CN102584909A - Method for preparing hydrochloride through substituting glucose carbon glycoside isoflavone with dimethylamine methylene - Google Patents
Method for preparing hydrochloride through substituting glucose carbon glycoside isoflavone with dimethylamine methylene Download PDFInfo
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Abstract
The invention discloses a method for preparing hydrochloride through substituting glucose carbon glycoside isoflavone with dimethylamine methylene, which belongs to the technical field of medical chemistry. The invention aims to provide the method which can lead a dimethylamine methylene segment into a glucose carbon glycoside isoflavone molecular structure and prepare the hydrochloride. The method has the characteristics of cheap and easily-obtained raw materials, simplicity and safety for operation, low cost, no contamination, easiness in amplification for industrial production and the like.
Description
Technical field
The present invention relates to the preparation method that a kind of dimethylin methylene radical replaces grape sugar charcoal glycosides NOVASOY 400 hydrochloride, belong to the medical chemistry technical field.
Background technology
Puerarin is a kind of cardiovascular and cerebrovascular diseases medicine, its chemical name is 7,4 '-dihydroxyl-8-β-D-glucone isoflavone.
Cardiovascular and cerebrovascular diseases is harm humans life and healthy common disease and frequently-occurring disease, is the principal disease that the elderly causes death and disables.According to World Health Organization's statistics, the whole world has 1,500 ten thousand people to die from cardiovascular and cerebrovascular diseases every year approximately, accounts for more than 50% of total sick mortality ratio, and human beings'health in serious threat.By 2015, almost there are 2,000 ten thousand people will die from cardiovascular diseases, mainly die from heart disease and stroke.Estimate that they are with continuing to become a dead major cause.The cardiovascular and cerebrovascular diseases epidemic data shows that cardiovascular and cerebrovascular diseases such as heart disease and stroke are the first causes of death of China.The data that ministry of Health of China was announced in 2005 shows: cardiovascular and cerebrovascular diseases mortality ratio height ranks first in the general mortality rate of Chinese population, and city resident's cerebrovascular mortality ratio reaches 21.2%, deaths from heart disease rate 17.9%; And urban residents' cerebrovascular mortality ratio also reaches 21.2%, deaths from heart disease rate 11.8%.
Puerarin is found in the seventies in last century, is a kind of isoflavonoid that from the legume pueraria lobata dry root, extracts.Its chemistry is by name 7,4 '-dihydroxyl-8-β-D-glucone isoflavone.Be mainly used in the treatment of cardiovascular and cerebrovascular diseases.Puerarin has the effect of tangible cardiovascular and cerebrovascular pharmacology, and successfully listing dropped into clinical use in 1994, is widely used in the treatment of cardiovascular and cerebrovascular diseases, has determined curative effect and medicine source and characteristics such as enriches.But the puerarin poorly water-soluble, oral administration biaavailability is low, and in clinical use, serious acute intravascular hemolysis occurred, and can cause death, this big limitations the clinical application of puerarin.Therefore, press for its structure is transformed, prepare its verivate, be superior to puerarin in the hope of finding physico-chemical property and bioavailability, activity with it quite or better has no adverse reaction or the new compound of the cardiovascular and cerebrovascular diseases aspect that untoward reaction reduces.We are to the shortcoming of puerarin poorly water-soluble; Through on the puerarin phenyl ring, introducing water soluble group alkylamino radical alkyl; A series of verivates have been synthesized in design, and water-soluble and anoxia and extension vessel activity have carried out preliminary assessment and applied for Chinese invention patent (CN02159418.X (2002)) to it.The result shows that the introducing of water soluble group alkylamino radical alkyl is beneficial to water-soluble enhancing greatly, and most compound kept anoxia and extension vessel activity, and indivedual compound activities are better than puerarin.The substituted grape sugar charcoal of dimethylin methylene radical glycosides NOVASOY 400 is one of them.Its constitutional features is: introduced the dimethylin methylene radical at precursor structure 4 ' hydroxyl ortho position, position through reacting with formaldehyde and n n dimetylaniline.But the compound method that relates among the patent CN02159418.X (2002); Be with puerarin and formaldehyde and n n dimetylaniline reflux in ethanol 5 hours, carry out the dimethylin methylene radical that column chromatographic isolation and purification obtains non-hydrochloric acid form through a large amount of silica gel (80 times of quality) and replace grape sugar charcoal glycosides NOVASOY 400.This method only is suitable for restraining the preparation of amount below the level, when amplifying macro preparation, separates difficulty, and the purification process cost is high.
