阅读说明：本技术 多替诺德的制备方法 (Preparation method of dortinode ) 是由 许学农 于 2020-07-17 设计创作，主要内容包括：本发明揭示了一种多替诺德(Dotinurad)的制备方法,以2-氨基苯硫醇为起始原料,依次进行酰化、二碘甲烷的环合和氧化等反应,制得目标产物多替诺德。该制备过程原料易得、快捷方便、经济环保,克服了现行工艺中的甲醛使用,适于大规模工业化生产。(The invention discloses a preparation method of dortinode (Dotinurad), which takes 2-aminobenzenethiol as a starting material to carry out acylation, cyclization and oxidation of diiodomethane and the like in sequence to prepare a target product dortinode. The preparation process has the advantages of easily available raw materials, rapidness, convenience, economy and environmental protection, overcomes the defect of using formaldehyde in the prior art, and is suitable for large-scale industrial production.)

1. A method for preparing dortinode (Dotinurad), wherein the chemical structural formula of dortinode is as follows:

the preparation method is characterized by comprising the following steps: carrying out acylation reaction on 2-aminobenzenethiol and 3, 5-dichloro-4-hydroxybenzoyl chloride under the action of an acid-binding agent to prepare N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol; the N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol and diiodomethane are subjected to cyclization reaction under the action of hexamethyldisilazane lithium amide to prepare (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone; the (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone is oxidized under the action of an oxidant to prepare the polytriode.

2. The method for preparing dortinode according to claim 1, wherein the acylation reaction is carried out in a feed ratio of 2-aminobenzenethiol (1 equivalent), 3, 5-dichloro-4-hydroxybenzoyl chloride (1-2 equivalents) and acid-binding agent (1-3 equivalents).

3. The process for preparing dortinode according to claim 1, wherein the acid-binding agent used in the acylation reaction is triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

4. The process for preparing dortinode according to claim 1, wherein the solvent for the acylation reaction is dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, dioxane, N-dimethylformamide or acetonitrile; the temperature of the acylation reaction is 0-100 ℃.

5. The process for preparing dortinode according to claim 1, wherein the charge ratio of the cyclization reaction is N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (1 equivalent), diiodomethane (1-1.2 equivalents) and hexamethyldisilazane (1-3 equivalents).

6. The process for preparing dortinode according to claim 1, characterized in that the solvent for the cyclization reaction is toluene, xylene, acetonitrile, dichloromethane, chloroform, dioxane or tetrahydrofuran; the temperature of the cyclization reaction is 0-100 ℃.

7. The process for preparing dortinode according to claim 1, wherein the oxidation reaction is carried out in a feed ratio of (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (1 equivalent) to oxidant (1-3 equivalents).

8. The process for preparing dortinode according to claim 1, wherein the oxidizing agent for the oxidation reaction is peracetic acid, perbenzoic acid, hydrogen peroxide, hypochlorous acid, ozone or m-chloroperoxybenzoic acid.

9. The process for preparing dortinode according to claim 1, characterized in that the solvent for the oxidation reaction is toluene, xylene, acetonitrile, dichloromethane, 1, 2-dichloroethane, chloroform or tetrahydrofuran; the temperature of the oxidation reaction is 0-100 ℃.

Technical Field

The invention belongs to the technical field of organic synthesis route design and preparation of raw material medicines and intermediates thereof, and particularly relates to a preparation method of a medicine dortinode for treating partial hyperuricemia and gout.

Background

Dolinode (Dotinurad) is an oral tablet developed by Fuji Yakuhin (Fuji Yakuhin), yotankan (Mochida) in combination for the treatment of partial hyperuricemia and gout. Dotinurad was approved by the Japan pharmaceutical and medical device integration agency (PMDA) for sale as URECE on 23.1.2020. The medicine is a urate reabsorption inhibitor, and can be used for inhibiting the activity of a urate reabsorption transporter (URAT1) in a targeted manner. Uric acid reabsorption is inhibited and blood uric acid levels are reduced by a transporter (URAT1) that selectively inhibits uric acid reabsorption in the kidney. Because the medicine is not yet put on the market formally in China and does not have a standard Chinese translation name, the applicant translates the medicine into the 'Duotinoded' here.

The chemical name of dortinode is: (3, 5-dichloro-4-hydroxyphenyl) (1, 1-dioxo-3 (2H) -benzothiazolyl) methanone.

