A method for preparing nicorandil polymer

Abstract

The present invention discloses a method for preparing a nicorandil polymer. The present invention provides a method for preparing a plurality of nicorandil polymers, comprising the following key points: dissolving nicorandil in an organic solvent, such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and the like, and a mixed solution of two or more thereof, adding hydrogen peroxide and stirring at high temperature for a period of time; after the reaction is completed, nicorandil dimer, nicorandil trimer and nicorandil tetramer are obtained at one time by a reverse preparation method. The present invention can prepare impurities of nicorandil polymers in large quantities and efficiently, promote the research work on impurities of nicorandil polymers, and provide a basis for the quality research of nicorandil.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to Nicorandil. Background Art

[0002] Nicorandil (nicotinamide nitrate) is a new drug for the treatment of coronary heart disease and heart failure developed by Chugai Pharmaceutical Company in Japan in the 1970s. It is a derivative of nicotinamide with a nitro group on the side chain. Nicorandil is a promising drug in this field and has been widely used in clinical practice in recent years. Its chemical structure is as follows:

[0003] Since there is a nitro group on the side chain, it is easy to polymerize during the degradation process to generate Nicorandil dimer, Nicorandil trimer, and Nicorandil tetramer. The specific pathways are as follows:

[0004] The synthesis method of Nicorandil trimer reported in document CN109516951 is to obtain it by degradation and destruction in an organic solvent at a high temperature above 70°C for a long time.

[0005] Patent CN109516951 only involves the synthesis of trimers and has certain limitations on the synthesis of other polymers, which greatly restricts the impurity research work of Nicorandil polymers. Summary of the invention

[0006] The purpose of the present invention is to efficiently prepare impurities of nicorandil polymers in large quantities and promote the research work on impurities of nicorandil polymers. The present invention provides a method for preparing nicorandil dimer, trimer and tetramer, wherein nicorandil is dissolved in an organic solvent and kept warm for a period of time for reaction; after the reaction is completed, nicorandil dimer, nicorandil trimer and nicorandil tetramer are obtained at one time by a reverse preparation method.

[0007] According to one aspect of the technical solution of the present invention, the present invention provides a method for preparing a nicorandil polymer, wherein nicorandil is dissolved in an organic solvent, hydrogen peroxide is added and stirred at high temperature for reaction, and the organic solvent is selected from one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0008] According to one aspect of the technical solution of the present invention, the present invention provides a method for preparing a Nicorandil polymer, wherein the temperature of the high temperature stirring reaction is 80 to 100°C.

[0009] According to one aspect of the technical solution of the present invention, the present invention provides a method for preparing a nicorandil polymer, wherein the organic solvent is acetonitrile, and the method steps are as follows: adding nicorandil and hydrogen peroxide to acetonitrile, heating and reflux, and keeping warm for 12 hours. After the reaction is completed, the reaction is concentrated under reduced pressure, and the solid residue is separated by a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer.

[0010] According to one aspect of the technical solution of the present invention, the present invention provides a method for preparing a nicorandil polymer, wherein the organic solvent is N,N-dimethylformamide, and the method steps are as follows: adding nicorandil and hydrogen peroxide to N,N-dimethylformamide, heating to 100° C., and keeping the temperature for reaction for 12 hours. After the reaction is completed, the reaction is concentrated under reduced pressure, and the solid residue is separated by a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer.

[0011] According to one aspect of the technical solution of the present invention, the present invention provides a method for preparing a nicorandil polymer, wherein the organic solvent is N,N-dimethylacetamide, and the method steps are as follows: add nicorandil and hydrogen peroxide to N,N-dimethylacetamide, heat to 100°C, and keep the temperature for reaction for 12 hours. After the reaction is completed, reduce the pressure and concentrate, separate the solid residue using a reverse preparative column, and collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer respectively.

[0012] According to one aspect of the technical solution of the present invention, the present invention provides a method for preparing a nicorandil polymer, wherein the organic solvent is dimethyl sulfoxide, and the method steps are as follows: add nicorandil and hydrogen peroxide to dimethyl sulfoxide, raise the temperature to 100°C, and keep the temperature for reaction for 12 hours. After the reaction is completed, concentrate under reduced pressure, separate the solid residue using a reverse preparative column, and collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer respectively.

