Process for preparing benzimidazole compounds

1. A process for the preparation of a compound of Formula Ib-1

and salts and solvates thereof, wherein:

Z is —C(═O)OR 1 , —C(═O)NR 6 R 7 , CN, —C(═O)H, or

or a moiety that can be transformed into any one of said Z groups;

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 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 halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl;

X 1 and X 2 are independently selected from hydrogen, F, Cl, Br, I, 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 and C 1 -C 10 thioalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl and thioalkyl portions are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy and azido;

X 5 is H, F, Cl, Br, I or C 1 -C 6 alkyl;

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 or heterocyclic rings are optionally substituted with one or more groups independently selected from 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 OH, —O—(C 1 -C 10 -alkyl) and O—(C 1 -C 1 O-alkenyl);

R 10 is C 1 -C 10 alkyl, C 3 -C 10 cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein said alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from 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 ; and

R 12a and R 12b are independently selected from 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 and heteroarylalkyl,

or R 12a and R 12b together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring;

said method comprising:

nitrating a compound having the Formula

wherein X 3 and X 4 are independently F, Cl, Br, I, or a sulfonate ester, to provide a compound of Formula II

reacting said compound of Formula II with (i) a reagent that contains or generates ammonia, (ii) a primary amine other than an aromatic amine or (iii) a reagent that delivers a group that can subsequently be converted into an amine, under conditions that allow selective displacement of X 4 , to provide a compound of Formula III-11 wherein A is NR 2 R 2a , or reacting said compound of Formula II with (iv) a metal azide under conditions that allow selective displacement of X 4 to provide a compound of Formula III-12 wherein A is N 3

and R 2a is hydrogen and R 2 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 halogen, hydroxyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl and C 2 -C 4 alkynyl;

reacting said compound of Formula III-11 or III-12, optionally at elevated temperatures, with (i) a reagent that contains or generates ammonia, (ii) a primary amine other than an aromatic amine or (iii) a reagent that delivers a group that can subsequently be converted into an amine to provide a compound having Formula Vb-11 wherein B is —NR 2b R 2c and A is —NR 2 R 2a or N 3 , or reacting said compound of Formula III-11 or III-12 with (iv) a metal azide, optionally at elevated temperatures, to provide a compound of Formula Vb-12 wherein B is N 3 and A is —NR 2 R 2a or N 3 ,

wherein R 2c 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 —NH-benzyl, N 3 , —NHOR 1 or —NHNHR 1 , then R 2 and/or R 2b , respectively, of Formula VIIb-1 are hydrogen;

cyclizing said compound of Formula VIIb-1 to provide a compound of Formula VIIIb-1

and

coupling said compound of Formula VIIIb-1 with a compound having the formula

wherein X 6 is F, Cl, Br, I, —OSO 2 CF 3 , alkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, —B(OR 8 ) 2 , —BF 3 or —Bi(R 1 ) 2 , optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a metal-based catalyst and a base, to provide said compound of Formula Ib-1.

2. The process of claim 1 further comprising:

reacting said compound of Formula III with a compound having the formula R 1 OH, optionally in the presence of an activating agent that activates the Z group towards reaction with said compound of formula R 1 OH, to provide a compound of Formula IV-21 or IV-22

reacting said compound of Formula IV-21 or IV-22 at elevated temperatures with (i) a reagent that contains or generates ammonia, (ii) a primary amine other than an aromatic amine or (iii) a reagent that delivers a group that can subsequently be converted into an amine to provide a compound of Formula Vb-11 wherein Z is —COOR 1 , or reacting said compound of Formula IV-21 or IV-22 with (iv) a metal azide at elevated temperatures to provide a compound of Formula Vb-12 wherein Z is —COOR 1 ;

reducing said compound of Formula Vb-21 or Vb-22 to provide said compound of Formula VIIb-1 wherein Z is —COOR 1 ;

cyclizing said compound of Formula VIIb-1 to provide said compound of Formula VIIIb-1 wherein Z is —COOR 1 ; and

coupling said compound of Formula VIIIb-1 with said compound having the formula

optionally either (i) at elevated temperature and optionally in the presence of a base, or (ii) in the presence of a metal-based catalyst and a base, to provide said compound of Formula Ib-1 wherein Z is COOR 1 .

3. The process of claim 1 , wherein said cyclization comprises reacting said compound of Formula VIIb-1, wherein R 2 is 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 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

and

(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 is 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 is 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, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein said alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from 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

and

(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 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, arylalkyl, heteroarylalkyl or heterocyclylalkyl, wherein said alkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from 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

and

(d) removing the R 2 group from the N−1 position to provide said compound of Formula VIIIb-1.