The objective of the invention is to provide a kind of can be incorporated into dimethylin methylene radical fragment in the puerarin drug molecular structure and be prepared into the economy of hydrochloride, the compound method of scalable (more than 2 kilograms).
Summary of the invention
The object of the present invention is to provide a kind of dimethylin methylene radical to replace the preparation method of grape sugar charcoal glycosides NOVASOY 400 hydrochloride.
It is a kind of Mannich base that the dimethylin methylene radical replaces grape sugar charcoal glycosides NOVASOY 400, can synthesize through Mannich reaction, and conventional method is with raw material and n n dimetylaniline and formolite reaction, but has defective:
The compound method that relates among the patent CN02159418.X (2002); Be with 7; 4 '-dihydroxyl-8-β-D-glucone isoflavone and formaldehyde and n n dimetylaniline be reflux in ethanol 5 hours; Through a large amount of silica gel (bullion quality 80 times), and be that eluent carries out the dimethylin methylene radical that column chromatographic isolation and purification obtains non-hydrochloric acid form and replaces grape sugar charcoal glycosides NOVASOY 400 with the methylene chloride-methanol combination solvent.This method only is suitable for restraining the preparation of amount below the level, when amplifying macro preparation, separates difficulty, and the purification process cost is high, and is seriously polluted.
The contriver finds with N N through the extensive work optimized choice; N '; N '-tetramethyl-diamines methylmethane n n dimetylaniline and formaldehyde react, and product is prepared into hydrochloride then through decolouring and recrystallization, can realize the preparation and the purifying of the above title product of 2 feather weight.Specifically, this method may further comprise the steps:
(1) in polar solvent, 7,4 '-dihydroxyl-8-β-D-glucone isoflavone and N, N, N ', N '-tetramethyl-diamines methylmethane reaction, preparation 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-thick product of D glucone isoflavone;
(2) 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-thick product of D glucone isoflavone and hydrochloric acid reaction, preparation 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-thick product of D glucone isoflavone hydrochloride;
(3) 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-thick product of D glucone isoflavone hydrochloride is through silica decoloration and recrystallization, preparation 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-pure article of D glucone isoflavone hydrochloride.
Among the preparation method of the present invention, the available polar solvent comprises water, methyl alcohol, ethanol, 95% ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, the trimethyl carbinol, amylalcohol, N, dinethylformamide and N, N-DEF, preferred alcohol; Solvent volume and 7,4 '-quality of dihydroxyl-8-β-D-glucone isoflavone is 10-40 than scope, preferred 25; 7,4 '-dihydroxyl-8-β-D-glucone isoflavone and N, N, N ', the mole ratio range of N '-tetramethyl-diamines methylmethane is 1: 0.5-1: 2, preferred 1: 1.5; Range of reaction temperature is 50 a ℃-solvent refluxing temperature, preferred solvent reflux temperature (78.5 ℃ of interior temperature); Reaction time range is 1-30 hour, preferred 10 hours; The silica gel scope that decolouring is selected for use is a Qingdao Haiyang column chromatography silica gel 100-400 order, preferred 200-300 order; The solvent that decolouring is selected for use is selected from water, methyl alcohol and ethanol, preferred alcohol; Recrystallization solvent is selected from water, methyl alcohol, ethanol and ETHYLE ACETATE and combination thereof, preferred water-ethanol-ETHYLE ACETATE combination.
