Processes for preparing benzimidazole compounds
Provided are processes for the preparation of benzimidazole structures having Formula VIIIb-1: and salts and solvates thereof, wherein Z, X 5 , R 2b , R 2c and R 10 are as defined herein. Compounds of Formula VIIIb-1 are useful for the preparation of benzimidazole derivatives.
1. A process for the preparation of a compound of Formula VIIIb-1
and salts and solvates thereof, wherein:
Z is —C(═O)OR 1 ;
X 5 is F, Cl, Br, or I;
R 1 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;
R 2b and R 2c are independently hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, —COR 6 , —C(O)OR 6 or —C(O)NR 6 R 7 , wherein said alkyl, alkenyl, alkynyl, and arylalkyl portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl;
R 6 and R 7 are independently hydrogen, trifluoromethyl, —OR 8 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl,
or R 6 and R 7 together with the atom to which they are attached form a 4 to 10 membered heteroaryl or heterocyclic ring, wherein said heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from the group consisting of halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR 8 ;
R 8 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, aryl or arylalkyl, wherein said alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from the group consisting of OH, —O—(C 1 -C 10 -alkyl) and O—(C 1 -C 10 -alkenyl); and
R 10 is C 1 -C 10 alkyl, C 3 -C 10 cycloalkylalkyl, or arylalkyl, wherein said alkyl, cycloalkylalkyl, and arylalkyl, portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, —NR 6 R 7 and —OR 8 ;
said method comprising cyclizing a compound of Formula VIIb-1
wherein R 2 hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, benzyl, allyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, —COR 6 , —C(O)OR 6 or —C(O)NR 6 R 7 , wherein said alkyl, alkenyl, alkynyl, benzyl, allyl, and arylalkyl portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl, and
R 2a is hydrogen,
to provide said compound of Formula VIIIb-1.
2. A process for the preparation of a compound of Formula VIIIb-1
and salts and solvates thereof, wherein:
Z is —C(═O)OR 1 ;
X 5 is F, Cl, Br, or I;
R 1 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, trialkylsilyl or dialkylarylsilyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;
R 2b is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, —COR 6 , —C(O)OR 6 or —C(O)NR 6 R 7 , wherein said alkyl, alkenyl, alkynyl, and arylalkyl portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl;
R 2c is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, benzyl, allyl, arylalkyl, trialkylsilyl, dialkylarylsilyl, —COR 6 , —C(O)OR 6 , —C(O)NR 6 R 7 , —OR 1 or —NHR 1 , wherein said alkyl, alkenyl, alkynyl, benzyl, allyl and arylalkyl portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl;
R 6 and R 7 are independently hydrogen, trifluoromethyl, —OR 8 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl,
or R 6 and R 7 together with the atom to which they are attached form a 4 to 10 membered heteroaryl or heterocyclic ring, wherein said heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from the group consisting of halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and OR 8 ;
R 8 is hydrogen, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, aryl or arylalkyl, wherein said alkyl, alkenyl, aryl and arylalkyl are optionally substituted with one or more groups independently selected from the group consisting of OH, —O—(C 1 -C 10 -alkyl) and O—(C 1 -C 10 -alkenyl);
R 10 is C 1 -C 10 alkyl, C 3 -C 10 cycloalkylalkyl, or arylalkyl, wherein said alkyl, cycloalkylalkyl, and arylalkyl, portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, —NR 6 R 7 and —OR 8 ;
said method comprising:
providing a compound of Formula Vb-11 wherein B is NR 2b R 2c and A is NR 2 R 2a or N 3 , or a compound of Formula Vb-12 wherein B is N 3 and A is NR 2 R 2a or N 3 ,
wherein R 2 is hydrogen, substituted or unsubstituted benzyl, allyl or —C(O)OR 6 and R 2a is hydrogen;
reducing said compound of Formula Vb-11 or Vb-12 to provide a compound of Formula VIIb-1
wherein when A and/or B of Formula Vb-11 or Vb-12 is N 3 , then R 2 and R 2a and/or R 2b and R 2c , respectively, of Formula VIIb-1 are hydrogen; and
when R 2a is hydrogen, cyclizing said compound of Formula VIIb-1 to provide said compound of Formula VIIIb-1.
3. The process of claim 1 , wherein said cyclization comprises reacting said compound of Formula VIIb-1, wherein R 2 and R 2a are H, with (i) formic acid, optionally in the presence of an additional acid, or (ii) a formic acid derivative in the presence of an acid, to provide said compound of Formula VIIIb-1 wherein R 10 is H.
