CN112826817B - Medicinal composition of andrographolide sulfonate and preparation method thereof - Google Patents
Medicinal composition of andrographolide sulfonate and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a novel sulfonated composition of andrographolide with good water solubility, which comprises the following components: 17-hydrogen-9-dehydroandrographolide-3, 19-disulfate and salt thereof, andrographolide-19-sulfate-16-sodium carboxylate, 17-hydrogen-9-dehydroandrographolide-19-sulfate and salt thereof, 17-hydrogen-9-dehydroandrographolide, and a preparation method of a sulfonation composition of andrographolide.
Description
Technical Field
The invention relates to 17-hydrogen-9-dehydroandrographolide-3, 19-disulfate and salt thereof, andrographolide-19-sulfate-16-sodium carboxylate, 17-hydrogen-9-dehydroandrographolide-19-sulfate and salt thereof, 17-hydrogen-9-dehydroandrographolide composition and a preparation method thereof.
Background
Andrographolide is diterpenoid compound in herba Andrographis, and its molecular formula: c 20H30O5, which is colorless square or rectangular crystals, is insoluble in water, and brings difficulty to the preparation of the preparation, and at present, various methods are available for preparing andrographolide into various derivatives in order to improve the water solubility of andrographolide, such as sodium bisulphite andrographolide, succinic acid half-ester monopotassium salt, 14-dehydroxy-11, 12-didehydroandrographolide-3, 19-disuccinate half-ester potassium sodium salt or 14-dehydroxy-11, 12-didehydroandrographolide-3, 19-disuccinate half-potassium salt, but the solubility of the above salts in water is not particularly good.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a novel andrographolide sulfonate composition with better water solubility and a preparation method thereof.
The invention provides a sulfonated composition of andrographolide, which comprises the following components: 17-hydro-9-dehydroandrographolide-3, 19-disulfate and salt thereof, andrographolide-19-sulfate-16-carboxylic acid sodium, 17-hydro-9-dehydroandrographolide-19-sulfate and salt thereof, and 17-hydro-9-dehydroandrographolide.
The synthetic route of the sulfonated composition of andrographolide of the invention is shown in the following chart:
R is H; or alternatively
R can be sodium, potassium or NH 4
The invention also provides a preparation method of the sulfonated composition, which comprises the following steps:
(1) Taking andrographolide raw materials, placing the andrographolide raw materials into a reactor, adding hydrobromic acid aqueous solution for reaction, filtering, adding ethyl acetate into filtrate, adding sodium bicarbonate solution for regulating pH to 6.0-6.5, continuously stirring, filtering to obtain a filtrate, and vacuum drying for 24 hours to obtain an intermediate.
(2) Weighing the dried intermediate, pouring the intermediate into a reactor, weighing acetone, adding the acetone into andrographolide, and enabling the volume ratio of the intermediate to the acetone to be 1g:2-6ml; weighing sulfuric acid, adding acetone to prepare a sulfonation reagent solution, and the dosage volume ratio of the sulfuric acid to the acetone is as follows: 1:1-3; adding the sulfonation reagent solution into a reactor, stirring and controlling the temperature of the reaction solution to be 5-15 ℃, and continuing stirring and reacting for 5-7 hours after the addition; adding sodium bicarbonate solution to adjust pH to 6.0-6.5, adding water, rotary evaporating and concentrating, extracting with ethyl acetate, discarding organic layer, rotary evaporating and concentrating water layer, adding ethanol, standing at room temperature, and filtering.
(3) And (3) taking the filtrate obtained in the step (2), passing through a silica gel column, eluting for a plurality of times by using water and 5% -100% ethanol in sequence, combining eluting fractions of water and ethanol with different concentrations, concentrating the fractions into thick paste, and drying in vacuum.
Preferably, in the step (1), the weight-volume ratio of the andrographolide raw material to the hydrobromic acid aqueous solution to the ethyl acetate is 1g:1-6ml:1-2ml.
Preferably, the reaction temperature in step (1) is from 5 to 10℃and/or the stirring speed is from 150rpm to 300rpm.
Preferably, the concentration of hydrobromic acid in the aqueous solution in the step (1) is 40% -60%.
Preferably, after the water layer in the step (2) is concentrated by rotary evaporation, 95% ethanol is added while stirring to make the ethanol concentration of the solution 85%.
