CN108484543B - Preparation method of potassium dehydroandrographolide succinate or potassium dehydroandrographolide succinate - Google Patents
Preparation method of potassium dehydroandrographolide succinate or potassium dehydroandrographolide succinate Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D307/58—One oxygen atom, e.g. butenolide
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Abstract
The invention discloses a preparation method of potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate, which comprises the following steps: crude preparation of dehydroandrographolide disuccinate: taking andrographolide and succinic anhydride as raw materials, adding a catalyst, introducing nitrogen or argon for protection, and performing reflux reaction to obtain a crude dehydroandrographolide succinate; a purification step: extracting the crude product, loading to a column, detecting by thin layer chromatography, collecting dehydroandrographolide disuccinate chromatography liquid, concentrating, and vacuum drying to obtain pure product; the preparation method of potassium dehydroandrographolide succinate or potassium dehydroandrographolide succinate comprises the following steps: dissolving a purified dehydroandrographolide succinate into a solution by using an organic solvent; dripping potassium alkaline compound solution into the solution to react to generate potassium dehydroandrographolide succinate, or dripping potassium alkaline compound solution and sodium alkaline compound solution into the solution to react to generate potassium dehydroandrographolide succinate; the purity of the generated potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate is greatly improved by combining the improvement of the reagent and the process, and the safety of the process and the product is improved.
Description
Technical Field
The invention relates to a preparation method of potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate, belonging to the technical field of chemical synthesis.
Background
Potassium dehydroandrographolide succinate is 14-dehydroxy-11, 12-didehydro andrographolide-3, 19-succinate monopotassium salt; the antibiotic is widely used for treating acute upper respiratory tract infection, acute bronchitis and infantile bronchopneumonia caused by viral pneumonia and influenza virus, is particularly effective on viral and bacterial upper respiratory tract infection and dysentery, has excellent effect on infant pneumonia, and is an ideal important antibiotic at present.
The potassium sodium dehydroandrographolide succinate is potassium sodium dehydroandrographolide 14-dehydroxy-11, 12-didehydro andrographolide-3, 19-disuccinate. The potassium sodium dehydroandroan drographolide succinate is suitable for viral pneumonia and viral upper respiratory tract infection, and the potassium sodium dehydroandroan drographolide succinate is one of main varieties of heat-clearing injection medicaments in the market at present due to obvious effects of resisting viruses, clearing heat and diminishing inflammation.
The main processes for preparing potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate in the prior art mainly comprise:
the first synthesis process comprises the following steps: CN102584752B method for preparing Andrographolide A raw material drug, wherein andrographolide reacts with succinic anhydride in pyridine under the protection of inert gas and the action of catalyst under heating at 50-100 deg.C, and is subjected to post-treatment to obtain dehydroandrographolide succinateSuccinic acid half ester and KHCO in mixed solvent3Or K2CO3And NaHCO3Or Na2CO3The mixed aqueous solution reacts at the temperature of 40-60 ℃, and the potassium sodium dehydroandroan drographolide succinate is obtained after post-treatment.
And a second synthesis process: CN103360350B "A preparation method of high-purity andrographolide for injection", under the protection of nitrogen, using andrographolide and succinic anhydride as starting materials, pyridine as solvent, anhydrous sodium sulfite as antioxidant, heating, cooling after reaction, removing pyridine with nonpolar solvent-weak acid hydrate, concentrating, and decolorizing; then taking acetone-water as a solvent, carrying out a salt forming reaction under the protection of nitrogen, adding acetone-water for crystallization, and carrying out suction filtration under the protection of nitrogen.
And a third synthesis process: CN100465171C method for preparing Andrographolide, Andrographolide preparation and its preparation method, reacting andrographolide with succinic anhydride at 50-90 deg.C in pyridine under inert gas protection, heating and refluxing, post-treating to obtain andrographolide disuccinic acid half ester, reacting andrographolide disuccinic acid half ester with potassium hydroxide, potassium bicarbonate or potassium carbonate in water to form potassium andrographolide disuccinic acid half ester monopotassium salt, adjusting pH to 7-8 with sodium hydroxide, sodium bicarbonate or sodium carbonate, and post-treating Andrographolide.
And the synthesis process is four: CN102617527A "preparation method of Chuanhuning or Yanhuning", andrographolide is used as raw material, in a specific non-pyridine solvent (ethyl acetate, acetonitrile, tetrahydrofuran, butanone, propionitrile), under the action of catalyst and the protection of anhydrous sodium sulfite, heating and refluxing with succinic anhydride to react to prepare andrographolide disuccinic acid half ester, then in methanol, ethanol or water solvent, reacting the purified andrographolide disuccinic acid half ester with alkaline potassium salt and alkaline sodium salt to prepare Chuanhuning or Yanhuning.
And a fifth synthesis process: CN102863408B A process for preparing andrographolide, under the protection of inert gas, using andrographolide and succinic anhydride as raw materials, in aprotic solvent (halogenated hydrocarbons, esters, ethers, ketones, nitriles, etc.), using aliphatic small molecular amine as catalyst, reacting at 30-90 deg.C to obtain andrographolide disuccinate half ester, then reacting with potassium alkali compound and sodium alkali compound to obtain andrographolide.
In the first, second and third synthesis processes, toxic and malodorous pyridine is used as a solvent, and the pyridine is difficult to remove, so that the pyridine solvent residue in the product is relatively high. In the fourth synthesis process, a specific non-pyridine solvent is used, the reflux reaction is carried out at the temperature of the boiling point of the solvent, but the boiling point of the solvent is low (below 100 ℃), even if the reaction time is prolonged, the reaction is not complete (the succinic anhydride can firstly react with one hydroxyl group on andrographolide to form dehydroandrographolide succinate monoester, and then reacts with the other hydroxyl group along with the prolonging of the reaction time and the increasing of the temperature to form the target intermediate dehydroandrographolide disuccinate half ester, and more dehydroandrographolide succinate monoester is not converted into the dehydroandrographolide disuccinate half ester at the reaction temperature below 100 ℃), in addition, a large amount of water is used for refining in the fourth process, so that the water is wasted, and the purity of the obtained dehydroandrographolide disuccinate half ester is not high. In the fifth synthesis process, the reaction temperature (30-90 ℃) is low, so that the reaction is incomplete. In addition, after the completion of the reaction, the solvent and the catalyst are removed by concentration under reduced pressure, and thus it is difficult to remove the solvent having a relatively high boiling point such as propyl acetate, butyl acetate, etc., and the excessive starting material succinic anhydride cannot be removed by concentration. Therefore, the product of potassium sodium dehydroandroan drographolide succinate has low purity and content.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a preparation method of potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate, which takes no pyridine as a solvent, combines the improvement of a reagent and a process, greatly improves the purity of the generated potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate, and greatly improves the safety of the process and the product.
The purpose of the invention can be achieved by adopting the following technical scheme: a preparation method of potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate comprises the following steps:
crude preparation of dehydroandrographolide disuccinate: taking andrographolide and succinic anhydride as raw materials, taking at least one of propyl acetate and butyl acetate as a solvent, adding a catalyst, introducing nitrogen or argon for protection, vacuumizing, heating to more than 100 ℃, and performing reflux reaction to obtain a crude dehydroandrographolide disuccinate product;
the purification method of the dehydroandrographolide succinate comprises the following steps: extracting the crude dehydroandrographolide succinate, loading onto column, detecting with thin layer chromatography, collecting chromatography liquid, concentrating, and vacuum drying to obtain pure dehydroandrographolide succinate;
the preparation method of the potassium dehydroandrographolide succinate comprises the following steps: dissolving a purified dehydroandrographolide succinate into a solution by using an organic solvent; dripping potassium alkaline compound solution into dehydroandrographolide succinate solution for reaction to generate potassium dehydroandrographolide succinate;
or, the preparation steps of potassium sodium dehydroandroan drographolide succinate are as follows: dissolving a purified dehydroandrographolide succinate into a solution by using an organic solvent; dripping potassium alkaline compound solution and sodium alkaline compound solution into dehydroandrographolide disuccinate solution for reaction to obtain potassium sodium dehydroandroan drographolide succinate.
Further, in the step of roughly preparing the dehydroandrographolide succinate, the mass ratio of the andrographolide to the succinic anhydride is 1: 1-3; the mass of the solvent is 5-15 times of that of andrographolide; the mass ratio of the andrographolide to the catalyst is 1: 1-2; the catalyst is diethylamine or triethylamine.
Further, in the step of roughly preparing the dehydroandrographolide succinate, the degree of vacuum pumping is-0.08 to-0.1 MPa, the heating temperature is 100-.
Further, in the step of purifying the dehydroandrographolide succinate, the crude dehydroandrographolide succinate is extracted by dichloromethane, wherein the mass of the dichloromethane is 5-10 times of that of the crude dehydroandrographolide succinate.
Further, in the purification step of the dehydroandrographolide succinate, silica gel column is used, the mesh number of the silica gel column is 100-600 meshes, and the volume ratio of dichloromethane to methanol to formic acid is 500 (10-20) to 1-10.
Further, in the preparation step of the andrographolide or potassium sodium dehydroandroan drographolide succinate, the organic solvent is methanol or ethanol, and the mass of the organic solvent is 3-8 times of that of the dehydroandrographolide succinate.
Further, in the preparation step of potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate, the alkaline compound of potassium is potassium hydroxide, potassium carbonate or potassium bicarbonate; the mass percentage concentration of the alkaline compound solution of potassium is 15-25%.
Further, in the preparation step of the andrographolide, the molar ratio of the dehydroandrographolide disuccinate to the potassium alkaline compound is 1:0.8-1.2, the reaction temperature of the dehydroandrographolide disuccinate and the potassium alkaline compound is 30-40 ℃, and the reaction time is 3-5 h.
Further, in the preparation step of potassium sodium dehydroandroan drographolide succinate, the alkaline compound of sodium is sodium hydroxide, sodium carbonate or sodium bicarbonate; the mass percentage concentration of the alkaline compound solution of sodium is 10-20%.
Further, in the preparation step of the andrographolide, the mole ratio of the dehydroandrographolide disuccinate to the potassium alkaline compound to the sodium alkaline compound is 1 (0.8-1.2) to (0.4-0.6), the reaction temperature of the dehydroandrographolide disuccinate with the potassium alkaline compound to the sodium alkaline compound is 20-40 ℃, and the reaction time is 3-4 h.
Compared with the prior art, the invention has the beneficial effects that:
1. the method takes propyl acetate and butyl acetate as solvents to replace stink and toxic pyridine as the solvent, avoids pyridine residue in the product, and greatly improves the safety of the process and the product;
2. the heating temperature is increased to more than 100 ℃ by the crude dehydroandrographolide succinate, the reaction is carried out by matching with the methods of vacuum, heating and reflux, and the high performance liquid chromatography shows that the total concentration of two dehydroandrographolide succinate monoesters is not more than 4% after the reaction of the raw material andrographolide is finished;
3. the purification of dehydroandrographolide disuccinate is carried out by using a column and a thin-layer chromatography to remove excessive succinic anhydride and dehydroandrographolide succinate monoester generated by incomplete reaction, so that the product purity is improved, a mobile phase of the chromatography can be recycled, a large amount of waste acid water is avoided, and the environmental protection pressure is reduced.
Detailed Description
The invention will be further described with reference to specific embodiments:
example 1:
preparation of potassium dehydroandrographolide succinate:
the mass of andrographolide is 50g, the mass of succinic anhydride is 110g, the mass of butyl acetate is 353g, and triethylamine is 60 g;
crude preparation of dehydroandrographolide disuccinate: taking andrographolide and succinic anhydride as raw materials, taking butyl acetate as a solvent, adding triethylamine as a catalyst, introducing nitrogen or argon for protection, vacuumizing to 0.085MPa, heating to 105 ℃, and performing reflux reaction for 6 hours to obtain a crude dehydroandrographolide succinate product;
the purification method of the dehydroandrographolide succinate comprises the following steps: extracting the crude dehydroandrographolide succinate with dichloromethane for three times (the mass of dichloromethane added each time is 397.5g), passing through a silica gel column (the mesh number of silica gel is 200-300 meshes, the volume ratio of mobile phase dichloromethane to methanol to formic acid is 500:15:3), detecting by thin layer chromatography, collecting the chromatography liquid of the dehydroandrographolide succinate, concentrating the chromatography liquid, and drying in vacuum to obtain 52g of a pure dehydroandrographolide succinate product;
the preparation method of the potassium dehydroandrographolide succinate comprises the following steps: dissolving 52g of the pure dehydroandrographolide succinate product with 197.25g of ethanol to obtain a solution; at the temperature of 35 ℃, potassium bicarbonate solution (10g of potassium bicarbonate is dissolved in 50mL of water) is dripped into dehydroandrographolide disuccinate solution for reaction for 4 hours, and after absolute ethyl alcohol is filtered for washing and drying, potassium dehydroandrographolide succinate 44.8g is obtained, the yield is 88.4 percent, and the purity is 99.3 percent.