Its technique effect is: replace grape sugar charcoal glycosides NOVASOY 400 compound method with the dimethylin methylene radical that relates among the patent CN02159418.X (2002) and compare; Present method is prepared into dimethylin methylene radical replacement grape sugar charcoal glycosides NOVASOY 400 hydrochloride and has low in raw material cost and is easy to get; Safety simple to operate; Cost is low, pollution-free be easy to amplify the characteristics such as suitability for industrialized production of carrying out.
Description of drawings
Accompanying drawing 1 replaces the synthetic route of grape sugar charcoal glycosides NOVASOY 400 hydrochloride for the dimethylin methylene radical;
Accompanying drawing 2 replaces the carbon atoms numbered of grape sugar charcoal glycosides NOVASOY 400 hydrochloride for the dimethylin methylene radical;
Accompanying drawing 3 replaces the mass spectrum of grape sugar charcoal glycosides NOVASOY 400 hydrochloride for the dimethylin methylene radical;
Accompanying drawing 4 replaces the ultimate analysis report of grape sugar charcoal glycosides NOVASOY 400 hydrochloride for the dimethylin methylene radical;
Accompanying drawing 5 replaces the hydrogen nuclear magnetic resonance spectrogram of grape sugar charcoal glycosides NOVASOY 400 hydrochloride for the dimethylin methylene radical;
Accompanying drawing 6 replaces the carbon-13 nmr spectra figure of grape sugar charcoal glycosides NOVASOY 400 hydrochloride for the dimethylin methylene radical;
Accompanying drawing 7 is the color atlas of colleges and universities' liquid phase solvent for use water;
Accompanying drawing 8 replaces the high-efficient liquid phase chromatogram of grape sugar charcoal glycosides NOVASOY 400 hydrochloride for the dimethylin methylene radical.
Embodiment
Embodiment 1:
For investigating N; N, N ', N '-tetramethyl-diamines methylmethane (methylamine contracts), solvent and consumption thereof are to the influence of bullion purity; It is following that the spy carries out parallel laboratory test: the solvent of puerarin and respective amount is placed round-bottomed flask; Heated and stirred makes solvent reach reflux state under the oil bath, adds the methylamine that contracts of respective amount, continues backflow 1-30 hour.Remove the yellow solid of the solvent and the unnecessary methylamine that contracts under reduced pressure, weigh and measure content with HPLC.Detailed data is as shown in table 1.
Table 1 technology is explored condition and result
Embodiment 2:
7,4 '-dihydroxyl-3 '-preparation method of dimethylamino methyl-8-C-β-D glucone isoflavone
Add 125L ethanol and 5Kg7 in reaction kettle, 4 '-dihydroxyl-8-β-D-glucone isoflavone, be warming up to about 45 ℃, add N, N, N ', N '-tetramethyl-diamines methylmethane 2.485L continues to reflux 10 hours.Decompression steam behind the solvent and the excessive methylamine that contracts the 5.75Kg light yellow solid.
