Methods for producing cyclic benzamidine derivatives

1. A method for producing a fluorinated cyclic benzamidine derivative (A) represented by formula (II) (wherein Et represents an ethyl group), or a salt thereof,

wherein the method comprises the step of reacting a compound represented by formula (I)

(wherein, X represents a leaving group) with ammonia or an imide.

2. The method of claim 1 , comprising the step of reacting the compound represented by formula (I) in which X is —OSO 2 R 1 (wherein, R 1 represents a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 6-10 aryl group, or a halogenated C 6-10 aryl group) with ammonia.

3. The method of claim 1 , comprising the steps of:

(a) reacting the compound represented by formula (I) in which X is —OSO 2 R 1 (wherein, R 1 represents a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 6-10 aryl group, or a halogenated C 6-10 aryl group), with a phthalimide or a succinimide, or a metal salt thereof, and

(b) converting the compound obtained in step (a) into an amine derivative.

4. The method of claim 1 , comprising the step of reacting the compound represented by formula (I) in which X represents a halogen atom, with ammonia.

5. The method of claim 1 , comprising the steps of:

(a) reacting the compound represented by formula (I) in which X represents a halogen atom, with a phthalimide or a succinimide, or a metal salt thereof, and

(b) converting the compound obtained in step (a) into an amine derivative.

6. The method of claim 2 or 3 , wherein a compound represented by formula (I′)

(wherein, R 1 represents a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 6-10 aryl group, or a halogenated C 6-10 aryl group) is obtained by reacting a compound represented by formula (III)

(wherein, Et represents an ethyl group), with R 1 SO 2 Y or (R 1 SO 2 ) 2 O (wherein, R 1 represents a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 6-10 aryl group, or a halogenated C 6-10 aryl group, and Y represents a halogen atom).

7. The method of claim 4 or 5 , wherein the compound represented by formula (I″)

(wherein, Hal represents a halogen atom) is obtained by reacting a compound represented by formula (III)

(wherein, Et represents an ethyl group) with a halogenating reagent.

8. The method of claim 4 or 5 , wherein the compound represented by formula (I″)

(wherein, Hal represents a halogen atom), is obtained by reacting a compound represented by formula (IV)

(wherein, Et represents an ethyl group), with a halogenating reagent.

9. The method of claim 6 , wherein the compound represented by formula (III) is obtained by steps comprising the following (1) to (3):

(1) reacting a compound represented by formula (V)

(wherein, Hal′ represents a halogen atom) with a cyanation reagent to obtain a compound represented by formula (VI)

(2) obtaining a compound represented by formula (VII)

through a formylation reaction of the compound represented by formula (VI); and

(3) obtaining the compound represented by formula (III)

(wherein, Et represents an ethyl group) by reducing the compound represented by formula (VII).

10. The method of claim 4 or 5 , wherein the compound represented by formula (I″)

(wherein, Hal represents a halogen atom) is obtained by steps (1′) to (3′) described below:

(1′) reacting a compound represented by formula (V)

(wherein, Hal′ represents a halogen atom) with a cyanation reagent to obtain a compound represented by formula (VI)

(2′) obtaining the compound represented by formula (IV)

through a methylation reaction of the compound represented by formula (VI); and

(3′) obtaining the compound represented by formula (I″) (wherein Et represents an ethyl group) by reacting the compound represented by formula (IV) with a halogenating reagent.

11. A method for producing a morpholine-substituted phenacyl derivative (B) represented by formula (VIII)

(wherein, Hal″ represents a halogen atom) or a salt thereof, wherein the method comprises the following steps of (1″) to (3″):

(1″) reacting a compound represented by formula (IX)

(wherein, each of the two R 2 s represents a C 1-4 alkyl group, and the two R 2 s may be bonded to each other to form a cyclic group represented by —(CH 2 ) n — (wherein, n represents an integer of 2 to 4); Hal′″ represents a halogen atom) with morpholine to obtain a compound represented by formula (X)

(wherein, R 2 represents the same group as in formula (IX));

(2″) reacting a compound represented by formula (X) with a halogenating reagent to obtain a compound represented by formula (XI)

(wherein, R 2 represents the same group as in formula (IX), and Hal″ represents a halogen atom);

(3″) performing a deketalization reaction on a compound represented by formula (XI) to obtain a morpholine-substituted phenacyl derivative (B) represented by formula (VIII) (In the above formulas, Me represents a methyl group).

12. The method of claim 11 , wherein the compound represented by formula (IX)

(wherein, each of the two R 2 s represents a C 1-4 alkyl group, and the two R 2 s may be bonded to each other to form a cyclic group represented by —(CH 2 ) n — (wherein, n represents an integer of 2 to 4, and Me represents a methyl group); Hal′″ represents a halogen atom) is obtained through the steps of: ketalization of a compound represented by formula (XII)

(wherein, Hal″″ represents a halogen atom), by reacting with R 2 OH, HC(OR 2 ) 3 (wherein R 2 represents a C 1-4 alkyl group), or HO—(CH 2 ) n —OH (wherein, n represents an integer of 2 to 4); and methoxylation of the hydroxyl group in the compound represented by formula (XII).

13. A method for recrystallizing a cyclic benzamidine derivative (C), wherein the method comprises the steps of dissolving a compound represented by formula (XIII)

(wherein, Me represents a methyl group, and Et represents an ethyl group)), or the salt thereof, in a mixed solvent comprising an alcohol and water, or a mixed solvent comprising an ether and water; and

after dissolution, adding additional water to precipitate crystals of the compound represented by formula (XIII)), or the salt thereof.

14. The recrystallization method of claim 13 , wherein the mixed solvent is a mixed solvent comprising an alcohol and water.

15. A compound represented by formula (XIV)

(wherein, R 3 represents a halogen atom or CN; R 4 represents a hydrogen atom, a methyl group, —CHO, —CH 2 OH, —CH 2 Hal (wherein, Hal represents a halogen atom), —CH 2 —OSO 2 R 1 (wherein, R 1 represents a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 6-10 aryl group, or a halogenated C 6-10 aryl group), a phthalimide methyl group, or a succinimide methyl group; and Et represents an ethyl group).

16. A compound represented by formula (XV)

(wherein, each of the two R 2 s represents an alkyl group of 1-4 carbon atoms, and the two R 2 s may be bonded to each other to form a cyclic group represented by —(CH 2 ) n — (wherein, n represents an integer of 2 to 4); R 5 represents a hydrogen atom or a halogen atom, R 6 represents a halogen atom or a morpholino group, and Me represents a methyl group), or a salt thereof.

17. The method of claim 7 , wherein the compound represented by formula (III) is obtained by steps comprising the following (1) to (3):

(1) reacting a compound represented by formula (V)

(wherein, Hal′ represents a halogen atom) with a cyanation reagent to obtain a compound represented by formula (VI)

(2) obtaining a compound represented by formula (VII)

through a formylation reaction of the compound represented by formula (VI); and

(3) obtaining the compound represented by formula (III)

(wherein, Et represents an ethyl group) by reducing the compound represented by formula (VII).