Preferably, the particle size of the silica gel column in the step (3) is 100-300 meshes; and/or the elution times are two times.
Preferably, the primary elution in the step (3) adopts ethanol with the volume fraction of 5% -30%.
Preferably, the secondary elution in the step (3) adopts 40% -80% ethanol by volume fraction.
Preferably, the combined fractions of step (3) correspond to ethanol having an elution concentration of 5% -60% ethanol.
The beneficial technical effects of the invention are as follows:
1. The sulfonated composition of andrographolide disclosed by the invention comprises the following components: 17-hydrogen-9-dehydroandrographolide-3, 19-disulfate and salt thereof, andrographolide-19-sulfate-16-sodium carboxylate, 17-hydrogen-9-dehydroandrographolide-19-sulfate and salt thereof, and 17-hydrogen-9-dehydroandrographolide have the advantage of good water solubility.
2. The preparation method of the andrographolide sulfonate composition adopts the use amount volume ratio of the intermediate to the acetone of 1g:2-6ml; the volume ratio of the sulfuric acid to the acetone is as follows: 1:1-3, and controlling the reaction temperature to be 5-15 ℃ to react to obtain the components: an andrographolide sulfonate composition of 17-hydrogen-9-dehydroandrographolide-3, 19-disulfate and its salt, andrographolide-19-sulfate-16-carboxylic acid sodium, 17-hydrogen-9-dehydroandrographolide-19-sulfate and its salt, and 17-hydrogen-9-dehydroandrographolide.
Further, the obtained crude product of the andrographolide sulfonated composition is subjected to concentration, extraction and filtration, and filtrate is subjected to silica gel column, water and 5% -80% ethanol are sequentially used for eluting for a plurality of times (for example, twice), eluting fractions of the water and the 5% -60% ethanol are combined, the fractions are concentrated into thick paste, and vacuum drying is carried out, so that the yield of the sulfonated composition can reach more than 90% (calculated by theoretical mole number of andrographolide-19-sulfate-16-sodium carboxylate).
Detailed Description
Example 1
300G of andrographolide raw material is taken, added into a reactor, 600ml of 60% hydrobromic acid aqueous solution is added, the reaction is carried out for 3 hours at the stirring speed of 150rpm at the temperature of 5-10 ℃, the filtration is carried out, 500ml of ethyl acetate is added into the filtrate, the pH is regulated to 6.0 by adding sodium bicarbonate solution, the stirring is continued for 10 hours, the filtration is carried out to obtain a filtrate, and the vacuum drying is carried out for 24 hours to obtain 290g of intermediate.
Weighing 175g of the dried intermediate, pouring into a reactor, weighing 700ml of acetone, and adding into andrographolide. 316ml of sulfuric acid was placed in a beaker, and 732ml of acetone was added to prepare a sulfonation reagent solution. Adding the sulfonation reagent solution into a reactor, stirring and controlling the temperature of the reaction liquid to be 5 ℃, and continuing stirring and reacting for 5 hours after the addition. Adding sodium bicarbonate solution to adjust pH to 6.5, adding 600ml of water, concentrating to relative density of 1.15 by a rotary evaporator, extracting with ethyl acetate for 3 times, discarding an organic layer, concentrating to relative density of 1.15 by a rotary evaporator of a water layer, adding 95% ethanol while stirring to make the ethanol concentration of the solution 85%, standing at room temperature for 24 hours, filtering, taking filtrate, passing through a silica gel column, eluting once by water, 5% -10%, 20% and 30% ethanol in sequence, eluting twice by 40%, 60% and 80%, mixing the eluting fractions of water and 5% -80% ethanol, concentrating to thick paste by a rotary evaporator, and vacuum drying for 24 hours to obtain 235g of andrographolide sulfonate composition.
Through separation and purification and structural identification, the andrographolide sulfonate composition mainly comprises four components of 17-hydrogen-9-dehydroandrographolide (compound I), 17-hydrogen-9-dehydroandrographolide-3, 19-disulfate and salt thereof (compound II), 17-hydrogen-9-dehydroandrographolide-19-sulfate and salt thereof (compound III) and andrographolide-19-sulfate-16-sodium carboxylate (compound IV).