Embodiment 3:
7,4 '-dihydroxyl-3 '-purification process of dimethylamino methyl-8-C-β-D glucone isoflavone hydrochloride
Above-mentioned light yellow solid 5.75Kg thermosol in 11.5L (2 times of volumes) ethanol, is added concentrated hydrochloric acid, transfer pH=2～3, get yellowish or the off-white color solid through Qingdao Haiyang column chromatography 200-300 order silica decoloration.This solid with (water-ethanol-ETHYLE ACETATE) mixed solvent recrystallization once gets the 2.41Kg white solid.Through mass spectrum (FAB-MS is shown in accompanying drawing 3): mass-to-charge ratio (M/Z) is the molion-HCl+1 peak for these article, 474 peak; Ultimate analysis (%, analysis report is shown in accompanying drawing 4): C (theory 56.53, mensuration 56.51), H (theory 5.53 measures 5.61), N (theory 2.75, mensuration 2.77), Cl (theory 6.95, mensuration 6.97); Proton nmr spectra
1HNMR (DMSO-d6,400M) δ (carbon atom position is numbered shown in accompanying drawing 2, and collection of illustrative plates is shown in accompanying drawing 5): 10.29 (3H, b, 7,4 ' OH and HCl), 8.42 (1H, s, 2), 7.94 (1H, d, 5); 7.66 (1H, d, A2), 7.55 (1H, d, A6), 7.04 (2H, d, 6, A5), 4.85 (1H, d; G1), 4.38～4.69 (3H, b, sugared OH), 4.23 (1H, s, N2), 4.00 (1H, t, G2), 3.71; 3.48 (1H, dd, G6), 3.23～3.34 (3H, m, G3, G4, G5), 2.74 (6H, s, N1) and carbon-13 nmr spectra
13CNMR (DMSO-d6,400M) δ (carbon atom position is numbered shown in accompanying drawing 2, and collection of illustrative plates is shown in accompanying drawing 6): 174.50 (1C, 4), 160.98 (1C, 7), 156.06 (1C, A4), 155.91 (1C; A), 152.67 (1C, 2), 132.95 (1C, A2), 131.33 (1C, A6), 125.84 (1C; 5), 122.75 (1C, A1), 122.25 (1C, 3), 116.63 (1C, A3), 116.02 (1C; B), 115.29 (1C, A5), 115.00 (1C, 6), 112.59 (1C, 8), 81.47 (1C; G5), 78.57 (1C, G3), 73.32 (1C, G1), 70.84 (1C, G4), 70.31 (1C; G2), 61.20 (1C, G6), 54.73 (1C, N2), 41.80 (2C, N1) confirm as with 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-D glucone isoflavone hydrochloride.Calculate with puerarin, total recovery is 39.32%, and purity is 99.87% (shown in accompanying drawing 7), and fusing point (variable color decomposition) is 229.5-231.0 ℃.
Embodiment 4:
Performance liquid chromatography is for the Determination on content method
Instrument: Waters2695-2996
Condition and method: chromatographic column: Diamonsil C
184.6 * 250mm 5 μ m
Detect wavelength: 250nm
Flow velocity: 1ml/min
Sampling volume: 20 μ l
Column temperature: room temperature
Moving phase: mobile phase A is 0.02mol/L SODIUM PHOSPHATE, MONOBASIC (transferring PH to 3.0 with phosphoric acid);
Mobile phase B: methyl alcohol-0.02mol/L SODIUM PHOSPHATE, MONOBASIC (transferring PH to 3.0) (70: 30) with phosphoric acid
Adopt gradient elution, gradient table is following:
Result: press peak area normalization method and calculate.
Claims (3)
1. a dimethylin methylene radical replaces the preparation method of grape sugar charcoal glycosides NOVASOY 400 hydrochloride (being shown below), it is characterized in that may further comprise the steps:
(1) in polar solvent, 7,4 '-dihydroxyl-8-β-D-glucone isoflavone and N, N, N ', N '-tetramethyl-diamines methylmethane reaction, preparation 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-thick product of D glucone isoflavone;
(2) 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-thick product of D glucone isoflavone and hydrochloric acid reaction, preparation 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-thick product of D glucone isoflavone hydrochloride;
(3) 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-thick product of D glucone isoflavone hydrochloride is through silica decoloration and recrystallization, preparation 7,4 '-dihydroxyl-3 '-dimethylamino methyl-8-C-β-pure article of D glucone isoflavone hydrochloride.
