A method for synthesizing nicorandil trimer

Abstract

The present invention relates to a method for synthesizing a nicorandil trimer. The method comprises the following steps: (1) using N-(2-hydroxyethyl)-nicotinamide (I) as a raw material, dissolving it in an organic solvent, adding carbon tetrahalide and triphenylphosphine to carry out a halogenation reaction, and stirring; (2) after the reaction is completed, pouring the reaction solution into ice water, removing the organic solvent, extracting, drying, spin-drying, and purifying to obtain an intermediate (II); (3) dissolving nicorandil in an organic solvent, heating, dripping an organic solvent containing the intermediate (II), stirring, and removing the organic solvent to obtain a crude nicorandil trimer; and (4) recrystallizing the crude nicorandil trimer in a mixed solvent of water and alcohol to obtain the nicorandil trimer.

Description

Technical Field

[0001] The present invention relates to a method for preparing a nicotinic acid trimer, and in particular to a method for preparing 1-(2-(nicotinamido)ethyl)-3-((2-(3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium-1-yl)ethyl)carbamoyl)pyridin-1-ium chloride. Technical Background

[0002] Nicorandil, chemical name is N-(2-hydroxyethyl) nicotinamide nitrate, molecular formula is C8H9N3O4, structural formula:

[0003]

[0004] Nicorandil has a nitrate-like effect and is the first ATP-sensitive potassium channel opener used clinically. It is a coronary artery dilator. Nicorandil can promote the outflow of intracellular potassium ions, hyperpolarize the cell membrane, shorten the action potential duration, inhibit calcium overload, relax vascular smooth muscle, relax systemic resistance and capacity vessels, reduce preload and postload and myocardial oxygen consumption, improve myocardial ischemia, inhibit vascular inflammatory response, and promote the recovery of damaged vascular endothelial function. It can significantly reduce the incidence of angina pectoris.

[0005] Nicorandil is chemically unstable and easily degraded, producing a variety of harmful impurities, including nicorandil dimers, trimers, etc. In order to study the effect of nicorandil impurities on nicorandil, it is first necessary to purify and obtain nicorandil dimers or trimers. Currently, the acquisition of nicorandil impurities is mainly prepared from nicorandil reaction solution. Since nicorandil needs to be placed for a long time to undergo degradation reaction, and the content of nicorandil impurities obtained therefrom is small, the conversion rate is low, the acquisition is difficult, and a high-cost, cumbersome chromatographic method is required for separation and purification, it is necessary to find a preparation method for nicorandil impurities to obtain high-purity nicorandil dimers and trimers to promote the research work of nicorandil.

[0006] The invention patent with patent publication number CN 109516950 A discloses a method for preparing nicorandil dimer, which comprises taking nicorandil as a raw material, dissolving it in an organic solvent such as tetrahydrofuran, acetonitrile, propionitrile, etc., stirring and reacting for 2-6 hours, and adding dropwise a crystallization solvent such as dichloromethane, chloroform, etc. to obtain a crude product; after recrystallization, a solid nicorandil dimer nitrate is obtained, the structural formula of which is:

[0007]

[0008] The invention patent with patent publication number CN 109516951 A discloses a method for preparing a nicorandil trimer, wherein nicorandil is used as a raw material, dissolved in an organic solvent such as DMF, DMA, etc., stirred for reaction for 4-7 hours, and a crystallization solvent such as dichloromethane, chloroform, etc. is added dropwise to obtain a crude product; after recrystallization, a solid nicorandil trimer nitrate is obtained, with the structural formula:

[0009]

[0010] The nicorandil dimer and trimer obtained by the above preparation method are prepared by using nicorandil as a raw material, and undergoing high temperature degradation to produce dimers or trimers under different solvent and temperature conditions. During the preparation process, a mixture of dimers and trimers is easily generated and is not easy to separate. Therefore, it is necessary to find a simple, low-cost, high-yield preparation method for nicorandil trimer. The high-purity nicorandil trimer prepared can provide an impurity reference for the quality control of nicorandil.