Physical and chemical properties and Bopu data of compound I (17-hydrogen-9-dehydroandrographolide)
17-Hydrogen-9-dehydroandrographolide was white crystals (H 2 O), m.p.239 ℃, α ]20D-215.38 (50% acetonitrile, c=0.05). UV lambda nm max (50% CAN): 228,206; in IR (KBr), 3395cm -1 is an alcohol hydroxyl telescopic vibration absorption peak, 2937, 2865, 1443, 1375cm -1 is a methyl and methylene telescopic vibration and bending vibration absorption peak, 1743cm -1 is an ester carbonyl telescopic vibration absorption peak, and 1673cm -1 is a carbon-carbon double bond telescopic vibration absorption peak.
ESIMS m/z：351[M+H]+,373[M+Na]+,701[M+Na]+,723[2M+Na]+,HRESIMS:m/z349.2029[M–H]–(cald.for C20H29O5,349.2015);1H NMR And 13 C NMR data as follows:
1NMR(DMSO,600MHz)δ:1.04～1.07(m,1H,H-1α),1.58～1.75(m,1H,H-1β),1.58～1.75(m,2H,H-2),3.18(m,1H,H-3),1.11(brd,J＝12.6Hz,1H,H-5),1.43(m,1H,H-6α),1.58～1.75(m,1H,H-6β),1.92～2.02(m,2H,H-7),2.99(dd,J＝17.4,7.8Hz,1H,H-11α),3.14(dd,J＝17.4,5.6Hz,H-11β),6.46(ddd,J＝7.8,5.6,1.4Hz,1H,H-12),4.96(br s,1H,H-14),4.03(dd,J＝9.8,2.3Hz,1H,H-15α),4.44(dd,J＝9.8,6.0Hz,1H,H-15β),1.52(s,3H,H-17),1.08(s,3H,H-18),3.28(dd,J＝10.8,6.0Hz,1H,H-19α),3.84(d,J＝10.8Hz,1H,H-19β),0.92(s,1H,H-20),4.96(brs,1H,3-OH),5.73(brs,1H,14-OH),4.06(brd,J＝6.01H,19-OH).
13C-NMR(DMSO,150MHz)δ:35.0(C-1),28.1(C-2),78.8(C-3),42.6(C-4),51.7(C-5),19.5(C-6),34.5(C-7),128.6(C-8),137.4(C-9),38.5(C-10),27.9(C-11),146.1(C-12),128.9(C-13),65.0(C-14),74.8(C-15),170.5(C-16),19.7(C-17),23.4(C-18),63.4(C-19),20.6(C-20).
Physical and chemical properties and Bopu data of compound II (17-hydro-9-dehydroandrographolide-3, 19-sodium disulfate)
The 17-hydrogen-9-dehydroandrographolide-3, 19-sodium disulfate is white powder (CH 3OH),[α]20D-145.45(H2O,c＝0.05).UVλmax nm(H2 O) 224.6, 206.20; in IR (KBr), 3466cm -1 is an alcohol hydroxyl telescopic vibration absorption peak, 2956, 2860, 1447, 1377cm -1 is a methyl and methylene telescopic vibration and bending vibration absorption peak, 1746cm -1 is an ester carbonyl telescopic vibration absorption peak, 1670cm -1 is a carbon-carbon double bond telescopic vibration absorption peak, and 1220cm -1 is a sulfur-oxygen double bond telescopic vibration absorption peak.
ESI-MS m/z 531[M–H]–,HRESI-MS m/z 531.1014[M–Na]–(cald.for C20H28O11S2Na,531.0971).1H NMR And 13 C NMR data as follows:
1NMR(D2O,600MHz)δ:1.75～1.83(m,1H,H-1α),1.17(td,J＝13.6,3.5Hz,1H,H-1β),1.75～1.83(m,1H,H-2α),1.94～2.05(m,1H,H-2β),3.97(dd,J＝12.0,4.5Hz,1H,H-3),1.28(brd,J＝12.0,1H,H-5),1.56(m,1H,H-6α),175～1.83(m,1H,H-6β),1.75～1.83(m,1H,H-7α),1.94～2.05(m,1H,H-7β),3.05(dd,J＝17.7,8.6Hz,1H,H-11α),3.19(dd,J＝17.7,4.9Hz,H-11β),6.81(ddd,J＝8.0,5.0,1.4Hz,1H,H-12),5.13(dd,J＝6.0,1.8z,1H,H-14),4.23(dd,J＝10.6,1.8Hz,1H,H-15α),4.50(dd,J＝10.6,6.0Hz,1H,H-15β),1.52(s,3H,H-17),1.12(s,3H,H-18),3.96(d,J＝10.0Hz,1H,H-19α),4.20(d,J＝10.0Hz,1H,H-19β),1.00(s,1H,H-20).
