CN111646961A - Preparation method of ganoderma lucidum furan A - Google Patents
Preparation method of ganoderma lucidum furan A Download PDFInfo
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- CN111646961A CN111646961A CN202010741831.XA CN202010741831A CN111646961A CN 111646961 A CN111646961 A CN 111646961A CN 202010741831 A CN202010741831 A CN 202010741831A CN 111646961 A CN111646961 A CN 111646961A
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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
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of ganoderma lucidum furan A. The preparation method of the ganoderma lucidum furan A is to obtain a compound of a general formula I by condensation reaction of a compound of a general formula II and a compound of a general formula III, wherein the reaction equation is as follows. The technical scheme provided by the invention provides a device which is particularly suitable for amplification
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of ganoderma lucidum furan A.
Background
The incidence rate of chronic kidney disease in China and the world is over 10 percent, the chronic kidney disease can progress to end-stage renal failure through the process of renal fibrosis, and can also be accompanied by serious cardiovascular diseases, so that the harm is serious, and unfortunately, no better method for preventing the progress of the chronic kidney disease exists at present. Organ fibrosis is caused by the damage of organs caused by adverse factors and then in the process of repair, and is an organ scar, and the organ fibrosis can cause organ failure. Numerous studies have shown that TGF- β 1-induced phosphorylation of Smad3 is one of the major pathological mechanisms mediating fibrosis in various organs, and therefore inhibition, especially selective inhibition of Smad3 activation, is critical for anti-fibrosis, but the relevant molecular drugs are still relatively lacking.
Intensive research on fruiting bodies of Ganoderma lucidum (Ganoderma lucidum) by Kunming plant of Chinese academy of sciences in 2016 shows that Ganoderma furan A (Lingzhifufann A) can significantly inhibit kidney tissue fibrosis no matter in vivo or in vitro; ganoderan A on NRK-52E cells also selectively inhibits the phosphorylation level of Smad3, i.e., it has therapeutic effects on organ fibrosis including kidney fibrosis.
The structural formula of ganoderma lucidum furan A (Lingzhifunan A) is as follows:
chinese patent CN106279086A discloses ganoderan A and provides a method for extracting from Ganoderma lucidum, and in view of high extraction cost and low yield, the patent also provides a chemical synthesis route for synthesizing ganoderan A. The provided synthetic route takes p-hydroxyanisole and 3-chloro-2-fluorobenzonitrile as raw materials, and the target compound is obtained by condensation reaction, intramolecular chlorobenzene substituted ring closure, demethylation, tert-butyl dimethyl silicon-based protecting group addition, cyano reduction and HWE reaction in sequence. In the several steps, the reaction conditions such as replacement of phenolic hydroxyl protecting groups, coupling and reduction are harsh, DIBAL-H high-risk reduction reagents are required, the series of factors do not have the possibility of large-scale synthesis, in addition, one reactant of the HWE reaction in the last step needs to be prepared separately, the reactant is obtained by taking 1-bromo-3-methyl-2-butene and trimethyl phosphite as raw materials through the two steps of ARBUZOV reaction and allylic oxidation, and the two steps of reaction are tested to have low purity and poor yield, so that the mass synthesis of the target product is limited by one step of improvement.
In conclusion, the current extraction or synthesis method of ganoderan A is difficult and expensive to satisfy the amount of compounds required by the development of subsequent drugs, so a new synthetic route is urgently needed to be developed.
Disclosure of Invention
The invention provides a preparation method of ganoderma lucidum furan A, which is used for solving the problem that the ganoderma lucidum furan A is difficult to obtain at present.
In order to solve the technical problems, the technical scheme of the invention is as follows: the preparation method of the ganoderma lucidum furan A is to obtain a compound of a general formula I by condensation reaction of a compound of a general formula II and a compound of a general formula III, wherein the reaction equation is as follows:
wherein R is a hydroxyl protecting group or H;
when R is H, the compound in the general formula I is ganoderan A;
when R is a hydroxyl protecting group, the compound in the general formula I is subjected to deprotection to obtain the ganoderan A.
Alternatively, the solvent used in the condensation reaction is methanol, ethanol or isopropanol, preferably isopropanol.
Experiments show that the control of the reaction is closely related to the solubility of the compound in a system, and finally, the yield and the purity are optimal when isopropanol is used as a solvent in the reaction.
Alternatively, the specific process of the condensation reaction is as follows: dispersing the compound of the general formula II in a solvent, adding NaOH aqueous solution, then diluting the compound of the general formula III with the solvent at room temperature, dropwise adding the diluted compound of the general formula III into a system, adding hydrochloric acid to quench the reaction after the reaction is completed, and carrying out post-treatment and purification to obtain the compound of the general formula I.
