CN105153172A - Synthesis method of trisphaeridine - Google Patents
Synthesis method of trisphaeridine Download PDFInfo
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- CN105153172A CN105153172A CN201510668831.0A CN201510668831A CN105153172A CN 105153172 A CN105153172 A CN 105153172A CN 201510668831 A CN201510668831 A CN 201510668831A CN 105153172 A CN105153172 A CN 105153172A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of trisphaeridine alkaloid, which comprises the following steps: adding reactants N-protected aniline and 5-bromo-6-bromomethyl-1,3-benzodioxole into a solvent, adding a metal palladium catalyst, a ligand and an alkali, carrying out chemical reaction under heating and inert gas protective conditions, and after the reaction finishes, carrying out after-treatment to obtain the compound pure product. By using the simple accessible N-protected aniline and the commercial accessible 5-bromo-6-bromomethyl-1,3-benzodioxole as the raw materials, one-pot three-step cascade reaction is performed to obtain the trisphaeridine alkaloid. The method is simple to operate, and has the characteristics of simple after-treatment, higher yield and the like.
Description
Technical field
The invention belongs to natural product synthesis technical field, be specifically related to the alkaloidal preparation method of trisphaeridine.
Background technology
Trisphaeridine, be a kind of from amrallid Asturias narcissus (
narcissusasturiensis) a kind of alkaloid of separating.At present, the synthetic method about this compound is more, and most methods is all use comparatively complicated raw material to realize through polystep reaction, and the present invention is with simple and easy to get
nthe adjacent bromine bromobenzyl that the aniline of-protection and business are easy to get is raw material, adopts the method for " treating different things alike ", can easy, efficient synthesis trisphaeridine alkaloid.
Summary of the invention
The object of the present invention is to provide a kind of with
naniline and the adjacent bromine bromobenzyl of-protection are that the alkaloidal method of trisphaeridine prepared by raw material.
Its reaction process is as follows:
Wherein
for
nthe aromatic amine compound of-protection, PG(ProtectedGroup) be protecting group, comprise-Ms(methylsulfonyl) ,-Ts(is to Methyl benzenesulfonyl base) ,-Ns(p-nitrophenyl alkylsulfonyl) or-Ac(ethanoyl).
Catalyzer described above is zeroth order palladium [as tetrakis triphenylphosphine palladium, three (dibenzalacetone) two palladium etc.] and divalent palladium catalyzer [palladium, palladium trifluoroacetate, trimethylacetic acid palladium, Palladous chloride etc.].
In above-mentioned reaction, part is Phosphine ligands [triphenylphosphine, tri-n-butyl phosphine, two (diphenylphosphine) propane, 4 of 1,3-, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene, 2,2'-pair-(diphenyl phosphine)-1,1'-dinaphthalene, two (diphenylphosphine) ferrocene of 1,1'-etc.] and nitrogen ligand [pyridine, 1,10-phenanthroline etc.].
In above-mentioned reaction, alkali is mineral alkali, as sodium hydroxide, potassium hydroxide, Quilonum Retard, sodium carbonate, salt of wormwood, cesium carbonate, trimethylacetic acid sodium etc.
In above-mentioned reaction, solvent can be selected has better deliquescent solvent to reaction substrate and target product, is beneficial to carrying out smoothly of reaction, such as:
n,
n-dimethyl formamide, dimethyl sulfoxide (DMSO), toluene, Isosorbide-5-Nitrae-dioxane, acetonitrile etc.
In above-mentioned reaction, rare gas element is argon gas or nitrogen.
Above-mentioned temperature of reaction is 120 ~ 160 DEG C.
The time of above-mentioned reaction is 20-28 hour.
The separation of above-mentioned reaction gains can adopt the methods such as chromatogram, crystallization, chromatography, extraction, filtration, is preferably separated by column chromatography methods.
The present invention with
naniline and the adjacent bromine bromobenzyl of-protection are Material synthesis trisphaeridine alkaloid, have the following advantages:
1. the route short (step can obtain target compound) of synthesis, yield is higher.
2. raw material is easy to get, reaction easy handling.
3. obtain target compound by nucleophilic substitution/C-H activation/aromizing cascade reaction.
Accompanying drawing explanation
Fig. 1 is the alkaloidal collection of illustrative plates 1 of trisphaeridine obtained in the embodiment of the present invention.
Fig. 2 is the alkaloidal collection of illustrative plates 2 of trisphaeridine obtained in the embodiment of the present invention.
Embodiment
Introduce the present invention further below in conjunction with drawings and Examples, but the present invention is not limited only to following embodiment, can predict those skilled in the art when in conjunction with prior art, performance may produce many variations.
A kind of with
naniline and the adjacent bromine bromobenzyl of-protection are that the alkaloidal method of trisphaeridine prepared by raw material, and its reaction process is as follows:
。
Preparation method: will
naniline, the luxuriant alkane of 5-bromo-6-brooethyl-1,3-Ben Bing bis-oxazole of-protection, metal palladium catalyst, part and alkali join in organic solvent, react, reacted and obtained the compounds of this invention sterling through aftertreatment under heating and protection of inert gas condition.
Described
nthe structural formula of the aromatic amine compound of-protection is as follows:
PG(ProtectedGroup) be protecting group, comprise-Ms(methylsulfonyl) ,-Ts(is to Methyl benzenesulfonyl base) ,-Ns(p-nitrophenyl alkylsulfonyl) ,-Ac(ethanoyl) etc.
The structural formula of the luxuriant alkane of described 5-bromo-6-brooethyl-1,3-Ben Bing bis-oxazole is as follows:
The alkaloidal structural formula of described trisphaeridine is as follows:
The present invention prepares 6-
hin the preparation method of-phenanthridines, the solvent used in the method for purification by column chromatography is: ethyl acetate and sherwood oil (V:V=1:5).