[0011] Nicorandil trimer is an impurity that may be formed by nicorandil and needs to be controlled. For impurity control, a pure product of the impurity is generally required as a reference. However, it is currently difficult to find a high-purity nicorandil trimer. The present invention has conducted research to find a method for preparing nicorandil trimer, thereby providing a high-purity impurity reference for the quality research and development of nicorandil. Summary of the invention

[0012] The present invention provides a method for synthesizing nicorandil trimer 1-(2-(nicotinamido)ethyl)-3-((2-(3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium-1-yl)ethyl)carbamoyl)pyridin-1-ium chloride. By using the method, nicorandil trimer can be directly synthesized without separating nicorandil dimer, and the reaction conversion rate and purity are high, and separation and purification are convenient.

[0013] The present invention relates to a method for synthesizing nicorandil trimer 1-(2-(nicotinamido)ethyl)-3-((2-(3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium-1-yl)ethyl)carbamoyl)pyridin-1-ium chloride, which is achieved by the following technical scheme, and the reaction formula is as follows:

[0014]

[0015] In the reaction:

[0016] Compound I is N-(2-hydroxyethyl)-nicotinamide;

[0017] Compound II is N-(2-haloethyl)nicotinamide; wherein X represents a halogen;

[0018] Compound III is N-(2-hydroxyethyl) nicotinamide nitrate, i.e., Nicorandil;

[0019] The steps include:

[0020] (5) using N-(2-hydroxyethyl)-nicotinamide (I) as a raw material, dissolving it in an organic solvent, adding carbon tetrahalide and triphenylphosphine to carry out a halogenation reaction, and stirring;

[0021] (6) After the reaction is completed, the reaction solution is poured into ice water, the organic solvent is removed, and the intermediate (II) is obtained after extraction, drying, spin drying, and purification;

[0022] (7) dissolving Nicorandil in an organic solvent, raising the temperature, adding dropwise an organic solvent containing the intermediate (II), stirring, and removing the organic solvent to obtain a crude Nicorandil trimer;

[0023] (8) The crude nicorandil trimer is recrystallized in a mixed solvent of water and alcohol to obtain nicorandil trimer.

[0024] The organic solvent used in step (1) is selected from but not limited to one or more of the following solvents: dichloromethane, chloroform, ethyl acetate, tetrahydrofuran or acetonitrile;

[0025] The volume of the organic solvent is 2-30 times (mL / g) the mass of N-(2-hydroxyethyl)-nicotinamide (I), preferably 5-20 times;

[0026] The mass of the carbon tetrahalide is 2.2 times (g / g) the mass of N-(2-hydroxyethyl)-nicotinamide (I); wherein the halogen in the carbon tetrahalide is selected from: fluorine, chlorine, bromine, iodine, preferably chlorine;

[0027] The mass of triphenylphosphine is 1.12 times the mass of N-(2-hydroxyethyl)-nicotinamide (I) (g / g);

[0028] The reaction temperature is from -20°C to the boiling point of the solvent system, preferably from -10°C to 80°C.

[0029] The reaction time is 2-8 hours.

[0030] The mass of ice water in step (2) is 5 times the mass of N-(2-hydroxyethyl)-nicotinamide (I);

[0031] The temperature of ice water is 0℃;

[0032] The method for removing the organic solvent is rotary evaporation;

[0033] The solvent in step (3) is selected from but not limited to one or more of the following solvents: methanol, acetonitrile, DMF, isopropanol or dioxane;

[0034] The volume of the organic solvent is 1-30 times (mL / g) of the mass of Nicorandil, preferably 3-20 times;

[0035] The mass of the intermediate (II) is 2-4 times (g / g) the mass of nicorandil (III);

[0036] The heating method is oil bath heating;

[0037] The reaction temperature is from 20°C to the boiling point of the solvent system, preferably from 40°C to 100°C;

[0038] The reaction time is 4-18 hours;

[0039] The method for removing the organic solvent is rotary evaporation.

[0040] In step (4), the alcohol is isopropanol or ethanol;

[0041] The water content of the mixed solvent is 5%-15%.

[0042] The crystallization temperature is -10℃-0℃.

