CN108329255A - A kind of synthetic method of hexahydro carbazolone derivative - Google Patents
A kind of synthetic method of hexahydro carbazolone derivative Download PDFInfo
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- CN108329255A CN108329255A CN201810224441.8A CN201810224441A CN108329255A CN 108329255 A CN108329255 A CN 108329255A CN 201810224441 A CN201810224441 A CN 201810224441A CN 108329255 A CN108329255 A CN 108329255A
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- hexahydro
- carbazolone
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of synthetic methods of hexahydro carbazolone derivative, belong to technical field of organic synthesis.This approach includes the following steps：In the reactor, tryptamine derivatives, the concentrated sulfuric acid, 4 hexene, 3 ketone is added, reaction is stirred at room temperature, it is quenched after reaction with saturated solution of sodium bicarbonate, then it is extracted with ethyl acetate, vacuum rotary steam removes solvent and can be obtained crude product, and crude by column chromatography purifies to obtain the derivative of six hydrocarbzaolone.The present invention using tryptamine derivatives and 4 hexene, 3 ketone as the derivative of six hydrocarbzaolone of raw material one-step synthesis, have the advantages that synthesis step simple, safe operation, advantages of nontoxic raw materials and it is cheap and easy to get, yield is high, Atom economy is high.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of synthetic method of hexahydro carbazolone derivative.
Background technology
Hexahydro carbazole compound is widely present in the molecule with bioactivity and pharmaceutical activity, be some drugs and
The core skeleton of alkaloid, six hydrocarbzaolones are even more the important intermediate of some natural products synthesis.In recent years, about hexahydro click
The synthetic method of oxazolone is also rarely reported, and especially synthesizes polysubstituted six hydrocarbzaolone.2011, trip book power reported organic
The method of acid and chiral quinolinamine concerted catalysis inner molecular reaction synthesis hexahydro carbazolone derivative；2013, Jun-ichi
Matsuo reports indoles and cyclobutanone in TiCl4Effect issues raw intermolecular [4+2] cycloaddition reaction and synthesizes six hydrocarbzaolones
The method of derivative.But all there is certain substrate limitation in these synthetic methods, for synthesizing polysubstituted six hydrocarbzaolone,
The method of report cannot realize very well (Q.Cai, C.Zheng, J.-W., Zhang, S.-L.,
You.Angew.Chem.Int.Ed.2011,50,8665–8669；M.Kawano,T.Kiuchi,S.Negishi,H.Tanaka,
T.Hoshikawa,J.Matsuo,H.Ishibashi.Angew.Chem.Int.Ed.2013,52,906–910)。
Invention content
In order to solve the disadvantage that the above prior art and shortcoming, the purpose of the present invention is to provide a kind of synthesis hexahydros
Carbazolone derivative method.
The object of the invention is achieved through the following technical solutions.
A kind of synthetic method of hexahydro carbazolone derivative, includes the following steps：
Under an inert atmosphere, compound 1 is dissolved in solvent, acid is then added under ice bath, adds compound 2, often
It is stirred to react under temperature, after reaction with saturation NaHCO3Reaction is quenched, then separating-purifying obtains the hexahydro of 3 kinds of various configurations
Carbazolone derivative；
The compound 1 refers to the compound for having formula (1) structure；The compound 2 refers to formula (2) structure
Compound；
Reaction equation involved by above-mentioned synthetic method is shown below：
Preferably, the inert atmosphere is nitrogen atmosphere.
Preferably, the reaction is carried out in round-bottomed flask.
Preferably, the solvent is acetonitrile.
Preferably, the temperature of the ice bath is 0 DEG C.
Preferably, the acid is the concentrated sulfuric acid.
Preferably, the molar ratio of the addition Yu compound 1 of the acid is (1-1.5)：1.
Preferably, the molar ratio of the compound 1 and compound 2 is 1:(1~2).
It is further preferred that the molar ratio of the compound 1 and compound 2 is 1:1.2.
Preferably, the time being stirred to react is 12h.
Preferably, the separating-purifying includes being extracted with ethyl acetate, then vacuum rotary steam removes solvent and can be obtained thick production
Object, then crude by column chromatography purify to obtain 1 Hes of hexahydro carbazolone derivative Carbazolone of 3 kinds of various configurations
Then Carbazolone 2 and Carbazolone 3 can obtain pure Carbazolone 2 by recrystallization.
It is further preferred that the column chromatography is with petroleum ether:The volume ratio of ethyl acetate is (20~50):1 mixing
Solvent is eluent, most preferably petroleum ether:The volume ratio of ethyl acetate is 20:1.