13C-NMR(D2O,150MHz)δ:32.2(C-1),22.0(C-2),84.7(C-3),39.3(C-4),49.6(C-5),17.5(C-6),31.7(C-7),128.0(C-8),133.4(C-9),36.0(C-10),26.0(C-11),148.9(C-12),124.0(C-13),63.0(C-14),73.1(C-15),171.3(C-16),16.5(C-17),19.7(C-18),67.8(C-19),16.5(C-20).
Physicochemical properties and Bopu data of Compound III (17-hydro-9-dehydroandrographolide-19-sodium sulfate)
17-Hydro-9-dehydroandrographolide-19-sulfate sodium salt was white powder (CH 3OH),m.p.155℃,[α]20D-175.00(H2O,c＝0.05);UVλnm max(H2 O): 224, 207; the Legal and Kedde reagents reacted positively, suggesting the presence of an α, β -unsaturated lactone ring in the structure of the compound. In IR (KBr), 3439cm -1 is an alcohol hydroxyl group telescopic vibration absorption peak, 2937, 1459, 1378cm -1 is a methyl group and methylene group telescopic vibration and bending vibration absorption peak, 1743cm -1 is an ester carbonyl telescopic vibration absorption peak, 1670cm -1 is a carbon-carbon double bond telescopic vibration absorption peak, and 1214cm -1 is a sulfur-oxygen double bond telescopic vibration absorption peak.
ESI-MS m/z 429[M–Na]–,HRESI-MS m/z 429.1590[M–Na]–(cald.for:429.1583).1H NMR And 13 C NMR data as follows:
1NMR(DMSO,600MHz)δ:1.04～1.07(m,1H,H-1α),1.58～1.75(m,1H,H-1β),1.58～1.75(m,2H,H-2),3.18(m,1H,H-3),1.11(brd,J＝12.6Hz,1H,H-5),1.43(m,1H,H-6α),1.58～1.75(m,1H,H-6β),1.92～2.02(m,2H,H-7),2.99(dd,J＝17.4,7.8Hz,1H,H-11α),3.14(dd,J＝17.4,5.6Hz,H-11β),6.46(ddd,J＝7.8,5.6,1.4Hz,1H,H-12),4.96(brs,1H,H-14),4.03(dd,J＝9.8,2.3Hz,1H,H-15α),4.44(dd,J＝9.8,6.0Hz,1H,H-15β),1.52(s,3H,H-17),1.08(s,3H,H-18),3.28(dd,J＝10.8,6.0Hz,1H,H-19α),3.84(d,J＝10.9Hz,1H,H-19β),0.92(s,1H,H-20),4.96(br s,3-OH),5.73(br s,1H,14-OH),4.06(br d,J＝6.0Hz).
13C-NMR(DMSO,150MHz)δ:35.0(C-1),28.1(C-2),78.8(C-3),42.6(C-4),51.7
(C-5),19.5(C-6),34.5(C-7),128.6(C-8),137.4(C-9),38.5(C-10),27.9(C-11),146.1(C-12),128.9(C-13),65.0(C-14),74.8(C-15),170.5(C-16),19.7(C-17),23.4(C-18),63.4(C-19),20.6(C-20).
Physical and chemical properties and Bopu data of compound IV (Andrographolide-19-sulfate-16-sodium carboxylate)
Andrographolide-19-sulfate-16-carboxylic acid sodium salt is white powder; is easy to dissolve in methanol and water; UV lambda nm max (CH 3 OH) 204.0nm; in IR (KBr), 3431cm -1 is an alcohol hydroxyl telescopic vibration absorption peak, 2935, 1388cm -1 is telescopic vibration and bending vibration of methyl and methylene, 1653cm -1 is a carbon-carbon double bond telescopic vibration absorption peak, and 1242cm -1 is a telescopic vibration absorption peak of thioxy double bonds.
