Process for preparing benzimidazole compounds

1. A process for preparing a compound of Formula Ia-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 2 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 or 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;

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, azido, trifluoromethyl, difluoromethoxy and trifluoromethoxy;

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 and 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 10 -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

treating said compound of Formula II optionally at elevated temperatures and/or pressure with two or more equivalents of (i) a reagent that contains or generates ammonia, (ii) a primary or secondary 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 VI-11 wherein A is —NR 2 R 2a , or treating said compound of Formula II with (iv) two or more equivalents of a metal azide optionally at elevated temperatures and/or pressure to provide a compound of Formula VI-12 wherein A is N 3

wherein R 2a 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;

reducing said compound of Formula VI-11 or VI-12 to provide a compound of Formula VIIa-1

wherein when A of Formula VI-11 or VI-12 is —NH-benzyl, —NHOR 1 or —NHNHR 1 or N 3 , then R 2 and R 2a of Formula VIIa-1 are hydrogen;

when R 2a of Formula VIIa-1 is hydrogen, cyclizing said compound of Formula VIIa-1 to provide a compound of Formula VIIIa-1

when R 2a of Formula VIIIa-1 is hydrogen, coupling said compound of Formula VIIIa-1 with a reagent 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 Ia-1.

2. The process of claim 1 , further comprising:

reacting said compound of Formula VI-11 or VI-12 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 Va-11 wherein A is —NR 2 R 2a or a compound of Formula Va-12 wherein A is N 3

reducing said compound of Formula Va-11 or Va-12 to provide said compound of Formula VIIa-1 wherein Z is —COOR 1 ;

when R 2a of Formula VIIa-1 is hydrogen, cyclizing said compound of Formula VIIa-1 to provide said compound of Formula VIIIa-1 wherein Z is —COOR 1 ; and

coupling said compound of Formula VIIIa-1 with said reagent 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 Ia-1 wherein Z is COOR 1 .

3. The process of claim 1 , wherein said cyclization comprises

(a) reacting said compound of Formula VIIa-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 XIa-1

(b) alkylating said compound of Formula XIa-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 XIIa-1

(c) removing said R 2 group from the N-1 position to provide said compound of Formula VIIIa-1.

4. The process of claim 1 , wherein said cyclization comprises treating said compound of Formula VIIa-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 VIIIa-1 wherein R 10 is methyl.

5. The process of claim 1 , wherein said cyclization comprises:

(a) reacting said compound of Formula VIIa-1, wherein R 2 and R 2a are hydrogen, with an acylating agent to provide a compound of Formula IXa

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 IXa to provide a compound of Formula Xa

(c) reacting said compound of Formula Xa 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 VIIIa-1.

6. The process of claim 1 , wherein said cyclization comprises:

(a) reacting said compound of Formula VIIa-1, wherein R 2a is hydrogen and R 2 is not hydrogen, with an acylating agent to provide a compound of Formula IXa

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 IXa to provide a compound of Formula Xa

(c) reacting said compound of Formula Xa 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 XIIa-1

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

7. A process for preparing a compound of Formula Ia-1

and salts and solvates thereof, wherein:

Z is —C(═O)OR 1 ;

R 1 is C 1 -C 10 alkyl;

R 2 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 or 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;

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, azido, trifluoromethyl, difluoromethoxy and trifluoromethoxy;

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 and 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 10 -alkenyl); and

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 ;

said method comprising:

i) 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

ii) reacting the compound of Formula II with a compound of formula R 1 OH, to form the corresponding ester having the formula

iii) reacting the ester with two or more equivalents of a reagent that generates ammonia to form a compound of Formula VI-11

wherein R 2a is hydrogen;

iv) reducing said compound of Formula VI-11 to provide a compound of Formula VIIa-1

v) cyclizing said compound of Formula VIIa-1 to provide a compound of Formula VIIIa-1

vi) coupling said compound of Formula VIIIa-1 with a reagent 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 to provide said compound of Formula Ia-1.