Example 2
Preparation of potassium sodium dehydroandroan drographolide succinate:
the mass of andrographolide is 30g, the mass of succinic anhydride is 75g, the mass of propyl acetate is 399.51g, and triethylamine is 35 g;
crude preparation of dehydroandrographolide disuccinate: taking andrographolide and succinic anhydride as raw materials, taking propyl acetate as a solvent, adding triethylamine as a catalyst, introducing nitrogen or argon for protection, vacuumizing to 0.095MPa, heating to 115 ℃, and performing reflux reaction for 4 hours to obtain a crude dehydroandrographolide succinate product;
the purification method of the dehydroandrographolide succinate comprises the following steps: extracting the crude dehydroandrographolide succinate with dichloromethane for three times (the mass of dichloromethane added each time is 463.75g), passing through a silica gel column (the mesh number of silica gel is 300-400 meshes, the volume ratio of mobile phase dichloromethane to methanol to formic acid is 500:12:2), detecting by thin layer chromatography, collecting the chromatography liquid of the dehydroandrographolide succinate, concentrating the chromatography liquid, and drying in vacuum to obtain 30g of a pure dehydroandrographolide succinate product;
the preparation method of potassium sodium dehydroandroan drographolide succinate comprises the following steps: dissolving 30g of dehydroandrographolide succinate pure product with 158.36g of methanol to obtain a solution; at the temperature of 38 ℃, potassium bicarbonate solution (6g of potassium bicarbonate dissolved in 30mL of water) and sodium carbonate solution (3g of sodium carbonate dissolved in 25mL of water) are dripped into dehydroandrographolide disuccinate solution to react for 3.5 hours, and then anhydrous ethanol is filtered, washed and dried to obtain 26.3g of potassium sodium dehydroandroan drographolide succinate with the yield of 87.6 percent and the purity of 99.4 percent.
Example 3
Preparation of potassium sodium dehydroandroan drographolide succinate:
60g of andrographolide, 150g of succinic anhydride, 529.5g of butyl acetate and 95g of triethylamine;
crude preparation of dehydroandrographolide disuccinate: taking andrographolide and succinic anhydride as raw materials, taking butyl acetate as a solvent, adding triethylamine as a catalyst, introducing nitrogen or argon for protection, vacuumizing to 0.09MPa, heating to 110 ℃, and performing reflux reaction for 4 hours to obtain a crude dehydroandrographolide succinate product;
the purification method of the dehydroandrographolide succinate comprises the following steps: extracting the crude dehydroandrographolide succinate with dichloromethane for three times (the mass of dichloromethane added each time is 662.5g), passing through a silica gel column (the mesh number of silica gel is 200-300 meshes, the volume ratio of mobile phase dichloromethane to methanol to formic acid is 500:16:2), detecting by thin layer chromatography, collecting the chromatography liquid of the dehydroandrographolide succinate, concentrating the chromatography liquid, and drying in vacuum to obtain 63g of a pure dehydroandrographolide succinate product;
the preparation method of potassium sodium dehydroandroan drographolide succinate comprises the following steps: dissolving 63g of the pure dehydroandrographolide succinate product with 331.38g of ethanol to obtain a solution; at the temperature of 36 ℃, potassium carbonate solution (18g of potassium carbonate dissolved in 100mL of water) and sodium bicarbonate solution (19g of sodium bicarbonate dissolved in 125mL of water) are added into dehydroandrographolide disuccinate solution dropwise for reaction for 4 hours, and after absolute ethyl alcohol is filtered, washing and drying are carried out, so as to obtain 52.2g of potassium sodium dehydroandroan drographolide succinate with the yield of 87% and the purity of 99.3%.
Various other changes and modifications to the above-described embodiments and concepts will become apparent to those skilled in the art from the above description, and all such changes and modifications are intended to be included within the scope of the present invention as defined in the appended claims.
