Process for making n-hydroxy-3-[4-[[[2-(2-methyl-1h-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-2-propenamide and starting materials therefor

Abstract

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and starting materials therefor are prepared by new synthetic methods.

1 . A method of making N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide comprising the steps of:
 (a) combining sodium hydroxide and (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt to form an admixture at a temperature of less than about −15° C.; and subsequently   (b) adding hydroxylamine to the admixture to form the N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide.   
   
   
       2 . The method of  claim 1 , wherein the temperature in step (a) is less than about −10° C. 
   
   
       3 . The method of  claim 1 , wherein the (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt is provided in the form of a suspension in methanol. 
   
   
       4 . The method of  claim 1 , wherein the sodium hydroxide is provided in the form of a solution in methanol. 
   
   
       5 . The method of  claim 1 , wherein the sodium hydroxide is added to the (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt over about 30 minutes. 
   
   
       6 . The method of  claim 1 , wherein the sodium hydroxide is used in an amount ranging from about 2.5 to about 3.5 equivalents. 
   
   
       7 . The method of  claim 1 , wherein the hydroxylamine is supplied in the form of a solution in water. 
   
   
       8 . The method of  claim 1 , wherein the hydroxylamine is used in an amount ranging from about 4 to about 13 equivalents. 
   
   
       9 . The method of  claim 1 , wherein the hydroxylamine is added to the admixture over about 30 minutes. 
   
   
       10 . The method of  claim 1  further comprising the step of stirring at the temperature of step (a) until the reaction is complete or nearly complete. 
   
   
       11 . The method of  claim 1  further comprising step (c) crystallizing the N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide. 
   
   
       12 . The method of  claim 11 , wherein step (c) comprises the sub-steps of:
 (c1) heating the reaction mixture formed in step (b);   (c2) stirring the reaction mixture;   (c3) adding water to the reaction mixture;   (c4) filtering the reaction mixture to provide a filtrate;   (c5) adjusting the pH of the filtrate to a pH ranging from about 10 to about 11;   (c6) adding seed crystals of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide to the filtrate;   (c7) stirring the filtrate until a suspension results;   (c8) adjusting the pH of the suspension to a pH ranging from about 8.5 to about 9; and   (c9) stirring the suspension.   
   
   
       13 . The method of  claim 12 , wherein all of sub-steps (c1) to (c9) are conducted at the temperature achieved by the heating of su-step (c1). 
   
   
       14 . The method of  claim 12 , wherein the reaction mixture is heated to a temperature ranging from about 0° C. to about 25° C. 
   
   
       15 . The method of  claim 12 , wherein sub-steps (c1) and (c2) are repeated to achieve gradual heating. 
   
   
       16 . The method of  claim 12 , wherein the pH of the filtrate is adjusted to a pH ranging from about 10.3 to about 10.7 in sub-step (c5). 
   
   
       17 . The method of  claim 11  further comprising the step of (d) isolating the N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide. 
   
   
       18 . The method of  claim 17 , wherein step (d) comprises the sub-steps of:
 (d1) filtering the crystallized N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide from step (c); and   (d2) drying the crystallized N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide.   
   
   
       19 . The method of  claim 18 , wherein a filter cake obtained in sub-step (d1) is washed. 
   
   
       20 . A method of making (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt comprising the steps of:
 (a) combining 2-methyltryptamine and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester to form an admixture;   (b) stirring the admixture for a time and at a temperature sufficient to form an imine intermediate; and   (c) reducing the imine intermediate to form the (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt.   
   
   
       21 . The method of  claim 20 , wherein the temperature of step (a) ranges from about 20° C. to about 25° C. 
   
   
       22 . The method of  claim 20 , wherein the 2-methyltryptamine and the (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester are dissolved in methanol in step (a). 
   
   
       23 . The method of  claim 20 , wherein the admixture is stirred for about 1 hour at a temperature ranging from about 20 to about 25° C. 
   
   
       24 . The method of  claim 20 , wherein step (c) comprises the sub-steps of:
 (c1) cooling the admixture;   (c2) adding sodium borohydride to the admixture; and   (c3) combining the admixture with hydrochloric acid to precipitate the (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt.   
   
   
       25 . The method of  claim 24 , wherein the admixture is diluted with solvent prior to sub-step (c1). 
   
   
       26 . The method of  claim 24 , wherein the admixture is cooled to a temperature of about −15° C. in sub-step (c1). 
   
   
       27 . The method of  claim 24 , wherein the sodium borohydride in sub-step (c2) is added in portions. 
   
   
       28 . The method of  claim 24 , wherein the sodium borohydride in sub-step (c2) is added over about 1 hour while the temperature is maintained at a range from about −15° C. to about −10° C. 
   
   
       29 . The method of  claim 24 , wherein the sodium borohydride is added in solid form. 
   
   
       30 . The method of  claim 24 , wherein sub-step (c3) is carried out after a period of stirring the admixture of sub-step (c2). 
   
   
       31 . The method of  claim 24 , wherein sub-step (c3) is performed by slow addition of the admixture to pre-cooled hydrochloric acid. 
   
   
       32 . The method of  claim 31 , wherein the hydrochloric acid is cooled to a temperature of about 0° C. to about 5° C. 
   
   
       33 . The method of  claim 24 , wherein sub-step (c3) comprises the su steps of:
 (c3a) heating the admixture of sub-step (c2);   (c3b) adding water to the admixture; and   (c3c) adding hydrochloric acid to the admixture to precipitate (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt.   
   
   
       34 . The method of  claim 33 , wherein the admixture is heated to a temperature ranging from about 20° C. to about 25° C. over a period of time of about 25 minutes in sub-step (c3a). 
   
   
       35 . The method of  claim 33 , wherein water is added slowly after a period of stirring the admixture of sub-step (c3a). 
   
   
       36 . The method of  claim 33 , wherein the hydrochloric acid is added in portions. 
   
   
       37 . The method of  claim 34 , wherein the hydrochloric acid is added over a period of time of about 1.5 hours. 
   
   
       38 . The method of  claim 35 , wherein a first portion of hydrochloric acid is added over about 1 hour and a second portion of hydrochloric acid is added over about 30 minutes. 
   
   
       39 . The method of  claim 20  further comprising the step of (d) crystallizing the (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt. 
   
   
       40 . The method of  claim 39 , wherein step (d) comprises the sub-steps of:
 (d1) heating the suspension formed when the imine intermediate is reduced in step (c);   (d2) stirring the suspension at the temperature of sub-step (d1);   (d3) cooling the suspension; and   (d4) stirring the suspension at the temperature of sub-step (d3).   
   
   
       41 . The method of  claim 40 , wherein the temperature of sub-step (d1) ranges from about 60° C. to about 65° C. 
   
   
       42 . The method of  claim 40 , wherein the temperature of sub-step (d3) ranges from about −15° C. to about −10° C. 
   
   
       43 . The method of  claim 40 , wherein sub-steps (d1) through (d4) are repeated one or more times. 
   
   
       44 . The method of  claim 40  further comprising the step of (e) isolating (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt. 
   
   
       45 . The method of  claim 40 , wherein step (e) comprises the sub-steps of:
 (e1) filtering the suspension of step (d); and   (e2) drying the (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt.   
   
   
       46 . The method of  claim 45 , wherein a filter cake obtained in sub-step (e1) is washed. 
   
   
       47 . A method of making 2-methyltryptamine comprising the steps of:
 (a) providing an admixture of phenylhydrazine and 5-chloro-2-pentanone in ethanol at a first temperature;   (b) adding ethanol to the admixture and refluxing the mixture;   (c) distilling ethanol;   (d) adding water to the residual solution; and   (e) cooling the residual solution to form 2-methyltryptamine.   
   
   
       48 . The method of  claim 47 , wherein step (a) comprises the sub-steps:
 (a1) providing a solution of phenylhydrazine in ethanol;   (a2) warming the solution to a temperature ranging from about 30° C. to about 40° C.;   (a3) holding the reaction at a temperature ranging from about 35° C. to about 45° C., while 5-chloro-2-pentanone is added to the reaction mixture; and   (a4) holding the reaction for a period of about 30 minutes at the temperature of step (a3).   
   
   
       49 . The method of  claim 47 , wherein the reaction mixture is immediately warmed to reflux and held for 50 minutes. 
   
   
       50 . The method of  claim 47 , wherein the reaction mixture is cooled to room temperature over a period of about 20 minutes prior to step (c). 
   
   
       51 . The method of  claim 47 , wherein ethanol is partially distilled. 
   
   
       52 . The method of  claim 47 , wherein distillation is continued and additional water is added to the residual mixture prior to step (e). 
   
   
       53 . The method of  claim 47 , wherein the residual solution is cooled to a temperature of less than about 25° C. 
   
   
       54 . The method of  claim 47  further comprising the step of:
 (f) isolating and purifying the 2-methyltryptamine.   
   
   
       55 . The method of  claim 54 , wherein step (f) comprises the sub-steps of:
 (f1) washing the residual solution with toluene;   (f2) isolating the 2-methyltryptamine;   (f3) washing the 2-methyltryptamine with toluene; and   (f4) drying the 2-methyltryptamine.   
   
   
       56 . The method of  claim 55 , wherein cold toluene is used in step (i). 
   
   
       57 . The method of  claim 55 , wherein drying is accomplished under vacuum at 45° C. until a loss on drying of <1% is obtained. 
   
   
       58 . A method of making (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt comprising the steps of:
 (a) combining 2-methyltryptamine and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester to form an admixture;   (b) stirring the admixture for a time and at a temperature sufficient to form an imine intermediate;   (c) reducing the imine intermediate; and   (d) seeding to form the (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt.   
   
   
       59 . The method of  claim 58 , wherein the temperature of step (a) ranges from about 20° C. to about 25° C. 
   
   
       60 . The method of  claim 58 , wherein the 2-methyltryptamine and the (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester are dissolved in methanol in step (a). 
   
   
       61 . The method of  claim 58 , wherein the admixture in step (b) is stirred for about 30 minutes at a temperature ranging from about 20 to about 25° C. 
   
   
       62 . The method of  claim 58 , wherein step (c) comprises the sub-steps of:
 (c1) cooling the admixture;   (c2) adding sodium borohydride to the admixture; and   (c3) combining the admixture with hydrochloric acid.   
   
   
       63 . The method of  claim 58 , wherein the admixture is diluted with solvent prior to sub-step (c1). 
   
   
       64 . The method of  claim 62 , wherein the admixture is cooled to a temperature of about −15° C. in sub-step (c1). 
   
   
       65 . The method of  claim 62 , wherein the sodium borohydride in sub-step (c2) is added in portions. 
   
   
       66 . The method of  claim 62 , wherein the sodium borohydride in sub-step (c2) is added over about 1 hour while the temperature is maintained at a range from about −15° C. to about −10° C. 
   
   
       67 . The method of  claim 62 , wherein the sodium borohydride is added in solid form. 
   
   
       68 . The method of  claim 62 , wherein sub-step (c3) is performed by slow addition of the admixture to pre-cooled hydrochloric acid. 
   
   
       69 . The method of  claim 68 , wherein the hydrochloric acid is cooled to a temperature of about 0° C. to about 5° C. 
   
   
       70 . The method of  claim 69 , wherein sub-step (c3) comprises the sub-steps of:
 (c3a) heating the admixture of sub-step (c2);   (c3b) adding water to the admixture; and   (c3c) adding hydrochloric acid to the admixture.   
   
   
       71 . The method of  claim 70 , wherein the admixture is heated to a temperature ranging from about 20° C. to about 25° C. over a period of time of about 25 minutes in sub-step (c3a). 
   
   
       72 . The method of  claim 70 , wherein water is added slowly after a period of stirring the admixture of sub-step (c3a). 
   
   
       73 . The method of  claim 70 , wherein the hydrochloric acid is added in portions. 
   
   
       74 . The method of  claim 58 , wherein step (d) comprises the sub-steps of:
 (d1) heating the suspension formed when the imine intermediate is reduced in step (c);   (d2) stirring the suspension at the temperature of sub-step (d1);   (d3) cooling the suspension; and   (d4) stirring the suspension at the temperature of sub-step (d3).   
   
   
       75 . The method of  claim 74 , wherein the temperature of sub-step (d1) is about 65° C. 
   
   
       76 . The method of  claim 74 , wherein the temperature of sub-step (d3) ranges from about −15° C. to about −10° C. 
   
   
       77 . The method of  claim 71 , wherein sub-steps (d1) through (d4) are repeated one or more times. 
   
   
       78 . The method of  claim 71  further comprising the step of (e) isolating (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt.