CN111793039A - Preparation method of dortinode - Google Patents
Preparation method of dortinode Download PDFInfo
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- CN111793039A CN111793039A CN202010693795.4A CN202010693795A CN111793039A CN 111793039 A CN111793039 A CN 111793039A CN 202010693795 A CN202010693795 A CN 202010693795A CN 111793039 A CN111793039 A CN 111793039A
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- dortinode
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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
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Abstract
The invention discloses a preparation method of dortinode (Dotinurad), which takes 2-aminobenzenethiol as a starting material to carry out reactions such as condensation, cyclization, oxidation 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, environmental protection and suitability 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-dioxide-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, and the preparation method simplifies the protection and deprotection processes by changing a condensation reaction mode and a condensation and cyclization reaction sequence, is beneficial to quality improvement and industrial production of the medicine, and can promote economic and technical development of the bulk drug.
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 3, 5-dichloro-4-hydroxybenzoic acid (II) and the 2-aminobenzenethiol (III) are subjected to condensation reaction under the action of a condensing agent and an alkali promoter to prepare the N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV), the N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV) and paraformaldehyde carry out cyclization reaction to prepare (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (V) and (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (V), and the obtained product is 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 condensation reaction is 3, 5-dichloro-4-hydroxybenzoic acid (II) (1 equivalent), 2-aminobenzenethiol (III) (1-1.5 equivalents), the condensing agent (1-2 equivalents) and the alkali promoter (1-2 equivalents), preferably 3, 5-dichloro-4-hydroxybenzoic acid (II) (1 equivalent), 2-aminobenzenethiol (III) (1.1 equivalents), the condensing agent (1.5 equivalents) and the alkali promoter (1.5 equivalents).
The condensing agent for the condensation reaction is N, N-Dicyclohexylcarbodiimide (DCC), Carbonyldiimidazole (CDI), N' -Diisopropylcarbodiimide (DIC) and 1-hydroxy-benzotriazole (HOBt), O-benzotriazol-N, N ' -tetramethyluronium tetrafluoroborate (TBTU), O- (7-azobenzotriazol) -N, N ' -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N ' -tetramethyluronium Hexafluorophosphate (HBTU), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), preferably benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP).
The basic accelerator of the condensation reaction is Triethylamine (TEA), pyridine, 2, 6-lutidine, 4-Dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), Diisopropylethylamine (DIEA), 1, 5-diazabicyclo [4.3.0] -non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0] -undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2] octane (DABCO), preferably 1, 8-diazabicyclo [5.4.0] -undec-7-ene (DBU).
The solvent for the condensation reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, dimethyl sulfoxide, N-dimethylformamide or acetonitrile, preferably acetonitrile.
The condensation reaction temperature is 0-100 ℃, and preferably 60-70 ℃.
The charge ratio of the cyclization reaction is N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV) (1 equivalent) and paraformaldehyde (3-8 equivalents), and N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV) (1 equivalent) and paraformaldehyde (5 equivalents) are preferred.
The solvent for the cyclization reaction is methanol, ethanol, isopropanol, dichloromethane, chloroform, dioxane or tetrahydrofuran, and preferably ethanol.
The temperature of the cyclization reaction is 0-100 ℃, and preferably 70-80 ℃.
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 ℃.
According to the preparation method of the dortinode, 3, 5-dichloro-4-hydroxybenzoic acid (II) and 2-aminobenzenethiol (III) are used as starting materials, and condensation, cyclization, oxidation and other reactions are sequentially carried out, so that the raw materials in the preparation process are easy to obtain, fast, convenient, economical and environment-friendly, the processes of protection, deprotection and the like are particularly avoided, and the preparation method 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. Wherein the starting 3, 5-dichloro-4-hydroxybenzoic acid (II) is prepared in accordance with the references "European Journal of organic chemistry, (19), 4398-4404; 2006 "methods for the preparation of the same compounds.