It is further preferred that the recrystallization is with methanol:The volume ratio of dichloromethane is (5~10):1 mixing is molten
Agent, most preferably methanol:The volume ratio of dichloromethane is 5:1.
The present invention is mainly that cascade reaction one-step synthesis occurs with 4- hexene-3-ones by the tryptamines of acid catalysis benzyl protection
Polysubstituted hexahydro carbazolone derivative.Mainly obtain the derivative of six hydrocarbzaolones of following 3 kinds of configurations：
The preparation method of the present invention has the following advantages that and advantageous effect：
The present invention obtains polysubstituted six hydrocarbzaolone in next step in acid effect with 4- hexene-3-ones with tryptamine derivatives and spreads out
Biology, have the advantages that synthesis step simple, safe operation, advantages of nontoxic raw materials and it is cheap and easy to get, yield is high, Atom economy is high.
Description of the drawings
Fig. 1, Fig. 3, Fig. 5 are respectively the hydrogen spectrogram of Carbazolone 1, Carbazolone 2, Carbazolone 3；
Fig. 2, Fig. 4, Fig. 6 are respectively the carbon spectrogram of Carbazolone 1, Carbazolone 2, Carbazolone 3.
Specific implementation mode
The specific implementation mode of the present invention is further described below in conjunction with example, but embodiments of the present invention are not
It is limited to this.
Embodiment 1
It is put into stirrer in 100mL round-bottomed flasks, nitrogen is replaced three times, by (the color of benzyl protection of 10.2g compounds 1
Amine) it is dissolved in 20mL acetonitriles, the 3.3mL concentrated sulfuric acids (98wt%) are added under ice bath, 2 (4- hexenes -3- of 2.8g compounds is then added dropwise
Ketone).It drips to move to reaction system from ice bath after compound 2 and 12h is stirred at room temperature.With saturation NaHCO after the reaction was complete3It is water-soluble
Liquid is quenched, until system does not have bubble generation, is extracted with ethyl acetate three times, merges organic phase Na2SO4It is dry, vacuum rotary steam
Ethyl acetate is removed, then 2 He of pure Carbazolone 1 and Carbazolone can be obtained by column chromatographic isolation and purification
The mixture of Carbazolone 3, column chromatography eluant, eluent volume ratio 20 used:1 petroleum ether and ethyl acetate.Then pass through
50mL volume ratios are 5:1 methanol and recrystallize with dichloromethane detaches Carbazolone 2 and Carbazolone 3.Respectively
To three kinds of product Carbazolone 1 (5.0g, 40%), Carbazolone 2 (4.6g, 36%), Carbazolone 3
(1.7g, 11%), gross production rate 87%.
Embodiment 2
The charging sequence and dosage of the present embodiment are same as Example 1.Difference is to be added dropwise after compound 2 by reaction system
It is moved to from ice bath and 8h is stirred at room temperature.Post-processing step is same as Example 1.Three kinds of products are respectively obtained after isolating and purifying
Carbazolone 1 (1.9g, 15%), Carbazolone 2 (1.7g, 14%), Carbazolone 3 (0.5g, 4%), always
Yield is 33%.
Embodiment 3
The charging sequence and dosage of the present embodiment are same as Example 1.Difference is reactant to drip after compound 2
System moves to from ice bath is stirred at room temperature 16h.Post-processing step is same as Example 1.Three kinds of products are respectively obtained after isolating and purifying
Carbazolone 1 (4.8g, 38%), Carbazolone 2 (4.4g, 35%), Carbazolone 3 (1.5g, 12%), always
Yield is 85%.
Embodiment 4
The charging sequence and dosage of the present embodiment are same as Example 1.Difference is reactant to drip after compound 2
System moves to from ice bath to be stirred at room temperature for 24 hours.After complete reaction, post-processing step is same as Example 1.After isolating and purifying respectively
To three kinds of product Carbazolone 1 (3.9g, 31%), Carbazolone 2 (3.5g, 28%), Carbazolone 3
(1.0g, 8%), gross production rate 67%.
Embodiment 5
It is put into stirrer in 100mL round-bottomed flasks, nitrogen is replaced three times, by (the color of benzyl protection of 10.2g compounds 1
Amine) it is dissolved in 20mL acetonitriles, the 3.3mL concentrated sulfuric acids (98wt%) are added under ice bath, 2 (4- hexenes -3- of 2.3g compounds is then added dropwise
Ketone).It drips to move to reaction system from ice bath after compound 2 and 12h is stirred at room temperature.After the reaction was complete, post-processing step and reality
It is identical to apply example 1.Respectively obtain three kinds of product Carbazolone 1 (3.3g, 26%), Carbazolone 2 (2.8g, 23%),
Carbazolone 3 (0.9g, 7%), gross production rate 56%.
