CN110194733A - A kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound - Google Patents
A kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound Download PDFInfo
- Publication number
- CN110194733A CN110194733A CN201910555563.XA CN201910555563A CN110194733A CN 110194733 A CN110194733 A CN 110194733A CN 201910555563 A CN201910555563 A CN 201910555563A CN 110194733 A CN110194733 A CN 110194733A
- Authority
- CN
- China
- Prior art keywords
- fluoroalkyl
- hydroxyindole
- preparation
- ketone compound
- compound according
- 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
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
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The present invention relates to a kind of preparation methods of 3- fluoroalkyl -3-hydroxyindole ketone compound; under inert gas protection, α, the fluoro- beta-keto acid compound of α-two and isatin are added into organic solvent; heating carries out decarboxylation addition reaction, obtains 3- fluoroalkyl -3-hydroxyindole class compound.Compared with prior art, cost of material used in the present invention is cheap, it is easy to get, reaction condition is mild, can carry out without any catalyst, reacts easy to operate, post-processing is simple, it is applied widely, be it is a kind of prepare 3- fluoroalkyl -3-hydroxyindole ketone compound new method, have a good application prospect.
Description
Technical field
The invention belongs to technical field of organic synthesis, are related to a kind of system of 3- fluoroalkyl -3-hydroxyindole ketone compound
Preparation Method.
Background technique
2,3- dicarbapentaborane indoles, commonly referred to as isatin are a kind of important natural products.Meanwhile many natural products or
Person's bioactive molecule also all contains isatin or Oxoindole structural unit.Isatin class compound has multiple reaction performance, such as
Electrophilic substitution reaction on aromatic ring, the nucleophilic addition of carbonyl, spirocyclization reaction etc. is (referring to da Silva, J.F.M.；
Garden,S.J.；Pinto,A.C.J.Braz.Chem.Soc.2001,12,273.).Isatin and some structures simply take
It is cheap and easy to get for isatin, accordingly, with respect to the reaction of isatin class compound, either theoretic research or practical application, closely
There is very big development (referring to Mohammadi, S. over a little years；Heiran,R.；Herrera,R.P.；Marqués-López,
E.ChemCatChem 2013,5,2131.)。
There is very high reactivity in view of the carbonyl of No. 3 positions of isatin, and is can be used as in the potential chirality in synthesis again
The heart, converting 2- oxidized indole compounds for isatin class compound by nucleophilic addition or spirocyclization reaction is that a kind of application is wide
General and important methodology (Klein, J.E.M.N.；Taylor,R.J.K.Euro.J.Org.Chem.2011,2011,6821.
Deng).The 3-hydroxyindole ketones derivant that especially No. 3 positions replace, is much natural products or bioactive molecule, such as
Convolutamydines, diazonamides, leptosin D etc., these compounds usually have important biology living
Property, such as antibiotic property, cancer resistance, antiviral property etc. is (referring to Kamano, Y.；Zhang,H.-P.；Ichihara,Y.；Kizu,
H.；Komiyama,K.；Pettit, G.R.Tetrahedron Lett.1995,36,2783. etc.).
Since fluorine atom has stronger electron-withdrawing, lipophilicity and lesser steric hindrance, into organic molecule
Being selectively introducing fluorine atom can be changed its certain chemical property and physiological activity, be a kind of synthetic drug molecule important method and
Approach.The preparation method for introducing fluorine atom into organic molecule at present is less, generally requires expensive catalyst, ligand or anti-
Raw material preparation difficulty answered etc., the nucleophilic addition such as carried out using the silyl enol ether compound of two fluoroolefins and isatin class compound
Reaction.(such as Yu, J.-S.；Liu,Y.-L.；Tang,J.；Wang,X.；Zhou,J.Angew.Chem.Int.Ed.2014,53,
9512. equal documents are recorded)..
In above method, the preparation condition of difluoro silyl enol ether is harsher, needs to use highly basic and expensive fluorination examination
Agent, therefore the source of raw material is subject to certain restrictions, it is difficult to carry out large-scale production and preparation.In addition, reaction needs valuableness multiple
Miscellaneous organic ligand also limits its application.Therefore, it is necessary to a kind of new methods of demand to prepare 3- fluoroalkyl -3- hydroxyl
Indole ketone compound.
Summary of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of 3- fluoroalkyl -3-
The preparation method of oxyindole ketone compound.
The purpose of the present invention can be achieved through the following technical solutions:
A kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound, it is under inert gas protection, past organic molten
The α that phenyl replaces is added in agent, the fluoro- beta-keto acid compound of α-two and isatin, heating carry out decarboxylation addition reaction, obtain 3- bis-
Fluoroalkyl -3-hydroxyindole class compound.
Further, the molar ratio of the α that the phenyl replaces, the fluoro- beta-keto acid compound of α-two and isatin is (2-4): 1.
