CN101987832A - Preparation method of 2-trifluoromethyl indole derivatives - Google Patents
Preparation method of 2-trifluoromethyl indole derivatives Download PDFInfo
- Publication number
- CN101987832A CN101987832A CN200910165814XA CN200910165814A CN101987832A CN 101987832 A CN101987832 A CN 101987832A CN 200910165814X A CN200910165814X A CN 200910165814XA CN 200910165814 A CN200910165814 A CN 200910165814A CN 101987832 A CN101987832 A CN 101987832A
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparation
- compound
- compd
- reaction conditions
- 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.)
- Pending
Links
Landscapes
- Indole Compounds (AREA)
Abstract
The invention belongs to a preparation method of 2-trifluoromethyl indole derivatives. The method of the invention comprises the following steps: enabling F-113a serving as a fluorine raw material to react with o-chlorobenzaldehyde or o-bromobenzaldehyde to prepare alkenyl polyhalide, than reacting with any primary amine to selectively synthesize a series of 2- trifluoromethyl indole derivatives, and finally synthesizing a series of sertindole derivatives by structural modification. The reaction is characterized in that the Pd2(dba)3 is taken as a catalyst, sodium tert-butoxide is taken as alkali under participation of nitrogen and phosphorus ligands, and toluene as a solvent. The method has the advantages of short synthetic route, short reaction time, good reaction selectivity, good yield and the like, and is simple in operation.
Description
Technical field
The present invention relates to a kind of 2 bit strips has trifluoro methyl indole derivative and synthetic method thereof, belongs to organic compound process application technical field.
Background technology
Indoles not only occupies an important position in heterocyclic chemistry, and also is widely used in research fields such as Materials science, agricultural sciences, pharmaceutics, and in known more than 3000 natural indole derivatives biologies, it is the therapeutic type medicine that kind more than 40 is arranged.Indole derivatives, as tryptophane and its meta-bolites, indole alkaloid etc. all are distributed widely in occurring in nature.The sharp development of the discovery of indole derivatives provides main body frame for exploitation has bioactive new compound.At present, it has been found that the derivative that much has the indoles precursor structure all has various important biological.Have unique physiological property as the toadpoison pigment, anesthetic action is arranged; Psilocybin is that some toadstool causes unreal composition; Indolylacetic acid class medicine indomethacin is the anti-class medicine of non-steroidal, has anti-inflammatory, analgesic and analgesic activity; The sharp SaH-42548 energy of ring miaow indoles depress appetite loses weight, and is good diet pill; Indapamide is a kind of antihypertensive drug; Indole-3-carbinol is a kind of medicine of anti-uterus carcinoma; Indoles-3-acetaldehyde also has certain antitumous effect; Sertindole is the atypia antipsychotic drug; Tryptophane is an indispensable amino acid; Brazil's alkali etc. all has the precursor structure of indoles in the molecular structure of said medicine.As the indomethacin in the following structure iron (Indomethacin), Corindolan (Mepindolol) and Sertindole (Sertinole) all are at commercial widely used medicine.
Generally speaking, in compound, introduce fluorine atom after, particularly introduce trifluoromethyl group after because the puppet that produces is intended the blocking effect of effect and metabolic process, can make the physics of its parent molecule, chemical sharp physiologically active that significant variation has all taken place.Usually, introduce fluoro-containing group, particularly trifluoromethyl, carry out structure of modification again, can make it keep original characteristic and can obviously improve its biological activity to the some drugs molecular structure.Therefore, in molecule, introduce fluoro-containing group and become a kind of important means in the synthetic and triage techniques of novel drugs.For these reasons, at the introducing trifluoromethyl of two of indoles, can filter out many special bioactive drug molecules that have.As 2 Indole Molecular that contain trifluoromethyl in figure below, compound 1 is the antagonist of CCR5, and compound 2 is a kind of anesthetic,generals, and compound 3 is tyrosine-kinase enzyme antibodies, and compound 4 is antitumor drugs.
At present Synthetic 2-trifluoro methyl indole has two lines basically: one is to be raw material with ortho-aminotoluene or adjacent aminobenzyl alcohol, obtains through three-step reaction.Shortcoming is to be the uncommon reaction of raw material process ladder Wei with triphenyl phosphorus, trifluoracetic acid, and Atom economy is very low, and reaction yield is also very low.The second route is to be worth through linked reaction with adjacent Iodoaniline and diester malonate or trifluoropropyne derivative, and the shortcoming of this method is that selectivity is bad, the product kind of getable expansion very little, propine trifluoropropyne derivative also is difficult to preparation.
