METHOD FOR PREPARING DIAZOXIDE

Abstract

A method for preparing diazoxide includes reacting o-aminobenzenesulfonamide with N-chlorosuccinimide in a chlorine solvent to obtain 2-amino-5-chlorobenzenesulfonamide, mixing the 2-amino-5-chlorobenzenesulfonamide, an imidazole salt and an amide solvent, then heating same for reaction so as to obtain diazoxide; or mixing o-aminobenzenesulfonamide, an imidazole salt and an amide solvent, then heating same for reaction to obtain a compound IV; then reacting the compound IV with N-chlorosuccinimide in a chlorine solvent to obtain diazoxide. The application of imidazole hydrochloride as a catalyst in preparing diazoxide is also disclosed. The present invention avoids the use of highly corrosive and toxic chlorosulfonyl isocyanate, a strong acid (sulfuric acid), and a high reaction temperature (240-250° C.), and the reaction steps are short; the total yield of the two steps is more than 90%, and compared with publicly disclosed preparation methods for diazoxide, the synthesis route overcomes numerous shortcomings, thus being more suitable for industrial production.

Claims

1. A method for preparing a diazoxide, comprising the following steps: mixing and heating 2-amino-5-chlorobenzenesulfonamide, an imidazolium salt and an amide solvent to obtain the diazoxide.

2. The method of claim 1, wherein the 2-amino-5-chlorobenzenesulfonamide is synthesized by mixing o-aminobenzenesulfonamide and N-chlorosuccinimide in a chlorine solvent.

3. The method of claim 2, wherein the reaction is under reflux for 2-6 hours; the chlorine solvent is dichloromethane or chloroform.

4. The method of claim 1, wherein the imidazolium salt is imidazole hydrochloride; an amount of the imidazolium salt is 1-12 mol% of the 2-amino-5-chlorobenzenesulfonamide; the amide solvent is N,N-dimethylacetamide; and reaction is carried out between 120° C. to a reflux temperature, and a reaction time is 5-50 hours.

5. The method of claim 4, wherein the amount of the imidazolium salt is 3-10 mol% of the 2-amino-5-chlorobenzenesulfonamide; the reaction is carried out under reflux for 6-8 hours.

6. A method for preparing a diazoxide, comprising the following steps: mixing and heating o-aminobenzenesulfonamide, an imidazolium salt and an amide solvent to obtain a compound IV; reacting the compound IV with N-chlorosuccinimide in a chlorine solvent to obtain the diazoxide.

7. The method of claim 6, wherein the imidazolium salt is imidazole hydrochloride; an amount of the imidazolium salt is 1-12 mol% of the 2-amino-5-chlorobenzenesulfonamide; the amide solvent is N,N-dimethylacetamide and the reaction is carried out between 120° C. to a reflux temperature, and a reaction time is 5-50 hours.

8. The method of claim 7, wherein the amount of the imidazolium salt is 3-10 mol% of the 2-amino-5-chlorobenzenesulfonamide; the reaction is carried out under reflux for 6-8 hours.

9. The method of claim 6, wherein the reaction in the chlorine solvent is under reflux for 8-10 hours; the chlorine solvent is dichloromethane or chloroform.

10. An application of imidazole hydrochloride as a catalyst in the preparation of a diazoxide.

Description

DESCRIPTION OF FIGURES

[0019] FIG. 1 shows the mass spectrum of 2-amino-5-chlorobenzenesulfonamide prepared by the present invention;

[0020] FIG. 2 shows the mass spectrum of diazoxide prepared by the present invention;

[0021] FIG. 3 shows the .sup.1HNMR spectrum of diazoxide;

[0022] FIG. 4 shows the mass spectrum of compound (IV) prepared by the present invention;

[0023] FIG. 5 shows the .sup.1HNMR spectrum of compound (IV);

[0024] FIG. 6 shows the .sup.1H NMR spectrum of diazoxide.

DETAILED DESCRIPTION

[0025] The method for preparing diazoxide disclosed by the present invention is as follow:

[0026] Mixing and heating 2-amino-5-chlorobenzenesulfonamide, imidazolium salt and amide solvent to obtain diazoxide. Alternatively, 2-amino-5-chlorobenzenesulfonamide is synthesized by mixing o-aminobenzenesulfonamide and N-chlorosuccinimide in a chlorine solvent.

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[0027] Or, mixing and heating o-aminobenzenesulfonamide, imidazolium salt and amide solvent to obtain compound IV; reacting the compound IV and N-chlorosuccinimide in chlorine solvent to obtain diazoxide.

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[0028] The products of all examples were extracted with ethyl acetate and purified by column chromatography mixed with solvent of ethyl acetate/petroleum ether in a volume ratio of 1:1 was used as eluent, R.sub.f: 0.3.

Example 1

[0029] Mixing o-aminobenzenesulfonamide (1.72 g) and NCS (1.32 g, 1.0 equivalent), dissolving in dichloromethane (DCM), and stirring at reflux for about 5 h, removing the solvent DCM under reduced pressure, and purifying the residue with silica gel chromatography to obtain compound II, 2-amino-5-chlorobenzenesulfonamide (1.75 g), a yield of 85%, a purity of greater than 99%. Mass spectrum of compound: calculated value [M+H].sup.+C.sub.6H.sub.8ClN.sub.2O.sub.2 S, 206.99; experimental value: 206.83.

