CN111793049A - Preparation method of potassium sodium dehydroandroan drographolide succinate and intermediate thereof - Google Patents
Preparation method of potassium sodium dehydroandroan drographolide succinate and intermediate thereof Download PDFInfo
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- KYEPHZAHIRDQSR-SXASYTFBSA-L potassium;sodium;4-[[(1r,2r,4ar,5r,8as)-2-(3-carboxylatopropanoyloxy)-1,4a-dimethyl-6-methylidene-5-[(e)-2-(5-oxo-2h-furan-4-yl)ethenyl]-3,4,5,7,8,8a-hexahydro-2h-naphthalen-1-yl]methoxy]-4-oxobutanoate Chemical compound [Na+].[K+].C(/[C@@H]1C(=C)CC[C@H]2[C@@]1(C)CC[C@H]([C@]2(COC(=O)CCC([O-])=O)C)OC(=O)CCC([O-])=O)=C\C1=CCOC1=O KYEPHZAHIRDQSR-SXASYTFBSA-L 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 87
- YTHKMAIVPFVDNU-GPTWTFMPSA-N 4-[[(1r,2r,4ar,5r,8as)-2-(3-carboxypropanoyloxy)-1,4a-dimethyl-6-methylidene-5-[(e)-2-(5-oxo-2h-furan-4-yl)ethenyl]-3,4,5,7,8,8a-hexahydro-2h-naphthalen-1-yl]methoxy]-4-oxobutanoic acid Chemical compound C(/[C@@H]1C(=C)CC[C@H]2[C@@]1(C)CC[C@H]([C@]2(COC(=O)CCC(O)=O)C)OC(=O)CCC(O)=O)=C\C1=CCOC1=O YTHKMAIVPFVDNU-GPTWTFMPSA-N 0.000 claims abstract description 64
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 49
- 239000002904 solvent Substances 0.000 claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims abstract description 25
- 239000011736 potassium bicarbonate Substances 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 25
- 235000015497 potassium bicarbonate Nutrition 0.000 claims abstract description 24
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical group [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims abstract description 24
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 24
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims abstract description 15
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 15
- 230000035484 reaction time Effects 0.000 claims abstract description 12
- 239000011259 mixed solution Substances 0.000 claims description 146
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 132
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 claims description 75
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 claims description 75
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 66
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 65
- 229940014800 succinic anhydride Drugs 0.000 claims description 65
- 238000005886 esterification reaction Methods 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 29
- 239000007788 liquid Substances 0.000 claims description 26
- 229910001414 potassium ion Inorganic materials 0.000 claims description 14
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical group O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 13
- 229910001415 sodium ion Inorganic materials 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 8
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 239000011261 inert gas Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 description 74
- 238000002425 crystallisation Methods 0.000 description 47
- 230000008025 crystallization Effects 0.000 description 47
- 238000001291 vacuum drying Methods 0.000 description 36
- 238000003756 stirring Methods 0.000 description 35
- 239000000047 product Substances 0.000 description 28
- 238000001035 drying Methods 0.000 description 26
- 239000012295 chemical reaction liquid Substances 0.000 description 20
- 238000001914 filtration Methods 0.000 description 20
- 239000000463 material Substances 0.000 description 19
- 239000012065 filter cake Substances 0.000 description 18
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 14
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 12
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 230000014759 maintenance of location Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- MZXSMTFMRXUGGI-RYVVASIESA-L potassium;sodium;4-[[(1r,2r,4as,5r,8as)-2-(3-carboxylatopropanoyloxy)-1,4a-dimethyl-6-methylidene-5-[(2e)-2-(2-oxofuran-3-ylidene)ethyl]-3,4,5,7,8,8a-hexahydro-2h-naphthalen-1-yl]methoxy]-4-oxobutanoate Chemical compound [Na+].[K+].C([C@H]1[C@]2(C)CC[C@H]([C@]([C@H]2CCC1=C)(COC(=O)CCC([O-])=O)C)OC(=O)CCC([O-])=O)\C=C1/C=COC1=O MZXSMTFMRXUGGI-RYVVASIESA-L 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010020741 Hyperpyrexia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 229940101006 anhydrous sodium sulfite Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Images
Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of potassium sodium dehydroandroan drographolide succinate and an intermediate thereof. The preparation method of potassium sodium dehydroandroan drographolide succinate comprises the following steps: alcohol solvent and water, the dehydroandrographolide succinate and potassium salt and sodium salt are subjected to salt forming reaction in a microchannel reactor to prepare potassium sodium dehydroandroan drographolide succinate; the potassium salt is potassium bicarbonate and the sodium salt is sodium bicarbonate. The preparation method has the advantages of short reaction time, mild reaction conditions, low solvent consumption, cost saving, high safety, and high purity of the product obtained by simple post-treatment, and is more suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of potassium sodium dehydroandroan drographolide succinate and an intermediate thereof.
Background
The chemical name of the potassium sodium dehydroandrographolide succinate is 14-dehydroxy-11, 12-didehydro andrographolide-3, 19-disuccinate monohydrate, and the structural formula of the potassium sodium dehydroandrographolide succinate is as follows:
modern pharmacological research shows that potassium sodium dehydroandroan drographolide succinate has the effects of clearing away heat and toxic materials, resisting inflammation, inhibiting the growth and reproduction of microorganisms such as bacteria and viruses, relieving inflammatory exudation and edema by inhibiting capillary permeability, improving the activity and content of serum lysozyme by promoting the phagocytic function of neutrophil-macrophage, protecting the barrier structure of respiratory mucosa, and promoting the recovery of immune function, thereby playing the roles of enhancing the non-specific immunity of respiratory tract and the like. Is widely applied to treating respiratory tract infection, gastrointestinal tract infection, hyperpyrexia, epidemic virus and other toxic diseases clinically.
