Processes and intermediate for the large-scale preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate, and preparation of 2,4,6-trifluoro-n-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide acetate

Abstract

The embodiments of present invention provide processes and an intermediate for the large-scale preparation of 2,4,6-tri-fluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate, and formulations and product forms made by these processes. The embodiments of the present invention further provide for the preparation of lasmiditan acetate, 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide acetate salt, and/or pharmaceutical compositions thereof, and/or uses of lasmiditan acetate and formulations thereof in subcutaneous drug delivery.

We claim: 
     
         1 . A process for preparing a compound of the formula: 
       
         
           
           
               
               
           
         
       
       comprising the steps of:
 i.) Treatment of piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water with subsequent treatment with aqueous HCl followed by water distillation and acetonitrile addition, with repeated dilution/distillation until the water content is not more than 0.2% by Karl-Fischer analysis, to obtain solid 1-methylpiperidine-4-carboxylic acid hydrochloride; 
 ii.) Treatment of 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene to obtain 1-methylpiperidine-4-carboxylic acid chloride; 
 iii.) Treatment of 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine with subsequent base wash and subsequent treatment with aqueous HCl in isopropanol to obtain solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride; 
 iv.) Treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride with a mineral base such as aqueous NaOH in a non-polar solvent such as methyl-tert-butyl ether with subsequent water wash, phase separation, and distillation of the organic solvent until the water content is not more than 0.1 weight t % by Karl Fischer analysis to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide; 
 v.) Subsequent treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a non-polar organic solvent such as methyl-tert-butyl ether with subsequent extraction of the resulting mixture with water and a suitable organic solvent such as n-butanol, phase separation, and repeated distillation of the organic solvent until the water content is not more than 0.2 weight % by Karl-Fischer analysis, to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone; 
 vi.) Treatment of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr and subsequent extraction with n-butanol followed by repeated distillation of the organic solvent until the water content is not more than 0.3% by Karl-Fischer analysis, to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide; 
 vii.) Treatment of (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone hydrobromide with a solution of NH 3  in ethylene glycol in the presence of Cu 2 O catalyst at about 80° C. for about 2 hr, with subsequent washes with water, saturated aqueous NaCl, and 20% aqueous NaOH and subsequent extraction with a non-polar aprotic solvent such as methyl-tert-butyl ether, phase separation, and treatment of the organic phase with 5 weight % carbon; 
 viii.) Filtration of the above mixture, dilution with a suitable polar alcoholic solvent such as isopropanol, and repeated distillation of the organic solvent until the water content is not more than 0.2% by Karl-Fischer analysis, with subsequent treatment of the resulting residue with isopropanol, water, and 20 weight % HCl, wherein the water concentration of the resulting slurry is at least 2%, filtration of the resulting slurry, and drying under vacuum at 40° C. for 16-24 hr to obtain solid (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride; 
 ix.) Treatment of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone dihydrate dihydrochloride in chlorobenzene with 6 weight/weight % NaOH in water at about 54° C. for about 30 min, with subsequent phase separation and vacuum distillation of the aqueous solution to obtain (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone; 
 x.) Subsequent treatment of (6-amino-2-pyridyl)-(1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzoic acid chloride in chlorobenzene at about 100° C. for about 4 hr, with subsequent cooling, charging with acetonitrile and heating the resulting slurry to 80° C. for about 1 hr, and subsequent collection of the resulting solid by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride; 
 xi.) Treatment of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hydrochloride with saturated aqueous Na 2 CO 3  in methyl-tert-butyl ether; 
 xii.) Treatment of the mixture of step xi above with SiO 2  with subsequent filtration, treatment with carbon, filtration, and evaporation, dilution with ethanol, and distillation until the water content is not more than 1% by Karl-Fischer analysis, to obtain 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide; 
 xiii.) Treatment of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide in ethanol with a solution of 0.5 equivalents succinic acid in ethanol at about 55° C. for not less than 3 hr at RT, and subsequent collection of the solid by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate. 
 
     
     
         2 . A process for preparing a compound of the formula 
       
         
           
           
               
               
           
         
       
       comprising the steps of:
 i.) Treatment of piperidine-4-carboxylic acid under reductive amination conditions comprising formaldehyde and formic acid in water with subsequent treatment with aqueous HCl followed by water distillation and acetonitrile addition, with repeated dilution/distillation until the water content is not more than 0.2% by Karl-Fischer analysis, to obtain solid 1-methylpiperidine-4-carboxylic acid hydrochloride; 
 ii.) Treatment of 1-methylpiperidine-4-carboxylic acid hydrochloride with a chlorinating agent such as thionyl chloride in chlorobenzene obtain 1-methylpiperidine-4-carboxylic acid chloride; 
 iii.) Treatment of 1-methylpiperidine-4-carboxylic acid chloride with N,N-diethylamine in chlorobenzene containing triethylamine with subsequent base wash and subsequent treatment with aqueous HCl in isopropanol to obtain solid N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride; 
 iv.) Treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide hydrate hydrochloride with a mineral base such as aqueous NaOH in a non-polar solvent such as methyl-tert-butyl ether with subsequent water wash, phase separation, and distillation of the organic solvent until the water content is not more than 0.1 weight % by Karl Fischer analysis to obtain N,N-diethyl-1-methyl-piperidine-4-carboxamide; 
 v.) Subsequent treatment of N,N-diethyl-1-methyl-piperidine-4-carboxamide with (6-bromo-2-pyridyl)lithium in a non-polar organic solvent such as methyl-tert-butyl ether with subsequent extraction of the resulting mixture with water and a suitable organic solvent such as n-butanol, phase separation, and repeated distillation of the organic solvent until the water content is not more than 0.2 weight % by Karl-Fischer analysis, to obtain (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone; 
 vi.) Treatment of (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone with aqueous HBr and subsequent extraction with n-butanol followed by repeated distillation of the organic solvent until the water content is not more than 0.3% by Karl-Fischer analysis, to obtain solid (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone hydrobromide; 
 vii.) Treatment of (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone hydrobromide in a biphasic mixture of water and toluene with solid KOH for about 3 hr with subsequent separation of the organic layer and evaporation of the solvent to obtain of (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone; 
 viii.) Treatment of (6-bromo-2-pyridyl-1-methyl-4-piperidyl)methanone with 2,4,6-trifluorobenzamide in toluene containing K 2 CO 3 , water, Pd(OAc) 2 , and Xantphos at about 70° C. for about 12 hr, until the (6-bromo-2-pyridyl)-(1-methyl-4-piperidyl)methanone content is not more than 0.1% by HPLC, with subsequent dilution of the reaction mixture with water and EtOAc, subsequent treatment with thiourea-modified silica gel at 60° C. for about 8 hr, with subsequent filtration to obtain a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide; 
 ix.) Treatment of a solution of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide in EtOAc with a solution of about 0.5 equivalents of succinic acid dissolved in EtOH at 55° C. for about 3 hr, with subsequent cooling to RT over about 10 hr, and collection of the resulting solids by filtration, to obtain solid 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate. 
 
     
     
         3 . A process of  claim 1  or  2  wherein the reactions are performed using batch processing methodology. 
     
     
         4 . A process of  claim 3  wherein the batch produced is at process scale. 
     
     
         5 . A process of  claim 4  wherein the batch produced is at least 1 kilogram. 
     
     
         6 . A process of  claim 4  wherein the batch produced is at least 10 kilograms. 
     
     
         7 . A process of  claim 4  wherein the batch produced is at least 100 kilograms. 
     
     
         8 . A tablet produced by the process of  claim 1  or  2  wherein the tablet comprises 50 mg of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate. 
     
     
         9 . A tablet produced by the process of  claim 1  or  2  wherein the tablet comprises 100 mg of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate. 
     
     
         10 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 10  which is crystalline. 
     
     
         12 . The compound according to  claim 11  characterized by an X-ray powder diffraction pattern using CuKα radiation having an intense peak at diffraction angle 2-theta of 8.3° in combination with one or more of the peaks selected from the group consisting of 16.6°, 23.5°, and 33.7° (±0.2° respectively). 
     
     
         13 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 13  which is crystalline. 
     
     
         15 . The compound according to  claim 14  characterized by an X-ray powder diffraction pattern using CuKα radiation having an intense peak at diffraction angle 2-theta of 26.2° in combination with one or more of the peaks selected from the group consisting of 20.4°, 14.0°, and 17.9° (±0.2° respectively). 
     
     
         16 . A pharmaceutical composition comprising a compound according to any one of  claims 13  to  15  with one or more pharmaceutically acceptable carriers, diluents, or excipients. 
     
     
         17 . The pharmaceutical composition of  claim 16  further comprising acetic acid. 
     
     
         18 . A method of treating migraine in a patient comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of  claims 13  to  15 . 
     
     
         19 . A tablet produced by the process of  claim 1  or  2  wherein the tablet comprises 50 mg of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate and reactions are performed using batch processing methodology and the batch produced is at least 1 kilogram. 
     
     
         20 . A tablet produced by the process of  claim 1  or  2  wherein the wherein the tablet comprises 50 mg of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate and reactions are performed using batch processing methodology and the batch produced is at least 10 kilograms. 
     
     
         21 . A tablet produced by the process of  claim 1  or  2  wherein the wherein the tablet comprises 100 mg of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate and reactions are performed using batch processing methodology and the batch produced is at least 1 kilogram. 
     
     
         22 . A tablet produced by the process of  claim 1  or  2  wherein the wherein the tablet comprises 100 mg of 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)-2-pyridyl]benzamide hemisuccinate and reactions are performed using batch processing methodology and the batch produced is at least 10 kilograms.