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A kind of method for preparing diazoxide
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A technology of diazoxide and dimethylacetamide, applied in the field of compound preparation, can solve the problems of toxicity, easy moisture absorption, long steps and the like
Active Publication Date: 2021-06-18
SUZHOU UNIV
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Problems in the existing methods: the steps of routes A and B among the three methods are long, and route A requires a three-step reaction. Sulfurisocyanatidic chloride (chlorosulfonyl isocyanate) is used in the process. This reagent is poisonous, extremely active, and water-sensitive. Gas is released, the reaction is violent, the reagent AlCl used in the next step 3 It is also easy to absorb moisture, so the anhydrous conditions of the reaction are strictly required. The final step requires the use of acetic acid, which is processed at a high temperature of 130°C to obtain the final product. Acetic acid is highly volatile, irritating and corrosive; route B requires four steps to obtain The final product, the first two steps are the same as route A, and then in strong acid H 2 SO 4 After the treatment, the ring is opened, and then triethyl orthoacetate is used for ring-closing reaction to obtain the product. Compared with the above route A, this route has one more step of reaction, and uses strong corrosive sulfuric acid; route C requires an acid-binding agent and high temperature closed loop
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[0032] The method for preparing diazoxide disclosed by the present invention is as follows:
[0033] Mix 2-amino-5-chlorobenzenesulfonamide, imidazolium salt and amide solvent and react with heating to obtain diazoxide. The preparation method of further 2-amino-5-chlorobenzenesulfonamide is as follows, anthranilamide and N - Chlorosuccinimide is reacted in a solvent to give 2-amino-5-chlorobenzenesulfonamide.
[0034] or
[0035] Mix anthranilamide, imidazolium salt and amide solvent and heat to react to obtain compound IV; then compound IV and N - Chlorosuccinimide is reacted in a chlorine solvent to give diazoxide.
[0036]
[0037] The column chromatography purification of all embodiments adopts ethyl acetate / petroleum ether with a volume ratio of 1:1 as eluent, R f is 0.3.
Embodiment 1
[0039] Anthranilamide (1.72g) was mixed with NCS (1.32g, 1.0 equivalent), dissolved in dichloromethane, stirred at reflux temperature for 5 hours, and then purified by column chromatography to prepare compound II 2-amino -5-chlorobenzenesulfonamide, 1.75g, the yield of this step is 85%, and the purity is greater than 99%. Compound Mass Spectrum: Calculated [M+H] + C 6 h 8 ClN 2 o 2 S, 206.99; experimental value: 206.83.
[0040] Anthranilamide (1.72g) was mixed with NCS (1.32g, 1.0 equivalent), dissolved in chloroform, stirred at reflux temperature for 3 hours, and then purified by column chromatography to prepare compound II2-amino-5- Chlorobenzenesulfonamide 1.96g, the yield of this step is 95%, the purity is greater than 99%, the experimental value of mass spectrum: 206.9, see the mass spectrum figure 1 .
Embodiment 2
[0042] Dissolve 2-amino-5-chlorobenzenesulfonamide (2.05g) in 8.0ml N , N -In dimethylacetamide, add 0.14g (10mol%) imidazole hydrochloride again, reaction temperature 120 o C, after stirring for 48 hours, the reaction solution was distilled, and the excess N , N - Dimethylacetamide was recovered by distillation, and the residue was purified by column chromatography to obtain 2.07 g of the product diazoxide (compound III), with a yield of 90%, a purity greater than 99%, and an experimental value of mass spectrometry: 230.8.
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Abstract
The invention discloses a method for preparing diazoxide, which comprises anthranilamide and N ‑chlorosuccinimide is reacted in a chlorine solvent to obtain 2‑amino‑5‑chlorobenzenesulfonamide, and 2‑amino‑5‑chlorobenzenesulfonamide, imidazolium salt and amide solvent are mixed and reacted by heating to obtain di Azrazine; or anthranilamide, imidazolium salt and amide solvent are mixed and reacted by heating to obtain compound IV; then compound IV and N - Chloro-succinimide is reacted in a chlorine solvent to obtain diazoxide; the invention also discloses the application of imidazole hydrochloride as a catalyst in the preparation of diazoxide. The invention avoids the problems of using highly corrosive and highly toxic chlorosulfonyl isocyanate, strong acid (sulfuric acid) and high reaction temperature (240-250°C) in the reaction process, and the reaction steps are short; the total yield of the two steps can be It reaches more than 90%, and compared with the preparation method of diazoxide that has been publicly reported, the synthetic route provided by the present invention overcomes many shortcomings, so it is more suitable for industrial production.
Description
technical field [0001] The invention belongs to compound preparation technology, in particular to a method for preparing diazoxide. Background technique [0002] Diazoxide is a fast-acting antihypertensive drug. It is a first-aid drug for patients with hypertensive crisis, and it is also used to treat hypoglycemia symptoms caused by hyperinsulinemia, especially the drug of choice for congenital hyperinsulinemia. It is a kind of rare disease drug for infants and young children that is not yet available in China and is urgently needed in clinical practice. Molecular formula: C 8 h 7 ClN 2 o 2 S, alias: chloroxylazine; 7-chloro-3-methyl-2 H -1,2,4-Benzothiadiazine 1,1-dioxide; Hypotensine; 7-Chloro-3-methyl-2hydro-1,2,4-benzothiadiazine 1,1 -Dioxide; CAS number: 364-98-7; structural formula as follows: [0003] [0004] The reported synthetic route of the drug mainly contains the following three synthetic methods: A, B and C: [0005] [0006] [0007] Starting...
Claims
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