Chinese patent CN1927854A discloses a method for preparing andrographolide, an andrographolide preparation and a preparation method thereof, wherein the method for preparing andrographolide uses pyridine as a solvent, andrographolide reacts with succinic anhydride under the protection of nitrogen to obtain dehydroandrographolide succinate, and the dehydroandrographolide succinate is mixed with KOH and KHCO3Or K2CO3Reacting to generate potassium andrographolide succinate, and then using NaOH and NaHCO3Or Na2CO3Treating to obtain potassium sodium dehydroandroan drographolide succinate. The method needs high-temperature reflux, large solvent consumption, long reaction time, product purity of only 96 percent, and can reach the standard only by using various solvents for multiple purification.
Chinese patent CN103113331A discloses a method for synthesizing andrographolide, which comprises the steps of reacting andrographolide, succinic anhydride, pyridine and anhydrous sodium sulfite under the vacuum condition of 0.08MPa to obtain dehydroandrographolide succinate, then respectively dripping potassium salt and sodium salt, and reacting to obtain andrographolide. Although the yield of the product is high, the reaction is carried out under the low pressure of 0.08MPa, the charging treatment time is long, the industrial production is not facilitated, the product is not easy to crystallize and evacuate due to overhigh reaction temperature, the reaction kettle is large in size, and a large factory building is required during the industrial production.
Therefore, there is a need in the art for a method that has a short reaction time, a simple and easily controllable process, high safety and efficiency, and can improve the purity and yield of the product, so as to solve the above technical problems.
Disclosure of Invention
The invention aims to overcome the defects that the reaction time of potassium sodium dehydroandroan drographolide succinate in the prior art is long, the potassium sodium dehydroandroan drographolide succinate needs to be carried out under the protection of nitrogen or under vacuum, the post-treatment process is complex, a large amount of solvent needs to be used, and the like. The invention provides a preparation method of potassium sodium dehydroandroan drographolide succinate and an intermediate thereof. The method has the advantages of short reaction time, mild reaction conditions, low solvent consumption, cost saving, high safety, and high purity of the product obtained by simple post-treatment, and is more suitable for industrial production.
The invention mainly solves the technical problems through the following technical scheme.
The invention provides a preparation method of potassium sodium dehydroandroan drographolide succinate, which comprises the following steps:
alcohol solvent and water, the dehydroandrographolide succinate and potassium salt and sodium salt are subjected to salt forming reaction in a microchannel reactor to prepare potassium sodium dehydroandroan drographolide succinate;
the potassium salt is potassium bicarbonate, and the sodium salt is sodium bicarbonate.
The preparation method of the potassium sodium dehydroandroan drographolide succinate preferably comprises the following steps:
mixing the dehydroandrographolide succinate with the alcohol solvent to obtain a mixed solution A;
mixing the potassium salt, the sodium salt and the water to obtain a mixed solution B;
and (3) mixing the mixed solution A and the mixed solution B to carry out the salt forming reaction.
The preparation method of the potassium sodium dehydroandroan drographolide succinate preferably comprises the following steps:
and simultaneously feeding the mixed liquor A and the mixed liquor B into a micro-channel reactor through a metering pump.
The flow rates of the mixed liquor A and the mixed liquor B are within the flow rate allowable range of the microchannel reactor, and can be the flow rates which are conventionally used for carrying out the reactions by adopting the microchannel reactor in the field.
The flow rate of the mixed solution A may be 1.5 to 2.7mL/min, preferably 1.6 to 2.2mL/min, and more preferably 1.8 mL/min. The flow rate of the mixed solution B can be 1.1-2.7 mL/min, preferably 1.2-2.2 mL/min.
The alcohol solvent and the water may be solvents conventional in the art for such reactions, so as not to interfere with the reaction. The alcohol solvent can be ethanol water solution with the concentration of more than or equal to 95 vol%.
The mass-volume ratio of the dehydroandrographolide succinate to the alcohol solvent can be 0.5-1 kg/L.
The mass volume ratio of the potassium salt to the water may be 0.12 to 0.21kg/L, preferably 0.13 to 0.17kg/L, and more preferably 0.14 kg/L. The mass volume ratio of the sodium salt to the water can be 0.11-0.14 kg/L, preferably 0.12-0.13 kg/L.
The molar ratio of the dehydroandrographolide succinate to the potassium salt can be 1: 0.9-1.1, and 1:1 is preferred.
The molar ratio of the dehydroandrographolide succinate to the sodium salt can be 1: 0.9-1.1, preferably 1: 1.
In the salt forming reaction, the reaction time can be 50-100 s, preferably 70-85 s, and further preferably 80 s.
In the salt forming reaction, the reaction temperature can be the conventional temperature for the reaction in the field, and the reaction temperature is preferably 45-55 ℃, and further preferably 50 ℃.
The method can further comprise a post-treatment process of salt-forming reaction after the salt-forming reaction is finished. The post-treatment process of the salt-forming reaction can adopt the conventional post-treatment operation of the reaction in the field, and the invention preferably comprises the following steps: and mixing the reaction liquid obtained after the salt forming reaction is finished with ethanol, crystallizing, filtering and drying to obtain the potassium sodium dehydroandroan drographolide succinate.
In the post-treatment process of the salifying reaction, the dosage of the ethanol is not specifically limited, and the volume-to-mass ratio of the ethanol to the dehydroandrographolide succinate can be 1L/kg. The ethanol is preferably anhydrous ethanol.
In the post-treatment process of the salt-forming reaction, the crystallization temperature is the conventional crystallization temperature in the field, preferably-10-0 ℃, further preferably-4-8 ℃, and more preferably-6 ℃.
In the post-treatment process of the salt-forming reaction, the crystallization time is not particularly limited, and preferably 4-5 hours, and further preferably 4.5 hours, based on no crystal precipitation.
