CN112707795B - Preparation method of Icetexane type abietane diterpene - Google Patents
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
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- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
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- C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
Abstract
The invention discloses a preparation method of Icetexane type abietane diterpenoid, which comprises the following steps: s1: adding carnosic acid into a methylation system, carrying out solid-liquid separation, and collecting a solid phase to obtain an intermediate 2; s2: adding the intermediate 2 into a reduction system, carrying out solid-liquid separation, and collecting a solid phase to obtain a preparation intermediate 3; s3, adding the intermediate 3 into a rearrangement system, performing solid-liquid separation, and collecting a solid phase to obtain the Icetexane type abietane diterpene; the synthesis method has the characteristics of short reaction time, high selectivity, high yield, large-scale preparation and no need of protection in key steps, and can be widely popularized and applied.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of Icetexane type abietane diterpene.
Background
The Icetexane type abietane diterpenoid is a B-ring expanded-ring type abietane diterpenoid component, and about 70 natural products of the type reported at present are widely distributed and found in plants of multiple families. The (-) -barbavasol is the first to separate an Icetexane type abietane diterpene from Coleus barbatus Bentham, and animal experiments show that the Barbatusol has stronger hypotensive activity. (-) -Barbatisol (CAS 88515-76-8) is also present in Salvia przewalski.
(-) -Barbatisol has a low content in plants and is mainly prepared by synthetic methods. The total synthesis of iceteexane type abietane diterpenes is based on a metal-mediated cycloisomerization reaction strategy. In the related technology, a Lewis acid catalyzed intramolecular Friedel-Crafts reaction (Friedel-Crafts) is utilized to cyclize and fully synthesize a barbatisol racemate; furthermore, semisynthetic strategies based on high yield natural products have been reported; taking carnosic acid which is a high-yield natural product in rosemary as a raw material, carrying out strong acid catalyzed carbenium rearrangement reaction to obtain a mixture of Icetexane type diterpenoid derivatives, and carrying out functional group conversion to obtain other Icetexane type abietane diterpenoids; (-) -pisiferin (CAS 110659-76-2), (-) -barbatisol and other Icetexane type abietane diterpenes are synthesized by taking (+) -Pisiferic acid as a raw material, and the key step is that reduced (+) -Pisiferic acid derivatives are subjected to carbocation rearrangement under the condition of protonic acid to obtain an expanded ring type product. However, the above process is poor in chemical selectivity and a mixture is obtained.
Therefore, there is a need for a process for the preparation of an iceteexane-type abietane diterpene, which process has good selectivity.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: a preparation method of Icetexane type abietane diterpene has good selectivity.
In order to solve the technical problems, the technical scheme provided by the invention is as follows: a preparation method of Icetexane type abietane diterpene comprises the following steps:
s1, methylation: adding Carnosic Acid (Carnosic Acid) into a methylation system, carrying out solid-liquid separation, and collecting a solid phase to obtain an intermediate 2;
s2, reduction: adding the intermediate 2 into a reduction system, carrying out solid-liquid separation, and collecting a solid phase to obtain an intermediate 3;
s3, rearrangement: adding the intermediate 3 into a rearrangement system, performing solid-liquid separation, and collecting a solid phase to obtain the Icetexane type abietane diterpene;
wherein the rearrangement system comprises a rearrangement reagent and a rearrangement reaction solvent;
the rearrangement reagents include organophosphines and azo reagents.
According to some embodiments of the invention, the preparation method further comprises a process in which the starting Carnosic Acid (1)) is isolated and purified from rosemary extract; wherein the structural formula of carnosic acid is as follows:
according to some embodiments of the invention, the process of separation and purification comprises the following operations:
the preparation method comprises the steps of taking rosemary extract as a raw material, and preparing carnosic acid through dissolution, filtration and recrystallization.
According to some embodiments of the invention, the rosemary extract is a rosemary extract having a carnosic acid content of about 60% by weight.
According to some embodiments of the invention, the solvent in the dissolution process is at least one of petroleum ether, ethyl acetate, tetrahydrofuran, diethyl ether, 1, 2-dichloroethane, toluene, chlorobenzene, cyclohexane and n-heptane.
According to some embodiments of the invention, the solvent in the dissolving process is a mixed solvent of petroleum ether and ethyl acetate.
According to some preferred embodiments of the invention, the petroleum ether and ethyl acetate are present in a volume ratio of about 1: 3.
according to some embodiments of the invention, the recrystallization solvent is at least one of diethyl ether, tetrahydrofuran, acetone, methanol, ethanol, isopropanol, n-butanol, and ethyl acetate.