The first embodiment is as follows:
under the protection of nitrogen, 3, 5-dichloro-4-hydroxybenzoic acid (II) (4.14g, 20mmol), the condensing agent benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) (13.3g, 30mmol) and 150mL of acetonitrile were added to a reaction flask. Adding alkali accelerator 1, 8-diazabicyclo [5.4.0] under stirring]-tenMono-7-ene (DBU) (4.56g, 30mmol), heated to 60-70 deg.C and reacted for 12 hours. 2-Aminobenzenethiol (III) (2.75g,22mmol) was added and the reaction stirred for an additional 12 hours. And cooling to room temperature, quenching the reaction by using saturated saline solution, and adjusting the pH value to be 4-5 by using dilute hydrochloric acid. Concentrating under reduced pressure, and extracting the residue with ethyl acetate for 3 times. The combined organic phases are washed by pure water and brine in turn, dried and decompressed and distilled to recover the solvent, thus obtaining 5.5g of a light yellow oily matter N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV), the yield is 87.6 percent, and the EI-MSm/z is 315[ M + H ])]+。
Example two:
into a reaction flask were added N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (IV) (3.1g,10mmol), paraformaldehyde (1.5g, 50mmol) and 50mL of ethanol. Heating to 70-80 ℃, and stirring for reaction for 4-6 hours. Cooled to room temperature and quenched with water. Concentrated and extracted 3 times with ethyl acetate. The combined organic phases are washed by pure water and brine in turn, dried and decompressed and distilled to recover the solvent, and the yellow oily residue is recrystallized by ethanol to obtain 2.8g of light yellow solid (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (V), the yield is 85.9 percent, EI-MS M/z: 327M + H]+。
Example three:
to a reaction flask were added (3, 5-dichloro-4-hydroxyphenyl) (3(2H) -benzothiazolyl) methanone (V) (0.16g,5mmol) and 25mL of dichloromethane, and the mixture was stirred at room temperature to dissolve. Dropwise adding a solution of m-chloroperoxybenzoic acid (1.7g, 10mmol) and 15mL 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 1.48g of Polytenode (I), yield 82.7%, EI-MS M/z:359[ M + H ]]+；1HNMR(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 (10)
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 condensation reaction on 3, 5-dichloro-4-hydroxybenzoic acid and 2-aminobenzenethiol under the action of a condensing agent and an alkali promoter to prepare N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol; the N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol and paraformaldehyde carry out cyclization reaction 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 charge ratio of the condensation reaction is 3, 5-dichloro-4-hydroxybenzoic acid (1 equivalent), 2-aminobenzenethiol (1-1.5 equivalents), condensing agent (1-2 equivalents) and alkali promoter (1-2 equivalents).
3. The process for preparing dortinode as claimed in claim 1, wherein the condensing agent for the condensation reaction is N, N '-dicyclohexylcarbodiimide, carbonyldiimidazole, N, N' -diisopropylcarbodiimide, 1-hydroxy-benzotriazol, O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, O- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate.
4. The process for preparing dortinode according to claim 1, wherein the base accelerator for the condensation reaction is triethylamine, pyridine, 2, 6-lutidine, 4-dimethylaminopyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1, 5-diazabicyclo [4.3.0] -non-5-ene, 1, 8-diazabicyclo [5.4.0] -undec-7-ene or 1, 4-diazabicyclo [2.2.2] octane.
5. The process for preparing dortinode according to claim 1, characterized in that the solvent for the condensation reaction is toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, chloroform, dimethyl sulfoxide, N-dimethylformamide or acetonitrile; the temperature of the condensation reaction is 0-100 ℃.
6. The method for preparing dortinode according to claim 1, wherein the ring closure reaction is carried out at a feed ratio of N- (3, 5-dichloro-4-hydroxybenzoyl) -2-aminobenzenethiol (1 equivalent) and paraformaldehyde (3-8 equivalents).
7. The process for preparing dortinode according to claim 1, wherein the solvent for the cyclization reaction is methanol, ethanol, isopropanol, dichloromethane, chloroform, dioxane or tetrahydrofuran; the temperature of the cyclization reaction is 0-100 ℃.
8. 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).
9. 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.
10. 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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| Application Number | Priority Date | Filing Date | Title |
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| CN202010693795.4A CN111793039A (en) | 2020-07-17 | 2020-07-17 | Preparation method of dortinode |
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| CN202010693795.4A CN111793039A (en) | 2020-07-17 | 2020-07-17 | Preparation method of dortinode |
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Application publication date: 20201020 |