[0043] The reaction time is 2-6 hours.

[0044] The present invention provides an application of Nicorandil trimer, namely, providing a reference substance for the study of the quality of Nicorandil and its raw materials.

[0045] In the method for detecting the content of Nicorandil, the Nicorandil trimer synthesized by the method of the present invention can be used as a standard reference substance and applied to the detection of the impurity content in Nicorandil, its raw materials and its preparations.

[0046] The present invention further provides a method for detecting the content of Nicorandil trimer, wherein the method comprises the following steps:

[0047] Take the nicorandil trimer synthesized by the above method, and use the mobile phase to prepare a solution containing about 1 mg per 1 ml, which is used as the test solution; take 10 μl of the test solution and inject it into the liquid chromatograph. The peak with a retention time of 30.915 min is the impurity nicorandil trimer peak.

[0048] HPLC conditions: Column: 0.25m*4.6mm, 5μm, C18;

[0049] Mobile phase: trifluoroacetic acid: triethylamine: acetonitrile: water (3:5:10:982);

[0050] Flow rate: 1.0 ml / min;

[0051] Detection wavelength: 254nm;

[0052] Column temperature: 25°C.

[0053] Based on the above detection method, the nicorandil trimer synthesized by the method of the present invention can be used as a standard reference substance and applied to the detection of impurity content in nicorandil raw materials and preparations thereof, so as to perform qualitative and quantitative analysis of nicorandil.

[0054] The beneficial effects of the present invention are:

[0055] 1. The nicorandil trimer synthesized by the present invention does not need to be subjected to high temperature degradation of nicorandil, does not produce dimer impurities, and can be directly synthesized to facilitate separation and purification;

[0056] 2. The nicorandil trimer product obtained by this method has good quality and state, high conversion rate and purity. 1 The confirmation by HNMR and high-resolution mass spectrometry was consistent with the trimer structure of Nicorandil, providing a solid foundation for the study of Nicorandil impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 is the liquid chromatogram of Nicorandil trimer;

[0058] Figure 2 This is the high-resolution mass spectrum of Nicorandil trimer;

[0059] Figure 3 This is the H NMR spectrum of nicorandil trimer;

[0060] Figure 4 This is the carbon NMR spectrum of nicorandil trimer;

[0061] Figure 5 This is the NMR DEPT spectrum of nicorandil trimer;

[0062] Figure 6 This is the NMR COSY spectrum of nicorandil trimer;

[0063] Figure 7 This is the NMR HSQC spectrum of nicorandil trimer;

[0064] Figure 8 This is the HMBC NMR spectrum of nicorandil trimer. DETAILED DESCRIPTION

[0065] The following examples are intended to further illustrate the present invention and do not constitute any limitation to the present invention.

[0066] Example 1

[0067] Under the protection of dry nitrogen, tetrahydrofuran (50 mL), N-(2-hydroxyethyl)-nicotinamide (I) (5.0 g, 30.1 mmol) and triphenylphosphine (11.0 g, 36.1 mmol) were added to the reaction bottle in sequence and stirred to dissolve. The temperature was lowered to -0°C, and carbon tetrachloride (5.6 g, 36.1 mmol) was added dropwise. After the addition was complete, the temperature was raised to 60°C and the reaction was carried out for 8 hours. After the reaction was complete, the mixture was poured into ice water, and the solvent tetrahydrofuran was evaporated off by rotary evaporation. The mixture was extracted with ethyl acetate, dried and dried, and purified by silica gel column to obtain 4.0 g of intermediate (II).

[0068] Nicorandil (III) (1.0 g, 4.7 mmol) was dissolved in DMF (10 mL), heated to 100°C, intermediate (II) (3.5 g, 18.8 mol) was dissolved in DMF (10 mL), slowly added dropwise to the reaction solution, and the mixture was kept at 100°C for 6 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the crude nicorandil trimer was recrystallized in a 5% water-containing isopropanol solution at 0°C for 4.0 hours to obtain 1.68 g of nicorandil trimer, with a yield of 81%. HPLC content was 98.5%.

