CN111662247A - Synthesis method of dortinode - Google Patents
Synthesis method of dortinode Download PDFInfo
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- CN111662247A CN111662247A CN202010692741.6A CN202010692741A CN111662247A CN 111662247 A CN111662247 A CN 111662247A CN 202010692741 A CN202010692741 A CN 202010692741A CN 111662247 A CN111662247 A CN 111662247A
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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
Abstract
The invention discloses a method for synthesizing dortinode (Dotinurad), which takes 2, 3-dihydrobenzothiazole as an initial raw material and conveniently synthesizes a target product dortinode through oxidation and condensation reactions. 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 provide an improved synthesis method of dortinode (Dotinurad, I) according to a green chemical synthesis concept, the synthesis method takes 2, 3-dihydrobenzothiazole (II) as a raw material, and the protection and deprotection processes are simplified by changing a condensation reaction mode and a condensation and oxidation reaction sequence, so that the quality improvement and the industrial production of the medicine are facilitated, and the economic and technical development of the raw material medicine 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, 3-dihydrobenzothiazole (II) is oxidized under the action of an oxidant to prepare 2, 3-dihydro-1, 1-dioxo-benzothiazole (III), and the 2, 3-dihydro-1, 1-dioxo-benzothiazole (III) and 3, 5-dichloro-4-hydroxybenzoic acid (IV) are subjected to condensation reaction under the action of a condensing agent and an alkali promoter to prepare the polynitronow (I).
In addition, the invention also provides the following auxiliary technical scheme:
the feeding ratio of the oxidation reaction is 2, 3-dihydrobenzothiazole (II) (1 equivalent) and an oxidant (2-6 equivalents), and 2, 3-dihydrobenzothiazole (II) (1 equivalent) and an oxidant (4 equivalents) are preferred.
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 or hydrogen peroxide.
The solvent for the oxidation reaction is acetic acid, toluene, xylene or tetrahydrofuran, preferably acetic acid.
The temperature of the oxidation reaction is 0-120 ℃.
Wherein, when the oxidant is m-chloroperoxybenzoic acid, the temperature is preferably 25-30 ℃.
Wherein when the oxidant is hydrogen peroxide, the temperature is preferably 90-100 ℃.
The feeding ratio of the condensation reaction is 3, 5-dichloro-4-hydroxybenzoic acid (IV) (1 equivalent), 2, 3-dihydro-1, 1-dioxo-benzothiazole (III) (1-1.5 equivalents), a condensing agent (1-2 equivalents) and an alkali promoter (1-2 equivalents), preferably 3, 5-dichloro-4-hydroxybenzoic acid (II) (1 equivalent), 2-aminobenzenethiol (III) (1.1 equivalents), a condensing agent (1.5 equivalents) and an 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 preparation method of the dortinode takes 2, 3-dihydrobenzothiazole (II) as a starting material, and the target product is prepared by sequentially carrying out oxidation and condensation reactions. The synthesis method has the advantages of easily available raw materials, rapidness, convenience, economy, environmental protection, particularly avoiding the processes of protection, deprotection and the like, and 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 materials 2, 3-dihydrobenzothiazole (II) and 3, 5-dichloro-4-hydroxybenzoic acid (IV) are prepared as described in the respective references "Journal of Organic Chemistry,25,2062; 1960 "and" European Journal of organic chemistry, (19), 4398-4404; 2006 "methods for the preparation of the same compounds.