The drying temperature in the salt forming reaction post-treatment process can be a conventional drying temperature in the field, preferably 40-50 ℃, further preferably 42-47 ℃, and more preferably 45 ℃.
The drying time in the post-treatment process of the salt forming reaction is not particularly limited, and is preferably 6-8 hours, and further preferably 7 hours.
The preparation method of potassium sodium dehydroandroan drographolide succinate can further comprise the following steps:
in a solvent, performing esterification reaction on andrographolide and succinic anhydride in a microchannel reactor to prepare the dehydroandrographolide succinate.
In the esterification reaction, the molar ratio of andrographolide to succinic anhydride can be 1: 2-3.5, preferably 1: 2.5 to 3.1, and more preferably 1: 3.
in the esterification reaction, the solvent may be pyridine.
In the esterification reaction, the mass-volume ratio of the andrographolide to the solvent can be 1-2 kg/L, preferably 1.1-1.5 kg/L, and more preferably 1.4 kg/L.
In the esterification reaction, the reaction time can be 150-270 s, preferably 180-220 s, and more preferably 195 s.
In the esterification reaction, the reaction temperature can be the temperature conventional in the field, and the temperature is preferably 50-80 ℃ and is further preferably 60-70 ℃.
In the esterification reaction, the esterification reaction is preferably carried out under normal pressure conditions.
In the esterification reaction, the esterification reaction is preferably carried out without protection of inert gas or addition of an antioxidant.
In the esterification reaction, the esterification reaction can further comprise an esterification reaction post-treatment process after the esterification reaction is finished. The esterification post-treatment process may employ conventional post-treatment operations of such reactions in the art, and the present invention preferably comprises the steps of: and mixing the reaction liquid obtained after the esterification reaction with water, crystallizing, filtering and drying to obtain the dehydroandrographolide succinate.
In the post-treatment process of the esterification reaction, the amount of the water is not particularly limited, and the volume mass ratio of the water to the andrographolide can be 20L/kg.
In the post-treatment process of the esterification reaction, the crystallization temperature can be a crystallization conventional temperature in the field, preferably 0-10 ℃, further preferably 3-8 ℃, and more preferably 5 ℃.
In the post-treatment process of the esterification reaction, the crystallization time is not particularly limited, and is preferably 2 to 3 hours, and more preferably 2.5 hours, based on no more crystal precipitation. In the post-treatment process of the esterification reaction, the drying temperature is the conventional drying temperature in the field, preferably 40-50 ℃, further preferably 42-47 ℃, and more preferably 45 ℃. In the esterification reaction post-treatment process, the drying time is not particularly limited, preferably 6-8 hours, and more preferably 7 hours.
In the esterification reaction, the following steps are preferably included:
and simultaneously feeding the mixed solution formed by the andrographolide and the solvent and the mixed solution formed by the succinic anhydride and the solvent into a micro-channel reactor through a metering pump.
The flow rates of the mixed liquid of the andrographolide and the solvent and the mixed liquid of the succinic anhydride and the solvent are within the allowable range of the flow rate of the microchannel reactor, and can be the flow rates which are conventionally used in the field for carrying out the reactions by adopting the microchannel reactor.
The flow rate of the mixed solution of andrographolide and the solvent can be 0.9-1.6 mL/min, preferably 1.1-1.3 mL/min, and more preferably 1.2 mL/min.
The flow rate of the mixed solution of the succinic anhydride and the solvent may be 0.6 to 1.1mL/min, preferably 0.7 to 0.9mL/min, and more preferably 0.8 mL/min.
The preparation method of the dehydroandrographolide succinate has the same conditions as the above.
The invention also provides potassium sodium dehydroandroan drographolide succinate prepared by the preparation method of potassium sodium dehydroandroan drographolide succinate.
The HPLC purity of the potassium sodium dehydroandroan drographolide succinate can be 99.1-99.7%, for example, 99.2%, 99.3%, 99.6% or 99.7%.
The mass percentage of potassium ions in the potassium sodium dehydroandroan drographolide succinate can be 5.89-6.65%, such as 5.94%, 6.07%, 6.12%, 6.15%, 6.18%, 6.55%, 6.59% or 6.61%.
The mass percentage of sodium ions in the potassium sodium dehydroandroan drographolide succinate can be 3.48-3.85%, for example, 3.52%, 3.57%, 3.68%, 3.71%, 3.79%, 3.81% or 3.82%.
The invention also provides a preparation method of the dehydroandrographolide succinate, which comprises the following steps: in a solvent, performing esterification reaction on andrographolide and succinic anhydride in a microchannel reactor to prepare dehydroandrographolide succinate; the molar ratio of the andrographolide to the succinic anhydride is 1: 2-3.5; the flow rate of a mixed solution formed by the andrographolide and the solvent is 0.9-1.6 mL/min; the flow rate of the mixed liquid formed by the succinic anhydride and the solvent is 0.6-1.1 mL/min.
In the present invention, the letter s in the description of time means seconds, and h in the description of time means hours.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the invention adopts the microreactor to react under normal pressure, and the reaction condition is easy to control, thereby ensuring the stability of product quality and the safety of reaction. The esterification reaction does not need to be carried out under the protection of inert gas, and an antioxidant does not need to be added. The reaction time is shortened from traditional hours to tens of seconds to minutes, and a large amount of reaction time is saved. The product purity is improved by simple post-treatment. According to the invention, potassium bicarbonate and sodium bicarbonate are used, the ratio of potassium ion to sodium potassium dehydroandroan drographolide succinate is strictly controlled to be 0.9-1.1, the national standard of potassium dehydroandroan drographolide succinate is met, the quality of the product is improved, and the phenomenon of raw material or product precipitation does not occur in the preferable range of the invention.
Drawings
FIG. 1 is a schematic process flow diagram of a microchannel reactor used in the present invention.