Embodiment 6
It is put into stirrer in 100mL round-bottomed flasks, nitrogen is replaced three times, by (the color of benzyl protection of 10.2g compounds 1
Amine) it is dissolved in 20mL acetonitriles, the 3.3mL concentrated sulfuric acids (98wt%) are added under ice bath, 2 (4- hexenes -3- of 3.5g compounds is then added dropwise
Ketone).It drips to move to reaction system from ice bath after compound 2 and 12h is stirred at room temperature.After the reaction was complete, post-processing step and reality
It is identical to apply example 1.Respectively obtain three kinds of product Carbazolone 1 (4.4g, 35%), Carbazolone 2 (4.2g, 34%),
Carbazolone 3 (1.2g, 10%), gross production rate 79%.
The structure of products therefrom determines that hydrogen spectrogram is shown in Fig. 1-Fig. 6, nuclear-magnetism with carbon spectrogram by nuclear magnetic resonance spectroscopy and carbon spectrum
Data are as follows：
Carbazolone 1:
1H NMR(400MHz,CDCl3) δ 7.26 (ddt, J=15.9,9.2,7.8Hz, 13H), 7.08 (d, J=7.5Hz,
2H), 6.95 (t, J=7.9Hz, 1H), 6.80 (d, J=7.4Hz, 1H), 6.63 (t, J=7.2Hz, 1H), 6.19 (d, J=
7.7Hz, 1H), 4.12 (d, J=17.0Hz, 1H), 3.90 (d, J=16.6Hz, 1H), 3.61 (d, J=13.4Hz, 2H), 3.49
(d, J=12.8Hz, 2H), 2.72 (d, J=7.0Hz, 1H), 2.36 (dd, J=20.7,16.3Hz, 1H), 2.34-2.20 (m,
2H), 2.19-2.06 (m, 3H), 2.03 (s, 1H), 1.93-1.68 (m, 3H), 1.06 (d, J=7.1Hz, 3H), 0.94 (d, J=
6.4Hz,3H).
13C NMR(100MHz,CDCl3)δ:212.6,154.8,139.6,138.9,129.7,128.9,128.8,
128.6,128.3,128.2,127.1,126.9,126.7,125.8,118.2,108.9,100.0,73.8,58.9,57.6,
51.6,50.1,48.7,44.4,43.6,35.2,34.8,15.7,12.6.
Carbazolone 2:
1H NMR(400MHz,CDCl3) δ 7.35-7.16 (m, 15H), 6.97 (t, J=7.6Hz, 1H), 6.77 (d, J=
7.2Hz, 1H), 6.60 (t, J=7.3Hz, 1H), 6.30 (d, J=7.8Hz, 1H), 4.25 (d, J=16.7Hz, 1H), 4.07
(d, J=16.7Hz, 1H), 3.60 (d, J=13.5Hz, 2H), 3.46 (d, J=13.5Hz, 2H), 3.20 (d, J=4.2Hz,
1H), 2.73 (dd, J=12.1,6.4Hz, 1H), 2.44 (dt, J=12.0,6.4Hz, 3H), 2.38-2.28 (m, 1H), 2.28-
2.16 (m, 1H), 2.10 (dt, J=16.6,9.0Hz, 1H), 1.77 (d, J=40.7Hz, 1H), 1.63-1.47 (m, 1H),
0.96 (d, J=7.1Hz, 3H), 0.93 (d, J=6.6Hz, 3H)
13C NMR(100MHz,CDCl3)δ:212.8,151.4,139.6,138.8,132.8,128.8,128.6,
128.2,127.8,127.0,126.9,126.8,123.8,117.8,108.1,75.8,58.9,52.6,49.3,45.7,
43.0,35.0,25.8,15.5,15.2.