The first embodiment is as follows:
2, 3-Dihydrobenzothiazole (II) (3.43g,25mmol), m-chloroperoxybenzoic acid (17.2g, 0.1mol) and acetic acid 150mL are added into a reaction flask, and stirred for 60 hours at 30-35 ℃. The acetic acid was distilled off under reduced pressure and the residue was neutralized with 50mL of sodium thiosulfate solution. The mixture was extracted with ethyl acetate three times, and the organic phases were combined, washed successively with a saturated sodium bicarbonate solution, a saturated brine and water, and dried over anhydrous sodium sulfate. Vacuum concentrating, recrystallizing the residue with n-hexane to obtain white solid 2, 3-dihydro-1, 1-dioxo-benzothiazole (III)4.1g with yield 97.0%, EI-MS M/z 170[ M + H ]]+。
Example two:
adding 2, 3-dihydrobenzothiazole (II) (3.43g,25mmol), 30% hydrogen peroxide (11.3g, 0.1mol) and 50mL of acetic acid into a reaction bottle, heating to 90-100 ℃, and stirring for reaction for 2 hours. The acetic acid is distilled off under reduced pressure and the residue is taken up in 50mL of sulfurNeutralizing with sodium thiosulfate solution. The mixture was extracted with ethyl acetate three times, and the organic phases were combined, washed successively with a saturated sodium bicarbonate solution, a saturated brine and water, and dried over anhydrous sodium sulfate. Vacuum concentrating, recrystallizing the residue with n-hexane to obtain white solid 2, 3-dihydro-1, 1-dioxo-benzothiazole (III)4.0g with yield of 94.7%, EI-MS M/z 170[ M + H ]]+。
Example three:
under the protection of nitrogen, 3, 5-dichloro-4-hydroxybenzoic acid (IV) (1.04g, 5mmol), the condensing agent benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) (3.33g, 7.5mmol) and acetonitrile 50mL were added to a reaction flask. Adding alkali accelerator 1, 8-diazabicyclo [5.4.0] under stirring]-undec-7-ene (DBU) (1.16g, 7.5mmol), heating to 60-70 deg.C, and reacting for 12 hr. 2, 3-dihydro-1, 1-dioxo-benzothiazole (III) (0.93g,5.5mmol) was added and the reaction was 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 were washed successively with purified water and brine, dried and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to give 1.6g of Polytenode (I) in 89.4% yield, EI-MS M/z:359[ M + H: (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 (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: 2, 3-dihydrobenzothiazole is oxidized under the action of an oxidant to prepare 2, 3-dihydro-1, 1-dioxo-benzothiazole; the 2, 3-dihydro-1, 1-dioxo-benzothiazole and the 3, 5-dichloro-4-hydroxybenzoic acid are subjected to condensation reaction under the action of a condensing agent and an alkali promoter to prepare the polynitropin.
2. The process for preparing dortinode according to claim 1, wherein the oxidation reaction is carried out at a feed ratio of 2, 3-dihydrobenzothiazole (1 equivalent) to the oxidizing agent (2 to 6 equivalents).
3. 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.
4. The process for preparing dortinode according to claim 1, wherein the solvent for the oxidation reaction is acetic acid, toluene, xylene or tetrahydrofuran.
5. The process for preparing dortinode according to claim 1, wherein the temperature of the oxidation reaction is 0 to 120 ℃.
6. The process for preparing dortinode according to claim 1, wherein the charge ratio of the condensation reaction is 3, 5-dichloro-4-hydroxybenzoic acid (IV) (1 equivalent), 2, 3-dihydro-1, 1-dioxo-benzothiazole (III) (1 to 1.5 equivalents), the condensing agent (1 to 2 equivalents) and the alkali promoter (1 to 2 equivalents).
7. 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 (HBTU) or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate.
8. 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.
9. 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 ℃.
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| CN202010692741.6A CN111662247A (en) | 2020-07-17 | 2020-07-17 | Synthesis method of dortinode |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112430221A (en) * | 2020-11-20 | 2021-03-02 | 成都诺和晟泰生物科技有限公司 | Compound for preventing, treating or relieving hyperuricemia or gout and application thereof |
Citations (1)
| 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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Patent Citations (1)
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112430221A (en) * | 2020-11-20 | 2021-03-02 | 成都诺和晟泰生物科技有限公司 | Compound for preventing, treating or relieving hyperuricemia or gout and application thereof |
| CN112430221B (en) * | 2020-11-20 | 2023-06-23 | 成都诺和晟泰生物科技有限公司 | Compound for preventing, treating or relieving hyperuricemia or gout and application thereof |
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