HRESIMS m/z 447.1673[M–Na]–(cald.for.C20H31O9S,447.1689)。
1 H-NMR data (Table 1) showed 3 methyl signals δ H 0.93 (3H, S), 1.03 (3H, S), 1.44 (3H, S); 1 olefinic proton 6.16 (1 h, dd, j= 8.4,4.4); 2 aldehyde base 3.90 (1 h, d, j=10.4), 3.80 (1 h, d, j=10.4).
13 C-NMR data (Table 1) shows 20 carbons in the molecule, including 1 carbonyl carbon delta C 172.6;4 allyl carbons delta C 127.0.0, 135.9,136.4, 139.4;4 carbon oxygen delta C 66.9.9, 68.0, 70.8, 78.0.
NOESY spectra showed the following correlation between protons, 3.05/1.03, 3.05/4.31, 1.07/3.05: H-3/H 3 -18, H-3/H-14, H-5/H-3, and the signals associated with H 3-20、H3 -18 and H 3 -20 are not visible, so that H-3, H-5, H-14, 4-CH 3 are determined to be beta configurations, and 10-CH 3、4-CH2 OH and 14-OH are determined to be alpha configurations.
TABLE 1 Hydrogen and carbon Spectrum data for Andrographolide-19-sulfate-16-carboxylate sodium (400/100 MHz, DMSO)
Example 2
300G of andrographolide raw material is taken, added into a reactor, added with 180 ml of 40% hydrobromic acid aqueous solution, reacted for 3 hours at the stirring speed of 150rpm at the temperature of 5-10 ℃, filtered, added with 500ml of ethyl acetate, added with sodium bicarbonate solution to adjust the pH to 6.0, continuously stirred for 10 hours, filtered to obtain a filtrate, and dried in vacuum for 24 hours to obtain 276g of intermediate.
175G of the dried intermediate was weighed into a reactor, and 1050ml of acetone was measured and added to andrographolide. 316ml of sulfuric acid was taken into a beaker, and 316ml of acetone was added to prepare a sulfonation reagent solution. Adding the sulfonation reagent solution into a reactor, stirring and controlling the temperature of the reaction liquid to 15 ℃, and continuing stirring and reacting for 6 hours after the addition. Adding sodium bicarbonate solution to adjust pH to 6.5, adding 600ml of water, concentrating to relative density of 1.15 by a rotary evaporator, extracting with ethyl acetate for 3 times, discarding an organic layer, concentrating to relative density of 1.15 by a rotary evaporator of a water layer, adding 95% ethanol while stirring to make the ethanol concentration of the solution 85%, standing at room temperature for 24 hours, filtering, taking filtrate, passing through a silica gel column, eluting once with water, 5%, 10%, 20% and 30% ethanol sequentially, eluting twice with 40% and 60% ethanol, mixing the eluting components of water and 5% and 60% ethanol, concentrating to thick paste by a rotary evaporator, and vacuum drying for 24 hours to obtain 229g of andrographolide sulfonate composition.
Example 3
300G of andrographolide raw material is taken, added into a reactor, added with 1200ml of 50% hydrobromic acid aqueous solution, reacted for 3 hours at the stirring speed of 150rpm at 15-20 ℃, filtered, added with 500ml of ethyl acetate into filtrate, added with sodium bicarbonate solution to adjust the pH to 6.0, continuously stirred for 10 hours, filtered to obtain a filtrate, and dried in vacuum for 24 hours to obtain 257g of intermediate.
Weighing 175g of the dried intermediate, pouring into a reactor, weighing 350ml of acetone, and adding into andrographolide. 316ml of sulfuric acid was taken into a beaker, and 948ml of acetone was added to prepare a sulfonation reagent solution. Adding the sulfonation reagent solution into a reactor, stirring and controlling the temperature of the reaction liquid to be 10 ℃, and continuing stirring and reacting for 7 hours after the addition. Adding sodium bicarbonate solution to adjust pH to 6.5, adding 600ml of water, concentrating to relative density of 1.15 by a rotary evaporator, extracting with ethyl acetate for 3 times, discarding an organic layer, concentrating to relative density of 1.15 by a rotary evaporator of a water layer, adding 95% ethanol while stirring to make the ethanol concentration of the solution 85%, standing at room temperature for 24 hours, filtering, taking filtrate, passing through a silica gel column, eluting with water, 5%, 10%, 20% and 30% ethanol sequentially, eluting with 60% and 80% for the second time, mixing the eluting components of water and 5% -60% ethanol, concentrating to thick paste by a rotary evaporator, and vacuum drying for 24 hours to obtain 226g of andrographolide sulfonate composition.
