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
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.