According to some preferred embodiments of the invention, the recrystallization solvent is ethanol.
According to some embodiments of the invention, the methylation system comprises a methylating agent, a base and a methylation reaction solvent.
According to some embodiments of the invention, the methylating agent is at least one of methyl iodide, diethyl sulfate, diazomethane and trisilyldiazomethane.
According to some preferred embodiments of the invention, the methylating agent is diazomethane.
According to some embodiments of the invention, the base is at least one of carbonate, triethylamine and 4-dimethylaminopyridine.
According to some embodiments of the invention, the carbonate is at least one of potassium carbonate and cesium carbonate.
According to some embodiments of the invention, the methylation reaction solvent is at least one of acetone, dimethyl sulfoxide, dimethylformamide, methanol, tetrahydrofuran, toluene, and chlorobenzene.
According to some preferred embodiments of the invention, the methylation reaction solvent is methanol.
According to some embodiments of the invention, the reducing system comprises a reducing agent and a reducing reaction solvent.
According to some embodiments of the invention, the reducing agent is lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride, and sodium dihydrobis (2-methoxyethoxy) aluminate.
According to some embodiments of the invention, the reducing agent is lithium aluminum hydride.
According to some embodiments of the invention, the reduction reaction solvent is at least one of tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether and toluene.
According to some preferred embodiments of the invention, the reduction reaction solvent is tetrahydrofuran.
According to some embodiments of the invention, the azo reagent is at least one of diisopropyl azodicarboxylate (DIAD) and diethyl azodicarboxylate (DEAD).
According to some embodiments of the invention, the organophosphine comprises triphenylphosphine (PPh)3) At least one of tri-tert-butylphosphine, tricyclohexylphosphine, and Binaphthyldiphenylphosphine (BINAP).
According to some embodiments of the invention, the ratio of the amounts of substance of the organophosphine and the azo reagent is 0.5: 1-5: 1.
according to some embodiments of the invention, the concentration of said intermediate 3 in the rearrangement system ranges from 0.01mol/L to 5.0 mol/L.
According to some embodiments of the invention, the rearrangement reagent is PPh3And DIAD.
According to some embodiments of the invention, the rearrangement reaction solvent is at least one of tetrahydrofuran, methyltetrahydrofuran, 1, 4-dioxane, diethyl ether, methyl tert-butyl ether, and toluene.
According to some embodiments of the invention, the rearrangement reaction solvent is tetrahydrofuran.
The preparation method of the Icetexane type abietane diterpenoid provided by the embodiment of the invention has at least the following beneficial effects: preparing the reduced carnosic acid derivative into Icetexane type abietane diterpene with high efficiency and high selectivity by utilizing organic phosphine and an azo reagent; the preparation method has the characteristics of short reaction time, high selectivity, high yield, large-scale preparation and no need of protection in key steps, and can be widely popularized and applied.
Drawings
FIG. 1 is a synthetic route diagram according to an embodiment of the present invention.
Detailed Description
The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.
The chemicals used in the reactions of the following steps are all commercially available starting materials and do not require further processing. The reaction yield of each step is calculated as the separation yield of column chromatography, and each step of reaction is detected by a Qingdao silica gel thin-layer analysis plate under UV and is heated and developed after being soaked by an ethanol solution of sulfuric acid and phosphomolybdic acid.
The nuclear magnetic spectrum was obtained by analysis of Bruker Advance 500 (1H: 500MHz, 13C: 125 MHz). The following abbreviations are used for the split case, s for singlet, d for doubtlet, t for triplet, q for quartz, m for multiplex, and b for broad.
The embodiment of the invention is as follows: a method for preparing an iceteexane type abietane diterpene, as shown in figure 1, comprising the following steps:
s1, methylation:
1.0g (3mmol) of Compound 1 (carnosic acid) was weighed out into a 100mL round-bottomed flask, dissolved by adding 12.5mL of toluene and 2.5mL of methanol, and 3mL of a trimethylsilyl diazomethane-in-hexane solution (2.0mol/L, 6mmol) was slowly added dropwise at 0 ℃. TLC detection, after completion of the reaction, 1mL of glacial acetic acid was added dropwise to the reaction mixture, the reaction solvent was removed by rotary evaporation, 50mL of saturated brine was added, extraction was performed 3 times with ethyl acetate in an amount of 30mL each time, and the ethyl acetate layer was dried over anhydrous sodium sulfate and subjected to silica gel column chromatography (volume ratio of PE (petroleum ether) to EA (ethyl acrylate) was 10:1) to obtain 945mg of an intermediate (yellow solid, yield 91%).