[0030] Mixing o-aminobenzenesulfonamide (1.7 2 g) and NCS (1.32 g, 1.0 equivalent), dissolving in trichloromethane, and stirring at reflux for about 3 h, and purifying the residue with silica gel chromatography to obtain the compound II, 2-amino-5-chlorobenzenesulfonamide (1.96 g), a yield of 95%, and a purity of greater than 99%. Mass spectrum experimental value: 206.9, the mass spectrum is shown in FIG. 1.

Example 2

[0031] 2-Aminochlorobenzenesulfonamide (2.05 g) and imidazole hydrochloride (0.14 g, 10 mol%) were added into N,N-dimethylacetamide (0.008 g), and the mixture was stirred at 120° C. for 48 h. The reaction solution was distilled to recover the excess N,N-dimethylacetamide, and the residue was purified with flash column chromatography on silica gel to obtain compound III diazoxide (2.07 g), a yield of 90%, and a purity of greater than 99%. Mass spectrum experimental value: 230.8.

Example 3

[0032] 2-Aminochlorobenzenesulfonamide (2.05 g) and imidazole hydrochloride (0.11 g, 7 mol%) were added into N,N-dimethylacetamide (0.008 g), and the mixture was stirred at 150° C. for 16 h. The reaction solution was distilled to recover the excess N,N-dimethylacetamide, and the residue was purified with flash column chromatography on silica gel to obtain compound III diazoxide (2.17 g), a yield of 94%, and a purity of greater than 99%. Mass spectrum experimental value: 230.9.

Example 4

[0033] 2-Aminochlorobenzenesulfonamide (2.05 g) and imidazole hydrochloride (0.08 g, 5 mol%) were added into N,N-dimethylacetamide (0.008 g), and the mixture was stirred at reflux for 7 h. The reaction solution was distilled to recover the excess N,N-dimethylacetamide, and the residue was purified with flash column chromatography on silica gel to obtain compound III diazoxide (2.26 g), a yield of 98%, and a purity of greater than 99%. The mass spectrum and .sup.1H NMR of diazoxide are shown in FIG. 2 and FIG. 3, respectively. The characterization of compound (III): mass spectrum of compound: calculated value [M+H].sup.+ C.sub.8H.sub.8ClN.sub.2O.sub.2S, 230.99; experimental value: 230.8. .sup.1HNMR (400 MHz, CDCl.sub.3): 12.70 (br, 1H, NH), 7.82 (d, J = 1.6 Hz 1H), 7.74 (dd, J = 2.0,8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 2.32 (s, 3H).

[0034] When the solvent was changed from N,N-dimethylacetamide to DMF, and other conditions remained the same, the product diazoxide could not be obtained.

Example 5

[0035] o-Aminobenzenesulfonamide (1.72 g) and imidazole hydrochloride (0.08 g, 5 mol%) were added into N,N-Dimethylacetamide(0.008 g), and the mixture was stirred at reflux for 6 h. The reaction solution was distilled to recover the excess N,N-dimethylacetamide, and the residue was purified with flash column chromatography on silica gel to obtain compound IV (1.84 g), a yield of 94%, and a purity of greater than 99%. The mass spectrum is shown in FIG. 4, experimental value: 196.8, calculated value: 197.04. .sup.1HNMR of compound IV: .sup.1HNMR (400 MHz, CDCl.sub.3): 812.09 (br, 1H), 7.79 (dd, J = 1.2 Hz, 8.0 Hz, 1H), 7.67 (dt, J = 1.6 Hz, 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 2.3(s, 3H), as shown FIG. 5. Part A of FIG. 5 is a partially enlarged view of part B of FIG. 5.

[0036] The chemical structure is shown as follows:

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[0037] A mixture of compound IV (1.96 g) and NCS (1.32 g, 1.0 equivalent) in trichloromethane was stirred at reflux for about 9 h, and then purified by column chromatography to obtain the product diazoxide (III), 2.06 g, a yield of 90%, a purity of greater than 99%, the experimental value: 230.9; the .sup.1HNMR spectrum is shown in FIG. 6.

[0038] If the solvent was changed from N,N-dimethylacetamide to DMF, and other conditions remained the same, the product compound IV could not be obtained.

Example 6

[0039] o-Aminobenzenesulfonamide (1.72 g) and imidazole hydrochloride (0.11 g, 7 mol%) were added into N,N-dimethylacetamide (0.008 g), and the mixture was stirred at 140° C. for 15 h. The reaction solution was distilled to recover the excess N,N-dimethylacetamide, and the residue was purified with flash column chromatography on silica gel to obtain compound IV (1.76 g), a yield of 90%. A mixture of compound IV (1.96 g) and NCS (1.32 g, 1.0 equivalent) in trichloromethane was stirred at reflux for about 10 h, and then purified by column chromatography to prepare the product diazoxide (III), 2.07 g, a yield of 90%, a purity of greater than 99%, the experimental value: 231.1.