol to obtain 1.98 g of an off-white solid rociletinib, wherein the yield is 7 1.4%. Mass spec (El): El-MS mlz: 556 [M+H], 'H NMR (DMSO-d5):o 2.05 (s, 3H), 3.01 (m, 4H), 3.55 (m, 4H), 3.77 (m, 3H), 5.78 (d, 1H), 6.25 (d, 2H), 6.44 (m, 1H), 6.61 (s, 1H), 7.17 (s, 1H), 7.28 (m, 1H), 7.52 (m, 2H), 7.76 (s, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.63 (s, 1H), 10.21 (s, 1H).Adding 2-[[4-(4-acetyl-1 -piperazinyl)-2-methoxy- phenyl]amino]-5-(trifluoromethyl)-pyrimidin-4-one (IV) (2.06 g, 5 mmol) and phosphorus oxychloride (7.5 mL) into a reaction flask, starting stirring, cooling to 0 C. or below, and dropwisely adding 3.5 mL of 2, 6-dimethylpyridine. Slowly heating to 50-70 C., and stirring to react for 9 hours while maintaining the temperature. Reducing the pressure to recover the phosphorus oxychloride, cooling the residue to room temperature, and quenching the reaction with ice watet Extracting with dichloromethane for 3 times, combining organic phases, washing with water, drying with anhydrous sodium sulfate, reducing the pressure to recover the solvent, dissolving an obtained oily matter 2-[[4-(4- acetyl- 1 -piperazinyl)-2-methoxyphenyl]amino] -5-(trifluo- romethyl)-4-chloro-pyrimidine (V) with 25 mL of N, Ndimethylformamide, transferring into the reaction flask, and adding N-(3-aminophenyl)-2-acrylamide (1.0 g, 6 mmol) and a catalyst cesium carbonate (0.3 g). Stirring to react for 12 hours while maintaining the temperature at 90-110 C., and performing TLC detection until the reaction is finished. Filtering, concentrating under reduced pressure, adding ethyl acetate and water into the residue, and regulating pH to 5-6 with dilute acid. Separating out the organic phases, and extracting a water phase with ethyl acetate for 3 times. Combining the organic phases, washing the organic phases sequentially with pure water and brine, drying, performing reduced pressure distillation to recover the solvent, and washing with ethanol to obtain 2.15 g of an off-white solid rociletinib, wherein the yield is 77.5%. Mass spec (El):El-MS mlz: 556 [M+H], 'H NMR (DMSO-d5): oe 2.05 (s, 3H), 3.01 (m, 4H), 3.55 (m, 4H), 3.77 (m, 3H), 5.78 (d, 1H), 6.25 (d, 2H), 6.44 (m, 1H), 6.61 (s, 1H), 7.17 (s, 1H), 7.28 (m, 1H), 7.52 (m, 2H), 7.76 (s, 1H), 8.08 (s, 1H), 8.28 (s, 1H), 8.63 (s, 1H), 10.21 (s, 1H).5g of intermediate V with 150mlTHF dissolved, then 75ml of water was dissolved 2.3g of sodium bicarbonate and water was added to the reaction mixture a solvent, 0 placed in the reaction, the reaction liquid at this time as a red supernatant, the chloropropionyl chloride with 1.3g 75mlTHF dilution, was slowly added dropwise to the reaction mixture.TLC analysis after the addition was complete the reaction was complete feed.The reaction solution was spin to most of the tetrahydrofuran, was added 100ml of saturated aqueous sodium bicarbonate, 3 × 100ml extracted three times with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, and ethyl acetate was removed by rotary evaporation 2/3.Was added to the rotovap 7gDBU, 60 stirred for 12h, TLC detection starting material the reaction was complete, the aqueous solution was washed with 100ml × 3 was added, the organic phase is retained, dried over anhydrous sodium sulfate, filtered, spin-dries off-white solid, ethyl acetate was added heavy crystallized 4.7g, HPLC purity 99.6% detection productsCompound (X) 40.12g (0.08mol) dissolved in 280 ml methylene chloride, then adding 16.2g (0.16mol) triethylamine, acryloyl chloride dropwise under ice bath 9.05g (0.10mol), and then room temperature reaction 4-5h. Remove the solvent under reduced pressure, to residue 200 ml water, stirring after-filtration, to obtain a kind of white solid, dichloromethane/methanol is recrystallized to get kind of white powder 41.0g, purity 99.6%, yield 92%.

Molecular Weight:555.6
XLogP3:4
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:11
Rotatable Bond Count:8
Exact Mass:555.22057227
Monoisotopic Mass:555.22057227
Topological Polar Surface Area:112
Heavy Atom Count:40
Complexity:871
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes