US 12,291,495 B2
Process for the production of substituted 2-[2-(phenyl)ethylamino] alkaneamide derivatives
William Leong, Westfield, NJ (US); Dongxiao Lan, Shanghai (CN); Weifang Zhang, Shanghai (CN); Xiang Fang, Shanghai (CN); and Sizhong Wu, Shanghai (CN)
Assigned to Newron Pharmaceuticals S.p.A., Bresso (IT)
Appl. No. 17/603,019
Filed by Newron Pharmaceuticals S.p.A., Bresso (IT)
PCT Filed Apr. 14, 2020, PCT No. PCT/EP2020/060470
§ 371(c)(1), (2) Date Oct. 12, 2021,
PCT Pub. No. WO2020/212352, PCT Pub. Date Oct. 22, 2020.
Claims priority of application No. 19169715 (EP), filed on Apr. 17, 2019.
Prior Publication US 2022/0185766 A1, Jun. 16, 2022
Int. Cl. C07C 231/14 (2006.01); C07B 59/00 (2006.01); C07C 41/14 (2006.01); C07C 45/64 (2006.01); C07C 231/12 (2006.01)
CPC C07C 231/14 (2013.01) [C07B 59/001 (2013.01); C07C 41/14 (2013.01); C07C 45/64 (2013.01); C07C 231/12 (2013.01); C07B 2200/05 (2013.01)] 20 Claims
 
1. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof:

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wherein R is (C3-C10)alkyl, or ω-trifluoro(C3-C10)alkyl;
R1 and R2 are, independently, hydrogen, hydroxy, (C1-C8)alkoxy, (C1-C8) alkylthio, halo, trifluoromethyl or 2,2,2-trifluoroethyl; or one of R1 and R2 is in ortho position to the R—O— group and, taken together with the same R—O—, represents a

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group where R0 is (C2-C9)alkyl;
R3 and R4 are, independently, hydrogen, (C1-C4)alkyl; or R4 is hydrogen and R5 is a group selected from —CH2—OH, —CH2—O—(C1-C6)alkyl, —CH(CH3)—OH, —(CH2)2—S—CH3, benzyl and 4-hydroxybenzyl; or R4 and R5, taken together with the adjacent carbon atom, form a (C3-C6)cycloalkyl residue;
R5 and R6 are independently hydrogen or (C1-C6)alkyl; or taken together with the adjacent nitrogen atom form a 5-6 membered monocyclic saturated heterocycle, optionally containing one additional heteroatom chosen among —O—, —S— and —NR7— where R7 is hydrogen or (C1-C6) alkyl;
and wherein optionally one or more hydrogen atom in the groups R, R1, R2, R3, R4, R5 and R6 can be substituted by a deuterium atom;
said process comprising the steps of:
a) reacting a compound of formula (II):

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wherein R, R1 and R2 are as above defined with a compound of formula (III):
[(R9)3P CH2OR8]+X−  (III)
wherein
R9 is aryl or a (C1-C6) alkyl;
X is Cl, Br or I;
R8 is (C1-C6) alkyl or aryl; in the presence of a strong base to obtain a compound of formula (IV):

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wherein R, R1, R2 and R8 are as above defined and
b) hydrolyzing the obtained compound of formula (IV) to obtain a compound of formula (V):

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wherein R, R1 and R2 are as above defined and
c) reacting the obtained compound of formula (V) with a compound of formula (VI) or a salt thereof:

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wherein R3, R4, R5 and R6 are as above defined and G is hydrogen or a protecting group of the amino group, to obtain a condensation compound;
d) reducing the obtained condensation compound to obtain the compound of formula (I)
or alternatively
c′) directly reacting the compound of formula (IV) as above defined with the compound of formula (VI) as above defined and reducing the obtained condensation compound to obtain the compound of formula (I); and
e) optionally converting the obtained compound of formula (I) into a pharmaceutically acceptable salt thereof.