If the amount of ketone acid is less, as the molar ratio of ketone acid compound and isatin be 1:1 when, then isatin is unable to fully reacting.If ketone acid
Amount is excessive, then causes the waste of redundance.
Further, the α that the phenyl replaces, the molecular structural formula of the fluoro- beta-keto acid compound of α-two are as follows:
Further, the inert gas is nitrogen or argon gas.
Further, the organic solvent is any one or several in DMSO, DMF, NMP, toluene, dioxane or THF
Mixing, solvent is preferably toluene.
Further, reaction temperature is 80-120 DEG C.If temperature is lower than 80 DEG C, decarboxylation procedure is difficult to carry out, if temperature mistake
Height will lead to yield reduction.
Further, reaction time 6-18h.
Further, after reaction, reaction product is obtained using column chromatographic isolation and purification.
Reaction equation of the invention is as follows:
The present invention is not necessarily to any catalyst, the α that can be replaced by isatin class reagent and phenyl, the fluoro- beta-keto acid of α-two into
Row decarboxylation addition reaction is prepared for a kind of 3- fluoroalkyl -3-hydroxyindole compound being easy to get with high yield.
Compared with prior art, 3- fluoroalkyl -3- hydroxyl directly and is easily and efficiently synthesized the present invention provides a kind of
The method of oxindole compounds, required raw material is cheap and easy to get, and synthetic method is easy to operate, and the reaction time is short, the yield of product compared with
Height has a good application prospect.
Specific embodiment
The present invention is described in detail combined with specific embodiments below.The present embodiment is based on the technical solution of the present invention
Implemented, the detailed implementation method and specific operation process are given, but protection scope of the present invention be not limited to it is following
Embodiment.
In following embodiment, the molecular structural formula of the fluoro- beta-keto acid compound of used α, α-two are as follows:(Yang, M.-H. is prepared by referring to following documents in it；Orsi,D.L.；Altman,
R.A.Angew.Chem.Int.Ed.2015,54,2361.).And remaining raw material or processing technique unless otherwise noted, then table
Bright is the conventional commercial raw material or Technology development of this field.
Embodiment 1
Under nitrogen protection, it is once added into reaction tube isatin (30.0mg, 0.2mmol), the fluoro- beta-keto acid of α, α-two
It closes object (120.1mg, 0.6mmol), toluene 1ml, is to slowly warm up to 100 DEG C under stirring conditions, react 12h.Reaction terminates
Afterwards, it is transferred in egg type bottle, rotates, column chromatographs to obtain product 57.9mg, yield 95.5%.
Products therefrom is as follows through detecting:
1H NMR (400MHz, DMSO) δ 10.64 (s, 1H), 8.09 (d, J=7.7Hz, 2H), 7.74 (t, J=7.4Hz,
1H), 7.58 (t, J=7.8Hz, 2H), 7.26-7.40 (m, 3H), 6.99 (t, J=7.6Hz, 1H), 6.88 (d, J=7.7Hz,
1H).19F NMR (376MHz, DMSO) δ -108.75 (d, J=271.9Hz, 1F), -109.62 (d, J=271.9Hz, 1F).
Embodiment 2
Compared with Example 1, the overwhelming majority is all identical, in addition in the present embodiment: the fluoro- beta-keto acid compound of α, α-two and indigo
Red molar ratio is 2:1.
Embodiment 3
Compared with Example 1, the overwhelming majority is all identical, in addition in the present embodiment: the fluoro- beta-keto acid compound of the α, α-two
Molar ratio with isatin is 4:1.
Embodiment 4
Compared with Example 1, the overwhelming majority is all identical, and in addition in the present embodiment: inert gas is argon gas.
Embodiment 5-10
Compared with Example 1, the overwhelming majority it is all identical, in addition in the present embodiment: organic solvent be changed to respectively using DMSO,
DMF, NMP, dioxane, THF or DMSO, DMF and toluene according to volume ratio 1:1:1 mixture.
Embodiment 11
Compared with Example 1, the overwhelming majority is all identical, in addition in the present embodiment: reaction temperature is 80 DEG C, and the reaction time is
18h。
Embodiment 12
Compared with Example 1, the overwhelming majority is all identical, in addition in the present embodiment: reaction temperature is 120 DEG C, the reaction time
For 6h.
Comparative example 1
Compared with Example 1, the overwhelming majority is all identical, in addition in the present embodiment: reaction temperature is 60 DEG C.After reacting 12h,
TLC observation, almost without product, does not carry out subsequent processing.
Comparative example 2
Compared with Example 1, the overwhelming majority is all identical, in addition in the present embodiment: reaction temperature is 140 DEG C.Reaction terminates
Afterwards, it is transferred in egg type bottle, rotates, column chromatographs to obtain product 31.5mg, yield 51.9%.
The above description of the embodiments is intended to facilitate ordinary skill in the art to understand and use the invention.
Person skilled in the art obviously easily can make various modifications to these embodiments, and described herein general
Principle is applied in other embodiments without having to go through creative labor.Therefore, the present invention is not limited to the above embodiments, ability
Field technique personnel announcement according to the present invention, improvement and modification made without departing from the scope of the present invention all should be of the invention
Within protection scope.
Claims (8)
1. a kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound, which is characterized in that in inert gas shielding
Under, the α that phenyl replaces, the fluoro- beta-keto acid compound of α-two and isatin are added into organic solvent, it is anti-that heating carries out decarboxylation addition
It answers, obtains 3- fluoroalkyl -3-hydroxyindole class compound.
2. a kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound according to claim 1, feature exist
In, the α that the phenyl replaces, the molar ratio of the fluoro- beta-keto acid compound of α-two and isatin is (2-4): 1.
3. a kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound according to claim 1, feature exist
In, the α that the phenyl replaces, the molecular structural formula of the fluoro- beta-keto acid compound of α-two are as follows:
4. a kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound according to claim 1, feature exist
In the inert gas is nitrogen or argon gas.
5. a kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound according to claim 1, feature exist
In the organic solvent is mixing any one or several in DMSO, DMF, NMP, toluene, dioxane or THF.
6. a kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound according to claim 1 or 5, special
Sign is that the organic solvent is toluene.
7. a kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound according to claim 1, feature exist
In reaction temperature is 80-120 DEG C, reaction time 6-18h.
8. a kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound according to claim 1, feature exist
In after reaction, reaction product is obtained using column chromatographic isolation and purification.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910555563.XA CN110194733B (en) | 2019-06-25 | 2019-06-25 | Preparation method of 3-difluoroalkyl-3-hydroxyindolone compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910555563.XA CN110194733B (en) | 2019-06-25 | 2019-06-25 | Preparation method of 3-difluoroalkyl-3-hydroxyindolone compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110194733A true CN110194733A (en) | 2019-09-03 |
| CN110194733B CN110194733B (en) | 2022-11-15 |
Family
ID=67755136
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910555563.XA Active CN110194733B (en) | 2019-06-25 | 2019-06-25 | Preparation method of 3-difluoroalkyl-3-hydroxyindolone compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110194733B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128320A (en) * | 2019-06-25 | 2019-08-16 | 上海应用技术大学 | A kind of preparation method of 5- chloro-3-hydroxyl -3- fluoroalkyl-indole-2-ketone compound |
| CN111793019A (en) * | 2020-07-30 | 2020-10-20 | 上海应用技术大学 | Preparation method of polyfluoro-substituted phenylsulfonyl indolone compounds |
| CN113979869A (en) * | 2021-11-26 | 2022-01-28 | 赣南师范大学 | Diflunisal benzylation reagent and preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432523A (en) * | 2011-09-21 | 2012-05-02 | 温州大学 | Method for synthesizing 3-hydroxy-3-arylindole-2-one derivative |
| CN102516151A (en) * | 2011-11-11 | 2012-06-27 | 华东师范大学 | 3-substituted-3-hydroxyindazolone derivatives, and preparation method and application thereof |
| CN104098501A (en) * | 2014-06-23 | 2014-10-15 | 华东师范大学 | 3-difluoro alkyl substituted all-carbon quaternary carbon oxoindole derivative and synthetic method thereof |
| CN105837494A (en) * | 2016-05-14 | 2016-08-10 | 上海大学 | Difluoroalky lindolone derivative and preparation method thereof |
| CN107382641A (en) * | 2017-08-08 | 2017-11-24 | 上海应用技术大学 | A kind of preparation method of α, α difluoro beta hydroxy ketone class compound |
-
2019
- 2019-06-25 CN CN201910555563.XA patent/CN110194733B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432523A (en) * | 2011-09-21 | 2012-05-02 | 温州大学 | Method for synthesizing 3-hydroxy-3-arylindole-2-one derivative |
| CN102516151A (en) * | 2011-11-11 | 2012-06-27 | 华东师范大学 | 3-substituted-3-hydroxyindazolone derivatives, and preparation method and application thereof |