Carbazolone 3:
1H NMR(400 MHz,CDCl3) δ 7.31-7.07 (m, 13H), 7.00 (d, J=6.6 Hz, 2H), 6.91 (t, J=
7.6 Hz, 1H), 6.64 (d, J=7.3 Hz, 1H), 6.51 (t, J=7.4 Hz, 1H), 6.23 (d, J=7.9 Hz, 1H),
4.10 (d, J=16.4 Hz, 1H), 3.80 (d, J=16.3 Hz, 1H), 3.49 (d, J=13.5 Hz, 2H), 3.38 (d, J=
13.5 Hz, 2H), 3.33 (d, J=1.8 Hz, 1H), 2.58 (dd, J=8.0,1.9 Hz, 1H), 2.20 (d, J=8.2 Hz,
2H), 2.01 (dd, J=15.7,11.1 Hz, 3H), 1.62-1.48 (m, 2H), 1.08 (d, J=8.0 Hz, 3H), 0.86 (d, J
=6.6 Hz, 3H)
13C NMR(100 MHz,CDCl3)δ214.5,152.9,139.7,138.2,129.1,128.8,128.6,
128.2,128.1,127.2,127.1,126.9,126.2,117.7,108.0,70.9,59.0,52.2,49.6,49.4,
44.6,44.2,36.0,35.8,16.4,16.1。
Claims (10)
1. a kind of synthetic method of hexahydro carbazolone derivative, which is characterized in that include the following steps：
Under an inert atmosphere, compound 1 is dissolved in solvent, acid is then added under ice bath, adds compound 2, under room temperature
It is stirred to react, after reaction with saturation NaHCO3Reaction is quenched, then separating-purifying obtains hexahydro carbazolone derivative；
The compound 1 refers to the compound for having formula (1) structure；The compound 2 refers to having the change of formula (2) structure
Close object；
2. a kind of synthetic method of hexahydro carbazolone derivative according to claim 1, it is characterised in that：The inertia
Atmosphere is nitrogen atmosphere.
3. a kind of synthetic method of hexahydro carbazolone derivative according to claim 1, it is characterised in that：The solvent
For acetonitrile.
4. a kind of synthetic method of hexahydro carbazolone derivative according to claim 1, it is characterised in that：The ice bath
Temperature is 0 DEG C.
5. a kind of synthetic method of hexahydro carbazolone derivative according to claim 1, it is characterised in that：The acid is
The concentrated sulfuric acid.
6. a kind of synthetic method of hexahydro carbazolone derivative according to claim 1, it is characterised in that：The acid adds
The molar ratio for entering amount and compound 1 is (1-1.5)：1.
7. a kind of synthetic method of hexahydro carbazolone derivative according to claim 1, it is characterised in that：The compound
1 with the molar ratio of compound 2 is 1:(1~2).
8. a kind of synthetic method of hexahydro carbazolone derivative according to claim 7, it is characterised in that：The compound
1 with the molar ratio of compound 2 is 1:1.2.
9. a kind of synthetic method of hexahydro carbazolone derivative according to claim 1, it is characterised in that：The stirring is anti-
The time answered be 8~for 24 hours.
10. a kind of synthetic method of hexahydro carbazolone derivative according to claim 1, it is characterised in that：The separation
Purification includes being extracted with ethyl acetate, then vacuum rotary steam removes solvent and obtains crude product, and then crude by column chromatography purifies
Obtain hexahydro carbazolone derivative.
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| WO2011155983A1 (en) * | 2010-06-07 | 2011-12-15 | Bikam Pharmaceuticals Inc. | Opsin-binding ligands, compositions and methods of use |
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| WO2012134971A2 (en) * | 2011-03-25 | 2012-10-04 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
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2018
- 2018-03-19 CN CN201810224441.8A patent/CN108329255A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102281904A (en) * | 2008-11-20 | 2011-12-14 | 通用电气医疗集团股份有限公司 | Dye conjugate imaging agents |
| WO2011155983A1 (en) * | 2010-06-07 | 2011-12-15 | Bikam Pharmaceuticals Inc. | Opsin-binding ligands, compositions and methods of use |
| WO2012134971A2 (en) * | 2011-03-25 | 2012-10-04 | Bikam Pharmaceuticals, Inc. | Opsin-binding ligands, compositions and methods of use |
| CN102382031A (en) * | 2011-08-16 | 2012-03-21 | 河北博伦特药业有限公司 | 3 - substituted allylic ester oxindole and preparation method thereof |
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| Title |
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| MIZUKI KAWANO，等: "Regioselective Inter- and Intramolecular Formal [4+2] Cycloaddition of Cyclobutanones with Indoles and Total Synthesis of (±)-Aspidospermidine", 《ANGEW. CHEM. INT. ED.》 * |
| QUAN CAI，等: "Enantioselective Michael/Mannich Polycyclization Cascade of Indolyl Enones Catalyzed by Quinine-Derived Primary Amines", 《ANGEW. CHEM. INT. ED.》 * |
| ROBERT L. GARNICK，等: "Addition and Annulation Reactions between Indoles and ,ß-Unsaturated Ketones", 《J. ORG. CHEM.》 * |
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