Process and intermediates for the preparation of benzo[b]thiophene compounds
A process for preparing compounds of formula (I), or a salt or solvate thereof, including Brexpiprazole, which process comprises cyclization of a compound of formula (II) or (III), or a salt or solvate thereof. The invention also refers to intermediates of said process.
1. A process for preparing a compound of formula (I), or a salt or solvate thereof
wherein
R 1 is selected from the group consisting of hydrogen, an amino protecting group, —(CH 2 ) n —X, —(CH 2 ) n —OR,
n is an integer from 1 to 6;
X is a leaving group;
R is selected from the group consisting of H and a hydroxyl protecting group;
which process comprises cyclization of a compound of formula (II), or a salt or solvate thereof
wherein
R 1 is as defined above;
R 2 is selected from the group consisting of —CHO, —CN, —C(O)OR′ and —C(O)X′;
X′ is halogen;
R′ is selected from the group consisting of H, C 1 -C 6 alkyl, C 6 -C 10 aryl and (C 6 -C 10 )aryl(C 1 -C 6 )alkyl;
R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, —C(O)OR″, —C(S)OR″ and —C(O)R″; and
R″ is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl and (C 6 -C 10 )aryl(C 1 -C 6 )alkyl.
2. A process for preparing a compound of formula (I), or a salt or solvate thereof
wherein
R 1 is selected from the group consisting of hydrogen, an amino protecting group, —(CH 2 ) n —X, —(CH 2 ) n —OR,
n is an integer from 1 to 6;
X is a leaving group;
R is selected from the group consisting of H and a hydroxyl protecting group;
which process comprises cyclization of a compound of formula (III), or a salt or solvate thereof
wherein
R 1 is as defined above;
R′ is selected from the group consisting of halogen and —OR′;
R′ is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl and (C 6 -C 10 )aryl(C 1 -C 6 )alkyl;
R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 0 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, —C(O)OR″, —C(S)OR″ and —C(O)R″; and
R″ is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl and (C 6 -C 10 )aryl(C 1 -C 6 )alkyl.
3. The process according to claim 1 , which further comprises obtaining the compound of formula (II), or a salt or solvate thereof, by a process comprising homologation of a compound of formula (IV), or a salt or solvate thereof
wherein
R 5 is selected from the group consisting of —CHO, —CN, —C(O)OR′″ and —C(O)X″;
X″ is halogen; and
R′″ is selected from the group consisting of H, C 1 -C 6 alkyl, C 6 -C 10 aryl and (C 6 -C 10 )aryl(C 1 -C 6 )alkyl.
4. The process according to claim 2 , which further comprises obtaining the compound of formula (III), or a salt or solvate thereof, by a process comprising alkenylation of a compound of formula (V), or a salt or solvate thereof
wherein
R 5 is —CHO.
5. The process according to claim 3 , wherein R 2 and R 5 are —CHO.
6. The process according to claim 5 ,
wherein
R 1 is selected from the group consisting of hydrogen, an amino protecting group, —(CH 2 ) n —X, —(CH 2 ) n —OR,
n is 4;
X is a leaving group;
R is selected from the group consisting of H and a hydroxyl protecting group;
R 2 is —CHO;
R 3 is C 1 -C 6 alkyl;
R 4 is selected from the group consisting of halogen and —OC 1 -C 6 alkyl;
R 5 is —CHO.
7. The process according to claim 1 , wherein the cyclization of a compound of formula (II), or a salt or solvate thereof, is carried out in the presence of an acid.
8. The process according to claim 1 , which further comprises converting a compound of formula (I), or a salt or solvate thereof, wherein R′ is selected from the group consisting of hydrogen, an amino protecting group, —(CH 2 ) 4 —X and —(CH 2 ) 4 —OR; X is a leaving group; and R is selected from the group consisting of H and a hydroxyl protecting group; into a compound of formula (I), or a salt or solvate thereof, wherein R 1 is selected from the group consisting of
9. The process according to claim 1 , wherein the compound of formula (I) is (1-benzothiophen-4-yl)piperazine or Brexpiprazole, or a salt or solvate thereof.
10. The process according to claim 1 for preparing Brexpiprazole which comprises cyclization in the presence of an acid of a compound of formula (IIa), or a salt or solvate thereof
wherein
R 1 is selected from the group consisting of hydrogen, an amino protecting group, —(CH 2 ) 4 —X, —(CH 2 ) 4 —OR, and
X is a leaving group;
R is selected from the group consisting of H and a hydroxyl protecting group;
R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, —C(O)OR″, —C(S)OR″ and —C(O)R″; and
R″ is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl and (C 6 -C 10 )aryl(C 1 -C 6 )alkyl.
11. The process according to claim 2 for preparing Brexpiprazole which comprises cyclization in the presence of an acid of a compound of formula (IIIa), or a salt or solvate thereof
wherein
R 1 is selected from the group consisting of hydrogen, an amino protecting group, —(CH 2 ) 4 —X, —(CH 2 ) 4 —OR, and
X is a leaving group;
R is selected from the group consisting of H and a hydroxyl protecting group;
R′ is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl and (C 6 -C 10 )aryl(C 1 -C 6 )alkyl;
R 3 is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, —C(O)OR″, —C(S)OR″ and —C(O)R″; and
R″ is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl and (C 6 -C 10 )aryl(C 1 -C 6 )alkyl.
12. The process according to claim 2 , wherein the cyclization of a compound of formula (III), or a salt or solvate thereof, is carried out in the presence of an acid.
13. The process according to claim 2 , which further comprises converting a compound of formula (I), or a salt or solvate thereof, wherein R 1 is selected from the group consisting of hydrogen, an amino protecting group, —(CH 2 ) 4 —X and —(CH 2 ) 4 —OR;
X is a leaving group; and
R is selected from the group consisting of H and a hydroxyl protecting group; into a compound of formula (I), or a salt or solvate thereof,
wherein R 1 is selected from the group consisting of
14. The process according to claim 2 , wherein the compound of formula (I) is (1-benzothiophen-4-yl)piperazine or Brexpiprazole, or a salt or solvate thereof.