Wherein 1 and 3 denote raw material tanks, 2 and 4 denote metering pumps, 5 and 6 denote microchannel reactors, and 6 denotes a product crystallization tank.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, the purity of potassium sodium dehydroandroan drographolide succinate refers to the HPLC purity, which is not specifically described.
Example 1 preparation of dehydroandrographolide succinate intermediate for Andrographolide
Dissolving andrographolide (100g) in pyridine (30mL), stirring to mix them uniformly to obtain mixed solution of andrographolide and pyridine, and injecting the mixed solution of andrographolide and pyridine into raw material tank 1; dissolving succinic anhydride (57g) in pyridine (20mL), stirring to uniformly mix the succinic anhydride and the pyridine to obtain a mixed solution of the succinic anhydride and the pyridine, and injecting the mixed solution of the succinic anhydride and the pyridine into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) feeding the mixed solution of andrographolide and pyridine in the raw material tank 1 into a microchannel reactor 5 through a metering pump 2, and feeding the mixed solution of succinic anhydride and pyridine in the raw material tank 3 into the microchannel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the molar ratio of andrographolide to succinic anhydride to be 1: 2; the flow rate of the mixed solution of andrographolide and pyridine is 0.9mL/min, the flow rate of the mixed solution of succinic anhydride and pyridine is 0.6mL/min, the temperature of the microchannel reactor is set to be 50 ℃, and the reaction retention time is 270 s; (3) after the materials are mixed in a microchannel reactor and subjected to esterification reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 2L of water into the reaction solution, carrying out crystallization at 10 ℃ for 2h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to 40 ℃, and carrying out drying for 6 h.
The yield of the dehydroandrographolide succinate solid was 87% and the purity was 99.4%.
Example 2 preparation of dehydroandrographolide succinate intermediate of Andrographolide
Dissolving andrographolide (144g) in pyridine (60mL), stirring to mix them uniformly to obtain mixed solution of andrographolide and pyridine, and injecting the mixed solution of andrographolide and pyridine into raw material tank 1; dissolving succinic anhydride (127g) in pyridine (40mL), stirring to uniformly mix the succinic anhydride and the pyridine to obtain a mixed solution of the succinic anhydride and the pyridine, and injecting the mixed solution of the succinic anhydride and the pyridine into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) feeding the mixed solution of andrographolide and pyridine in the raw material tank 1 into a microchannel reactor 5 through a metering pump 2, and feeding the mixed solution of succinic anhydride and pyridine in the raw material tank 3 into the microchannel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the molar ratio of andrographolide to succinic anhydride to be 1: 3.1, setting the temperature of the microchannel reactor to be 70 ℃ and the reaction retention time to be 180s, wherein the flow rate of the mixed solution of andrographolide and pyridine is 1.3mL/min, and the flow rate of the mixed solution of succinic anhydride and pyridine is 0.9 mL/min; (3) after the materials are mixed in a microchannel reactor and subjected to esterification reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 2.88L of water into the reaction solution, carrying out crystallization at 5 ℃ for 2.5h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven at 50 ℃, and carrying out drying for 7 h.
The yield of the dehydroandrographolide succinate solid was 90% and the purity was 99.7%.
Example 3 preparation of dehydroandrographolide succinate intermediate of Andrographolide
Dissolving andrographolide (200g) in pyridine (120mL), stirring to mix them uniformly to obtain mixed solution of andrographolide and pyridine, and injecting the mixed solution of andrographolide and pyridine into raw material tank 1; succinic anhydride (199g) is dissolved in pyridine (80mL), the mixture is stirred to be uniformly mixed to obtain a mixed solution of the succinic anhydride and the pyridine, and the mixed solution of the succinic anhydride and the pyridine is injected into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) feeding the mixed solution of andrographolide and pyridine in the raw material tank 1 into a microchannel reactor 5 through a metering pump 2, and feeding the mixed solution of succinic anhydride and pyridine in the raw material tank 3 into the microchannel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the molar ratio of andrographolide to succinic anhydride to be 1: 3.5, setting the temperature of the microchannel reactor to be 80 ℃ and the reaction retention time to be 150s, wherein the flow rate of the mixed solution of andrographolide and pyridine is 1.6mL/min, and the flow rate of the mixed solution of succinic anhydride and pyridine is 1.1 mL/min; (3) after the materials are mixed in a microchannel reactor and subjected to esterification reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 4L of water into the reaction solution, wherein the crystallization temperature is 0 ℃, the crystallization time is 3h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to 47 ℃, and the drying time is 8 h.
The yield of the dehydroandrographolide succinate solid was 93%, and the purity was 99.1%.
Example 4 preparation of dehydroandrographolide succinate intermediate of Andrographolide
Dissolving andrographolide (150g) in pyridine (45mL), stirring to mix them uniformly to obtain mixed solution of andrographolide and pyridine, and injecting the mixed solution of andrographolide and pyridine into raw material tank 1; dissolving succinic anhydride (107g) in pyridine (30mL), stirring to uniformly mix the succinic anhydride and the pyridine to obtain a mixed solution of the succinic anhydride and the pyridine, and injecting the mixed solution of the succinic anhydride and the pyridine into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) feeding the mixed solution of andrographolide and pyridine in the raw material tank 1 into a microchannel reactor 5 through a metering pump 2, and feeding the mixed solution of succinic anhydride and pyridine in the raw material tank 3 into the microchannel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the molar ratio of andrographolide to succinic anhydride to be 1: 2.5, setting the temperature of the microchannel reactor to be 60 ℃ and the reaction retention time to be 220s, wherein the flow rate of the mixed solution of andrographolide and pyridine is 1.1mL/min, and the flow rate of the mixed solution of succinic anhydride and pyridine is 0.7 mL/min; (3) after the materials are mixed in a microchannel reactor and subjected to esterification reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 3L of water into the reaction solution, wherein the crystallization temperature is 8 ℃, the crystallization time is 3h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to be 42 ℃, and drying for 6 h.