Claims (8)
1. A preparation method of potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate is characterized by comprising the following steps:
crude preparation of dehydroandrographolide disuccinate: taking andrographolide and succinic anhydride as raw materials, taking at least one of propyl acetate and butyl acetate as a solvent, adding a catalyst, introducing nitrogen or argon for protection, vacuumizing, heating to more than 100 ℃, and performing reflux reaction to obtain a crude dehydroandrographolide disuccinate product; the vacuum degree is-0.08 to-0.1 MPa, the heating temperature is 100 and 125 ℃, and the reflux reaction time is 3 to 8 hours; the mass ratio of the andrographolide to the succinic anhydride is 1: 1-3; the mass of the solvent is 5-15 times of that of andrographolide; the mass ratio of the andrographolide to the catalyst is 1: 1-2; the catalyst is diethylamine or triethylamine;
the purification method of the dehydroandrographolide succinate comprises the following steps: extracting the crude dehydroandrographolide succinate, loading onto column, detecting with thin layer chromatography, collecting chromatography liquid, concentrating, and vacuum drying to obtain pure dehydroandrographolide succinate;
the preparation method of the potassium dehydroandrographolide succinate comprises the following steps: dissolving a purified dehydroandrographolide succinate into a solution by using an organic solvent; dripping potassium alkaline compound solution into dehydroandrographolide succinate solution for reaction to generate potassium dehydroandrographolide succinate;
or, the preparation steps of potassium sodium dehydroandroan drographolide succinate are as follows: dissolving a purified dehydroandrographolide succinate into a solution by using an organic solvent; dripping potassium alkaline compound solution and sodium alkaline compound solution into dehydroandrographolide disuccinate solution for reaction to obtain potassium sodium dehydroandroan drographolide succinate.
2. The method of claim 1, wherein in the step of purifying dehydroandrographolide succinate, the crude dehydroandrographolide succinate is extracted with dichloromethane, and the mass of dichloromethane is 5-10 times of the crude dehydroandrographolide succinate.
3. The method for preparing andrographolide or andrographolide as claimed in claim 1, wherein in the step of purifying dehydroandrographolide succinate, silica gel column is used, the silica gel mesh of the silica gel column is 100-600 meshes, and the ratio of dichloromethane to methanol to formic acid in mobile phase volume is 500 (10-20) to (1-10).
4. The method for preparing dehydroandrographolide succinate or potassium dehydroandrographolide succinate according to claim 1, wherein in the step of preparing dehydroandrographolide succinate or potassium dehydroandrographolide succinate, the organic solvent is methanol or ethanol, and the mass of the organic solvent is 3-8 times that of the dehydroandrographolide succinate.
5. The process for preparing potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate as claimed in claim 1, wherein in the step of preparing potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate, the alkaline compound of potassium is potassium hydroxide, potassium carbonate or potassium hydrogen carbonate; the mass percentage concentration of the alkaline compound solution of potassium is 15-25%.
6. The process for preparing dehydroandrographolide succinate or potassium dehydroandrographolide succinate according to claim 1, wherein in the preparing step of dehydroandrographolide succinate, the molar ratio of dehydroandrographolide succinate to potassium alkali compound is 1:0.8-1.2, the reaction temperature of dehydroandrographolide succinate and potassium alkali compound is 30-40 ℃, and the reaction time is 3-5 h.
7. The process for producing potassium dehydroandrographolide succinate or potassium dehydroandroan drographolide succinate according to claim 1, wherein in the step of producing potassium dehydroandroan drographolide succinate, the alkaline compound of sodium is sodium hydroxide, sodium carbonate or sodium bicarbonate; the mass percentage concentration of the alkaline compound solution of sodium is 10-20%.
8. The method for preparing andrographolide or potassium sodium succinate according to claim 1, wherein in the step of preparing potassium sodium succinate, the mole ratio of the dehydroandrographolide disuccinate to the potassium alkaline compound to the sodium alkaline compound is 1 (0.8-1.2) (0.4-0.6), the reaction temperature of the dehydroandrographolide disuccinate with the potassium alkaline compound to the sodium alkaline compound is 20-40 ℃, and the reaction time is 3-4 h.
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| WO2001085709A2 (en) * | 2000-05-05 | 2001-11-15 | Dr. Reddy's Research Foundation | New compounds having anticancer activity: process for their preparation and pharmaceutical compositions containing them |
| CN102863408A (en) * | 2011-07-06 | 2013-01-09 | 重庆莱美药业股份有限公司 | Preparation method of andrographolide |
| CN104945357A (en) * | 2015-06-09 | 2015-09-30 | 湖北荆楚理工科技开发有限公司 | Refining method of dehydroandrographolide succinate |
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| WO2001085709A2 (en) * | 2000-05-05 | 2001-11-15 | Dr. Reddy's Research Foundation | New compounds having anticancer activity: process for their preparation and pharmaceutical compositions containing them |
| CN102863408A (en) * | 2011-07-06 | 2013-01-09 | 重庆莱美药业股份有限公司 | Preparation method of andrographolide |
| CN104945357A (en) * | 2015-06-09 | 2015-09-30 | 湖北荆楚理工科技开发有限公司 | Refining method of dehydroandrographolide succinate |
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