[0069] Example 2

[0070] Under the protection of dry nitrogen, tetrahydrofuran (50 mL), N-(2-hydroxyethyl)-nicotinamide (I) (5.0 g, 30.1 mmol) and triphenylphosphine (11.0 g, 36.1 mmol) were added to the reaction bottle in sequence and stirred to dissolve. The temperature was lowered to -10°C, and carbon tetraiodide (5.6 g, 36.1 mmol) was added in batches. After the addition was completed, the temperature was raised to 20°C and the reaction was carried out for 2 hours. After the reaction was complete, the mixture was poured into ice water, and the solvent tetrahydrofuran was evaporated off by rotary evaporation. The mixture was extracted with ethyl acetate, dried and dried by rotary evaporation, and purified by silica gel column to obtain 4.4 g of intermediate (II).

[0071] Nicorandil (III) (1.0 g, 4.7 mmol) was dissolved in DMF (10 mL), heated to 100°C, intermediate (II) (3.5 g, 18.8 mol) was dissolved in DMF (10 mL), slowly added dropwise to the reaction solution, and the mixture was kept at 100°C for 6 hours. After the reaction was completed, the solvent was removed by rotary evaporation, and the crude nicorandil trimer was recrystallized in an isopropanol solution with a water content of 5% at 0°C for 4.0 hours to obtain 1.61 g of nicorandil trimer with a yield of 78%. HPLC content was 97.6%.

[0072] Example 3

[0073] Step (1) The reaction solvent is acetonitrile, the reaction temperature is 80°C, and the rest is the same as in Example 2

[0074] The yield was 77% and the purity was 86.5%.

[0075] Example 4

[0076] In step (3), acetonitrile was used as the reaction solvent, the reaction temperature was 45° C., and the reaction was carried out for 18 hours. The rest of the reaction was the same as in Example 2.

[0077] The yield was 86% and the purity was 95.9%.

[0078] Example 5

[0079] The reaction solvent in step (3) is dioxane, the reaction temperature is 80° C., the reaction time is 10 hours, and the rest is the same as in Example 2.

[0080] The yield was 80% and the purity was 93.7%.

[0081] Example 6

[0082] The reaction of step (1) is the same as in Example 1, the reaction solvent of step (3) is isopropanol, the reaction temperature is reflux state (85° C.), the reaction time is 8 hours, and the rest is the same as in Example 5.

[0083] The yield was 82% and the purity was 94.8%.

[0084] Example 7

[0085] The crude nicorandil trimer obtained in Example 4 was recrystallized in an isopropanol solution having a water content of 10% at -5°C for 6.0 h to obtain the nicorandil trimer.

[0086] The yield was 83% and the purity was 97.3%.

[0087] Example 8

[0088] The recrystallization solvent is an ethanol solution with a water content of 10%, and the rest is the same as in Example 7.

[0089] The yield was 80% and the purity was 92.6%.

[0090] Example 9

[0091] The crude nicorandil trimer obtained in Example 6 was recrystallized in an isopropanol solution having a water content of 15% at -10°C for 2.0 h to obtain the nicorandil trimer.

[0092] The yield was 84% ​​and the purity was 91.3%.

[0093] Example 10

[0094] The sample used for confirming the chemical structure was the nicorandil trimer synthesized by the method of Example 1. The calibration chromatogram is shown in the attached Figure 1 .

[0095] Table 1. Sample information for confirmation of the structure of Nicorandil trimer

[0096] Product Name batch number purity% source Nicorandil trimer NK-190924-1 98.5％ self made

[0097] 1. Physical and chemical properties

[0098] This product is off-white solid or colorless oil.

[0099] This product is easily soluble in water, methanol and dimethyl sulfoxide.

[0100] 2. Mass spectrometry (MS)

[0101] Instrument: Shimadzu 30AD UPLC-IT TOF LC-MS;

[0102] Solvent: water;

[0103] Ionization method: ESI (+)

[0104] 2.1 Mass Spectrum

[0105] The mass spectrum of Nicorandil trimer is attached. Figure 2 .

