CN111675675A - Preparation method of dortinode - Google Patents
Preparation method of dortinode Download PDFInfo
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- CN111675675A CN111675675A CN202010692765.1A CN202010692765A CN111675675A CN 111675675 A CN111675675 A CN 111675675A CN 202010692765 A CN202010692765 A CN 202010692765A CN 111675675 A CN111675675 A CN 111675675A
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- dortinode
- dichloro
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- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
Abstract
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.
Description
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.
The first embodiment is as follows:
2-aminobenzenethiol (II) (6.25g, 50mmol), 3, 5-dichloro-4-hydroxybenzoyl chloride (III) (12.4g, 55mmol) and dichloromethane 200mL are added into a reaction bottle, triethylamine (10.1g, 0.1mol) is added under ice bath, stirring is carried out for 30 minutes, then the temperature is raised to 30-35 ℃, and reaction is carried out for 2-3 hours. Quenching the reaction with water, separating out the organic phase, extracting the aqueous phase twice with dichloromethane, combining the organic phases, washing with saturated brine and water in sequence, drying and concentrating. 13.8g of N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV) is obtained as a pale yellow oil with a yield of 87.9%, EI-MS M/z 315[ M + H ]]+。
Example two:
into a reaction flask were added N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV) (7.85g,25mmol), diiodomethane (6.45g, 25mmol), lithium hexamethyldisilazide (1.0M, 50mL), and tetrahydrofuran 200 mL. Stirring and reacting for 12 hours at the temperature of 40-45 ℃. Cooled to 0 ℃, quenched with water, and extracted 3 times with ethyl acetate. Mixing organic phases, washing with pure water and brine in sequence, drying, distilling under reduced pressure to recover solvent, recrystallizing the yellow oily residue with ethanol to obtain light yellow solid (3,5-Dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (V)5.5g, 67.5% yield, EI-MS M/z:327[ M + H ]]+。
Example three:
(3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (V) (3.3g,10mmol) and 50mL of dichloromethane were added to a reaction flask, and stirred at room temperature until dissolved. Dropwise adding a solution of 3.4g of m-chloroperoxybenzoic acid (20 mmol) and 25mL of dichloromethane, and after the dropwise adding is finished, keeping the temperature of 25-30 ℃ and stirring for reacting for 16 hours. Adding sodium thiosulfate solution for neutralization, separating an organic phase, washing with saturated sodium bicarbonate solution, saturated brine and water in sequence, and drying with anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give 3.05g of Polytenode (I), yield 85.2%, EI-MS M/z:359[ M + H ]]+；1H NMR(DMSO-d6)11.04(brs,1H),8.04(d,J＝8.4Hz,1H),7.90(d,J＝7.6Hz,1H),7.76(dd,J＝8.4,7.6Hz,1H),7.74(s,2H),7.44(dd,J＝7.6,7.6Hz,1H),5.35(s,2H)。
It should be noted that the above-mentioned preferred embodiments are merely illustrative of the technical concepts and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (9)
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 ℃.
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| CN202010692765.1A CN111675675A (en) | 2020-07-17 | 2020-07-17 | Preparation method of dortinode |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102639518A (en) * | 2009-09-30 | 2012-08-15 | 株式会社富士药品 | Novel phenol derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102639518A (en) * | 2009-09-30 | 2012-08-15 | 株式会社富士药品 | Novel phenol derivative |
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Application publication date: 20200918 |