The yield of the dehydroandrographolide succinate solid was 88%, and the purity was 99.5%.
Example 5 preparation of dehydroandrographolide succinate intermediate of Andrographolide
Dissolving andrographolide (160g) in pyridine (86mL), stirring to mix them uniformly to obtain mixed solution of andrographolide and pyridine, and injecting the mixed solution of andrographolide and pyridine into raw material tank 1; dissolving succinic anhydride (137g) in pyridine (58mL), stirring to uniformly mix the succinic anhydride and the pyridine to obtain a mixed solution of the succinic anhydride and the pyridine, and injecting the mixed solution of the succinic anhydride and the pyridine into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) feeding the mixed solution of andrographolide and pyridine in the raw material tank 1 into a microchannel reactor 5 through a metering pump 2, and feeding the mixed solution of succinic anhydride and pyridine in the raw material tank 3 into the microchannel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the molar ratio of andrographolide to succinic anhydride to be 1: 3, the flow rate of the mixed solution of andrographolide and pyridine is 1.2mL/min, the flow rate of the mixed solution of succinic anhydride and pyridine is 0.8mL/min, the temperature of the microchannel reactor is set to be 80 ℃, and the reaction retention time is 195 s; (3) after the materials are mixed in a microchannel reactor and subjected to esterification reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 3.2L of water into the reaction solution, carrying out crystallization at the temperature of 3 ℃ for 2h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to be 45 ℃, and carrying out drying for 8 h.
The yield of the dehydroandrographolide succinate solid was 91% and the purity was 99.2%.
EXAMPLE 6 preparation of Potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (100g) in 95 vol% ethanol water solution (100mL), stirring to mix uniformly to obtain mixed solution A, and injecting the mixed solution A into a raw material tank 1; dissolving potassium bicarbonate (17g) and sodium bicarbonate (14g) in water (100mL), stirring to mix uniformly to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the molar ratio of the dehydroandrographolide succinate to the potassium bicarbonate to the sodium bicarbonate to be 1: 0.9: 0.9, the flow rates of the mixed solution A and the mixed solution B are respectively 2.7mL/min and 2.7mL/min, the temperature of the microchannel reactor is set to be 55 ℃, and the reaction residence time is 50 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 100mL of absolute ethyl alcohol into the reaction solution, carrying out crystallization at the crystallization temperature of 0 ℃ for 4h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to 45 ℃, and carrying out drying for 8 h.
The yield of the potassium sodium dehydroandroan drographolide succinate is 86 percent, the purity is 99.3 percent, the potassium ion content in the potassium sodium dehydroandroan drographolide succinate is 5.89 percent, and the sodium ion content in the potassium sodium dehydroandroan drographolide succinate is 3.52 percent.
Example 7 preparation of Potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (150g) in 95 vol% ethanol water solution (300mL), stirring to mix uniformly to obtain mixed solution A, and injecting the mixed solution A into a raw material tank 1; dissolving potassium bicarbonate (28g) and sodium bicarbonate (23g) in water (200mL), stirring to mix them uniformly to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the mole ratio of the dehydroandrographolide succinate to the potassium bicarbonate to the sodium bicarbonate to be 1: 1:1, the flow rates of the mixed solution A and the mixed solution B are respectively 1.8mL/min and 1.2mL/min, the temperature of the microchannel reactor is set to be 55 ℃, and the reaction residence time is 85 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 150mL of absolute ethyl alcohol into the reaction solution, carrying out crystallization at the temperature of-4 ℃ for 4.5h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to be 50 ℃, and carrying out drying for 7 h.
The yield of potassium sodium dehydroandroan drographolide succinate is 89%, the purity is 99.6%, the potassium ion content is 6.15%, and the sodium ion content is 3.68%.
EXAMPLE 8 preparation of Potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (200g) in 95 vol% ethanol water solution (400mL), stirring to mix uniformly to obtain mixed solution A, and injecting the mixed solution A into a raw material tank 1; dissolving potassium bicarbonate (41g) and sodium bicarbonate (34g) in water (300mL), stirring to mix uniformly to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the mole ratio of the dehydroandrographolide succinate to the potassium bicarbonate to the sodium bicarbonate to be 1: 1.1: 1.1, the flow rates of the mixed solution A and the mixed solution B are respectively 1.5mL/min and 1.1mL/min, the temperature of the microchannel reactor is set to be 45 ℃, and the reaction residence time is 100 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 200mL of absolute ethyl alcohol into the reaction solution, carrying out crystallization at-8 ℃ for 4h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to 42 ℃, and carrying out drying for 6 h.
The yield of potassium sodium dehydroandroan drographolide succinate is 91%, the purity is 99.2%, the potassium ion content is 6.55%, and the sodium ion content is 3.79%.
Example 9 preparation of Potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (150g) in 95 vol% ethanol water solution (150mL), stirring to mix uniformly to obtain mixed solution A, and injecting the mixed solution A into raw material tank 1; dissolving potassium bicarbonate (25g) and sodium bicarbonate (26g) in water (200mL), stirring to mix them uniformly to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the mole ratio of the dehydroandrographolide succinate to the potassium bicarbonate to the sodium bicarbonate to be 1: 1:1, the flow rates of the mixed solution A and the mixed solution B are respectively 1.6mL/min and 2.2mL/min, the temperature of the microchannel reactor is set to be 45 ℃, and the reaction residence time is 70 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 150mL of absolute ethyl alcohol into the reaction solution, carrying out crystallization at-10 ℃ for 5h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to 40 ℃, and carrying out drying for 8 h.
