CN103787951A - Method for synthesizing natural product Glycozolicine - Google Patents

Method for synthesizing natural product Glycozolicine Download PDF

Info

Publication number
CN103787951A
CN103787951A CN201410027154.XA CN201410027154A CN103787951A CN 103787951 A CN103787951 A CN 103787951A CN 201410027154 A CN201410027154 A CN 201410027154A CN 103787951 A CN103787951 A CN 103787951A
Authority
CN
China
Prior art keywords
glycozolicine
natural product
synthesis
reaction
degrees celsius
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201410027154.XA
Other languages
Chinese (zh)
Other versions
CN103787951B (en
Inventor
孙江涛
丁冬
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CHANGZHOU XIAOGUO INFORMATION SERVICES Co.,Ltd.
Original Assignee
Changzhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Changzhou University filed Critical Changzhou University
Priority to CN201410027154.XA priority Critical patent/CN103787951B/en
Publication of CN103787951A publication Critical patent/CN103787951A/en
Application granted granted Critical
Publication of CN103787951B publication Critical patent/CN103787951B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles 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 carbon atoms of the ring system

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The invention discloses a method for synthesizing a natural product Glycozolicine, and belongs to the field of organic synthesis. The method comprises the following steps: catalyzing the reaction of 6-diazo-2-cyclohexene-1-ketone and paratoluidine by using copper to generate 2-(4-toluido) phenol; and then preparing the natural product (b) Glycozolicine (/b) through methylation and C-C bond coupling catalyzed by using palladium. The method disclosed by the invention has the advantages of few steps, easiness for operation and high yield.

Description

The method of synthesis of natural product Glycozolicine a kind of
Technical field
The invention belongs to organic synthesis field, specifically the method for synthesis of natural product Glycozolicine a kind of.
Background technology
Natural product Glycozolicine is a kind of alkaloid that contains carbazole structure, and it is separation and Extraction from Glycosmispentaphylla.
The method of reporting at present synthetic Glycozolicine is as follows:
1）Synthesis,(6),929-933;2011
2）Tetrahedron67(2011)5725e5731
Above-mentioned two kinds of equal Shortcomings of method: method (1) need to just can obtain target product by more step;
And method (2) problem is that the position of ring closure reaction exists selectivity to cause finally obtaining mixture.
Summary of the invention
The invention provides a kind of copper catalysis 6-diazo-2-tetrahydrobenzene-1-ketone of using and generate 2-(4-toluino) phenol with reacting of para-totuidine; Can obtain natural product Glycozolicine through the C-C key coupling of Hypermethylation and palladium catalysis again.Its reaction scheme is as follows:
Figure BDA0000459745950000021
A method of synthesis of natural product Glycozolicine, specifically carry out in accordance with the following steps:
(1) 6-diazo-2-tetrahydrobenzene-1-ketone, para-totuidine, copper catalyst and solvent are added in tube sealing, under 80 degrees Celsius, air-proof condition, react and can obtain 2-(4-toluino) phenol by high yield in 3 hours;
(2) under room temperature, in reaction flask, add 2-(4-toluino) phenol, methyl iodide, salt of wormwood and acetone, be then warming up to 60 degrees Celsius of reactions and can obtain N-(2-p-methoxy-phenyl) para-totuidine;
(3), under nitrogen protection condition, in tube sealing, add N-(2-p-methoxy-phenyl) para-totuidine, palladium and acetic acid; Then be warmed up to 140 degrees Celsius of lucifuge reactions and can obtain Glycozolicine in 24 hours.
Wherein the described copper catalyst of step (1) is: neutralized verdigris, cuprous chloride, cuprous bromide, cuprous iodide, cupric bromide, copper trifluoromethanesulfcomposite and acetylacetone copper, wherein neutralized verdigris is optimum catalyst.
Wherein the atmosphere of the reaction described in step (1) is respectively: nitrogen, air and oxygen, optimum reaction condition is oxygen atmosphere foxing part.
Wherein the solvent of the reaction described in step (1) is: methylene dichloride, 1, and 2-ethylene dichloride, Isosorbide-5-Nitrae-dioxane, DMF, methyl-sulphoxide, tetrahydrofuran (THF), toluene and acetonitrile, reaction optimum solvent is Isosorbide-5-Nitrae-dioxane.
Wherein the solvent of the reaction described in step (1) is: 40 degrees Celsius-110 degrees Celsius, reaction optimum temps is 80 degrees Celsius.
The wherein described 6-diazo-2-tetrahydrobenzene-1-ketone of step (1): para-totuidine: the molar ratio of copper catalyst is: 1～3:1:0.005～0.2.
Wherein described 2-(4-toluino) phenol of step (2): methyl iodide: the molar ratio of salt of wormwood is: 1:6:3.
Wherein described N-(2-p-methoxy-phenyl) para-totuidine of step (3): the molar ratio of palladium is: 1:1.3.
The invention provides in sum a kind of method simple to operate, the convenient and swift preparation that realizes natural product Glycozolicine.
Advantage of the present invention: method of the present invention have advantages of simple to operate, yield is high.
Embodiment
Give specific examples explanation to the present invention below:
I step: 2-(4-toluino) phenol synthetic
Embodiment 1: under oxygen atmosphere foxing part, add para-totuidine (2g), 6-diazo-2-tetrahydrobenzene-1-ketone (2.3g), neutralized verdigris (0.746g) and Isosorbide-5-Nitrae-dioxane (50mL) in tube sealing; Reaction system is warming up to 80 degrees Celsius of reactions 3 hours in confined conditions.Reaction solution is cooled to room temperature, and decompression evaporates after solvent, and residual solution obtains 2-(4-toluino) phenol (2.9g, productive rate: 80%) by column chromatography purification; 1hNMR (400MHz, CDCl 3) δ 7.16 (d, J=7.6Hz, 1H), 7.09-7.04 (m; 3H), 6.98 (d, J=8.0Hz; 1H), 6.91-6.87 (m, 1H); 6.73 (d, J=8.0Hz, 1H); 5.80 (s, 1H), 5.21 (s; 1H), 2.29 (s, 3H); 13c NMR (125MHz, CDCl 3) δ 150.6,142.8,129.9,129.8,125.5,123.9,121.0,116.4,115.2,20.5
Embodiment 2: under oxygen atmosphere foxing part, add para-totuidine (2g), 6-diazo-2-tetrahydrobenzene-1-ketone (6.9g), neutralized verdigris (0.0186g) and Isosorbide-5-Nitrae-dioxane (50mL) in tube sealing; Reaction system is warming up to 80 degrees Celsius of reactions 3 hours in confined conditions.Reaction solution is cooled to room temperature, and decompression evaporates after solvent, and residual solution obtains 2-(4-toluino) phenol (3.3g, productive rate: 88%) by column chromatography purification; 1h NMR (400MHz, CDCl 3) δ 7.16 (d, J=7.6Hz, 1H), 7.09-7.04 (m; 3H), 6.98 (d, J=8.0Hz; 1H), 6.91-6.87 (m, 1H); 6.73 (d, J=8.0Hz, 1H); 5.80 (s, 1H), 5.21 (s; 1H), 2.29 (s, 3H); 13c NMR (125MHz, CDCl 3) δ 150.6,142.8,129.9,129.8,125.5,123.9,121.0,116.4,115.2,20.5
II step: synthetic (literature method) of N-(2-p-methoxy-phenyl) para-totuidine
In single port bottle, add 2-(4-toluino) phenol (1.2g), methyl iodide (5.1g), salt of wormwood (2.4g) and acetone (10mL), reaction mixture is raised to 60 degrees Celsius of reactions 3 hours; Reaction solution cool to room temperature, evaporate solvent, raffinate with washing with salt solution after acetic acid ethyl dissolution; After organic phase is dry, evaporate to dryness; Resistates obtains N-(2-p-methoxy-phenyl) para-totuidine (1.15g, productive rate: 90%) by column chromatography purification
Synthetic (literature method) of III step: Glycozolicine
Under nitrogen protection condition, in tube sealing, add N-(2-p-methoxy-phenyl) para-totuidine (0.75g), palladium (1.02g) and acetic acid (40mL); After reaction tubes sealing, under condition of nitrogen gas, be warmed up to 140 degrees Celsius of lucifuge reactions 24 hours.Reaction solution cool to room temperature, decompression evaporates acetic acid, and residual solution is adjusted after alkali (pH=8), is used ethyl acetate access with sodium carbonate solution; Organic phase is dry, evaporate to dryness, and crude product obtains Glycozolicine(0.54g by column chromatography purification; Yield 73%) 1h NMR (400MHz, CDCl 3) δ 8.15 (s, 1H), 7.84 (s, 1H); 7.64 (d, J=7.6Hz, 1H), 7.34 (d; J=8.0Hz, 1H), 7.23 (d, J=8.4Hz; 1H), 7.13 (t, J=7.6Hz, 1H); 6.88 (d, J=8.0Hz, 1H), 4.00 (s; 3H), 2.52 (s, 3H); 13c NMR (100MHz, CDCl 3) δ 145.7,137.5,130.1,128.7,127.1,124.2,123.9,120.4,119.5,112.8,110.6,105.8,55.5,21.5
Shown by the above-mentioned example providing, can realize easily the synthetic of natural product Glycozolicine by method provided by the invention, have advantages of that step is few, simple to operate, yield is high.