Alternatively, the compound of the general formula II is synthesized by reacting a compound of the formula IV as a raw material, and the reaction equation is as follows:
wherein R is a hydroxyl protecting group or H;
when R is H, the compound shown in the formula IV is directly obtained by reaction;
when R is a hydroxyl protecting group, the compound is obtained by adding a protecting group on one step.
Optionally, the hydroxyl protecting group is an ester protecting group or a silyl ether protecting group.
Optionally, the hydroxyl protecting group is acetyl (Ac) or tert-butyldimethyl (TBS).
Optionally, R is H.
When R is H, the ganoderan A can be directly obtained from the compound shown in the formula IV only by two steps of reaction.
Optionally, the compound of formula IV is obtained from dibenzofuran.
Dibenzofurans are very inexpensive and readily available commercial products, well suited for the process requirements for scale-up synthesis.
Optionally, the dibenzofuran is subjected to an acylation reaction, a bayer-virger oxidation rearrangement reaction and a deacylation reaction in sequence to obtain the compound of the general formula IV, wherein the reaction equation is as follows:
the technical scheme provided by the invention provides a synthetic route which is particularly suitable for the amplified synthesis of ganoderma lucidum furan A, the selected raw materials of dibenzofuran and 2-methyl-2-butenal are mature chemical products, the source is wide, the price is low, the reaction conditions of the whole reaction route are mild, no special requirements exist, the obtained intermediate can be directly subjected to subsequent reaction without purification, and the elements enable the route to completely overcome the defects of the synthetic route in the prior art, and the synthetic route has the prospect of industrial amplified production.
Detailed Description
For the convenience of understanding, the preparation method of ganoderan A is described in the following examples, which are to be construed as merely illustrative and not a limitation of the scope of the present invention.
The reagents and instruments used in the examples were all commercially available products unless otherwise specified.
Example 1
The reaction equation is as follows:
preparation of the compound of formula IV:
adding 100g of dibenzofuran into a reaction bottle, adding 1L of dichloromethane, stirring uniformly, dissolving 95g of aluminum trichloride and 55.8g of acetyl chloride by using 1L of dichloromethane, slowly dropwise adding into the system at the temperature of below 20 ℃, standing at room temperature after dropwise adding is finished, and stirring until the reaction is complete. Adding the reaction solution into a mixed solution of ice water and hydrochloric acid (1mol/L), stirring uniformly, standing for liquid separation, extracting an aqueous phase with dichloromethane, and combining organic phases.
And (3) slowly adding trifluoroacetic acid (TFA) to the system by controlling the temperature of the obtained organic phase to be below 0 ℃, adding m-chloroperoxybenzoic acid (mCPBA) after the dropwise addition is finished, stirring for 3 days at room temperature, dropwise adding 450ml of saturated sodium bisulfite solution to the system until the reaction is complete, detecting that the system does not turn blue by using KI test paper, filtering solids to obtain filtrate, standing for layering, separating liquid, extracting a water phase by using dichloromethane, combining the organic phases, concentrating to obtain 211g of yellow solid, namely the crude compound of the formula V, and putting the crude compound of the formula V to the next step without purification.
130g of the crude compound of the formula V is added into a reaction bottle, 650ml of methanol is added, the mixture is stirred uniformly, 46.5g of sodium methoxide is added, nitrogen protection is carried out, and the mixture is stirred at room temperature until the reaction is completed. And (3) dropwise adding 2mol/L hydrochloric acid to quench at 15 ℃, adjusting the pH value of the system to be about 4, concentrating, extracting by using dichloromethane and a water system, concentrating an organic phase to obtain 124g of a crude product of the compound shown in the formula IV, and putting the crude product into the next step without purification.
Preparation of the compound of formula II:
adding 77g of the crude compound of the formula IV into a reaction bottle, adding 1.0L of Tetrahydrofuran (THF), stirring uniformly, under the protection of nitrogen, slowly dropwise adding n-butyllithium to the system at the temperature below 0 ℃ in an ice bath under the temperature control, naturally heating and stirring for 3 hours after dropwise adding is finished, cooling the system to about 0 ℃, and dropwise adding DMF to the system until the reaction is complete. Controlling the temperature below 10 ℃, dropwise adding hydrochloric acid (2mol/L) to quench the reaction, and adjusting the pH value to aboutTo 5, the organic phase was finally extracted and concentrated and purified to obtain 29.3g of the compound of formula II, in 61% overall yield from the previous four steps. Nuclear magnetism1H NMR (400MHz, deuterated dimethyl sulfoxide) 10.45(s,1H),9.64(s,1H),8.45(d,1H),7.96(m,1H),7.65(d,1H), 7.60-7.50 (m,2H),7.05(dd,1H).