The yield of potassium sodium dehydroandroan drographolide succinate is 93 percent, the purity is 99.1 percent, the potassium ion content is 6.07 percent, and the sodium ion content is 3.81 percent.
Example 10 preparation of Potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (200g) in 95 vol% ethanol water solution (400mL), stirring to mix uniformly to obtain mixed solution A, and injecting the mixed solution A into a raw material tank 1; dissolving potassium bicarbonate (41g) and sodium bicarbonate (28g) in water (200mL), stirring to mix them uniformly to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the mole ratio of the dehydroandrographolide succinate to the potassium bicarbonate to the sodium bicarbonate to be 1: 1.1: 0.9, the flow rates of the mixed solution A and the mixed solution B are respectively 2.2mL/min and 1.1mL/min, the temperature of the microchannel reactor is set to be 50 ℃, and the reaction residence time is 80 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 200mL of absolute ethyl alcohol into the reaction solution, carrying out crystallization at-6 ℃ for 4.5h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to 42 ℃, and carrying out drying for 7 h.
The yield of potassium sodium dehydroandroan drographolide succinate is 88 percent, the purity is 99.7 percent, the potassium ion content is 6.61 percent, and the sodium ion content is 3.48 percent.
Example 11 preparation of Potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (5kg) in 95 vol% ethanol water solution (5L), stirring to mix well to obtain mixed solution A, and injecting the mixed solution A into raw material tank 1; dissolving potassium bicarbonate (845g) and sodium bicarbonate (710g) in water (5L), stirring to mix uniformly to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the mole ratio of the dehydroandrographolide succinate to the potassium bicarbonate to the sodium bicarbonate to be 1: 0.9: 0.9, the flow rates of the mixed solution A and the mixed solution B are respectively 2.7mL/min and 2.7mL/min, the temperature of the microchannel reactor is set to be 55 ℃, and the reaction residence time is 50 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 5L of absolute ethyl alcohol into the reaction solution, wherein the crystallization temperature is 0 ℃, the crystallization time is 4h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to be 45 ℃, and the drying time is 8 h.
The yield of potassium sodium dehydroandroan drographolide succinate is 86%, the purity is 99.3%, the potassium ion content is 5.94%, and the sodium ion content is 3.57%.
EXAMPLE 12 preparation of Potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (5.1kg) in 95 vol% ethanol water solution (10.2L), stirring to mix well to obtain mixed solution A, and injecting the mixed solution A into raw material tank 1; dissolving potassium bicarbonate (957g) and sodium bicarbonate (804g) in water (6.8L), stirring to mix them uniformly to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the mole ratio of the dehydroandrographolide succinate to the potassium bicarbonate to the sodium bicarbonate to be 1: 1:1, the flow rates of the mixed solution A and the mixed solution B are respectively 1.8mL/min and 1.2mL/min, the temperature of the microchannel reactor is set to be 55 ℃, and the reaction residence time is 85 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 5.1L of absolute ethyl alcohol into the reaction solution, carrying out crystallization at the temperature of-4 ℃ for 4.5h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to be 50 ℃, and carrying out drying for 7 h.
The yield of potassium sodium dehydroandroan drographolide succinate is 89%, the purity is 99.6%, the potassium ion content is 6.18%, and the sodium ion content is 3.71%.
Example 13 preparation of Potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (5kg) in 95 vol% ethanol water solution (10L), stirring to mix well to obtain mixed solution A, and injecting the mixed solution A into raw material tank 1; dissolving potassium bicarbonate (1.032kg) and sodium bicarbonate (867g) in water (7.5L), stirring to mix them uniformly to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the mole ratio of the dehydroandrographolide succinate to the potassium bicarbonate to the sodium bicarbonate to be 1: 1.1: 1.1, the flow rates of the mixed solution A and the mixed solution B are respectively 1.5mL/min and 1.1mL/min, the temperature of the microchannel reactor is set to be 45 ℃, and the reaction residence time is 100 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 5L of absolute ethyl alcohol into the reaction solution, carrying out crystallization at-8 ℃ for 4h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to 42 ℃, and carrying out drying for 6 h.
The yield of potassium sodium dehydroandroan drographolide succinate is 91%, the purity is 99.2%, the potassium ion content is 6.59%, and the sodium ion content is 3.82%.
Example 14 preparation of Potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (5.2kg) in 95 vol% ethanol water solution (5.2L), stirring to obtain mixed solution A, and adding mixed solution A into raw material tank 1; dissolving potassium bicarbonate (878g) and sodium bicarbonate (902g) in water (6.9L), stirring to mix them uniformly to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the mole ratio of the dehydroandrographolide succinate to the potassium bicarbonate to the sodium bicarbonate to be 1: 0.9: 1.1, the flow rates of the mixed solution A and the mixed solution B are respectively 1.6mL/min and 2.2mL/min, the temperature of the microchannel reactor is set to be 45 ℃, and the reaction residence time is 70 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 5.2L of absolute ethyl alcohol into the reaction solution, carrying out crystallization at-10 ℃ for 5h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven at 40 ℃, and carrying out drying for 8 h.
The yield of potassium sodium dehydroandroan drographolide succinate is 93 percent, the purity is 99.1 percent, the potassium ion content is 6.12 percent, and the sodium ion content is 3.85 percent.
Example 15 preparation of Potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (5.1kg) in 95 vol% ethanol water solution (10.2L), stirring to mix well to obtain mixed solution A, and injecting the mixed solution A into raw material tank 1; dissolving potassium bicarbonate (1.053kg) and sodium bicarbonate (724g) in water (5.1L), stirring to mix them uniformly to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the mole ratio of the dehydroandrographolide succinate to the potassium bicarbonate to the sodium bicarbonate to be 1: 1.1: 0.9, the flow rates of the mixed solution A and the mixed solution B are respectively 2.2mL/min and 1.1mL/min, the temperature of the microchannel reactor is set to be 50 ℃, and the reaction residence time is 80 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 5.1L of absolute ethyl alcohol into the reaction solution, carrying out crystallization at-6 ℃ for 4.5h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to 47 ℃, and carrying out drying for 7 h.