1H NMR(400MHz,CDCl3)δ7.52(s,1H),6.59(s,1H),5.87(s,1H),3.71(s,3H),3.35(dd,J＝11.1,2.7Hz,1H),3.25(dt,J＝13.8,6.9Hz,1H),2.85(dd,J＝9.4,4.5Hz,2H),2.39–2.27(m,1H),1.94–1.87(m,1H),1.74(dt,J＝14.0,3.3Hz,1H),1.69–1.64(m,1H),1.61(dd,J＝12.7,1.9Hz,1H),1.54–1.47(m,1H),1.37(dd,J＝13.3,4.6Hz,1H),1.31(dd,J＝9.2,4.2Hz,1H),1.25(dd,J＝6.9,4.4Hz,6H),1.05(s,3H),0.84(s,3H).
S2, reduction:
228mg (6mmol) of lithium aluminum hydride are weighed into a dry two-necked flask, 5mL of anhydrous tetrahydrofuran are added, and 10mL of anhydrous tetrahydrofuran, N, in which 692mg (2mmol) of Compound 2 is dissolved are added dropwise at 0 deg.C2And (4) refluxing under protection. After completion of the reaction, sodium sulfate decahydrate was slowly added to the reaction solution at 0 ℃ until no air bubbles were generated, the reaction solution was suction-filtered with celite, and silica gel column chromatography was performed after the filtrate was spin-dried (volume ratio of PE to EA was 10:1), to obtain 458mg of intermediate 3 (white solid, yield 72%).
1H NMR(400MHz,DMSO)δ9.74(s,1H),7.52(s,1H),6.57(s,1H),6.35(s,1H),4.26(d,J＝10.0Hz,1H),3.72(d,J＝10.0Hz,1H),3.20(d,J＝13.7Hz,1H),3.09(dd,J＝13.8,6.9Hz,1H),2.74(dd,J＝8.7,3.7Hz,2H),1.74–1.60(m,2H),1.53–1.41(m,3H),1.24(d,J＝5.3Hz,2H),1.12(dd,J＝6.9,4.3Hz,6H),1.00(dd,J＝13.4,10.6Hz,1H),0.94(s,3H),0.88(s,3H).
S3, rearrangement:
636mg (2.0mmol) of Compound 3 and 786mg of triphenylphosphine (3.0mmol) are weighed into a 100mL dry round bottom flask, dissolved by adding 20mL of anhydrous tetrahydrofuran, and 606mg of DIAD (3.0mmol) are added dropwise at 0 ℃. The reaction is carried out at room temperature for about 10 min. After completion of the reaction, the reaction mixture was evaporated by rotary evaporation and subjected to silica gel column chromatography (volume ratio of PE to EA was 10:1) to obtain 552mg of compound 4 (brown oil, yield 92%).
1H NMR(400MHz,CDCl3)δ6.54(s,1H),5.53(d,J＝3.1Hz,1H),5.17(d,J＝49.9Hz,2H),3.70(d,J＝15.0Hz,1H),3.16–3.04(m,2H),2.89–2.70(m,2H),2.09–1.91(m,3H),1.83(dd,J＝11.7,4.3Hz,1H),1.41–1.35(m,1H),1.27(dd,J＝6.9,4.3Hz,6H),1.23–1.16(m,1H),1.12(ddd,J＝12.9,6.1,2.4Hz,1H),0.94(s,3H),0.90(s,3H).
The embodiment of the invention also comprises the purification of the rhamnolic acid, which comprises the following operations:
dissolving herba Rosmarini officinalis extract (60%, 20g) in ethyl acetate (500mL) at room temperature, slowly adding petroleum ether (150mL) while stirring, stirring at room temperature for half an hour, filtering off insoluble substances, collecting filtrate, concentrating, and recrystallizing with ethanol to obtain high-purity carnosic acid (95%, 9 g).
In conclusion, the method for preparing the Icetexane type abietane diterpene provided by the invention utilizes triphenylphosphine and an azo reagent to prepare the Icetexane type abietane diterpene from a reduced carnosic acid derivative with high efficiency and high selectivity; the preparation method has the characteristics of high selectivity, high yield, large-scale preparation and no need of protection in key steps, and can be widely popularized and applied.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the gist of the present invention. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention in the specification or directly or indirectly applied to the related technical field are included in the scope of the present invention.