[0106] 2.2 Test Data

[0107] Table 2. Nicorandil trimer mass spectrometry results

[0108]

[0109] 2.3 Analysis

[0110] By the attached Figure 2 It can be seen that the mass-to-charge ratio in this mass spectrum is 254.5925, corresponding to the mass-to-charge ratio (m / 2z), and the sample itself has two charges. 24 H 27 N7O6 2+ The measured values ​​are consistent with the theoretical values ​​(the exact molecular weight is 509.2012; the corresponding mass-to-charge ratio (m / 2z) is 254.6006).

[0111] 3. Nuclear Magnetic Resonance Spectroscopy (NMR)

[0112] Instrument: BRUKER AV-400 NMR instrument

[0113] Solvent: DMSO-d6

[0114] Temperature: 303K

[0115] Internal standard: TMS

[0116] 3.1 NMR spectrum

[0117] The H NMR spectrum and C NMR spectrum of this product are shown in the attached Figure 3, Attachment Figure 4 ; NMR DEPT spectrum is attached Figure 5 , NMR COSY spectrum is attached Figure 6 , NMR HSQC spectrum is attached Figure 7 , NMR HMBC spectrum is attached Figure 8 .

[0118] Chemical structure of Nicorandil trimer sample:

[0119]

[0120] 3.2 Test Data

[0121] Table 3. Proton spectrum measurement results of Nicorandil trimer samples

[0122]

[0123]

[0124] Table 4. Carbon spectrum determination results of Nicorandil trimer samples

[0125]

[0126]

[0127] 3.3 Analysis

[0128] The hydrogen spectrum, carbon spectrum, DEPT, COSY, HSQC and HMBC two-dimensional spectrum of this product tested by nuclear magnetic resonance can be seen in the attached Figure 3 , 4 , 5, 6, 7, 8.

[0129] 1 H-NMR test shows that the hydrogen spectrum of nicorandil has 14 component peaks, and its integral ratio (from low field to high field) is 1:2:1:2:2:2:2:1:1:4:2:4:2, with a total of 27 protons, which is consistent with the theoretical proton number of nicorandil trimer. From the chemical shift value, coupling constant value and various two-dimensional spectra, we can know that:

[0130] a.δ9.572(1H,s),δ9.434(1H,s),δ8.959(1H,s) are protons on nitrogen. Combining their chemical shift, atomic electronegativity and HH COSY correlation, we can know that they are H19 on the nitrogen atom, δ9.572(1H,s) is a single sharp peak, H8, δ9.434(1H,s) is a single peak, H30, δ8.959(1H,s) is a single peak, but it is wrapped in the multiple peaks δ8.938-9.973.

[0131] b.δ9.495-9.531 (2H, m) is a multiple peak. Combining its chemical shift, COSY spectrum and HMBC spectrum, it can be known that it is hydrogen H13 and H17 on the pyridine ring.

[0132] c.δ9.197-9.239 (1H, m) is a multiplet. Combining its chemical shift and HH COSY spectrum, it can be known that it is hydrogen H24 and H28 on the pyridine ring, which is further supported by the HSQC spectrum.

[0133] d.δ8.938-8.973 (2H, m) is a multiplet, one of the hydrogens has been identified as H30. Combining its chemical shift, COSY spectrum and HMBC spectrum, it can be known that it is hydrogen H14 on the pyridine ring based on its strong correlation with H13 and H17.

[0134] e.δ8.849 (1H, s) is a single peak. Combined with its chemical shift, the HMBC spectrum shows that it is hydrogen H15 on the pyridine ring.

[0135] f.δ8.849 (1H, s) is a single peak. Combined with its chemical shift, the HMBC spectrum shows that it is hydrogen H15 on the pyridine ring. δ8.815 (1H, d) is a d peak. Combined with its chemical shift, 13 C-NMR spectrum and HMBC spectrum show that it is hydrogen H3 on the pyridine ring.

[0136] g.δ8.710-8.726 (1H, dd) is a dd peak. Combined with its chemical shift, 13 C-NMR spectrum and HMBC spectrum show that it is hydrogen H25 on the pyridine ring, δ7.495-7.527 (1H, m) is a multiple peak, combined with its chemical shift, 13 C-NMR and HMBC spectra showed that it was hydrogen H26 on the pyridine ring, which was further supported by the HH COSY spectrum.

