# US 8,772,528 B2 · Method for producing aminothiazole derivative and production intermediate

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- Number: US 8,772,528 B2
- Document ID: US8772528B2
- Status: Granted
- Kind: B2
- Application number: 14/066,039
- Filed: 2013-10-29
- Published: 2014-02-13
- Granted: 2014-07-08
- Earliest claimed: 2004-08-23
- Assignees: Zeria Pharmaceutical Co., Ltd.
- Applicants: Masaaki Nagasawa; Kazuyasu Asami; Ryu Nakao; Nobuyuki Tanaka; Yoshiyuki Aida
- Inventors: Masaaki Nagasawa; Kazuyasu Asami; Ryu Nakao; Nobuyuki Tanaka; Yoshiyuki Aida
- Web page: https://patentgrep.com/patent/US8772528B2

## CPC

- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- C07C 69/92: with etherified hydroxyl groups
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- C07C 51/347: by reactions not involving formation of carboxyl groups
- C07C 51/377: by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups {(C07C51/36 - C07C51/373 take precedence)}
- C07C 67/08: by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
- C07C 67/14: from carboxylic acid halides
- C07C 205/60: in ortho-position to the carboxyl group, e.g. nitro-salicylic acids
- C07D 277/46: by carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D 277/56: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided is a method for selectively demethylating a 2-methoxy group. Specifically provided is a production method of a compound represented by formula (7) below through the following reactions.

## Claims

### Claim 1

A production method of a compound represented by formula (2):
wherein ring A represents a benzene ring or a 6-membered aromatic heterocycle; R1 represents a hydrogen atom, a C1-6 alkyl group, a halogen atom, a nitro group, an amino group, a mono-C1-6 alkylamino group, or a di-C1-6 alkylamino group; and at least one of R2, R3, and R4 represents a methoxy group, and the rest each represents a hydrogen atom, a C1-6 alkyl group, a halogen atom, a nitro group, an amino group, a mono-C1-6 alkylamino group, or a di-C1-6 alkylamino group,
the method comprising reacting a compound represented by formula (1):
wherein ring A and R1, R2, R3, and R4 are the same as defined in formula (2), with a Lewis acid selected from the group consisting of BF3, TiCl4, and AICl3 in an esteric, a ketonic or an amidic solvent selected from the group consisting of ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate, acetone, 2-butanone, cyclohexanone, cyclopentanone, dimethylformamide, and dimethylacetamide, with the proviso that when the Lewis acid is BF3, an alkali metal bromide or an alkali metal iodide coexists.

### Claim 2

A production method of a compound represented by formula (3):
wherein ring A represents a benzene ring or a 6-membered aromatic heterocycle; R1 represents a hydrogen atom, a Ci-6 alkyl group, a halogen atom, a nitro group, an amino group, a mono-C1-6 alkylamino group, or a di-C1-6 alkylamino group; at least one of R2, R3, and R4 represents a methoxy group, and the rest each represents a hydrogen atom, a C1-6 alkyl group, a halogen atom, a nitro group, an amino group, a mono-C1-6 alkylamino group, or a di-C1-6 alkylamino group; and R5 represents a hydrogen atom or a nitro group,
the method comprising reacting a compound represented by formula (1):
wherein ring A and R1, R2, R3, and R4 are the same as defined for formula (3), with a Lewis acid selected from the group consisting of BF3, TiCl4, and AlCl3 in an esteric, a ketonic or an amidic solvent selected from the group consisting of ethyl acetate, methyl acetate, butyl acetate, isobutyl acetate, acetone, 2-butanone, cyclohexanone, cyclopentanone, dimethylformamide, and dimethylacetamide, with the proviso that when the Lewis acid is BF3, an alkali metal bromide or an alkali metal iodide coexists, to provide a compound represented by formula (2):
wherein ring A and R1, R2, R3, and R4 are the same as defined for formula (3), and
then reacting the resultant compound with a phenol derivative selected from phenol and para-nitrophenol or a triphenyl phosphite derivative selected from triphenyl phosphite and tri-para-nitrophenyl phosphite.

### Claim 3 (depends on 2)

The production method according to claim 2, wherein the phenol derivative is reacted in the presence of thionyl chloride or phosphorus oxychloride.

### Claim 4 (depends on 2)

The production method according to claim 2, wherein the triphenyl phosphite derivative is reacted in the presence of an acid.

### Claim 5 (depends on 4)

The production method according to claim 4, wherein the acid is selected from the group consisting from sulfuric acid, methanesulfonic acid, toluenesulfonic acid and trifluoromethanesulfonic acid.