| CN104098501A (en) * | 2014-06-23 | 2014-10-15 | 华东师范大学 | 3-difluoro alkyl substituted all-carbon quaternary carbon oxoindole derivative and synthetic method thereof |
| CN105837494A (en) * | 2016-05-14 | 2016-08-10 | 上海大学 | Difluoroalky lindolone derivative and preparation method thereof |
| CN107382641A (en) * | 2017-08-08 | 2017-11-24 | 上海应用技术大学 | A kind of preparation method of α, α difluoro beta hydroxy ketone class compound |
Non-Patent Citations (2)
| Title |
|---|
| YIN-LONG LI 等: ""Organocatalytic Biomimetic Decarboxylative Aldol Reaction of Fluorinated b-Keto Acids with Unprotected Isatins"", 《ADV. SYNTH. CATAL.》 * |
| 陶红旗等: ""有机催化靛红与4-苯基-3-丁炔-2-酮高效合成3-取代-3-羟基氧化吲哚类衍生物"", 《中国科学: 化学》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110128320A (en) * | 2019-06-25 | 2019-08-16 | 上海应用技术大学 | A kind of preparation method of 5- chloro-3-hydroxyl -3- fluoroalkyl-indole-2-ketone compound |
| CN110128320B (en) * | 2019-06-25 | 2022-06-07 | 上海应用技术大学 | Preparation method of 5-chloro-3-hydroxy-3-difluoroalkyl-indolin-2-one compound |
| CN111793019A (en) * | 2020-07-30 | 2020-10-20 | 上海应用技术大学 | Preparation method of polyfluoro-substituted phenylsulfonyl indolone compounds |
| CN113979869A (en) * | 2021-11-26 | 2022-01-28 | 赣南师范大学 | Diflunisal benzylation reagent and preparation method and application thereof |
| CN113979869B (en) * | 2021-11-26 | 2024-04-30 | 赣南师范大学 | Difluoro benzylation reagent and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110194733B (en) | 2022-11-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110194733A (en) | A kind of preparation method of 3- fluoroalkyl -3-hydroxyindole ketone compound | |
| CN110156659A (en) | A kind of preparation method of how fluorine-substituted 3- hydroxyl oxidized indole compounds | |
| Zhu et al. | Nickel-catalyzed C (sp2)-H selenation of imidazo [1, 2-α] pyridines with arylboronic acids or alkyl reagents using selenium powder | |
| CN110128320A (en) | A kind of preparation method of 5- chloro-3-hydroxyl -3- fluoroalkyl-indole-2-ketone compound | |
| CN109562355A (en) | Metal oxide supported earth metallic catalyst abundant for efficient organic transformation | |
| Dhakshinamoorthy et al. | Cu3 (BTC) 2 as heterogeneous catalyst for the room temperature oxidative hydroxylation of arylboronic acids | |
| CN105131044B (en) | Three core N-heterocyclic carbine palladium compounds and synthetic method and application | |
| CN103965093A (en) | 2-perfluoroalkyl indole compound as well as preparation and application thereof | |
| Huang et al. | Palladium-catalyzed redox cascade for direct β-arylation of ketones | |
| CN113307804B (en) | Synthetic method and application of fluorine-containing indole quinoline compound | |
| CN105854947A (en) | Chiral pyridine biimidazole ligand transition metal complex catalyst and preparation method thereof | |
| Lv et al. | Synthesis and evaluation of stable, efficient, and recyclable carbonylation catalysts: Polyether-substituted lmidazolium carbonyl cobalt lonic liquids | |
| Murugan et al. | One-pot approach: Tandem consecutive Ugi-4CR/ACM-type reaction towards the synthesis of functionalised quinoline-2 (1H)-one scaffolds | |
| CN109535120A (en) | The preparation method of 7- substitution -3,4,4,7- tetrahydro cyclobutane and cumarin -5- ketone | |
| CN109400617A (en) | A kind of new indole and pyranone framework compound and preparation method thereof | |
| CN105968374B (en) | A kind of copper (I) coordination polymer and its preparation method and application | |
| Bergens et al. | Synthesis and structure of a biphenanthrol-palladium complex displaying an unusual bonding mode | |
| Wan et al. | Efficient access to 1, 3, 4-trisubstituted pyrroles via gold-catalysed cycloisomerization of 1, 5-diynes | |
| Lin et al. | Palladium‐Catalyzed Carbonylative Cross‐Coupling of Aryl Iodides and Alkenyl Bromides with Benzyl Halides under Reductive Conditions | |
| CN108484650B (en) | 3, 5-dibenzoimidazolyl-8-p-methylphenyl fluoroboron fluorescent derivative and preparation method and application thereof | |
| Gao et al. | Diastereoselective Palladium-Catalyzed Conjugate Addition of Arylboronic Acids to α-Substituted Cyclic Enones | |
| Zerguini et al. | Synthesis, crystal structure and Chan-Evans-Lam CN cross coupling catalysis of monohydrated tetrapyrazole copper (II) sulfate | |
| Shalini et al. | Suzuki Miyaura cross-coupling of 2-chloropyrazine with arylboronic acids catalyzed by novel palladium (II) ONO pincer complexes | |
| Ambroziak et al. | A synthesis of unsymmetrical chiral salen ligands derived from 2-hydroxynaphthaldehyde and substituted salicylaldehydes | |
| Chen et al. | Direct Trifluoromethoxylation of Aliphatic Compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |