Process for preparing 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1h,3h)-dione

Abstract

Provided herein is a process for preparing compound A comprising (a) admixing 2-isopropyl-4-methylpyridin-3-amine (Compound B), or a salt thereof, a first base, and a reactive compound comprising phosgene or a phosgene equivalent in an organic solvent to form 3-isocyanato-2-isopropyl-4-methylpyridine (Compound C); (b) admixing Compound C and 2,6-dichloro-5-fluoronicotinamide (Compound D) to form 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (Compound E); and (c) admixing Compound E and a second base to form a product mixture comprising Compound A and the second base. Also provided herein is a process for synthesizing AMG 510 comprising using Compound A prepared according to the disclosed processes [Insert Structure] (Compound A).

What is claimed: 
     
         1 . A process of preparing compound A 
       
         
           
           
               
               
           
         
       
       comprising:
 (a) admixing 2-isopropyl-4-methylpyridin-3-amine (Compound B), or a salt thereof, a first base, and a reactive compound comprising phosgene or a phosgene equivalent in an organic solvent to form 3-isocyanato-2-isopropyl-4-methylpyridine (Compound C); 
 (b) admixing Compound C and 2,6-dichloro-5-fluoronicotinamide (Compound D) to form 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (Compound E); and 
 (c) admixing Compound E and a second base to form a product mixture comprising Compound A. 
 
     
     
         2 . The process of  claim 1 , wherein step (a) comprises adding Compound B, or a salt thereof, and the first base to Solution X comprising the reactive compound and the organic solvent. 
     
     
         3 . The process of  claim 2 , wherein in step (a) the Compound B, or a salt thereof, and the first base are added as Solution Y comprising the Compound B, or a salt thereof, the first base and the organic solvent to the Solution X. 
     
     
         4 . The process of  claim 2 , wherein the Solution X, prior to the addition of Compound B, or a salt thereof, and the first base, further comprises an additional amount of the first base. 
     
     
         5 . The process of  claim 4 , wherein the Solution X, prior to the addition of Compound B, or a salt thereof, and the first base, is prepared by adding the additional amount of the first base to a solution comprising the reactive compound and the organic solvent. 
     
     
         6 . The process of  claim 5 , wherein the additional amount of the first base is added as a solution comprising the additional amount of the first base and the organic solvent. 
     
     
         7 . The process of  claim 2 , wherein the temperature of Solution X is kept at a temperature of up to 0° C. 
     
     
         8 . The process of  claim 2 , wherein the temperature of Solution X is kept at a temperature of −10° C. to 0° C. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The process of  claim 1 , wherein step (a) comprises admixing at a temperature of −35° C. to 0° C. for at least 15 minutes, then warming to 25° C. 
     
     
         12 . The process of  claim 1 , wherein Compound B is a free base. 
     
     
         13 . The process of  claim 1 , wherein the first base is an amine. 
     
     
         14 . (canceled) 
     
     
         15 . The process of  claim 13 , wherein the first base is N,N-diisopropylethylamine. 
     
     
         16 . The process of  claim 1 , wherein the first base is present at 0.8 to 1.2 molar equivalents, based upon Compound B. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The process of  claim 4 , wherein the additional amount of the first base in Solution X, prior to the addition of Compound B, or a salt thereof, and the first base, is present at 0.01 to 0.02 molar equivalents, based upon Compound B. 
     
     
         20 . (canceled) 
     
     
         21 . The process of  claim 1 , wherein the reactive compound is phosgene. 
     
     
         22 . (canceled) 
     
     
         23 . The process of  claim 1 , wherein the reactive compound is a phosgene equivalent and wherein the phosgene equivalent is trichloromethyl carbonochloridate, bis(trichloromethyl) carbonate, di(imidazol-1-yl)methanone, or bis(2,5-dioxopyrrolidin-1-yl) carbonate. 
     
     
         24 . The process of  claim 23 , wherein the phosgene equivalent is bis(trichloromethyl) carbonate. 
     
     
         25 . The process of  claim 1 , wherein the reactive compound is present at 1.0 to 1.8 molar equivalents, based upon Compound B. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . The process of  claim 24 , wherein the bis(trichloromethyl) carbonate is present at 0.3 to 0.6 molar equivalents, based upon Compound B. 
     
     
         30 . The process of  claim 24 , wherein the bis(trichloromethyl) carbonate is present at 0.4 molar equivalents, based upon Compound B. 
     
     
         31 . (canceled) 
     
     
         32 . The process of  claim 1 , wherein the organic solvent of step (a) is a polar organic solvent, optionally anhydrous. 
     
     
         33 . The process of  claim 32 , wherein the polar organic solvent comprises anhydrous acetonitrile. 
     
     
         34 . The process of  claim 1 , wherein the organic solvent comprises a solvent selected from the group consisting of 2-methyltetrahydrofuran, toluene, acetonitrile, NMP, DMSO, and sulfolane. 
     
     
         35 . The process of  claim 1 , wherein step (b) is performed at a temperature of 60° C. to 100° C. 
     
     
         36 . (canceled) 
     
     
         37 . The process of  claim 1 , wherein step (b) is performed at a temperature of 70° C. to 80° C. 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . The process of  claim 1 , wherein Compound D is present at 0.9 to 1.3 molar equivalents, based upon Compound B. 
     
     
         41 . (canceled) 
     
     
         42 . The process of  claim 1 , wherein Compound D is present at 1.1 molar equivalents, based upon Compound B. 
     
     
         43 . The process of  claim 1 , further comprising drying Compound D to a water content of less than 200 ppm prior to performing step (b). 
     
     
         44 . The process of  claim 1 , wherein step (c) comprises adding the second base to Compound E while maintaining a temperature of 25° C. or less. 
     
     
         45 . The process of  claim 44 , wherein the temperature is maintained at 12° C. to 20° C. 
     
     
         46 . The process of  claim 44 , wherein, after addition of the second base, the temperature is adjusted to 15° C. to 50° C. 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . The process of  claim 1 , wherein the second base comprises 1,5,7-triazabicyclo(4.4.0)dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), or a combination thereof. 
     
     
         50 . The process of  claim 1 , wherein the second base comprises TMG. 
     
     
         51 . The process of  claim 1 , wherein the second base comprises DBU. 
     
     
         52 . The process of  claim 1 , wherein the second base is present in 2 to 10 molar equivalents, based upon Compound B. 
     
     
         53 . The process of  claim 1 , wherein the second base is present in 4 to 7 molar equivalents, based upon Compound B. 
     
     
         54 . (canceled) 
     
     
         55 . (canceled) 
     
     
         56 . (canceled) 
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . The process of  claim 1 , further comprising crystallizing Compound A from the product mixture by adding an aqueous solution of an acid. 
     
     
         62 . The process of  claim 61 , wherein the acid is present in 3.0 to 7.0 molar equivalents, based upon Compound B. 
     
     
         63 . The process of  claim 61 , wherein the acid is present in 5.5 to 6.5 molar equivalents, based upon Compound B. 
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . (canceled) 
     
     
         67 . (canceled) 
     
     
         68 . (canceled) 
     
     
         69 . The process of  claim 61 , wherein the acid is phosphoric acid. 
     
     
         70 . The process of  claim 69 , wherein the aqueous solution comprises 3 to 6 molar phosphoric acid. 
     
     
         71 . The process of  claim 69 , wherein the aqueous solution comprises 6 molar phosphoric acid. 
     
     
         72 . The process of  claim 69 , wherein the aqueous solution comprises 4 to 5 molar phosphoric acid. 
     
     
         73 . The process of  claim 69 , wherein the aqueous solution comprises 4.3 to 4.7 molar phosphoric acid. 
     
     
         74 . The process of  claim 69 , wherein the aqueous solution comprises 4.5 molar phosphoric acid. 
     
     
         75 . The process of  claim 61 , further comprising isolating the crystalized Compound A by filtration. 
     
     
         76 . The process of  claim 1 , wherein Compound C or Compound E, or any combination thereof, are not isolated prior to subsequent reaction(s). 
     
     
         77 . The process of  claim 1 , further comprising using Compound A to synthesize Compound F: 
       
         
           
           
               
               
           
         
       
       a pharmaceutically acceptable salt, atropisomer, or a pharmaceutically acceptable salt of an atropisomer thereof.