US 12,139,490 B2
Process for preparing 1-(4-fluorophenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)butan-1-one
John Charles Tomesch, Succasunna, NJ (US); Peng Li, New Milford, NJ (US); Wei Yao, New Milford, NJ (US); Qiang Zhang, Somerset, NJ (US); James David Beard, New York, NY (US); Andrew S. Thompson, Mountainside, NJ (US); Hua Cheng, Plainsboro, NJ (US); and Lawrence P. Wennogle, Steamboat Springs, CO (US)
Assigned to INTRA-CELLULAR THERAPIES, INC., Bedminster, NJ (US)
Filed by INTRA-CELLULAR THERAPIES, INC., New York, NY (US)
Filed on Jun. 24, 2022, as Appl. No. 17/808,836.
Application 17/808,836 is a division of application No. 16/594,603, filed on Oct. 7, 2019, granted, now 11,407,751.
Application 13/593,097 is a division of application No. 12/531,016, granted, now 8,309,722, issued on Nov. 13, 2012, previously published as PCT/US2008/003340, filed on Mar. 12, 2008.
Application 16/594,603 is a continuation of application No. 16/439,361, filed on Jun. 12, 2019, granted, now 10,464,938, issued on Nov. 5, 2019.
Application 16/439,361 is a continuation of application No. 16/244,796, filed on Jan. 10, 2019, granted, now 10,597,395, issued on Mar. 24, 2020.
Application 16/244,796 is a continuation of application No. 15/660,762, filed on Jul. 26, 2017, granted, now 10,221,176, issued on Mar. 5, 2019.
Application 15/660,762 is a continuation of application No. 15/066,962, filed on Mar. 10, 2016, granted, now 9,751,883, issued on Sep. 5, 2017.
Application 15/066,962 is a continuation of application No. 14/323,545, filed on Jul. 3, 2014, granted, now 9,315,504, issued on Apr. 19, 2016.
Application 14/323,545 is a continuation of application No. 13/593,097, filed on Aug. 23, 2012, granted, now 8,779,139, issued on Jul. 15, 2014.
Claims priority of provisional application 60/906,473, filed on Mar. 12, 2007.
Prior Publication US 2022/0332716 A1, Oct. 20, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 471/16 (2006.01); C07D 471/04 (2006.01)
CPC C07D 471/16 (2013.01) [C07D 471/04 (2013.01)] 18 Claims
 
1. A process for preparing a compound of Formula 1J or Formula 2J:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt form thereof,
wherein:
R1 is:

OG Complex Work Unit Chemistry
each R5 is independently H;
R6a is H;
R6b is H;
R7 is H;
R8 is H;
R9 is H;
X is N;
R10 is CH3;
k is 1;
m is 1; and
n is 1;
wherein the process comprises the following steps:
(1)N-alkylating the free base form of a compound of Formula 1I or Formula 2I:

OG Complex Work Unit Chemistry
or a salt form thereof,
wherein:
each R5 is independently H;
R6a is H;
R6b is H;
R7 is H;
R8 is H;
R9 is H;
X is N;
R10 is CH3;
k is 1;
m is 1; and
n is 1;
with a compound of the following formula:
G-Z-R13,
wherein:
G is

OG Complex Work Unit Chemistry
Z is —C(O)—; and
R13 is

OG Complex Work Unit Chemistry
in the presence of a base selected from the group consisting of (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), and (k):
(a) an amine base selected from the group consisting of ammonia, triethylamine, N,N′-diisopropylethylamine, 4-(dimethylamino)pyridine (DMAP), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU);
(b) an alkali metal hydride selected from the group consisting of lithium hydride, sodium hydride, and potassium hydride;
(c) an alkali metal alkoxide selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, NaOAr, and KOAr, wherein Ar is aryl;
(d) an alkali metal carbonate selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate;
(e) an alkaline earth metal carbonate selected from the group consisting of magnesium carbonate, calcium carbonate, and barium carbonate;
(f) an alkali metal bicarbonate selected from the group consisting of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate;
(g) an alkaline earth metal bicarbonate selected from the group consisting of magnesium bicarbonate, calcium bicarbonate, and barium bicarbonate;
(h) an alkali metal hydroxide selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide;
(i) an alkaline earth metal hydroxide selected from the group consisting of magnesium hydroxide, calcium hydroxide, and barium hydroxide;
(j) an alkali metal phosphate selected from the group consisting of lithium phosphate, sodium phosphate, potassium phosphate, and cesium phosphate; and
(k) an alkaline earth metal phosphate selected from the group consisting of magnesium phosphate, calcium phosphate, and barium phosphate;
to provide the compound of Formula 1J or Formula 2J above; and
(2) when the process provides a pharmaceutically acceptable salt form of the compound of Formula 1J or Formula 2J above, optionally reacting the free base form of the compound of Formula 1J or Formula 2J provided in step (1) above with an acid selected from the group consisting of acetic acid, phenylacetic acid, trifluoroacetic acid, ascorbic acid, benzoic acid, 2-acetoxybenzoic acid, citric acid, ethanedisulfonic acid, fumaric acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, hydroxymaleic acid, malic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tartaric acid, and toluenesulfonic acid, in the presence of water or an organic solvent selected from the group consisting of 3-pentanone, dioxane, diethyl ether, ethanol, ethyl acetate, isopropanol, acetonitrile, and toluene, or a combination thereof, to provide a pharmaceutically acceptable salt form of the compound of Formula 1J or Formula 2J.