4. The process of claim 1 , wherein said cyclization comprises
(a) reacting said compound of Formula VIIb-1, wherein R 2a is hydrogen and R 2 is not hydrogen, with (i) formic acid, optionally in the presence of an additional acid, (ii) a formic acid derivative in the presence of an acid, or (iii) formaldehyde or a formaldehyde derivative in the presence of an acid, to provide a compound of Formula XIb-1
(b) alkylating said compound of Formula XIb-1 with a reagent having the formula R 10 —Y wherein Y is Cl, Br, I, or a sulfonate ester, to provide a compound of Formula XIIb-1
(c) removing said R 2 group from the N−1 position to provide said compound of Formula VIIIb-1.
5. The process of claim 1 , wherein said cyclization comprises treating said compound of Formula VIIb-1, wherein R 2 and R 2a are H, with two or more equivalents of formaldehyde or a formaldehyde derivative in the presence of an acid to provide said compound of Formula VIIIb-1 wherein R 10 is methyl.
6. The process of claim 1 , wherein said cyclization comprises:
(a) reacting said compound of Formula VIIb-1, wherein R 2 and R 2a are hydrogen, with an acylating agent to provide a compound of Formula IXb
wherein R 10a is H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkylalkyl, or arylalkyl, wherein said alkyl, cycloalkylalkyl, and arylalkyl portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, —NR 6 R 7 and —OR 8 ;
(b) reducing the amide group of said compound of Formula IXb to provide a compound of Formula Xb
(c) reacting said compound of Formula Xb with (i) formic acid optionally in the presence of an additional acid or (ii) a formic acid derivative in the presence of an acid to provide said compound of Formula VIIIb-1.
7. The process of claim 1 , wherein said cyclization comprises:
(a) reacting said compound of Formula VIIb-1, wherein R 2a is hydrogen and R 2 is not hydrogen, with an acylating agent to provide a compound of Formula IXb
wherein R 10a is H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkylalkyl, or arylalkyl, wherein said alkyl, cycloalkylalkyl, and arylalkyl portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, —NR 6 R 7 and —OR 8 ;
(b) reducing the amide group of said compound of Formula IXb to provide a compound of Formula Xb
(c) reacting said compound of Formula Xb with (i) formic acid optionally in the presence of an additional acid or (ii) a formic acid derivative in the presence of an acid to provide a compound of Formula XIIb-1
(d) removing the R 2 group from the N−1 position to provide said compound of Formula VIIIb-1.
8. The process of claim 2 , wherein said cyclization comprises
(a) reacting said compound of Formula VIIb-1, wherein R 2a is hydrogen and R 2 is not hydrogen, with (i) formic acid, optionally in the presence of an additional acid, (ii) a formic acid derivative in the presence of an acid, or (iii) formaldehyde or a formaldehyde derivative in the presence of an acid, to provide a compound of Formula XIb-1
(b) alkylating said compound of Formula XIb-1 with a reagent having the formula R 10 —Y wherein Y is Cl, Br, I, or a sulfonate ester, to provide a compound of Formula XIIb-1
(c) removing said R 2 group from the N−1 position to provide said compound of Formula VIIIb 1.
9. The process of claim 2 , wherein said cyclization comprises treating said compound of Formula VIIb-1, wherein R 2 and R 2a are H, with two or more equivalents of formaldehyde or a formaldehyde derivative in the presence of an acid to provide said compound of Formula VIIIb-1 wherein R 10 is methyl.
10. The process of claim 2 , wherein said cyclization comprises:
(a) reacting said compound of Formula VIIb-1, wherein R 2 and R 2a are hydrogen, with an acylating agent to provide a compound of Formula IXb
wherein R 10a is H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkylalkyl, or arylalkyl, wherein said alkyl, cycloalkylalkyl, and arylalkyl, portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, —NR 6 R 7 and —OR 8 ;
(b) reducing the amide group of said compound of Formula IXb to provide a compound of Formula Xb
(c) reacting said compound of Formula Xb with (i) formic acid optionally in the presence of an additional acid or (ii) a formic acid derivative in the presence of an acid to provide said compound of Formula VIIIb-1.
11. The process of claim 2 , wherein said cyclization comprises:
(a) reacting said compound of Formula VIIb-1, wherein R 2a is hydrogen and R 2 is not hydrogen, with an acylating agent to provide a compound of Formula IXb
wherein R 10a is H, C 1 -C 10 alkyl, C 3 -C 10 cycloalkylalkyl, or arylalkyl, wherein said alkyl, cycloalkylalkyl, and arylalkyl portions are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, azido, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, —NR 6 R 7 and —OR 8 ;
(b) reducing the amide group of said compound of Formula IXb to provide a compound of Formula Xb
(c) reacting said compound of Formula Xb with (i) formic acid optionally in the presence of an additional acid or (ii) a formic acid derivative in the presence of an acid to provide a compound of Formula XIIb-1
(d) removing the R 2 group from the N−1 position to provide said compound of Formula VIIIb-1.