[0137] h.δ8.226-8.268 (1H, m) is a multiple peak, combined with its chemical shift, 13 C-NMR spectrum and HMBC spectrum show that they are hydrogen H4 and H6 on the pyridine ring.

[0138] i.δ8.039-8.069 (1H, m) is a multiple peak, combined with its chemical shift, 13 C-NMR spectrum and HMBC spectrum show that it is hydrogen H2 on the pyridine ring.

[0139] j.δ4.816-4.871 (4H, m) is a multiplet. According to its chemical shift value, the chemical environment and HH COSY spectrum, it is the hydrogen H11 and H22 on the methylene. δ4.680 (2H, m) is a multiplet and has a strong correlation with H32, which is determined to be the methylene hydrogen H33.

[0140] k.δ3.688-3.727 (2H, m) is a multiplet, which is hydrogen H10 on the methylene group according to its chemical shift value combined with the chemical environment and HH COSY; δ3.868-3.895 (2H, m) is a multiplet, which is hydrogen H32 on the methylene group according to its chemical shift value combined with the chemical environment and HH COSY; δ3.908-3.960 (2H, m) is a multiplet, which is hydrogen H21 on the methylene group according to its chemical shift value combined with the chemical environment and HH COSY.

[0141] In summary, the test results of the hydrogen spectrum of this product are consistent with the structure of Nicorandil trimer.

[0142] By this product 13 From the C-NMR spectrum and DEPT spectrum, it can be seen that there are 24 resonance absorption peaks in the figure, which is consistent with the number of carbon atoms contained in the nicorandil trimer molecule.

[0143] According to its chemical shift and DEPT spectrum, δ165.94, δ162.60, and δ162.19 are the chemical shifts of the carbonyl carbon, which can be known to be C7, C18, and C29 respectively, and this is further supported by the COSY spectrum.

[0144] The carbon at δ152.19 is C25 from the chemical shift and HSQC; the carbon at δ148.36 is C3 from the chemical shift and HSQC, and according to the COSY spectrum, the carbon at δ135.85 is C2.

[0145] The carbons at δ147.72 and δ147.60 are C24 and C28, respectively, based on electronegativity and HSQC spectrum.

[0146] The carbons at δ145.74, δ145.57, δ143.90, and δ143.82 are C13, C17, C14, and C15, respectively, based on electronegativity and HSQC spectra.

[0147] According to CNMR and DEPT spectra, δ133.79, δ133.67, and δ129.87 are quaternary carbons C16, C5, and C27, respectively, which are further confirmed by COSY spectra.

[0148] From the HSQC spectrum, we can see that the carbon at δ124.14 has a large correlation with H26, so we know that the carbon is C26.

[0149] From the DEPT and HMBC spectra, we can see that δ72.42, δ61.50, δ61.29, δ40.57, δ40.28, and δ37.52 are methylene carbons, which are determined to be C33, C11, C22, C21, C32, and C10 respectively according to their electronegativity.

[0150] In summary, the carbon spectrum test results of this product are consistent with the structure of Nicorandil trimer, and the carbon attribution can be seen in Table 4.

[0151] The chemical shift of the resonance absorption peak of DMSO used in the NMR carbon spectrum test is 40.00. The extra solvent peak indicates that the sample and the solvent have interacted.

[0152] Comprehensive analysis:

[0153] 1. The mass-to-charge ratio in the sample mass spectrum is 254.5925, corresponding to the mass-to-charge ratio (m / 2z). The sample itself has two charges. 24 H 27 N7O6 2+ The measured values ​​are consistent with the theoretical values ​​(the exact molecular weight is 509.2012; the corresponding mass-to-charge ratio (m / 2z) is 254.6006).