International patent WO2011040449 reports synthetic routes and preparation methods for dortinode. The basic synthesis thought is that 2-aminobenzenethiol and formaldehyde are condensed to prepare benzothiazole, and the benzothiazole and side chain benzoyl chloride protected by hydroxyl are subjected to amidation reaction to prepare the benzothiazole benzamide intermediate protected by the hydroxyl. The intermediate can prepare a target compound, namely the dortinode, through the oxidation of thioether and deprotection of hydroxyl.

The analysis of the disclosed preparation method of the dortinode has the defects of difficult obtainment of raw materials, excessive reaction steps and the like, thereby causing the reduction of the product quality and the total yield. The process route which is more concise and convenient, has strong selectivity and controllable cost is sought, and is of great importance to the economic and technical development of the bulk drug.

Disclosure of Invention

The invention aims to overcome the defects of the prior art, and provides an improved preparation method of Dotinurad (I) according to a green chemical synthesis concept, the preparation method is novel in design and simple in steps, the quality improvement and the industrial production of the medicine are facilitated, and the economic and technical development of the bulk drug can be promoted.

In order to achieve the purpose, the main technical scheme provided by the invention is as follows: a process for preparing dortinode (I),

the preparation method comprises the following steps: the 2-amino benzenethiol (II) and the 3, 5-dichloro-4-hydroxybenzoyl chloride (III) are subjected to acylation reaction under the action of an acid-binding agent to prepare N- (3, 5-dichloro-4-hydroxybenzoyl) -2-amino benzenethiol (IV), the cyclization reaction of N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV) and diiodomethane under the action of hexamethyldisilazane lithium amide is carried out to prepare (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (V) and (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (V) which are oxidized under the action of an oxidant to prepare the polynitrode (I).

In addition, the invention also provides the following auxiliary technical scheme:

the feeding ratio of the acylation reaction is 2-aminobenzenethiol (II) (1 equivalent), 3, 5-dichloro-4-hydroxybenzoyl chloride (III) (1-2 equivalents) and an acid-binding agent (1-3 equivalents), and preferably 2-aminobenzenethiol (II) (1 equivalent), 3, 5-dichloro-4-hydroxybenzoyl chloride (III) (1 equivalent) and the acid-binding agent (2 equivalents).

The acid-binding agent used in the acylation reaction is triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and triethylamine is preferred.

The solvent for the acylation reaction is dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, dioxane, N-dimethylformamide or acetonitrile, preferably dichloromethane.

The temperature of the acylation reaction is 0-100 ℃, and preferably 30-35 ℃.

The charge ratio of the cyclization reaction is N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV) (1 equivalent), diiodomethane (1-1.2 equivalents) and hexamethyldisilazane (1-3 equivalents), and N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV) (1 equivalent), diiodomethane (1 equivalent) and hexamethyldisilazane (2 equivalents) are preferred.

The solvent for the cyclization reaction is toluene, xylene, acetonitrile, dichloromethane, chloroform, dioxane or tetrahydrofuran, and tetrahydrofuran is preferred.

The temperature of the cyclization reaction is 0-100 ℃, and preferably 40-45 ℃.

The charge ratio of the oxidation reaction is (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (V) (1 equivalent) and an oxidant (1-3 equivalents), preferably (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (V) (1 equivalent) and an oxidant (2 equivalents).

The oxidant for the oxidation reaction is peroxyacetic acid, peroxybenzoic acid, hydrogen peroxide, hypochlorous acid, ozone or m-chloroperoxybenzoic acid, and preferably m-chloroperoxybenzoic acid.

The solvent for the oxidation reaction is toluene, xylene, acetonitrile, dichloromethane, 1, 2-dichloroethane, chloroform or tetrahydrofuran, preferably dichloromethane.

The temperature of the oxidation reaction is 0-100 ℃, and preferably 25-30 ℃.

The preparation method of the dortinode takes the 2-aminobenzenethiol (II) as the initial raw material, and sequentially carries out acylation, cyclization and oxidation of diiodomethane and other reactions, so that the raw materials in the preparation process are easy to obtain, quick, convenient, economical and environment-friendly, and particularly the environmental problem of cyclization by using formaldehyde in the raw materials of the existing process is solved, and the preparation method of the dortinode is suitable for large-scale industrial production.

Detailed Description

The following non-limiting detailed description of the present invention is provided in connection with several preferred embodiments. Among them, the preparation of the starting 3, 5-dichloro-4-hydroxybenzoyl chloride (III) can be described in references "European Journal of medicinal Chemistry,17(6), 581-7; 1982 "methods for the preparation of the same compounds.