Claims (8)

1. a synthesis of natural product glycozolicinemethod, it is characterized in that carrying out in accordance with the following steps:
(1) 6-diazo-2-tetrahydrobenzene-1-ketone, para-totuidine, copper catalyst and solvent are added in tube sealing, under 80 degrees Celsius, air-proof condition, react 3hour can high yield obtain 2-(4-toluino) phenol;
(2) under room temperature, in reaction flask, add 2-(4-toluino) phenol, methyl iodide, salt of wormwood and acetone, be then warming up to 60 degrees Celsius of reactions and can obtain N-(2-p-methoxy-phenyl) para-totuidine;
(3), under nitrogen protection condition, in tube sealing, add N-(2-p-methoxy-phenyl) para-totuidine, palladium and acetic acid; Then being warmed up to 140 degrees Celsius of lucifuge reactions can obtain for 24 hours glycozolicine.
2. a kind of synthesis of natural product according to claim 1 glycozolicinemethod, it is characterized in that the described copper catalyst of step (1) is wherein: neutralized verdigris, cuprous chloride, cuprous bromide, cuprous iodide, cupric bromide, copper trifluoromethanesulfcomposite and acetylacetone copper, wherein neutralized verdigris is optimum catalyst.
3. a kind of synthesis of natural product according to claim 1 glycozolicinemethod, it is characterized in that the atmosphere of the described reaction of step (1) is wherein respectively: nitrogen, air and oxygen, optimum reaction condition is oxygen atmosphere foxing part.
4. a kind of synthesis of natural product according to claim 1 glycozolicinemethod, it is characterized in that the solvent of the described reaction of step (1) is wherein: methylene dichloride, 1,2-ethylene dichloride, 1,4-dioxane, N, dinethylformamide, methyl-sulphoxide, tetrahydrofuran (THF), toluene and acetonitrile, reaction optimum solvent is Isosorbide-5-Nitrae-dioxane.
5. a kind of synthesis of natural product according to claim 1 glycozolicinemethod, it is characterized in that the solvent of the described reaction of step (1) is wherein: 40 degrees Celsius-110 degrees Celsius, reaction optimum temps is 80 degrees Celsius.
6. a kind of synthesis of natural product according to claim 1 glycozolicinemethod, it is characterized in that 6-diazo-2-tetrahydrobenzene-1-ketone that step (1) is wherein described: para-totuidine: the molar ratio of copper catalyst is: 1 ~ 3:1:0.005 ~ 0.2.
7. a kind of synthesis of natural product according to claim 1 glycozolicinemethod, it is characterized in that 2-(4-toluino) phenol that step (2) is wherein described: methyl iodide: the molar ratio of salt of wormwood is: 1:6:3.
8. a kind of synthesis of natural product according to claim 1 glycozolicinemethod, it is characterized in that N-(2-p-methoxy-phenyl) para-totuidine that step (3) is wherein described: the molar ratio of palladium is: 1:1.3.
CN201410027154.XA 2014-01-21 2014-01-21 A kind of method of synthesis of natural product Glycozolicine Active CN103787951B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410027154.XA CN103787951B (en) 2014-01-21 2014-01-21 A kind of method of synthesis of natural product Glycozolicine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410027154.XA CN103787951B (en) 2014-01-21 2014-01-21 A kind of method of synthesis of natural product Glycozolicine

Publications (2)

Publication Number Publication Date
CN103787951A true CN103787951A (en) 2014-05-14
CN103787951B CN103787951B (en) 2016-04-13

Family

ID=50664063

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410027154.XA Active CN103787951B (en) 2014-01-21 2014-01-21 A kind of method of synthesis of natural product Glycozolicine

Country Status (1)

Country Link
CN (1) CN103787951B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103992233A (en) * 2014-05-16 2014-08-20 常州大学 Method for synthesizing 2-(aryl amino)phenol in presence of iron catalyst

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002155075A (en) * 2000-11-20 2002-05-28 Hanmi Pharm Co Ltd Method for producing 1,2,3,9-tetrahydro-9-methyl-3-[2(2- methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one
JP2002241365A (en) * 2001-02-14 2002-08-28 Asahi Kasei Fainkemu Kk Method for producing 2-hydroxycarbazole
CN1962635A (en) * 2006-11-17 2007-05-16 浙江工业大学 Indoles compound preparation method
CN102382038A (en) * 2011-09-22 2012-03-21 浙江大学 Preparation method for synthesizing carbazoles alkaloid Siamenol