Preparation of a Compound of formula I:
adding 100g of the compound shown in the formula II into a reaction bottle, adding 1L of isopropanol, uniformly stirring, carrying out nitrogen protection, cooling to 0 ℃, controlling the temperature below 0 ℃, dropwise adding 750ml of a solution of water and 75g of sodium hydroxide, gradually dissolving the compound shown in the formula II in the system, but not completely dissolving the compound, heating to room temperature after the dropwise adding is completed, stirring, weighing 47.5g of the compound shown in the formula III, diluting with 200ml of isopropanol, dropwise adding the compound shown in the formula II to the system at room temperature, completely dissolving the system in the dropwise adding process, continuously reacting to separate out solids, and waiting for complete reaction. The reaction was quenched by dropwise addition of HCl (3mol/L) at a temperature below 10 deg.C to adjust the pH to about 4, followed by extraction with dichloromethane, concentration of the organic phase and further purification of the compound to give 102g of the compound of formula I with an HPLC (liquid chromatograph) purity of 97.5% and a reaction yield of about 78% in this step. Nuclear magnetism1H NMR (400MHz, deuterated acetone) 9.46(s,1H),8.35(s,1H), 7.95-7.75 (m2H),7.63(d,1H), 7.53-7.12 (m,5H),6.95(dd,1H),1.86(s,3H).
Example 2
The difference from example 1 is that the compound of formula II is protected at the hydroxyl group with acetyl group, then condensed with the compound of formula III to obtain the compound of formula I-Ac, and finally deacetylated to obtain ganoderan A, the reaction equation is as follows:
preparation of a Compound of formula II A-Ac Compound of formula II is specifically:
adding 100g of the compound shown in the formula II, adding 1L of dichloromethane, stirring uniformly, protecting with nitrogen, adding 60g of triethylamine, adding 60g of acetic anhydride, stirring at room temperature until the reaction is complete, carrying out aftertreatment to obtain about 120g of a crude product of the compound shown in the formula II-Ac, and putting the crude product into the next reaction without purification.
Preparation of Compounds of formula II-Ac the compounds of formula I-Ac are specifically:
adding 120g of the compound of the formula II-Ac into a reaction bottle, adding 1L of isopropanol, uniformly stirring, protecting with nitrogen, cooling to 0 ℃, controlling the temperature below 0 ℃, dropwise adding 900ml of water and 90g of sodium hydroxide solution, gradually dissolving the compound of the formula II-Ac in the system, heating to room temperature after the dropwise adding is finished, stirring, weighing 57g of the compound of the formula III, diluting with 200ml of isopropanol, dropwise adding to the system at room temperature, separating out solids after the reaction, and completing the reaction. Controlling the temperature below 10 ℃, dropwise adding HCl (3mol/L) to quench the reaction, adjusting the pH to be about 4, then extracting with dichloromethane, concentrating an organic phase to obtain 120g of a crude product of the compound of the formula I-Ac, putting the crude product of the compound of the formula I-Ac into the next step of reaction without purification,
preparation of compounds of formula I-Ac the compounds of formula I are specifically:
120g of crude compound of formula I-Ac is put into a reaction bottle, 600ml of tetrahydrofuran is added, 600ml of water is added and stirred uniformly, 31g of sodium hydroxide solid is added and stirred for 1.5 hours at room temperature, after the reaction is completed, the temperature is controlled to be below 15 ℃, hydrochloric acid is used for adjusting the pH value to 3-4, the solid is separated out, the pressure is reduced and the filtration is carried out, the drying is carried out, 95g of compound of formula I is obtained, the HPLC purity is 98 percent, and the total yield of the three-step reaction is about 73.
Example 3
The difference from the example 2 is that the protecting group used for the hydroxyl group is tert-butyldimethyl, that is, the compound of the formula II reacts with tert-butyldimethylchlorosilane, then condensation reaction is carried out, and finally deprotection is carried out to obtain the ganoderan furan A, and specific reaction conditions and operation can refer to conventional reaction conditions and are not described again.
Comparative example 1
The difference from example 1 is that in the preparation of the compound of formula I-Ac from the compound of formula II-Ac, the solvent was changed from isopropanol to ethanol and purified after the reaction to obtain 86g of the compound of formula I with HPLC purity of 96.3% and a reaction yield of about 66% for this step.
Comparative example 2
The difference from example 2 is that in the preparation of the compound of formula I, the solvent was changed from isopropanol to ethanol and at the end of the reaction 89g of the compound of formula I were obtained with an HPLC purity of 97.4% and a reaction yield of about 68% for this step.