[0154] 2. 1 The H-NMR test of the hydrogen spectrum of the nicorandil trimer sample has 14 component peaks, and its integration ratio (from low field to high field) is 1:2:1:2:2:2:2:1:1:4:2:4:2, with a total of 27 protons, which is consistent with the theoretical proton number of nicorandil trimer. From the chemical shift values, coupling constant values ​​and various two-dimensional spectra, it can be seen that:

[0155] a.δ9.572(1H,s),δ9.434(1H,s),δ8.959(1H,s) are protons on nitrogen. Combining their chemical shift, atomic electronegativity and HH COSY correlation, we can know that they are H19 on the nitrogen atom, δ9.572(1H,s) is a single sharp peak, H8, δ9.434(1H,s) is a single peak, H30, δ8.959(1H,s) is a single peak, but it is wrapped in the multiple peaks δ8.938-9.973.

[0156] b.δ9.495-9.531 (2H, m) is a multiple peak. Combining its chemical shift, COSY spectrum and HMBC spectrum, it can be known that it is hydrogen H13 and H17 on the pyridine ring.

[0157] c.δ9.197-9.239 (1H, m) is a multiplet. Combining its chemical shift and HH COSY spectrum, it can be known that it is hydrogen H24 and H28 on the pyridine ring, which is further supported by the HSQC spectrum.

[0158] d.δ8.938-8.973 (2H, m) is a multiplet, one of the hydrogens has been identified as H30. Combining its chemical shift, COSY spectrum and HMBC spectrum, it can be known that it is hydrogen H14 on the pyridine ring based on its strong correlation with H13 and H17.

[0159] e.δ8.849 (1H, s) is a single peak. Combined with its chemical shift, the HMBC spectrum shows that it is hydrogen H15 on the pyridine ring.

[0160] f.δ8.849 (1H, s) is a single peak. Combined with its chemical shift, the HMBC spectrum shows that it is hydrogen H15 on the pyridine ring. δ8.815 (1H, d) is a d peak. Combined with its chemical shift, 13 C-NMR spectrum and HMBC spectrum show that it is hydrogen H3 on the pyridine ring.

[0161] g.δ8.710-8.726 (1H, dd) is a dd peak. Combined with its chemical shift, 13 C-NMR spectrum and HMBC spectrum show that it is hydrogen H25 on the pyridine ring, δ7.495-7.527 (1H, m) is a multiple peak, combined with its chemical shift, 13 C-NMR and HMBC spectra showed that it was hydrogen H26 on the pyridine ring, which was further supported by the HH COSY spectrum.

[0162] h.δ8.226-8.268 (1H, m) is a multiple peak, combined with its chemical shift, 13 C-NMR spectrum and HMBC spectrum show that they are hydrogen H4 and H6 on the pyridine ring.

[0163] i.δ8.039-8.069 (1H, m) is a multiple peak, combined with its chemical shift, 13 C-NMR spectrum and HMBC spectrum show that it is hydrogen H2 on the pyridine ring.

[0164] j.δ4.816-4.871 (4H, m) is a multiplet. According to its chemical shift value, the chemical environment and HH COSY spectrum, it is the hydrogen H11 and H22 on the methylene. δ4.680 (2H, m) is a multiplet and has a strong correlation with H32, which is determined to be the methylene hydrogen H33.

[0165] k.δ3.688-3.727 (2H, m) is a multiplet, which is hydrogen H10 on the methylene group according to its chemical shift value combined with the chemical environment and HH COSY; δ3.868-3.895 (2H, m) is a multiplet, which is hydrogen H32 on the methylene group according to its chemical shift value combined with the chemical environment and HH COSY; δ3.908-3.960 (2H, m) is a multiplet, which is hydrogen H21 on the methylene group according to its chemical shift value combined with the chemical environment and HH COSY.

[0166] 3. Nicorandil trimer sample 13 From the C-NMR spectrum and DEPT spectrum, it can be seen that there are 24 resonance absorption peaks in the figure, which is consistent with the number of carbon atoms contained in the molecule of Nicorandil trimer.

[0167] According to its chemical shift and DEPT spectrum, δ165.94, δ162.60, and δ162.19 are the chemical shifts of the carbonyl carbon, which can be known to be C7, C18, and C29 respectively, and this is further supported by the COSY spectrum.

