4-alkyl-2-haloaniline derivatives and process for producing the same

1. A compound of formula (1):

wherein

R 1 represents t-butyl;

R 2 represents a halogen atom, straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom; nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3-C8 cycloakly optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfony;

R 3 represents methyl;

n is zero; and

X represents a fluorine atom.

2. A process for producing the compound of formula (1), comprising the step of reacting the compound of the following formula (2) with an alkylating agent in the presence of an acid catalyst in an organic solvent or sulfuric acid to introduce group R 1 , into the 4-position of the compound of formula (2), thereby preparing the compound of formula (1):

wherein

R 1 represents branched chain C3-C10 alkyl or C3-C10 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl;

R 2 represents a halogen atom, straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3-C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl;

R3 represents straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; straight chained or branched chain C2-C6 alkenyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3-C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl;

n is an integer of 0 (zero) to 3; and

X represents a halogen atom,

 wherein

R 2 ,R 3 , n, and X are as defined in the formula (1), provided that R 2 is not in the 4-position on the aromatic ring,

wherein the acid catalysts are selected from the group consisting of 50 to 90% sulfuric acid and anhydrous aluminum chloride.

3. The process according to claim 2 , wherein the alkylating agent is selected from the group consisting of t-butyl alcohol, isobutene, t-butyl chloride, t-butyl bromide, isobutyl bromide, and isobutyl chloride.

4. The process according to claim 2 , wherein said alkylating agent is t-butyl alcohol and said t-butyl alcohol is used in an amount of 1.0 to 5.0 equivalents based on the number of moles of the compound of formula (2).

5. The process according to any one of claims 2 to 4 , wherein the acid catalyst is 70 to 90% (w/w) sulfuric acid.

6. The process according to any one of claims 2 to 4 , wherein the acid catalyst is 70 to 90% (w/w) sulfuric acid and the reaction is carried out at a temperature in the range of 60 to 80° C.

7. The process according to any one of claims 2 to 4 , which further comprises the step of reacting a compound of formula (4) or its salt with a chloroformic ester C1COOR 3 , wherein R 3 represents straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; straight chain or branched chain C2-C6 alkenyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3 -C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl, under basic conditions to protect amino in the compound of formula (4) or its salt and thus to prepare the compound of formula (2):

wherein

R 2 represents a halogen atom, straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3 -C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl;

n is an integer of 0 (zero) to 3; and

X represents a fluorine or chlorine atom.

8. A process for producing a compound of formula (3) or a pharmaceutically acceptable salt thereof, comprising the step of deprotecting the protected amino in the compound of formula (1) under acidic or basic conditions:

wherein

R 1 represents branched chain C3-C10 alkyl or C3-C10 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl;

R 2 represents a halogen atom, straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3-C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl;

R 3 represents straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; straight chained or branched chain C2 -C6 alkenyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3-C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl;

n is an integer of 0 (zero) to 3; and

X represents a halogen atom,

 wherein n, R 1 , R 2 ,and X are as defined in the formula (1).

9. The compound according to claim 8 , wherein R 1 represents t-butyl;

n is 0; and

X represents a fluorine atom.

10. The process according to claim 8 , wherein the deprotection reaction is carried out by heating the compound of formula (1) in a 20 to 53% aqueous sodium hydroxide solution or a 20 to 47% aqueous potassium hydroxide solution.

11. The process according to any one of claims 8 to 10 , which further comprises the step of reacting a compound of formula (2) with an alkylating agent in the presence of an acid catalyst in an organic solvent or sulfuric acid to introduce group R 1 , wherein R 1 represents branched chain C3-C10 alkyl or C3 to C10 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; into the 4-position of the compound of formula (2), thereby preparing the compound of formula (1):

wherein

R 2 represents a halogen atom, straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3-C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl;

R 3 represents straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; straight chained or branched chain C2-C6 alkenyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3-C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl;

n is an integer of 0 (zero) to 3; and

X represents a fluorine or chlorine atom, provided that R2 is not in the 4-position on the aromatic ring,

wherein the acid catalysts are selected from the group consisting of 50 to 90% sulfuric acid and anhydrous aluminum chloride.

12. The process according to claim 5 , which further comprises the step of reacting a compound of formula (4) or its salt with a chloroformic ester C1COOR 3 , wherein R 3 represents straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; straight chain or branched chain C2-C6 alkenyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3-C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl, under basic conditions to protect amino in the compound of formula (4) or its salt and thus to prepare the compound of formula (2):

wherein R 2 , n, and X are as defined in the formula (1).

13. The process according to claim 6 , which further comprises the step of reacting a compound of formula (4) or its salt with a chloroformic ester C1COOR 3 , wherein R 3 represents straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; straight chain or branched chain C2-C6 alkenyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3-C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl, under basic conditions to protect amino in the compound of formula (4) or its salt and thus to prepare the compound of formula (2):

wherein R 2 , n, and X are as defined in the formula (1).

14. A compound of formula (1):

wherein

R 1 represents t-butyl;

R 2 represents a halogen atom, straight chain or branched chain C1-C8 alkyl optionally substituted by a halogen atom; nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl; or C3-C8 cycloalkyl optionally substituted by a halogen atom, nitro, ester having 1 to 4 carbon atoms, C1-C4 alkyl, C1-C4 alkoxy, allyl, nitrophenyl, or C1-C4 alkylsulfonyl;

R 3 represents ethyl;

n is 0; and

X represents a fluorine atom.