[0013] According to one aspect of the technical solution of the present invention, the present invention provides a method for preparing a nicorandil polymer, wherein the organic solvent is a mixed solvent of N,N-dimethylformamide and acetonitrile, and the method steps are as follows: nicorandil and hydrogen peroxide are added to a mixed solvent composed of N,N-dimethylformamide and acetonitrile, the temperature is raised to 80°C, and the reaction is kept warm for 12 hours. After the reaction is completed, the reaction is concentrated under reduced pressure, and the solid residue is separated using a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer.

[0014] According to one aspect of the technical solution of the present invention, the present invention provides a method for preparing a nicorandil polymer, wherein any one of the above-mentioned reverse preparation column parameters is:

[0015] Chromatographic column: Octadecylsilane bonded silica gel as filler (250mm×30mm, 10μm)

[0016] Mobile phase: trifluoroacetic acid: triethylamine: tetrahydrofuran: water = 8:5:18:969

[0017] Flow rate: 30 ml / min

[0018] Detection wavelength: 254nm. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The mass spectrum of Nicorandil dimer in Example 1 of the present invention;

[0020] Figure 2 The nuclear magnetic resonance spectrum of Nicorandil dimer in Example 1 of the present invention;

[0021] Figure 3 Mass spectrum of Nicorandil trimer in Example 1 of the present invention;

[0022] Figure 4 The nuclear magnetic resonance spectrum of Nicorandil trimer in Example 1 of the present invention;

[0023] Figure 5 Mass spectrum of Nicorandil tetramer in Example 1 of the present invention;

[0024] Figure 6 The nuclear magnetic resonance spectrum of Nicorandil tetramer in Example 1 of the present invention;

[0025] Figure 7 The liquid chromatogram of Nicorandil dimer in Example 1 of the present invention;

[0026] Figure 8 Liquid chromatogram of Nicorandil trimer in Example 1 of the present invention;

[0027] Fig. 9 Liquid chromatogram of Nicorandil tetramer in Example 1 of the present invention. DETAILED DESCRIPTION

[0028] Example 1) Preparation of polymer using acetonitrile as solvent

[0029] Add 10.0 g of nicorandil and 1 ml of 30% hydrogen peroxide to 200 ml of acetonitrile, heat and reflux, and keep warm for 12 hours. After the reaction is completed, concentrate under reduced pressure, and separate the solid residue using a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer. The specific operation is as follows:

[0030] Preparation method:

[0031] Chromatographic column: Octadecylsilane bonded silica gel as filler (250mm×30mm, 10μm)

[0032] Mobile phase: trifluoroacetic acid: triethylamine: tetrahydrofuran: water = 8:5:18:969

[0033] Flow rate: 30 ml / min

[0034] Detection wavelength: 254nm

[0035] Test results of the obtained pure product: see attached Figures 7-9 .

[0036] Dimer purity: 93.466%; trimer purity: 96.487%; tetramer purity: 91.778%.

[0037] (1) Confirmation of the dimer structure of Nicorandil:

[0038]

[0039] 1 HNMR(DMSO,400MHz),δ:3.66-3.70(m,2H),3.86-3.90(m,2H),4.64-4.66(t,2H),4.82-4.84(t,2H),7.45-7.48(m,1H),8.00-8.03(m,1H), 8.23-8.27(m,1H),8.67-8.68(m,1H), 8.83-8.94(m,3H), 9.19-9.20(d,1H),9.45-9.47(d,2H). LC-ESI-MS(m / z):361[M+H] + .

[0040] (2) Confirmation of the trimer structure of Nicorandil:

[0041]

[0042] 1 HNMR(D2O,400MHz),δ:3.66-3.69(t,2H),3.95-3.97(t,4H),4.58-4.60(t,2H),4.82-4.83(d,4H),8.03-8.11(m,3H ),8.67-8.69(d,2H),8.75-8.77(d,1H),8.82-8.84(d,1H),8.95-8.97(d,2H),9.00-9.01(d,1H),9.19-9.22(d,2H). LC-ESI-MS(m / z):509[M] + .

[0043] (3) Confirmation of the tetramer structure of Nicorandil:

[0044]

[0045] 1 HNMR(D2O,500MHz),δ:3.66-3.69(t,2H),3.95-3.98(m,6H),4.58-4.61(t,2H),4.82(m,6H),8 .03-8.12(m,4H),8.67-8.69(d,3H),8.76-8.84(m,2H),8.95-9.01(m,4H),9.19-9.22(d,3H). LC-ESI-MS(m / z):658[M] + .

[0046] The above structure confirmation spectrum is attached Figures 1 to 6 .