The alkaloidal operation steps of synthesis trisphaeridine:
Take
n-methanesulfonylaniline (154.1mg; 0.9mmol) with the bromo-6-brooethyl-1 of 5-; luxuriant alkane (the 264.5mg of 3-Ben Bing bis-oxazole; 0.9mmol) in the reaction flask of drying, and add cesium carbonate (1173.0mg, 3.6mmol); palladium trifluoroacetate (15.0mg; 0.045mmol), triphenylphosphine (47.2mg, 0.18mmol) and 6mL anhydrous
n,
n-dimethyl formamide, under nitrogen protection, 160 ° of C react 24 hours.After completion of the reaction reaction solution is poured in 30mL saturated aqueous common salt, be extracted with ethyl acetate (5x30mL), merge organic phase, anhydrous Na
2sO
4drying, filters, and concentrates to obtain crude product.Target compound trisphaeridine (110.5mg, 55%) is obtained through pillar layer separation.
The present embodiment obtains
trisphaeridinecompound data:
Trisphaeridine:Whitesolid,mp145.1-146.7°C;
1HNMR(400MHz,CDCl
3)
δ9.09(s,1H),8.37(d,
J=8.0Hz,1H),8.14(d,
J=8.0Hz,1H),7.91(s,1H),7.71-7.67(m,1H),7.65-7.61(m,1H),7.34(s,1H),6.17(s,2H);
13CNMR(100MHz,CDCl
3)
δ151.9,151.7,148.3,144.2,130.4,130.2,128.2,126.8,124.4,123.2,122.1,105.7,102.1,100.1;HRMS(ESI-TOF)Calcd.forC
14H
10NO
2[M+H]
+:224.0706;found:224.0706。
Claims (9)
1. the alkaloidal preparation method of trisphaeridine, is characterized in that: its reaction formula is:
；
Described
for
nthe aromatic amine compound of-protection, PG(ProtectedGroup) be protecting group, comprise-Ms(methylsulfonyl) ,-Ts(is to Methyl benzenesulfonyl base) ,-Ns(p-nitrophenyl alkylsulfonyl) or-Ac(ethanoyl).
2. preparation method according to claim 1, is characterized in that: the alkali of described reaction is mineral alkali, comprises sodium hydroxide, potassium hydroxide, Quilonum Retard, sodium carbonate, salt of wormwood, cesium carbonate or trimethylacetic acid sodium.
3. preparation method according to claim 1, is characterized in that: the solvent of described reaction is
n,
n-dimethyl formamide, dimethyl sulfoxide (DMSO), toluene, Isosorbide-5-Nitrae-dioxane or acetonitrile.
4. preparation method according to claim 1, it is characterized in that: the Pd catalyzer of described reaction be zeroth order palladium or/and divalent palladium catalyzer, comprise tetrakis triphenylphosphine palladium, three (dibenzalacetone) two palladium, palladium, palladium trifluoroacetate, trimethylacetic acid palladium and Palladous chloride.
5. preparation method according to claim 1, it is characterized in that: the part of described reaction be Phosphine ligands or/and nitrogen ligand, comprise triphenylphosphine, tri-n-butyl phosphine, 1, two (diphenylphosphine) propane, 4 of 3-, two diphenylphosphine-9, the 9-dimethyl xanthene of 5-, 2,2'-two-(diphenyl phosphine)-1,1'-dinaphthalene, 1,1'-two (diphenylphosphine) ferrocene, pyridine and 1,10-phenanthroline.
6. preparation method according to claim 1, is characterized in that: the rare gas element of described reaction is argon gas or nitrogen.
7. according to the preparation method one of claim 1-6 Suo Shu, it is characterized in that: the temperature of described reaction is 120 ~ 160 DEG C.
8. according to the preparation method one of claim 1-6 Suo Shu, it is characterized in that: the time of described reaction is 20-28 hour.
9. preparation method according to claim 1, is characterized in that: the separation of described reaction gains adopts chromatography, crystallization process, chromatography or extraction process.
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| CN201510668831.0A CN105153172A (en) | 2015-10-13 | 2015-10-13 | Synthesis method of trisphaeridine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114773354A (en) * | 2022-04-08 | 2022-07-22 | 武汉理工大学 | Simple synthesis method of Trisphaeridine |
-
2015
- 2015-10-13 CN CN201510668831.0A patent/CN105153172A/en active Pending
Non-Patent Citations (4)
| Title |
|---|
| JOYDEV K. LAHA ET AL.: "Palladium-Catalyzed Regiocontrolled Domino Synthesis of N Sulfonyl Dihydrophenanthridines and Dihydrodibenzo[c,e]azepines: Control over the Formation of Biaryl Sultams in the Intramolecular Direct Arylation", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| MAESTRI G ET AL.: "Expeditious Synthesis of Phenanthridines from Benzylamines via Dual Palladium Catalysis", 《ORGANIC LETTERS》 * |
| ROBERTO SANZ ET AL.: "Functionalized Phenanthridine and Dibenzopyranone Derivatives through Benzyne Cyclization-Application to the Total Syntheses of Trisphaeridine and N-Methylcrinasiadine", 《EUR.J.ORG.CHEM》 * |
| SOURABH MISHRA ET AL.: "Expeditious approach to the Amarylidaceae alkaloids, crinasiadine and its analogues, via a palladium-catalyzed intramolecular direct C-H arylation", 《INDIAN JOURNAL OF CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114773354A (en) * | 2022-04-08 | 2022-07-22 | 武汉理工大学 | Simple synthesis method of Trisphaeridine |
| CN114773354B (en) * | 2022-04-08 | 2023-03-24 | 武汉理工大学 | Simple synthesis method of Trisphaeridine |
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