Process for the production of substituted 2-[2-(phenyl)ethylamino] alkaneamide derivatives
The present invention refers to a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R is (C 3 -C 10 )alkyl, or ω-trifluoro(C 3 -C 10 )alkyl; R 1 and R 2 are, independently, hydrogen, hydroxy, (C 1 -C 8 ) alkoxy, (C 1 -C 8 ) alkylthio, halo, trifluoromethyl or 2,2,2-trifluoroethyl; or one of R 1 and R 2 is in ortho position to the R—O— group and, taken together with the same R—O—, represents a Formula (A) group where R 0 is (C 2 -C 9 )alkyl; R 3 and R 4 are, independently, hydrogen, (C 1 -C 4 )alkyl; or R 4 is hydrogen and R 5 is a group selected from —CH 2 —OH, —CH 2 —O—(C 1 -C 6 )alkyl, —CH(CH 3 )—OH, —(CH 2 ) 2 —S—CH 3 , benzyl and 4-hydroxybenzyl; or R 4 and R 5 , taken together with the adjacent carbon atom, form a (C 3 -C 6 )cycloalkyl residue; R 5 and R 6 are independently hydrogen or (C 1 -C 6 )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 —NR 7 — where R 7 is hydrogen or (C 1 -C 6 ) alkyl; and wherein optionally one or more hydrogen atom in the groups R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , preferably in the R group, can be substituted by a deuterium atom.
1. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein R is (C 3 -C 10 )alkyl, or ω-trifluoro(C 3 -C 10 )alkyl;
R 1 and R 2 are, independently, hydrogen, hydroxy, (C 1 -C 8 )alkoxy, (C 1 -C 8 ) alkylthio, halo, trifluoromethyl or 2,2,2-trifluoroethyl; or one of R 1 and R 2 is in ortho position to the R—O— group and, taken together with the same R—O—, represents a
group where R 0 is (C 2 -C 9 )alkyl;
R 3 and R 4 are, independently, hydrogen, (C 1 -C 4 )alkyl; or R 4 is hydrogen and R 5 is a group selected from —CH 2 —OH, —CH 2 —O—(C 1 -C 6 )alkyl, —CH(CH 3 )—OH, —(CH 2 ) 2 —S—CH 3 , benzyl and 4-hydroxybenzyl; or R 4 and R 5 , taken together with the adjacent carbon atom, form a (C 3 -C 6 )cycloalkyl residue;
R 5 and R 6 are independently hydrogen or (C 1 -C 6 )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 —NR 7 — where R 7 is hydrogen or (C 1 -C 6 ) alkyl;
and wherein optionally one or more hydrogen atom in the groups R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 can be substituted by a deuterium atom;
said process comprising the steps of:
a) reacting a compound of formula (II):
wherein R, R 1 and R 2 are as above defined with a compound of formula (III):
[(R 9 ) 3 P CH 2 OR 8 ] + X − (III)
wherein
R 9 is aryl or a (C1-C6) alkyl;
X is Cl, Br or I;
R 8 is (C 1 -C 6 ) alkyl or aryl; in the presence of a strong base to obtain a compound of formula (IV):
wherein R, R 1 , R 2 and R 8 are as above defined and
b) hydrolyzing the obtained compound of formula (IV) to obtain a compound of formula (V):
wherein R, R 1 and R 2 are as above defined and
c) reacting the obtained compound of formula (V) with a compound of formula (VI) or a salt thereof:
wherein R 3 , R 4 , R 5 and R 6 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.
2. The process according to claim 1 for obtaining a compound of formula (I′):
wherein R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in claim 1 .
3. The process according to claim 1 for obtaining a compound of formula (I) wherein:
R is (C 4 -C 6 )alkyl or CD 3 -CD 2 -(C 2 -C 4 )alkyl;
R 1 and R 2 are, independently, hydrogen or halo;
R 3 and R 4 are both hydrogen; and
R 5 and R 6 are, independently, hydrogen or (C 1 -C 3 )alkyl.
4. The process according to claim 1 for obtaining a compound of formula (I) wherein R is n-butyl or CD 3 -CD 2 -CH 2 —CH 2 — and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen.
5. The process according to claim 1 wherein the strong base of step a) is selected in the group consisting of alkyl lithium, lithium hexamethylsilazide, lithium isopropylamide and potassium tert-butoxide.
6. The process according to claim 5 wherein the strong base is lithium hexamethylsilazide.
7. The process according to claim 1 , wherein the side product (R 9 ) 3 P formed in step a), wherein R 9 is as defined in claim 1 , is oxidized to (R 9 ) 3 PO and removed.
8. The process according to claim 7 wherein (R9)3 PO is removed by filtration.
9. The process according to claim 7 wherein the obtained product (IV) is purified by chromatography.
10. The process according to claim 1 , wherein the hydrolysis of step b) is carried out in aqueous acidic conditions.
11. The process according to claim 10 wherein the hydrolysis of step b) is carried out in acetonitrile and aqueous hydrochloric acid.
12. The process according to claim 1 , wherein G in the compound of formula (VI) is hydrogen.
13. The process according to claim 1 , wherein G in the compound of formula (VI) is a protecting group of the amino group selected from the group consisting of a carbamate N-carboxy alkyl group, N-t-butyl carbamate (BOC), N-benzyl carbamate (Cbz), bromobenzyl carbamate, p-chlorobenzylcarbamate and 9-fluorenylmethyl carbamate (Fmoc).
14. The process according to claim 1 , wherein the reducing agent used in step d) is selected from the group consisting of sodium borohydride, sodium triacetoxyborohydride (STAB-H), Pd/H 2 , and NaBH3CN.
15. The process according to claim 1 , wherein the reducing agent used in step d) is sodium triacetoxyborohydride (STAB-H).
16. The process according to claim 1 , wherein step b), step c) and step d) are carried out without isolating the intermediate products.
17. The process according to claim 16 wherein step b), step c) and step d) are carried out in acetonitrile and aqueous hydrochloric acid.
18. The process according to claim 1 , wherein the pharmaceutically acceptable acid of step e) is selected from the group consisting of HCl, HBr, CH 3 SO 3 H, paratoluenesulfonic acid and phosphoric acid.
19. The process according to claim 1 wherein the compound of formula (II) wherein R, R 1 and R 2 are as defined in claim 1 is prepared by alkylation of a compound of formula (II) wherein R is hydrogen by reaction with a compound of formula RY wherein R is as defined in claim 1 and Y is a leaving group.
20. The process according to claim 19 wherein Y is selected from the group consisting of chloride, bromide, mesylate, para-toluenesulphonate, brosylate, nosylate and phosphate.