IP Library › Granted Patent US 11,312,708
Granted Patent B2
US 11,312,708 · App. 16/785,002 · Granted Apr 26, 2022

Process and intermediates for the preparation of benzo[b]thiophene compounds

Inventors: Alfonso Pérez Encabo (Valladolid, ES); José Ángel Turiel Hernandez (Valladolid, ES); Yolanda Fernández Sainz (Valladolid, ES); Antonio Lorente Bonde-Larsen (Valladolid, ES)
Assignee: CRYSTAL PHARMA, S.A.U.
C07D409/04C07D215/227C07D241/12C07D295/033C07D295/15C07D401/12C07D409/12C07D417/14
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Quick Facts
Patent No.
US 11,312,708
App. No.
16/785,002
Granted
Apr 26, 2022
Kind
B2
Abstract

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.

Claims (126)

1. A compound of formula (II), or a salt or solvate thereof,

wherein in formula (II):

R 1 is selected from the group consisting of hydrogen and an amino protecting group selected from:

—COOR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—COR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—R where 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, and

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—(CH 2 ) n —X, —(CH 2 ) n —OR,

n is an integer from 1 to 6;

X is a leaving group selected from the group consisting of halogen, C 1 -C 6 alkylsulfonates, C 6 -C 10 arylsulfonates and C 1 -C 6 alkylC 6 -C 10 arylsulfonates;

R is selected from the group consisting of H and a hydroxyl protecting group selected from:

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—R or —CH 2 —OR where 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,

—COR where 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, and

—COOR where 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 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;

or a compound of formula (III), or a salt or solvate thereof,

wherein in formula (III):

R 1 is selected from the group consisting of hydrogen and an amino protecting group selected from:

—COOR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—COR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—R where 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, and

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—(CH 2 ) n —X, —(CH 2 ) n —OR,

n is an integer from 1 to 6;

X is a leaving group selected from the group consisting of halogen, C 1 -C 6 alkylsulfonates, C 6 -C 10 arylsulfonates and C 1 -C 6 alkylC 6 -C 10 arylsulfonates;

R is selected from the group consisting of H and a hydroxyl protecting group selected from:

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—R or —CH 2 —OR where 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,

—COR where 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, and

—COOR where 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 4 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 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;

or a compound of formula (IV), or a salt or solvate thereof,

wherein in formula (IV):

R 1 is selected from the group consisting of hydrogen and an amino protecting group selected from:

—COOR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—COR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—R where 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, and

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—(CH 2 ) n —X, —(CH 2 ) n —OR,

n is an integer from 1 to 6;

X is a leaving group selected from the group consisting of halogen, C 1 -C 6 alkylsulfonates, C 6 -C 10 arylsulfonates and C 1 -C 6 alkylC 6 -C 10 arylsulfonates;

R is selected from the group consisting of H and a hydroxyl protecting group selected from:

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—R or —CH 2 —OR where 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,

—COR where 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, and

—COOR where 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″;

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 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 H, 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

with the proviso that when R 1 is hydrogen and R 3 is methyl, then R 5 is not —CN.

2. The compound of formula (II), or a salt or solvate thereof, according to claim 1

wherein in formula (II):

R 1 is selected from the group consisting of hydrogen and an amino protecting group selected from:

—COOR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—COR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—R where 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, and

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—(CH 2 ) n —X, —(CH 2 ) n —OR,

n is an integer from 1 to 6;

X is a leaving group selected from the group consisting of halogen, C 1 -C 6 alkylsulfonates, C 6 -C 10 arylsulfonates and C 1 -C 6 alkylC 6 -C 10 arylsulfonates;

R is selected from the group consisting of H and a hydroxyl protecting group selected from:

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—R or —CH 2 —OR where 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,

—COR where 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, and

—COOR where 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 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.

3. The compound of formula (III), or a salt or solvate thereof, according to claim 1

wherein in formula (III):

R 1 is selected from the group consisting of hydrogen and an amino protecting group selected from:

—COOR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—COR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—R where 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, and

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—(CH 2 ) n —X, —(CH 2 ) n —OR,

n is an integer from 1 to 6;

X is a leaving group selected from the group consisting of halogen, C 1 -C 6 alkylsulfonates, C 6 -C 10 arylsulfonates and C 1 -C 6 alkylC 6 -C 10 arylsulfonates;

R is selected from the group consisting of H and a hydroxyl protecting group selected from:

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—R or —CH 2 —OR where 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,

—COR where 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, and

—COOR where 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 4 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 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, —C(O) OR″, —O(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.

4. The compound of formula (IV), or a salt or solvate thereof, according to claim 1

wherein in formula (IV):

R 1 is selected from the group consisting of hydrogen and an amino protecting group selected from:

—COOR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—COR where R is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl,

—R where 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, and

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—(CH 2 ) n —X, —(CH 2 ) n —OR,

n is an integer from 1 to 6;

X is a leaving group selected from the group consisting of halogen, C 1 -C 6 alkylsulfonates, C 6 -C 10 arylsulfonates and C 1 -C 6 alkylC 6 -C 10 arylsulfonates;

R is selected from the group consisting of H and a hydroxyl protecting group selected from:

—Si(R)(R′)(R″) where R, R′ and R″ are independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy and halogen,

—R or —CH 2 —OR where 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,

—COR where 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, and

—COOR where 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″;

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 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 H, 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

with the proviso that when R′ is hydrogen and R 3 is methyl, then R 5 is not —CN.

5. The compound as defined in claim 2 , which is

or a salt or solvate thereof.

6. The compound as defined in claim 3 , which is

or a salt or solvate thereof.

7. The compound as defined in claim 4 , which is

or a salt or solvate thereof.

Assignments (2)
CHANGE OF NAME Recorded Nov 5, 2025
From: CRYSTAL PHARMA, S.A.U.
To: CURIA SPAIN, S.A.U.
Reel/Frame 073449/0630 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 8, 2020
From: PEREZ ENCABO, ALFONSO; TURIEL HERNANDEZ, JOSE ANGEL; FERNANDEZ SAINZ, YOLANDA; LORENTE BONDE-LARSEN, ANTONIO
To: CRYSTAL PHARMA, S.A.U.
Reel/Frame 053152/0759 →