Finally, it should be noted that: the above examples are only for illustrating the technical solutions of the present invention, and are not limited thereto. Although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: it is to be understood that modifications may be made to the technical solutions described in the foregoing embodiments, or some or all of the technical features may be equivalently replaced, and such modifications or replacements may not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (9)
1. A preparation method of ganoderma lucidum furan A is characterized in that a compound of a general formula I is obtained by condensation reaction of a compound of a general formula II and a compound of a general formula III, and the reaction equation is as follows:
wherein R is a hydroxyl protecting group or H;
when R is H, the compound in the general formula I is ganoderan A;
when R is a hydroxyl protecting group, the compound in the general formula I is subjected to deprotection to obtain the ganoderan A.
2. The method for preparing ganoderan A according to claim 1, wherein the solvent used in the condensation reaction is ethanol, methanol or isopropanol, preferably isopropanol.
3. The method for preparing ganoderan A according to claim 2, wherein the condensation reaction comprises the following steps: dispersing the compound of the general formula II in a solvent, adding NaOH aqueous solution, then diluting the compound of the general formula III with the solvent at room temperature, dropwise adding the diluted compound of the general formula III into a system, adding hydrochloric acid to quench the reaction after the reaction is completed, and carrying out post-treatment and purification to obtain the compound of the general formula I.
4. The method for preparing ganoderan A according to claim 1, wherein the compound of formula II is synthesized by reacting a compound of formula IV as a raw material, wherein the reaction equation is as follows:
wherein R is a hydroxyl protecting group or H;
when R is H, the compound shown in the formula IV is directly obtained by reaction;
when R is a hydroxyl protecting group, the compound is obtained by adding a protecting group on one step.
5. The method for preparing ganoderan A according to claim 4, wherein the compound of formula IV is obtained from dibenzofuran.
6. The method for preparing ganoderan A according to claim 5, wherein said dibenzofuran is subjected to acylation reaction, Bayer-Virgiger oxidation rearrangement reaction and deacylation reaction in sequence to obtain the compound of formula IV, wherein the reaction equation is as follows:
7. the method for preparing ganoderan A according to any one of claims 1-6, wherein the hydroxyl protecting group is an ester protecting group or a silyl ether protecting group.
8. The method according to claim 7, wherein the hydroxyl-protecting group is acetyl (Ac) or tert-butyldimethyl (TBS).
9. The method for preparing ganoderan A according to any one of claims 1-6, wherein R is H.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102414164A (en) * | 2009-04-24 | 2012-04-11 | 出光兴产株式会社 | Aromatic amine derivative and organic electroluminescent element using same |
| JP2014198682A (en) * | 2013-03-29 | 2014-10-23 | 新日鉄住金化学株式会社 | Aromatic heterocyclic compound and production method thereof, and organic semiconductor material and organic semiconductor device |
| CN105073754A (en) * | 2013-03-29 | 2015-11-18 | 新日铁住金化学株式会社 | Aromatic heterocyclic compound, manufacturing method thereof, organic semiconductor material, and organic semiconductor device |
| CN106279086A (en) * | 2016-08-08 | 2017-01-04 | 中国科学院昆明植物研究所 | Ganoderma furan A and pharmaceutical composition thereof and its application in pharmacy and food |
-
2020
- 2020-07-29 CN CN202010741831.XA patent/CN111646961A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102414164A (en) * | 2009-04-24 | 2012-04-11 | 出光兴产株式会社 | Aromatic amine derivative and organic electroluminescent element using same |
| JP2014198682A (en) * | 2013-03-29 | 2014-10-23 | 新日鉄住金化学株式会社 | Aromatic heterocyclic compound and production method thereof, and organic semiconductor material and organic semiconductor device |
| CN105073754A (en) * | 2013-03-29 | 2015-11-18 | 新日铁住金化学株式会社 | Aromatic heterocyclic compound, manufacturing method thereof, organic semiconductor material, and organic semiconductor device |
| CN106279086A (en) * | 2016-08-08 | 2017-01-04 | 中国科学院昆明植物研究所 | Ganoderma furan A and pharmaceutical composition thereof and its application in pharmacy and food |
Non-Patent Citations (2)
| Title |
|---|
| CHIRANJEEVI, BARREDDI: "Iron-catalyzed aryl-aryl cross coupling route for the synthesis of 1-(2-amino)-phenyl dibenzo[b,d]furan-2-ol derivatives and their biological evaluation", 《RSC ADVANCES》 * |
| RIVEIRA, MARTIN J: "One-Pot Organocatalytic Tandem Aldol/Polycyclization Reactions between 1,3-Dicarbonyl Compounds and a,b,g,d-Unsaturated Aldehydes for the Straightforward Assembly of Cyclopenta[b]furan-Type Derivatives: New Insight into the Knoevenagel Reaction", 《CHEMISTRY - A EUROPEAN JOURNAL》 * |
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