2. preparation method according to claim 1 is characterized in that:
(1) polar solvent is selected from water, methyl alcohol, ethanol, 95% ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, the trimethyl carbinol, amylalcohol, N, dinethylformamide and N, N-DEF;
(2) solvent volume and 7,4 '-quality of dihydroxyl-8-β-D-glucone isoflavone is 10-40 than scope;
(3) 7,4 '-dihydroxyl-8-β-D-glucone isoflavone and N, N, N ', the mole ratio range of N '-tetramethyl-diamines methylmethane is 1: 0.5-1: 2;
(4) range of reaction temperature is 50 a ℃-solvent refluxing temperature;
(5) reaction time range is 1-30 hour;
(6) the silica gel scope selected for use of decolouring is a Qingdao Haiyang column chromatography silica gel 100-400 order;
(7) solvent selected for use of decolouring is selected from water, methyl alcohol and ethanol;
(8) recrystallization solvent is selected from water, methyl alcohol, ethanol and ETHYLE ACETATE and combination thereof.
3. preparation method according to claim 2 is characterized in that:
(1) polar solvent is an ethanol;
(2) solvent volume and 7,4 '-mass ratio of dihydroxyl-8-β-D-glucone isoflavone is 25;
(3) 7,4 '-dihydroxyl-8-β-D-glucone isoflavone and N, N, N ', the mole proportioning of N '-tetramethyl-diamines methylmethane is 1: 1.5;
(4) temperature of reaction is solvent refluxing temperature (78.5 ℃ of an interior temperature);
(5) reaction times is 10 hours;
(6) silica gel selected for use of decolouring is Qingdao Haiyang column chromatography silica gel 200-300 order;
(7) solvent selected for use of decolouring is an ethanol;
(8) recrystallization solvent is water-ethanol-ETHYLE ACETATE combination.
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| CN201110005326XA CN102584909A (en) | 2011-01-05 | 2011-01-05 | Method for preparing hydrochloride through substituting glucose carbon glycoside isoflavone with dimethylamine methylene |
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| CN201110005326XA CN102584909A (en) | 2011-01-05 | 2011-01-05 | Method for preparing hydrochloride through substituting glucose carbon glycoside isoflavone with dimethylamine methylene |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110075067A (en) * | 2018-07-02 | 2019-08-02 | 中国人民解放军军事科学院军事医学研究院 | A kind of hydrochloric acid Portugal ketoamine microemulsion formulation and the preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006042454A1 (en) * | 2004-10-20 | 2006-04-27 | Hong Kong Jockey Club Institute Of Chinese Medicine Limited | Puerarin derivatives and their medical uses |
| CN101591370A (en) * | 2008-05-27 | 2009-12-02 | 中国农业科学院兰州畜牧与兽药研究所 | The synthetic method of puerarin derivatives |
| CN101805332A (en) * | 2010-04-30 | 2010-08-18 | 西安力邦制药有限公司 | Preparation method and application of puerarin derivatives |
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- 2011-01-05 CN CN201110005326XA patent/CN102584909A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006042454A1 (en) * | 2004-10-20 | 2006-04-27 | Hong Kong Jockey Club Institute Of Chinese Medicine Limited | Puerarin derivatives and their medical uses |
| CN101591370A (en) * | 2008-05-27 | 2009-12-02 | 中国农业科学院兰州畜牧与兽药研究所 | The synthetic method of puerarin derivatives |
| CN101805332A (en) * | 2010-04-30 | 2010-08-18 | 西安力邦制药有限公司 | Preparation method and application of puerarin derivatives |
Non-Patent Citations (2)
| Title |
|---|
| 何兰，等: "《天然产物资源化学》", 31 July 2008, article "天然产物资源化学", pages: 353-354 * |
| 刘湘，等: "《天然产物化学（第二版）》", 30 April 2010, article "天然产物化学", pages: 32-34 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110075067A (en) * | 2018-07-02 | 2019-08-02 | 中国人民解放军军事科学院军事医学研究院 | A kind of hydrochloric acid Portugal ketoamine microemulsion formulation and the preparation method and application thereof |
| CN110075067B (en) * | 2018-07-02 | 2021-03-23 | 中国人民解放军军事科学院军事医学研究院 | Glutamine hydrochloride microemulsion preparation and preparation method and application thereof |
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Application publication date: 20120718 |