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002155075A (en) * 2000-11-20 2002-05-28 Hanmi Pharm Co Ltd Method for producing 1,2,3,9-tetrahydro-9-methyl-3-[2(2- methyl-1h-imidazol-1-yl)methyl]-4h-carbazol-4-one
JP2002241365A (en) * 2001-02-14 2002-08-28 Asahi Kasei Fainkemu Kk Method for producing 2-hydroxycarbazole
CN1962635A (en) * 2006-11-17 2007-05-16 浙江工业大学 Indoles compound preparation method
CN102382038A (en) * 2011-09-22 2012-03-21 浙江大学 Preparation method for synthesizing carbazoles alkaloid Siamenol

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KIRIL TISHINOV，等: "Cu(I)-catalysed N–H insertion in water: a new tool for chemical biology", 《CHEM. SCI.》, vol. 4, 31 December 2013 (2013-12-31), pages 4401 - 4406 *
MARC-OLIVIER SIMON，等: "Catalytic Aerobic Synthesis of Aromatic Ethers from Non-Aromatic Precursors", 《ANGEW. CHEM.》, vol. 124, 31 December 2012 (2012-12-31), pages 7655 - 7658 *
RAFAEL BAUTISTA，等: "Total Synthesis of the Natural Carbazoles Glycozolicine, Mukoline, and Mukolidine, Starting from 4,5-Dimethyleneoxazolidin-2-ones", 《SYNTHESIS》, vol. 6, 31 December 2011 (2011-12-31), pages 0929 - 0933 *
STRAKOVA, I.，等: "Reactions of 5-diazo-6,6-dimethyl-4-oxo-1-phenyl-4,5,6,7- tetrahydroindazole with amines and enamines in the presence of dirhodium tetraacetat", 《LATVIJAS KIMIJAS ZURNALS》, 31 December 2008 (2008-12-31), pages 357 - 362 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103992233A (en) * 2014-05-16 2014-08-20 常州大学 Method for synthesizing 2-(aryl amino)phenol in presence of iron catalyst
CN103992233B (en) * 2014-05-16 2016-06-08 常州大学 A kind of method of synthesis 2-(arylamino) phenol of ferrum catalysis

Also Published As

Publication number Publication date
CN103787951B (en) 2016-04-13

Similar Documents

Publication Publication Date Title
Liu et al. Organocatalytic asymmetric reaction of indol-2-yl carbinols with enamides: synthesis of chiral 2-indole-substituted 1, 1-diarylalkanes
SG187140A1 (en) Process for preparing aminobenzoylbenzofuran derivatives
CN103613498B (en) The synthetic method of Win-35833
CN105384788A (en) Tildipirosin preparation method
CN109734686B (en) Catalytic synthesis method of 2-substituted benzofuran compound
CN104031029A (en) Synthesis method of 2-[(-4-chlorophenyl)(4-piperidinyl-oxy)methyl]pyridine having single optical isomer
CN105713063A (en) Abiraterone acetate preparation method
CN103787951B (en) A kind of method of synthesis of natural product Glycozolicine
CN103180325A (en) Method for preparing beta-artemether
CN104004006B (en) A kind of synthetic method of 3,6-dihydro-2H-pyrans-4-pinacol borate
CN103319356A (en) One-step green synthesis process of antimalarial raw material benflumetol
CN103497138B (en) A kind ofly utilize zinc chloride, method that POTASSIUM BOROHYDRIDE prepares cis-hexahydroisoindoline
CN103387547B (en) A kind of method preparing phonetic mite amine
CN105294556A (en) Method for preparing montelukast acid
CN101891569B (en) Preparation method of alpha-aromatic ketone compound
CN103787952B (en) A kind of method of synthesis of natural product C lausenine
CN107382640B (en) β -aryl phenylpropanone compound synthesis method
CN107325078B (en) Preparation method of cilostazol
CN105017146A (en) Synthetic method for 3,4-dihydro-7-hydroxy-2(1H)-quinolinone
CN104478791A (en) Preparation method of (S)-5-R-5-azaspiro (2,4) heptane-6-carboxylic acid
CN103073498A (en) Novel preparation method for (R)-Alpha-amino-e-caprolactam
CN105085460B (en) A kind of preparation method of 4 phenyl coumarin class compound
CN103613531B (en) Synthesis method of 1-tert-butylmethoxycarbonyl-3-piperidone
CN103819392A (en) Method for synthesizing Murrayafoline A as alkaloid
CN102875344A (en) Method for preparing 2, 3, 4-trimethoxybenzaldehyde

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20210316

Address after: Room 407-2-6, building C, Tian'an Digital City, 588 Changwu South Road, Wujin high tech Industrial Development Zone, Changzhou City, Jiangsu Province 213000

Patentee after: CHANGZHOU XIAOGUO INFORMATION SERVICES Co.,Ltd.

Address before: Gehu Lake Road Wujin District 213164 Jiangsu city of Changzhou province No. 1

Patentee before: CHANGZHOU University