CN114621138A - Synthesis method of nicorandil trimer - Google Patents
Synthesis method of nicorandil trimer Download PDFInfo
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- CN114621138A CN114621138A CN202011439615.6A CN202011439615A CN114621138A CN 114621138 A CN114621138 A CN 114621138A CN 202011439615 A CN202011439615 A CN 202011439615A CN 114621138 A CN114621138 A CN 114621138A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- G—PHYSICS
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Abstract
The invention relates to a method for synthesizing nicorandil trimer, which comprises the following steps: (1) dissolving N- (2-hydroxyethyl) -nicotinamide (I) serving as a raw material in an organic solvent, adding carbon tetrahalide and triphenyl phosphorus to carry out halogenation reaction, and stirring; (2) after the reaction is finished, 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, dropwise adding the organic solvent containing the intermediate (II), stirring, and removing the organic solvent to obtain a nicorandil tripolymer crude product; (4) recrystallizing the nicorandil trimer crude product in a mixed solvent of water and alcohol to obtain the nicorandil trimer.
Description
Technical Field
The present invention relates to a process for preparing nicorandil trimer, in particular to a process 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 Field
Nicorandil, chemical name is N- (2-hydroxyethyl) nicotinamide nitrate, molecular formula is C8H9N3O4The structural formula:
nicorandil has nitrate-like action, is the first ATP-sensitive potassium ion channel opener for clinical use, and is a coronary artery dilator. Nicorandil can promote the outflow of potassium ions in cells, hyperpolarize cell membranes, shorten action potential time limit, inhibit calcium overload, cause vascular smooth muscle to relax, relax systemic resistance and volume blood vessels, reduce front and back loads and myocardial oxygen consumption, improve myocardial ischemia, inhibit vascular inflammatory reaction and promote the recovery of damaged vascular endothelial functions. Can obviously reduce the attack rate of angina.
Nicorandil is unstable in chemical properties and extremely easy to degrade, and generates various harmful impurities including nicorandil dimer, trimer and the like. In order to study the effect of nicorandil impurities on nicorandil, it was first necessary to purify to obtain nicorandil dimers or trimers. At present, the nicorandil impurity is mainly obtained from nicorandil reaction liquid. The nicorandil needs to be placed for a long time to generate degradation reaction, the content of the nicorandil impurities obtained by the method is low, the conversion rate is low, the obtaining difficulty is high, and a high-cost and complex-operation chromatographic method is needed for separation and purification, so that a preparation method of the nicorandil impurities needs to be found, high-purity nicorandil dimers and tripolymers are obtained, and research work of the nicorandil is promoted.
The invention patent with the patent publication number of CN 109516950A discloses a preparation method of nicorandil dimer, which comprises the steps of taking nicorandil as a raw material, dissolving the nicorandil in organic solvents such as tetrahydrofuran, acetonitrile, propionitrile and the like, stirring for reacting for 2-6h, and dropwise adding crystallization solvents such as dichloromethane, chloroform and the like to obtain a crude product; after recrystallization, solid nicorandil dimer nitrate is obtained, and the structural formula is as follows:
the invention patent with the patent publication number of CN 109516951A discloses a preparation method of nicorandil trimer, which comprises the steps of taking nicorandil as a raw material, dissolving the nicorandil in organic solvents such as DMF, DMA and the like, stirring for reaction for 4-7h, and dropwise adding crystallization solvents such as dichloromethane, chloroform and the like to obtain a crude product; after recrystallization, solid nicorandil tripolymer nitrate is obtained, and the structural formula is as follows:
the nicorandil dimer and trimer obtained by the preparation method take nicorandil as a raw material, and generate the dimer or trimer under different solvents and temperature conditions through high-temperature degradation, and the mixture of the dimer and the trimer is easy to generate and is difficult to separate in the preparation process. Therefore, the method for preparing the nicorandil trimer is necessary, which is simple, low in cost and high in yield, and the high-purity nicorandil trimer obtained by preparation can provide an impurity reference substance for quality control of nicorandil.
The nicorandil tripolymer is used as an impurity possibly formed by nicorandil, the nicorandil tripolymer needs to be controlled, for impurity control, a pure product of the impurity is generally needed as a reference, but the nicorandil tripolymer with high purity is difficult to find at present.
Disclosure of Invention
The invention provides a method for synthesizing nicorandil trimer 1- (2- (nicotinamido) ethyl) -3- ((2- (3- ((2- (nitrooxy) ethyl) carbamoyl) pyridine-1-onium-1-yl) ethyl) carbamoyl) pyridine-1-onium chloride.
The invention relates to a method for synthesizing nicorandil trimer 1- (2- (nicotinamido) ethyl) -3- ((2- (3- ((2- (nitrooxy) ethyl) carbamoyl) pyridine-1-onium-1-radical) ethyl) carbamoyl) pyridine-1-onium chloride, which is realized by the following technical scheme, and the reaction formula is as follows:
in the reaction:
the compound I is N- (2-hydroxyethyl) -nicotinamide;
the compound II is N- (2-haloethyl) nicotinamide; wherein, X represents halogen;
the compound III is N- (2-hydroxyethyl) nicotinamide nitrate, namely nicorandil;
the operation steps comprise:
(5) dissolving N- (2-hydroxyethyl) -nicotinamide (I) serving as a raw material in an organic solvent, adding carbon tetrahalide and triphenyl phosphorus to carry out halogenation reaction, and stirring;
(6) after the reaction is finished, pouring the reaction solution into ice water, removing the organic solvent, extracting, drying, spin-drying and purifying to obtain an intermediate (II);
(7) dissolving nicorandil in an organic solvent, heating, dropwise adding the organic solvent containing the intermediate (II), stirring, and removing the organic solvent to obtain a nicorandil tripolymer crude product;
(8) recrystallizing the nicorandil trimer crude product in a mixed solvent of water and alcohol to obtain the nicorandil trimer.
The organic solvent used in the step (1) is selected from one or more of the following solvents: dichloromethane, chloroform, ethyl acetate, tetrahydrofuran or acetonitrile;
the volume of the organic solvent is 2-30 times (mL/g), preferably 5-20 times of the mass of the N- (2-hydroxyethyl) -nicotinamide (I);
the mass of the carbon tetrahalide is 2.2 times (g/g) of the mass of the N- (2-hydroxyethyl) -nicotinamide (I); wherein the halogen in the carbon tetrahalide is selected from: fluorine, chlorine, bromine, iodine, preferably chlorine;
the mass of the triphenyl phosphine is 1.12 times (g/g) of the mass of the N- (2-hydroxyethyl) -nicotinamide (I);
the reaction temperature is from-20 ℃ to the boiling point of the solvent system, preferably from-10 ℃ to 80 ℃.
The reaction time is 2-8 hours.
The mass of the ice water in the step (2) is 5 times of that of the N- (2-hydroxyethyl) -nicotinamide (I);
the temperature of the ice water is 0 ℃;
the method for removing the organic solvent is rotary evaporation;
the solvent in the step (3) is selected from one or more of the following solvents: methanol, acetonitrile, DMF, isopropanol, or dioxane;
the volume of the organic solvent is 1-30 times (mL/g) of the mass of nicorandil, preferably 3-20 times;
the mass of the intermediate (II) is 2-4 times (g/g) of the mass (III) of nicorandil;
the heating mode is oil bath heating;
the reaction temperature is 20 ℃ to the boiling point of the solvent system, and is preferably between 40 ℃ and 100 ℃;
the reaction time is 4-18 hours;
the method for removing the organic solvent is rotary evaporation.
The alcohol in the step (4) is isopropanol or ethanol;
the water content of the mixed solvent is 5-15%.
The crystallization temperature is-10 ℃ to 0 ℃.
The reaction time is 2-6 hours.
The invention aims to provide application of nicorandil trimer, namely a reference substance for research on quality of nicorandil and raw materials thereof.
In the method for detecting the content of nicorandil, nicorandil tripolymer synthesized by the method can be used as a standard reference substance and applied to the detection of the content of impurities in nicorandil and raw materials and preparations thereof.
The invention further provides a content detection method of nicorandil trimer, which comprises the following steps:
taking nicorandil trimer synthesized by the method, and preparing a solution containing about 1mg per 1ml by using a mobile phase to serve as a test solution; injecting 10 μ l of the sample solution into a liquid chromatograph, wherein the peak with the retention time of 30.915min is the impurity nicorandil trimer peak.
High performance liquid chromatography conditions: a chromatographic column: 0.25m by 4.6mm, 5 μm, C18;
mobile phase: trifluoroacetic acid: triethylamine: acetonitrile: water (3:5:10: 982);
the flow rate is: 1.0 ml/min;
the detection wavelength is as follows: 254 nm;
the column temperature was: at 25 ℃.
Based on the detection method, the nicorandil trimer synthesized by the method can be used as a standard reference substance and applied to the detection of the impurity content in nicorandil bulk drugs and preparations thereof so as to carry out qualitative and quantitative analysis on nicorandil.
The invention has the beneficial effects that:
1. the nicorandil tripolymer synthesized by the method does not need to degrade nicorandil at high temperature, does not generate dimer impurities, directly synthesizes the nicorandil tripolymer, and is convenient to separate and purify;
2. the nicorandil trimer obtained by the method has good quality and state, high conversion rate and purity, and can be used for preparing nicorandil trimer1The confirmation of H NMR and high-resolution mass spectrum is consistent with the structure of nicorandil tripolymer, and provides a solid foundation for the research of nicorandil impurities.
Drawings
FIG. 1 is a liquid chromatogram of nicorandil trimer;
FIG. 2 is a nicorandil trimer high-resolution mass spectrogram;
FIG. 3 is a hydrogen nuclear magnetic resonance spectrum of nicorandil trimer;
FIG. 4 is a carbon nuclear magnetic resonance spectrum of nicorandil trimer;
FIG. 5 is a nuclear magnetic resonance DEPT spectrum of nicorandil trimer;
FIG. 6 is a Nicorandil trimer NMR COSY spectrum;
FIG. 7 is a Nicorandil trimer NMR HSQC spectrum;
FIG. 8 is a Nicorandil trimer NMR HMBC spectrum.
Detailed Description
The following examples are intended to further illustrate the invention and are not to be construed as limiting the invention in any way.
Example 1
Tetrahydrofuran (50mL), N- (2-hydroxyethyl) -nicotinamide (I) (5.0g, 30.1mmol), and triphenylphosphine (11.0g, 36.1mmol) were added sequentially to the flask under dry nitrogen, and dissolved with stirring. Cooling to-0 deg.C, dripping carbon tetrachloride (5.6g, 36.1mmol), heating to 60 deg.C after dripping, reacting for 8 hr, pouring into ice water after reaction, rotary evaporating to remove solvent tetrahydrofuran, extracting with ethyl acetate, drying, and purifying with silica gel column to obtain 4.0g of intermediate (II).
Dissolving nicorandil (III) (1.0g, 4.7mmol) in DMF (10mL), heating to 100 ℃, dissolving intermediate (II) (3.5g, 18.8mol) in DMF (10mL), slowly dripping into reaction liquid, finishing dripping, keeping the temperature at 100 ℃ for reaction for 6 hours, removing the solvent by rotary evaporation after the reaction is finished, recrystallizing the nicorandil tripolymer crude product in isopropanol solution with the water content of 5% for 4.0 hours to obtain 1.68g of nicorandil tripolymer, and the yield is 81%. HPLC content 98.5%.
Example 2
Tetrahydrofuran (50mL), N- (2-hydroxyethyl) -nicotinamide (I) (5.0g, 30.1mmol), and triphenylphosphine (11.0g, 36.1mmol) were added sequentially to the flask under dry nitrogen, and dissolved with stirring. Cooling to-10 deg.C, adding carbon tetraiodide (5.6g, 36.1mmol) in batches, heating to 20 deg.C after adding, reacting for 2 hr, pouring into ice water after reaction, rotary evaporating to remove solvent tetrahydrofuran, extracting with ethyl acetate, drying, and purifying with silica gel column to obtain 4.4g of intermediate (II).
Dissolving nicorandil (III) (1.0g, 4.7mmol) in DMF (10mL), heating to 100 ℃, dissolving intermediate (II) (3.5g, 18.8mol) in DMF (10mL), slowly dripping into the reaction solution, finishing dripping, keeping the temperature at 100 ℃ for 6 hours, removing the solvent by rotary evaporation after the reaction is finished, recrystallizing the nicorandil trimer crude product in isopropanol solution with the water content of 5% for 4.0 hours to obtain 1.61g of nicorandil trimer, and the yield is 78%. HPLC content 97.6%.
Example 3
The reaction solvent in step (1) was acetonitrile, the reaction temperature was 80 ℃ and the rest was the same as in example 2
The yield was 77% and the purity was 86.5%.
Example 4
The reaction solvent in step (3) was acetonitrile, the reaction temperature was 45 ℃ and the reaction time was 18 hours, and the rest was the same as in example 2.
The yield was 86% and the purity was 95.9%.
Example 5
The reaction solvent in the step (3) is dioxane, the reaction temperature is 80 ℃, the reaction time is 10 hours, and the rest is the same as that in the example 2.
The yield was 80% and the purity 93.7%.
Example 6
The reaction of step (1) was carried out in the same manner as in example 1, and the reaction solvent of step (3) was isopropanol at reflux (85 ℃ C.) for 8 hours, as in example 5.
The yield was 82%, and the purity was 94.8%.
Example 7
The nicorandil tripolymer crude product obtained in the example 4 is recrystallized for 6.0h at the temperature of minus 5 ℃ in isopropanol solution with the water content of 10 percent to obtain the nicorandil tripolymer.
The yield was 83% and the purity was 97.3%.
Example 8
The recrystallization solvent was an ethanol solution containing 10% of water, and the rest was the same as in example 7.
The yield was 80% and the purity was 92.6%.
Example 9
The nicorandil tripolymer is obtained by recrystallizing the nicorandil tripolymer crude product obtained in the example 6 in isopropanol solution with the water content of 15 percent at the temperature of minus 10 ℃ for 2.0 h.
The yield was 84% and the purity was 91.3%.
Example 10
The sample for confirming the chemical structure is nicorandil trimer synthesized by the method of example 1, and the calibration chromatogram is shown in figure 1.
TABLE 1 Nicorandil trimer structure corroboration sample information
| Name of article | Batch number | Purity% | Source |
| Nicorandil trimer | NK-190924-1 | 98.5％ | Self-made |
1. Physical and chemical properties
The product is a white solid or colorless oil.
The product is easily soluble in water, methanol and dimethyl sulfoxide.
2. Mass Spectrum (MS)
The instrument comprises the following steps: shimadzu 30AD UPLC-IT TOF LC MS;
solvent: water;
an ionization mode: ESI (+)
2.1 mass spectrogram
The mass spectrum of nicorandil trimer is shown in figure 2.
2.2, test data
TABLE 2 Mass spectrometric determination of nicorandil trimer
2.3 analysis
As can be seen from FIG. 2, the mass-to-charge ratio in the mass spectrum of this product is 254.5925, corresponding to the mass-to-charge ratio (m/2z), the sample itself has two charges. With nicorandil trimer of formula C24H27N7O6 2+Anastomosis (exact molecular weight 509.2012; corresponding to a mass to charge ratio (m/2z) of 254.6006). These test values are in agreement with the theoretical values.
3. Nuclear magnetic resonance spectroscopy (NMR)
The instrument comprises the following steps: BRUKER AV-400 type nuclear magnetic resonance spectrometer
Solvent: DMSO-d6
Temperature: 303K
Internal standard: TMS
3.1NMR Spectrum
The nuclear magnetic resonance hydrogen spectrum and carbon spectrum of the product are shown in figures 3 and 4 respectively; the DEPT spectrum, COSY spectrum, HSQC spectrum, and HMBC spectrum are shown in figure 5, 6, 7 and 8, respectively.
Chemical structural formula of nicorandil tripolymer sample:
3.2 test data
TABLE 3 hydrogen spectra determination of nicorandil trimer samples
TABLE 4 carbon Spectroscopy of Nicorandil trimer samples
3.3 analysis
The hydrogen spectrum, carbon spectrum, DEPT, COSY, HSQC and HMBC two-dimensional spectrum of the product can be shown in figures 3, 4, 5, 6, 7 and 8.
1H-NMR tests show that the hydrogen spectrum of the nicorandil has 14 component peaks, the integral ratio (from low field to high field) is 1:2:1:2:2:2:1:2:1: 4:2:4:2, and the total number of 27 protons is consistent with the theoretical number of protons of the nicorandil tripolymer. From the chemical shift values, coupling constant values and various two-dimensional spectra:
a. δ 9.572(1H, s), δ 9.434(1H, s) and δ 8.959(1H, s) are protons on nitrogen, and in combination with chemical shift, atomic electronegativity and H-H COSY correlation, it is known that they are H19 on nitrogen atom, δ 9.572(1H, s) are single peak, H8, δ 9.434(1H, s) are single peak, H30, δ 8.959(1H, s) are single peak, but are wrapped in multiple peaks δ 8.938-9.973.
b. Delta 9.495-9.531(2H, m) is a multiple peak, and combined with its chemical shifts, COSY and HMBC spectra are known as the hydrogens H13 and H17 on the pyridine ring.
c. Delta 9.197-9.239(1H, m) is a multiple peak, and the chemical shift and the H-H COSY spectrum are combined to indicate that the peaks are hydrogen H24 and H28 on a pyridine ring, and an HSQC spectrum is further proved.
d. δ 8.938-8.973(2H, m) is a multiplet in which one hydrogen has been identified as H30, which, in combination with its chemical shift, COSY spectrum and HMBC spectrum, is strongly correlated with H13 and H17 and is known as hydrogen H14 on the pyridine ring.
e. δ 8.849(1H, s) is a single peak and, in combination with its chemical shift, HMBC spectra reveal it as hydrogen H15 on the pyridine ring.
f. δ 8.849(1H, s) is a singlePeak, combined with its chemical shift, the HMBC spectrum is known as hydrogen H15 on the pyridine ring. Delta 8.815(1H, d) is a d peak, combined with its chemical shift,13C-NMR spectrum and HMBC spectrum were found to be hydrogen H3 on the pyridine ring.
g. Delta 8.710-8.726(1H, dd) is a dd peak, combined with its chemical shift,13C-NMR spectrum and HMBC spectrum show that the hydrogen on pyridine ring is H25, delta 7.495-7.527(1H, m) is a multiple peak, and the chemical shifts are combined,13the C-NMR spectrum and the HMBC spectrum can indicate that the hydrogen is H26 on the pyridine ring, and an H-H COSY spectrum is further proved.
h. Delta 8.226-8.268(1H, m) is a multiple peak, combined with its chemical shifts,13C-NMR spectrum and HMBC spectrum are known as hydrogen on pyridine ring H4 and H6.
i. Delta 8.039-8.069(1H, m) is a multiple peak, combined with its chemical shifts,13C-NMR spectrum and HMBC spectrum were found to be hydrogen H2 on the pyridine ring.
j. Delta.4.816-4.871 (4H, m) is a multiple peak, which is hydrogen on methylene H11 and H22 according to the combination of the chemical shift value and the chemical environment and H-H COSY spectrum. δ 4.680(2H, m) is a multiplet and strongly correlated with H32, identified as methylene hydrogen H33.
k. Delta 3.688-3.727(2H, m) is a multiple peak, which is hydrogen on methylene H10 according to the combination of the chemical shift value and the chemical environment and H-H COSY; delta 3.868-3.895(2H, m) is a multiple peak, which is hydrogen on methylene H32 according to the combination of the chemical shift value and the chemical environment and H-H COSY; delta 3.908-3.960(2H, m) is a multiple peak, which is hydrogen on methylene H21 according to the combination of the chemical shift value and the chemical environment and H-H COSY.
In conclusion, the test result of the hydrogen spectrum of the product is consistent with the structure of nicorandil tripolymer.
Prepared from the product13The C-NMR spectrum and the DEPT spectrum show that the figure has 24 resonance absorption peaks which are consistent with the carbon number contained in the nicorandil tripolymer molecule.
From the chemical shifts and the DEPT spectra, δ 165.94, δ 162.60, and δ 162.19 are chemical shifts of the carbon of the carbonyl group, and are respectively identified as C7, C18, and C29, which are further confirmed from the COSY spectra.
The carbon at δ 152.19 is known as C25 by chemical shift and HSQC; the carbon at δ 152.19 is known as C25 by chemical shift and HSQC; the carbon at δ 148.36 is known to be C3 from chemical shift and HSQC, and the carbon at δ 135.85 is known to be C2 from COSY spectra.
The carbons at δ 147.72 and δ 147.60 were identified as C24 and C28, respectively, from electronegativity and HSQC spectra.
The carbons at δ 145.74, δ 145.57, δ 143.90, δ 143.82 are known as C13, C17, C14, C15 from electronegativity and HSQC spectra, respectively.
According to CNMR and DEPT spectra, quaternary carbons C16, C5 and C27 are respectively found at delta 133.79, delta 133.67 and delta 129.87, and further confirmed by COSY spectra.
From the HSQC spectrum, the carbon at δ 124.14 is greatly related to H26, and the carbon is C26.
According to DEPT and HMBC spectrums, methylene carbon is positioned at delta 72.42, delta 61.50, delta 61.29, delta 40.57, delta 40.28 and delta 37.52, and the methylene carbon is respectively determined as C33, C11, C22, C21, C32 and C10 according to electronegativity.
In conclusion, the carbon spectrum test result of the product is consistent with the structure of nicorandil trimer, and the attribution of each carbon can be seen in table 4.
The chemical shift of the resonance absorption peak of the solvent DMSO used in the nuclear magnetic resonance carbon spectrum test is 40.00. The extra solvent peak indicates that the sample and the solvent are in effect.
Comprehensive analysis:
1. the mass to charge ratio in the mass spectrum of the sample was 254.5925, corresponding to a mass to charge ratio (m/2z), with the sample itself carrying two charges. With nicorandil trimer of formula C24H27N7O6 2+Anastomosis (exact molecular weight 509.2012; corresponding to a mass to charge ratio (m/2z) of 254.6006). These test values are in agreement with the theoretical values.
2、1H-NMR test the hydrogen spectrum of a nicorandil tripolymer sample has 14 component peaks, the integral ratio (from low field to high field) of the peaks is 1:2:1:2:2:2:1:2:1:1:4:2:4:2, 27 protons are totally contained, and the peaks and the theoretical substances of the nicorandil tripolymer haveThe sub-numbers match. From the chemical shift values, coupling constant values and various two-dimensional spectra:
a. δ 9.572(1H, s), δ 9.434(1H, s) and δ 8.959(1H, s) are protons on nitrogen, and in combination with chemical shift, atomic electronegativity and H-H COSY correlation, it is known that they are H19 on nitrogen atom, δ 9.572(1H, s) are single peak, H8, δ 9.434(1H, s) are single peak, H30, δ 8.959(1H, s) are single peak, but are wrapped in multiple peaks δ 8.938-9.973.
b. Delta 9.495-9.531(2H, m) is a multiple peak, and combined with its chemical shifts, COSY and HMBC spectra are known as the hydrogens H13 and H17 on the pyridine ring.
c. Delta 9.197-9.239(1H, m) is a multiple peak, and the chemical shift and the H-H COSY spectrum are combined to indicate that the peaks are hydrogen H24 and H28 on a pyridine ring, and an HSQC spectrum is further proved.
d. δ 8.938-8.973(2H, m) is a multiplet in which one hydrogen has been identified as H30, which, in combination with its chemical shift, COSY spectrum and HMBC spectrum, is strongly correlated with H13 and H17 and is known as hydrogen H14 on the pyridine ring.
e. δ 8.849(1H, s) is a single peak and, in combination with its chemical shift, HMBC spectra reveal it as hydrogen H15 on the pyridine ring.
f. δ 8.849(1H, s) is a single peak and, in combination with its chemical shift, HMBC spectra reveal it as hydrogen H15 on the pyridine ring. Delta 8.815(1H, d) is a d peak, combined with its chemical shift,13C-NMR spectrum and HMBC spectrum were found to be hydrogen H3 on the pyridine ring.
g. Delta 8.710-8.726(1H, dd) is a dd peak, combined with its chemical shift,13C-NMR spectrum and HMBC spectrum show that the hydrogen on pyridine ring is H25, delta 7.495-7.527(1H, m) is a multiple peak, and the chemical shifts are combined,13the C-NMR spectrum and the HMBC spectrum can indicate that the hydrogen is H26 on the pyridine ring, and an H-H COSY spectrum is further proved.
h. Delta 8.226-8.268(1H, m) is a multiple peak, combined with its chemical shift,13C-NMR spectrum and HMBC spectrum, which indicates the hydrogen H4 and H6 on the pyridine ring.
i. Delta 8.039-8.069(1H, m) is a multiple peak, combined with its chemical shifts,13C-NMR spectrum and HMBC spectrum were found to be hydrogen H2 on the pyridine ring.
j. Delta.4.816-4.871 (4H, m) is a multiple peak, which is hydrogen on methylene H11 and H22 according to the combination of chemical shift value and chemical environment and H-H COSY spectrum. δ 4.680(2H, m) is a multiplet and strongly correlated with H32, identified as methylene hydrogen H33.
k. Delta 3.688-3.727(2H, m) is a multiple peak, which is hydrogen on methylene H10 according to the combination of the chemical shift value and the chemical environment and H-H COSY; delta 3.868-3.895(2H, m) is a multiple peak, which is hydrogen on methylene H32 according to the combination of the chemical shift value and the chemical environment and H-H COSY; delta 3.908-3.960(2H, m) is a multiple peak, which is hydrogen on methylene H21 according to the combination of the chemical shift value and the chemical environment and H-H COSY.
3. From samples of nicorandil trimer13The C-NMR spectrum and DEPT spectrum showed 24 resonance absorption peaks, corresponding to the number of carbons contained in the molecule of nicorandil trimer.
According to the chemical shift and DEPT spectrum, the chemical shifts of carbon of carbonyl are respectively known as delta 165.94, delta 162.60 and delta 162.19, and are respectively known as C7, C18 and C29, and further proved by COSY spectrum.
The carbon at δ 152.19 is known as C25 by chemical shift and HSQC; the carbon at δ 152.19 is known as C25 by chemical shift and HSQC; the carbon at δ 148.36 is known to be C3 from chemical shift and HSQC, and the carbon at δ 135.85 is known to be C2 from COSY spectra.
The carbons at δ 147.72 and δ 147.60 were identified as C24 and C28, respectively, from electronegativity and HSQC spectra.
The carbons at δ 145.74, δ 145.57, δ 143.90, δ 143.82 are known as C13, C17, C14, C15 from electronegativity and HSQC spectra, respectively.