Claims (12)
1. A preparation method of Icetexane type abietane diterpenoid is characterized by comprising the following steps: the method comprises the following steps:
s1, methylation: adding carnosic acid into a methylation system, carrying out solid-liquid separation, and collecting a solid phase to obtain an intermediate 2;
s2, reduction: adding the intermediate 2 into a reduction system, carrying out solid-liquid separation, and collecting a solid phase to obtain an intermediate 3;
s3, rearrangement: adding the intermediate 3 into a rearrangement system, performing solid-liquid separation, and collecting a solid phase to obtain the Icetexane type abietane diterpene;
wherein the rearrangement system comprises a rearrangement reagent and a rearrangement reaction solvent;
the rearrangement reagent comprises an organic phosphine and an azo reagent;
the methylation system comprises a methylation reagent, a base and a methylation reaction solvent;
the methylating agent is at least one of methyl iodide, diethyl sulfate, diazomethane and trimethylsilyl diazomethane.
2. The method of claim 1, wherein the process for preparing an iceteexane-type abietane diterpene comprises the steps of: the preparation method also comprises the separation and purification of carnosic acid.
3. The method of claim 1, wherein the process for preparing an iceteexane-type abietane diterpene comprises the steps of: the alkali is at least one of carbonate, triethylamine and 4-dimethylamino pyridine.
4. The method of claim 1, wherein the process for preparing an iceteexane-type abietane diterpene comprises the steps of: the methylation reaction solvent is at least one of acetone, dimethyl sulfoxide, dimethylformamide, methanol, tetrahydrofuran, toluene and chlorobenzene.
5. The method of claim 1, wherein the process for preparing an iceteexane-type abietane diterpene comprises the steps of: the reduction system comprises a reduction reagent and a reduction reaction solvent.
6. The method of claim 5, wherein the process for preparing Icetexane-type abietane diterpenes comprises the steps of: the reducing agent is lithium aluminum hydride, sodium borohydride, diisobutyl aluminum hydride and sodium dihydro bis (2-methoxyethoxy) aluminate.
7. The method of claim 5, wherein the process for preparing Icetexane-type abietane diterpenes comprises the steps of: the reduction reaction solvent is at least one of tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether and toluene.
8. The method of claim 1, wherein the process for preparing an iceteexane-type abietane diterpene comprises the steps of: the azo reagent is at least one of DIAD and DEAD.
9. The method of claim 1, wherein the process for preparing an iceteexane-type abietane diterpene comprises the steps of: the organic phosphine comprises at least one of triphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine and binaphthyldiphenylphosphine.
10. The method of claim 8, wherein the process for preparing an iceteexane-type abietane diterpene comprises the steps of: the mass ratio of organic phosphine to azo reagent is 0.5: 1-5: 1.
11. the method of claim 8, wherein the process for preparing an iceteexane-type abietane diterpene comprises the steps of: the concentration range of the intermediate 3 in a rearrangement system is 0.01 mol/L-5.0 mol/L.
12. The method of claim 1, wherein the process for preparing an iceteexane-type abietane diterpene comprises the steps of: the rearrangement reaction solvent is at least one of tetrahydrofuran, methyltetrahydrofuran, 1, 4-dioxane, diethyl ether, methyl tert-butyl ether and toluene.
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| WO2008061720A2 (en) * | 2006-11-24 | 2008-05-29 | Dsm Ip Assets B.V. | Use of tricyclic diterpenes and their derivatives for the treatment, co-treatment or prevention of inflammatory disorders and/or joint disorders |
| CN104804014A (en) * | 2015-03-27 | 2015-07-29 | 云南民族大学 | Icetexane type diterpene dimer compound as well as preparation method and application thereof |
| CN108191812A (en) * | 2017-12-13 | 2018-06-22 | 昆明医科大学 | Carnosic acid derivative and preparation method and application |
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| CN111606917B (en) * | 2020-06-02 | 2021-10-01 | 杭州济蒿医药科技有限公司 | Abietane compound with C-ring-fused lactone ring novel skeleton and preparation method and application thereof |
| CN112707795B (en) * | 2020-12-31 | 2022-04-01 | 中南大学 | Preparation method of Icetexane type abietane diterpene |
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| WO2008061720A2 (en) * | 2006-11-24 | 2008-05-29 | Dsm Ip Assets B.V. | Use of tricyclic diterpenes and their derivatives for the treatment, co-treatment or prevention of inflammatory disorders and/or joint disorders |
| CN104804014A (en) * | 2015-03-27 | 2015-07-29 | 云南民族大学 | Icetexane type diterpene dimer compound as well as preparation method and application thereof |
| CN108191812A (en) * | 2017-12-13 | 2018-06-22 | 昆明医科大学 | Carnosic acid derivative and preparation method and application |
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