[0168] The carbon at δ152.19 is C25 from the chemical shift and HSQC; the carbon at δ148.36 is C3 from the chemical shift and HSQC, and according to the COSY spectrum, the carbon at δ135.85 is C2.

[0169] The carbons at δ147.72 and δ147.60 are C24 and C28, respectively, based on electronegativity and HSQC spectrum.

[0170] The carbons at δ145.74, δ145.57, δ143.90, and δ143.82 are C13, C17, C14, and C15, respectively, based on electronegativity and HSQC spectra.

[0171] According to CNMR and DEPT spectra, δ133.79, δ133.67, and δ129.87 are quaternary carbons C16, C5, and C27, respectively, which are further confirmed by COSY spectra.

[0172] From the HSQC spectrum, we can see that the carbon at δ124.14 has a large correlation with H26, so we know that the carbon is C26.

[0173] From the DEPT and HMBC spectra, we can see that δ72.42, δ61.50, δ61.29, δ40.57, δ40.28, and δ37.52 are methylene carbons, which are determined to be C33, C11, C22, C21, C32, and C10 respectively according to their electronegativity.

[0174] In summary, the structure of this product is consistent with the structure of Nicorandil trimer, which is as follows:

[0175]

Claims

1. A method for synthesizing a nicorandil trimer, wherein the reaction formula is as follows: In the reaction formula: Compound I is N-(2-hydroxyethyl)-nicotinamide; Compound II is N-(2-haloethyl) nicotinamide; wherein, X represents halogen; Compound III is N-(2-hydroxyethyl) nicotinamide nitrate, i.e., Nicorandil; The method comprises the following steps: (1) Compound I is used as a raw material, dissolved in an organic solvent, and carbon tetrahalide and triphenylphosphine are added to carry out a halogenation reaction, and stirred; (2) After the reaction is completed, the reaction solution is poured into ice water, the organic solvent is removed, and the intermediate II is obtained after extraction, drying, spin drying, and purification; (3) dissolving Nicorandil in an organic solvent, raising the temperature, adding dropwise an organic solvent containing the intermediate II, stirring, and removing the organic solvent to obtain a crude Nicorandil trimer; (4) recrystallizing the crude nicorandil trimer in a mixed solvent of water and alcohol to obtain the nicorandil trimer; The organic solvent used in step (1) is selected from: dichloromethane, chloroform, ethyl acetate, tetrahydrofuran or acetonitrile; the volume of the organic solvent is 2-30 times the mass of compound I, and the mass of carbon tetrahalide is 2.2 times the mass of compound I; wherein the halogen in carbon tetrahalide is selected from: fluorine, chlorine, bromine, iodine; the mass of triphenylphosphine is 1.12 times the mass of compound I; the reaction temperature is -20°C to the boiling point of the solvent system; and the reaction time is 2-8 hours; The solvent in step (3) is selected from the group consisting of methanol, acetonitrile, DMF, isopropanol or dioxane; The volume of the organic solvent is 1-30 times the mass of Nicorandil; The mass of intermediate II is 2-4 times that of nicorandil; The heating method is oil bath heating; The reaction temperature is from 20°C to the boiling point of the solvent system; The reaction time is 4-18 hours; The method for removing the organic solvent is rotary evaporation.

2. The method according to claim 1, characterized in that The method comprises the following steps: In step (1), the volume of the organic solvent is 5-20 times the mass of compound I; Wherein, the halogen in the carbon tetrahalide is selected from: chlorine; The reaction temperature is -10°C-80°C.

3. The method according to claim 1, characterized in that The method comprises the following steps: The mass of ice water in step (2) is 5 times the mass of compound I; The method for removing the organic solvent is rotary evaporation.

4. The method according to claim 1, characterized in that: The method comprises the following steps: In step (3), the volume of the organic solvent is 3-20 times the mass of Nicorandil; The reaction temperature is 40°C-100°C.

5. The method according to claim 1, characterized in that The method comprises the following steps: In step (4), the alcohol is isopropanol or ethanol; The water content of the mixed solvent is 5%-15%; The crystallization temperature is -10℃-0℃; The reaction time is 2-6 hours.

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