According to CNMR and DEPT spectra, quaternary carbons C16, C5 and C27 are respectively found at delta 133.79, delta 133.67 and delta 129.87, and further confirmed by COSY spectra.
From the HSQC spectrum, the carbon at δ 124.14 is greatly related to H26, and the carbon is C26.
According to DEPT and HMBC spectrums, methylene carbon is positioned at delta 72.42, delta 61.50, delta 61.29, delta 40.57, delta 40.28 and delta 37.52, and the methylene carbon is respectively determined as C33, C11, C22, C21, C32 and C10 according to electronegativity.
In conclusion, the structure of the product conforms to the structure of nicorandil tripolymer, namely the structure is as follows:
Claims (8)
1. a method for synthesizing nicorandil trimer, which comprises the following reaction formula:
in the reaction formula:
the compound I is N- (2-hydroxyethyl) -nicotinamide;
the compound II is N- (2-haloethyl) nicotinamide; wherein, X represents halogen;
the compound III is N- (2-hydroxyethyl) nicotinamide nitrate, namely nicorandil.
2. The method according to claim 1, characterized in that it comprises the following steps:
(1) dissolving a compound I serving as a raw material in an organic solvent, adding carbon tetrahalide and triphenyl phosphorus to carry out halogenation reaction, and stirring;
(2) after the reaction is finished, 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, dropwise adding the organic solvent containing the intermediate II, stirring, and removing the organic solvent to obtain a nicorandil tripolymer crude product;
(4) recrystallizing the nicorandil trimer crude product in a mixed solvent of water and alcohol to obtain the nicorandil trimer.
3. The method of claim 2, characterized in that it comprises the following steps:
the organic solvent used in the step (1) is selected from: dichloromethane, chloroform, ethyl acetate, tetrahydrofuran or acetonitrile;
the volume of the organic solvent is 2 to 30 times of the mass of the compound I,
the mass of the carbon tetrahalide is 2.2 times of that of the compound I;
wherein the halogen in the carbon tetrahalide is selected from: fluorine, chlorine, bromine, iodine;
the mass of the triphenyl phosphine is 1.12 times of that of the compound I;
the reaction temperature is between-20 ℃ and the boiling point of a solvent system;
the reaction time is 2-8 hours.
4. A method according to claim 3, characterized in that the method comprises the following steps:
the volume of the organic solvent is 5-20 times of the mass of the compound I;
wherein the halogen in the carbon tetrahalide is selected from: chlorine;
the reaction temperature is-10-80 ℃.
5. The method according to claim 2, characterized in that it comprises the following steps:
the mass of the ice water in the step (2) is 5 times of that of the compound I;
the method for removing the organic solvent is rotary evaporation.
6. The method according to claim 2, characterized in that it comprises the following steps:
the solvent in the step (3) is selected from: methanol, acetonitrile, DMF, isopropanol, or dioxane;
the volume of the organic solvent is 1-30 times of the mass of nicorandil;
the mass of the intermediate II is 2-4 times of that of nicorandil;
the heating mode is oil bath heating;
the reaction temperature is 20 ℃ 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.
7. The method according to claim 6, characterized in that it comprises the following steps:
the volume of the organic solvent is 3-20 times of the mass of nicorandil;
the reaction temperature is 40-100 ℃.
8. The method according to claim 2, characterized in that it comprises the following steps:
the alcohol in the step (4) is isopropanol or ethanol;
the water content of the mixed solvent is 5-15%.
The crystallization temperature is-10 ℃ to 0 ℃.
The reaction time is 2-6 hours.
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| CN116359394A (en) * | 2023-04-21 | 2023-06-30 | 本溪匠成医药科技有限公司 | High performance liquid chromatography for separating and detecting related substances in nicorandil tablets |
| CN116359394B (en) * | 2023-04-21 | 2023-11-17 | 本溪匠成医药科技有限公司 | High performance liquid chromatography for separating and detecting related substances in nicorandil tablets |
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