Claims (7)
1. A method for preparing an andrographolide sulfonate composition, the andrographolide sulfonate composition comprising 17-hydro-9-dehydroandrographolide-3, 19-disulfate and salts thereof, andrographolide-19-sulfate-16-carboxylate sodium, 17-hydro-9-dehydroandrographolide-19-sulfate and salts thereof, and 17-hydro-9-dehydroandrographolide, the method comprising the steps of:
(1) Taking andrographolide raw materials, placing the andrographolide raw materials into a reactor, adding hydrobromic acid aqueous solution for reaction, filtering, adding ethyl acetate into filtrate, adding sodium bicarbonate solution for regulating pH to 6.0-6.5, continuously stirring, filtering to obtain a filtrate, and vacuum drying for 24 hours to obtain an intermediate;
(2) Weighing the dried intermediate, pouring the intermediate into a reactor, weighing acetone, and adding the acetone into the intermediate, wherein the volume ratio of the intermediate to the acetone is 1g:2-6ml; weighing sulfuric acid, adding acetone to prepare a sulfonation reagent solution, wherein the dosage volume ratio of the sulfuric acid to the acetone is 1:1-3; adding the sulfonation reagent solution into a reactor, stirring and controlling the temperature of the reaction solution to be 5-15 ℃, and continuing stirring and reacting for 5-7 hours after the addition; adding sodium bicarbonate solution to adjust pH to 6.0-6.5, adding water, rotary evaporating and concentrating, extracting with ethyl acetate, discarding organic layer, rotary evaporating and concentrating water layer, adding ethanol, standing at room temperature, and filtering;
(3) Taking the filtrate obtained in the step (2), passing through a silica gel column, and eluting with water and 5% -100% ethanol for several times in sequence; wherein the elution times of 5% -100% ethanol are two times, wherein the volume fraction of 5% -30% ethanol is adopted in the primary elution, and the volume fraction of 40% -80% ethanol is adopted in the secondary elution; mixing water and the elution fractions of ethanol with different concentrations, concentrating the fractions into thick paste, and vacuum drying.
2. The method according to claim 1, wherein the weight-volume ratio of the andrographolide raw material to the hydrobromic acid aqueous solution to the ethyl acetate in the step (1) is 1g:1-6ml:1-2ml.
3. The process according to claim 1, wherein the reaction temperature in step (1) is 5 to 10℃and the stirring speed is 150 to 300rpm.
4. The process according to claim 1 or 2, wherein the concentration of aqueous hydrobromic acid in step (1) is 40-60%.
5. The method according to claim 1 or 2, wherein after the water layer is concentrated by rotary evaporation in the step (2), 95% ethanol is added while stirring to make the ethanol concentration of the solution 85%.
6. The method according to claim 1 or 2, wherein the silica gel column of step (3) has a particle size of 100 to 300 mesh.
7. The method of claim 1 or 2, wherein the combined fractions of step (3) correspond to ethanol having an elution concentration of 5% -60% ethanol.
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| CN1687049A (en) * | 2005-03-25 | 2005-10-26 | 唐春山 | Sulfonated derivative of andrographolide and combination of medication |
| CN106810520A (en) * | 2015-12-02 | 2017-06-09 | 江西青峰药业有限公司 | A kind of pharmaceutical composition of andrographolide sulfonate and preparation method thereof |
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| CN109942520B (en) * | 2019-04-10 | 2023-08-01 | 大理金明动物药业有限公司 | Andrographolide sulfonate and preparation method and application thereof |
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| CN106810520A (en) * | 2015-12-02 | 2017-06-09 | 江西青峰药业有限公司 | A kind of pharmaceutical composition of andrographolide sulfonate and preparation method thereof |
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