The yield of potassium sodium dehydroandroan drographolide succinate is 88 percent, the purity is 99.7 percent, the potassium ion content is 6.65 percent, and the sodium ion content is 3.53 percent.
Comparative example 1 preparation of potassium sodium dehydroandroan drographolide succinate
Dissolving dehydroandrographolide succinate (150g) in 95 vol% ethanol water solution (300mL), stirring to mix uniformly to obtain mixed solution A, and injecting the mixed solution A into a raw material tank 1; dissolving potassium carbonate (39g) and sodium carbonate (29g) in water (200mL), stirring to uniformly mix the solution to obtain a mixed solution B, and injecting the mixed solution B into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) the mixed liquid A in the raw material tank 1 enters a micro-channel reactor 5 through a metering pump 2, and the mixed liquid B in the raw material tank 3 enters the micro-channel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the molar ratio of the dehydroandrographolide succinate to the potassium carbonate to the sodium carbonate to be 1: 1:1, the flow rates of the mixed solution A and the mixed solution B are respectively 1.8mL/min and 1.2mL/min, the temperature of the microchannel reactor is set to be 55 ℃, and the reaction residence time is 85 s; (3) after the materials are mixed in a microchannel reactor to generate salt forming reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 150mL of absolute ethyl alcohol into the reaction solution, carrying out crystallization at the temperature of-4 ℃ for 4.5h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven to be 50 ℃, and carrying out drying for 7 h.
The yield of potassium sodium dehydroandroan drographolide succinate is 72 percent, the purity is 71.5 percent, the potassium ion content is 3.32 percent, and the sodium ion content is 2.15 percent.
Comparative example 2 preparation of dehydroandrographolide succinate intermediate for Andrographolide succinate
Dissolving andrographolide (144g) in pyridine (60mL), stirring to mix them uniformly to obtain mixed solution of andrographolide and pyridine, and injecting the mixed solution of andrographolide and pyridine into raw material tank 1; dissolving succinic anhydride (78g) in pyridine (40mL), stirring to uniformly mix the succinic anhydride and the pyridine to obtain a mixed solution of the succinic anhydride and the pyridine, and injecting the mixed solution of the succinic anhydride and the pyridine into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) feeding the mixed solution of andrographolide and pyridine in the raw material tank 1 into a microchannel reactor 5 through a metering pump 2, and feeding the mixed solution of succinic anhydride and pyridine in the raw material tank 3 into the microchannel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the molar ratio of andrographolide to succinic anhydride to be 1: 1.9, the flow rate of the mixed solution of andrographolide and pyridine is 1.3mL/min, the flow rate of the mixed solution of succinic anhydride and pyridine is 0.9mL/min, the temperature of the microchannel reactor is set to be 70 ℃, and the reaction retention time is 180 s; (3) after the materials are mixed in a microchannel reactor and subjected to esterification reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 2.88L of water into the reaction solution, carrying out crystallization at 5 ℃ for 2.5h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven at 50 ℃, and carrying out drying for 7 h.
The yield of the dehydroandrographolide succinate solid was 75% and the purity was 74.6%.
Comparative example 3 preparation of dehydroandrographolide succinate intermediate for Andrographolide
Dissolving andrographolide (144g) in pyridine (60mL), stirring to mix them uniformly to obtain mixed solution of andrographolide and pyridine, and injecting the mixed solution of andrographolide and pyridine into raw material tank 1; dissolving succinic anhydride (127g) in pyridine (40mL), stirring to uniformly mix the succinic anhydride and the pyridine to obtain a mixed solution of the succinic anhydride and the pyridine, and injecting the mixed solution of the succinic anhydride and the pyridine into a raw material tank 3;
with the apparatus of the invention, FIG. 1, the following steps are followed: (1) feeding the mixed solution of andrographolide and pyridine in the raw material tank 1 into a microchannel reactor 5 through a metering pump 2, and feeding the mixed solution of succinic anhydride and pyridine in the raw material tank 3 into the microchannel reactor 5 through a metering pump 4; (2) setting the flow rates of the metering pump 2 and the metering pump 4, and controlling the molar ratio of andrographolide to succinic anhydride to be 1: 3.1, setting the temperature of the microchannel reactor to be 70 ℃ and the reaction retention time to be 180s, wherein the flow rate of the mixed solution of andrographolide and pyridine is 0.7mL/min, and the flow rate of the mixed solution of succinic anhydride and pyridine is 0.5 mL/min; (3) after the materials are mixed in a microchannel reactor and subjected to esterification reaction, collecting reaction liquid into a product crystallization tank 6; (4) adding 2.88L of water into the reaction solution, carrying out crystallization at 5 ℃ for 2.5h, filtering, transferring the filter cake into a vacuum drying oven to constant weight, setting the temperature of the vacuum drying oven at 50 ℃, and carrying out drying for 7 h.
The yield of the dehydroandrographolide succinate solid was 81%, and the purity was 59.8%.
Claims (10)
1. The preparation method of potassium sodium dehydroandroan drographolide succinate is characterized by comprising the following steps: alcohol solvent and water, the dehydroandrographolide succinate and potassium salt and sodium salt are subjected to salt forming reaction in a microchannel reactor to prepare the potassium sodium dehydroandroan drographolide succinate;
the potassium salt is potassium bicarbonate, and the sodium salt is sodium bicarbonate.