[0047] Example 2) Preparation of polymer using N,N-dimethylformamide (DMF) as solvent

[0048] To 120 ml of DMF, 10.0 g of nicorandil and 1 ml of 30% hydrogen peroxide were added, the temperature was raised to 100° C., and the reaction was kept warm for 12 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the solid residue was separated using a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer, respectively. The specific separation operation was as in Example 1.

[0049] Example 3) Preparation of polymer using N,N-dimethylacetamide (DMA) as solvent

[0050] To 150 ml of DMA, 10.0 g of nicorandil and 1 ml of 30% hydrogen peroxide were added, the temperature was raised to 100° C., and the reaction was kept warm for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, and the solid residue was separated using a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer, respectively. The specific separation operation was as in Example 1.

[0051] Example 4) Preparation of polymer using dimethyl sulfoxide (DMSO) as solvent

[0052] To 150 ml of DMSO, 10.0 g of nicorandil and 1 ml of 30% hydrogen peroxide were added, the temperature was raised to 100° C., and the reaction was kept warm for 12 hours. After the reaction was completed, it was concentrated under reduced pressure, and the solid residue was separated using a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer, respectively. The specific separation operation was as in Example 1.

[0053] Example 5) Preparation of polymer using a mixed solvent of N,N-dimethylformamide (DMF) and acetonitrile

[0054] To a mixed solvent consisting of 10 ml of DMF and 100 ml of acetonitrile were added 10.0 g of nicorandil and 1 ml of 30% hydrogen peroxide, the temperature was raised to 80° C., and the reaction was maintained for 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the solid residue was separated using a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer, respectively. The specific separation operation was as in Example 1.

[0055] It should be pointed out that the above preferred embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing a nicorandil polymer, characterized in that: The method comprises dissolving Nicorandil in hydrogen peroxide and an organic solvent for high temperature stirring reaction, wherein the organic solvent is selected from one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; and the temperature of the high temperature stirring reaction is 80 to 100°C.

2. The method for preparing a nicorandil polymer according to claim 1, characterized in that: The organic solvent is acetonitrile, and the method has the following steps: adding nicorandil and hydrogen peroxide to acetonitrile, heating and reflux, and keeping warm for 12 hours. After the reaction is completed, the reaction is concentrated under reduced pressure, and the solid residue is separated by a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer.

3. The method for preparing a Nicorandil polymer according to claim 1, characterized in that: The organic solvent is N,N-dimethylformamide, and the method has the following steps: adding nicorandil and hydrogen peroxide to N,N-dimethylformamide, heating to 100°C, keeping the temperature for reaction for 12 hours, and after the reaction is completed, concentrating under reduced pressure, separating the solid residue using a reverse preparative column, and collecting the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer respectively.

4. The method for preparing a Nicorandil polymer according to claim 1, characterized in that: The organic solvent is N,N-dimethylacetamide, and the method has the following steps: adding nicorandil and hydrogen peroxide to N,N-dimethylacetamide, heating to 100°C, and keeping the temperature for reaction for 12 hours. After the reaction is completed, the reaction is concentrated under reduced pressure, and the solid residue is separated by a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer.

5. The method for preparing a Nicorandil polymer according to claim 1, characterized in that: The organic solvent is dimethyl sulfoxide, and the method has the following steps: adding nicorandil and hydrogen peroxide to dimethyl sulfoxide, heating to 100° C., keeping the temperature for reaction for 12 hours, and after the reaction is completed, concentrating under reduced pressure, separating the solid residue using a reverse preparative column, and collecting the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer respectively.

6. The method for preparing a Nicorandil polymer according to claim 1, characterized in that: The organic solvent is a mixed solvent of N,N-dimethylformamide and acetonitrile. The method comprises the following steps: adding nicorandil and hydrogen peroxide to a mixed solvent of N,N-dimethylformamide and acetonitrile, heating the mixture to 80°C, and reacting the mixture for 12 hours. After the reaction is completed, the mixture is concentrated under reduced pressure, and the solid residue is separated by using a reverse preparative column to collect the corresponding nicorandil dimer, nicorandil trimer, and nicorandil tetramer.

7. The method for preparing a Nicorandil polymer according to any one of claims 2 to 6, characterized in that: The reverse preparative column parameters are: Chromatographic column: octadecylsilane bonded silica gel as filler 250mm×30mm, 10μm Mobile phase: trifluoroacetic acid: triethylamine: tetrahydrofuran: water = 8:5:18:969 Flow rate: 30 ml / min Detection wavelength: 254nm.

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