2. The process for preparing potassium sodium dehydroandroan drographolide succinate as claimed in claim 1, wherein: which comprises the following steps:
mixing the dehydroandrographolide succinate with the alcohol solvent to obtain a mixed solution A;
mixing the potassium salt, the sodium salt and the water to obtain a mixed solution B;
and (3) mixing the mixed solution A and the mixed solution B to carry out the salt forming reaction.
3. The process for preparing potassium sodium dehydroandroan drographolide succinate as claimed in claim 2, wherein: which comprises the following steps: simultaneously feeding the mixed solution A and the mixed solution B into the microchannel reactor through a metering pump;
the flow rate of the mixed solution A is preferably 1.5-2.7 mL/min, more preferably 1.6-2.2 mL/min, and even more preferably 1.8 mL/min; the flow rate of the mixed solution B is preferably 1.1 to 2.7mL/min, and more preferably 1.2 to 2.2 mL/min.
4. A process for the preparation of potassium sodium dehydroandroan drographolide succinate as claimed in any one of claims 1 to 3, characterized in that: the alcohol solvent is ethanol water solution with the concentration of more than or equal to 95 vol%;
and/or the mass-volume ratio of the dehydroandrographolide succinate to the alcohol solvent is 0.5-1 kg/L;
and/or the mass volume ratio of the potassium salt to the water is 0.12-0.21 kg/L;
and/or the mass volume ratio of the sodium salt to the water is 0.11-0.14 kg/L;
and/or the molar ratio of the dehydroandrographolide succinate to the potassium salt is 1: 0.9-1.1;
and/or the molar ratio of the dehydroandrographolide succinate to the sodium salt is 1: 0.9-1.1;
and/or in the salt forming reaction, the reaction time is 50-100 s;
and/or in the salt forming reaction, the reaction temperature is 45-55 ℃.
5. The process for preparing potassium sodium dehydroandroan drographolide succinate as claimed in claim 4, wherein: the mass volume ratio of the potassium salt to the water is 0.13-0.17 kg/L, preferably 0.14 kg/L;
and/or the mass volume ratio of the sodium salt to the water is 0.12-0.13 kg/L;
and/or the molar ratio of the dehydroandrographolide succinate to the potassium salt is 1: 1;
and/or the molar ratio of the dehydroandrographolide succinate to the sodium salt is 1: 1;
and/or in the salt forming reaction, the reaction time is 70-85 s, preferably 80 s;
and/or in the salt forming reaction, the reaction temperature is 50 ℃.
6. The process for the preparation of potassium sodium dehydroandroan drographolide succinate as claimed in any one of claims 1 to 5, wherein: it further comprises the following steps: in a solvent, performing esterification reaction on andrographolide and succinic anhydride in a microchannel reactor to prepare the dehydroandrographolide succinate.
7. The method for preparing potassium sodium dehydroandroan drographolide succinate as claimed in claim 6, wherein: in the esterification reaction, the molar ratio of andrographolide to succinic anhydride is 1: 2-3.5, preferably 1: 2.5 to 3.1, and more preferably 1: 3;
and/or, in the esterification reaction, the solvent is pyridine;
and/or in the esterification reaction, the mass-volume ratio of the andrographolide to the solvent is 1-2 kg/L, preferably 1.1-1.5 kg/L, and more preferably 1.4 kg/L;
and/or in the esterification reaction, the reaction time is 150-270 s, preferably 180-220 s, and further preferably 195 s;
and/or in the esterification reaction, the reaction temperature is 50-80 ℃, and preferably 60-70 ℃;
and/or, in the esterification reaction, the esterification reaction is carried out under normal pressure;
and/or in the esterification reaction, the esterification reaction does not need to be carried out under the protection of inert gas, and does not need to be carried out under the condition of adding an antioxidant.
8. The method for preparing potassium sodium dehydroandroan drographolide succinate as claimed in claim 6 or 7, wherein: the preparation method of the dehydroandrographolide succinate comprises the following steps:
simultaneously feeding the mixed solution formed by the andrographolide and the solvent and the mixed solution formed by the succinic anhydride and the solvent into a micro-channel reactor through a metering pump;
the flow rate of the mixed solution of the andrographolide and the solvent is preferably 0.9-1.6 mL/min, more preferably 1.1-1.3 mL/min, and even more preferably 1.2 mL/min; the flow rate of the mixed solution of the succinic anhydride and the solvent is preferably 0.6 to 1.1mL/min, more preferably 0.7 to 0.9mL/min, and still more preferably 0.8 mL/min.
9. An potassium sodium dehydroandroan drographolide succinate prepared by the potassium sodium dehydroandroan drographolide succinate preparation method as claimed in any one of claims 1-8, wherein the HPLC purity of the potassium sodium dehydroandroan drographolide succinate is 99.1-99.7%, such as 99.2%, 99.3%, 99.6% or 99.7%; the mass percentage of potassium ions in the potassium sodium dehydroandroan drographolide succinate is 5.89-6.65%, such as 5.94%, 6.07%, 6.12%, 6.15%, 6.18%, 6.55%, 6.59% or 6.61%; the mass percentage of sodium ions in the potassium sodium dehydroandroan drographolide succinate is 3.48-3.85%, for example, 3.52%, 3.57%, 3.68%, 3.71%, 3.79%, 3.81% or 3.82%.
10. A preparation method of dehydroandrographolide succinate is characterized by comprising the following steps: which comprises the following steps: in a solvent, performing esterification reaction on andrographolide and succinic anhydride in a microchannel reactor to prepare dehydroandrographolide succinate; the molar ratio of the andrographolide to the succinic anhydride is 1: 2-3.5; the flow rate of a mixed solution formed by the andrographolide and the solvent is 0.9-1.6 mL/min; the flow rate of the mixed liquid formed by the succinic anhydride and the solvent is 0.6-1.1 mL/min;
the method for preparing dehydroandrographolide succinate comprises the same conditions as those for preparing dehydroandrographolide succinate according to any one of claims 6-8.
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