From the result who obtains at present, present method is from industrial raw material F-113a cheap and easy to get, with adjacent bromine or the simple prepared in reaction compd A of o-chlorobenzaldehyde process, again by transition metal-catalyzed linked reaction and any primary amine reaction Synthetic 2-trifluoro methyl indole B.In addition, again by the catalytic linked reaction of palladium, introduce the 4-piperidone 3 of 2-trifluoro methyl indole and carry out structural modification, brush has been selected and has been removed the derivative that many and Sertindole structural similitude have very high physiologically active.This synthetic route has following advantage: (1) reactions steps is short, and speed of response is fast, the productive rate height; (2) good reaction selectivity, and control easily can be carried out large-scale substrate and be expanded; (3) catalyst levels is few, the catalytic efficiency height, thereby reaction cost is low etc.Therefore, transition metal-catalyzed Synthetic 2-trifluoro methyl indole derivative is with a wide range of applications aspect industrial applications.
Summary of the invention
The object of the present invention is to provide synthetic a kind of two bit strips of the catalytic selectivity of a kind of transition metal palladium that the method for trifluoro methyl indole derivative is arranged.
Another object of the present invention is to provide the indole derivatives of serial tool biological activity and efficacy, for the improvement of new drug provides powerful technology dynamics.
The invention provides two kinds of compounds that contain trifluoromethyl, the structural formula of this compounds is as follows:
R in compd B and the Compound C in the compound
1Group can be hydrogen atom, halogen or other alkyl.R in B and the Compound C
2Group can be in aliphatic group or the aryl radical any one.
The invention provides the preparation method of above-claimed cpd A on the other hand.
Compound of the present invention can be by compd A under palladium catalysis, under the acting in conjunction of nitrogen phosphorus part primary amine is carried out two ammonifications and carry out cascade reaction, and for example reaction formula is as follows:
X=Br,Cl
R
1=H,Cl,F... R
2=Aryl,Alkyl
The following many category-B compounds that synthesized
Could take place when above-mentioned reaction must have the N-P part to exist, alkali is best with the sodium tert-butoxide reaction effect.
Above-mentioned reaction must could take place under the catalysis of palladium reagent, and the palladium catalyst in the condition can be Pd
2(dba)
3, Palladous chloride, dichloro diacetonitrile palladium etc., wherein Pd
2(dba)
3Reaction effect best.
Above-mentioned reaction is when being solvent with toluene, and when reacting under reflux temperature, effect is best.
The top condition of above-mentioned reaction is with Pd
2(dba)
3Be catalyzer, the N-P part participates in coordination, and sodium tert-butoxide is an alkali, and toluene is solvent, reacts under the reflux temperature condition.Reaction times under this condition is the shortest, and the product productive rate is the highest.
The invention provides the preparation method of above-claimed cpd B and chemicals C (Sertindole derivative) on the other hand
This compound can be by the 2-trifluoro methyl indole under palladium catalysis, and 4-piperidone reaction that replaces with suitable 1-and the tetrahydropyridine based compound that obtains subsequently are reduced and obtain.
Synthetic following many C compounds:
Embodiment
For further describing two bit strips the synthetic method of trifluoro methyl indole derivative is arranged, its embodiment is specifically stated at this.
Two bit strips have the preparation of trifluoro methyl indole derivative B:
With compd A (0.2mmol), primary amine (0.24mmol), [Pd] are (10mol%), N-P part (20mol%), sodium tert-butoxide (4equiv) are placed in the band fluorinated ethylene propylene pipe sealing round-bottomed flask of 25mL, inject toluene (3mL) then, sealed flask, reaction is 3-32 hour under reflux temperature, and reaction finishes back ethyl acetate extraction, collected organic layer, dry, concentrate, purifying obtains compound, and productive rate is excellent.
For further describing two bit strips the synthetic method of trifluoromethyl Sertindole derivative is arranged, its embodiment is specifically stated at this.
Two bit strips have the preparation of trifluoromethyl Sertindole derivative C:
With 2-CF
3Benzazole compounds B (0.2mmol), the 4-piperidone (0.3mmol) that 1-replaces, [Pd] (5%), phosphorus part (10%), K
2CO
3(4equiv), be placed in the band fluorinated ethylene propylene pipe sealing round-bottomed flask of 25mL, inject DMSO (3mL) then, sealed flask, reaction is 1-32 hour under reflux temperature, with lithium aluminium hydride reduction, reaction finishes back ethyl acetate extraction, collected organic layer, dry, concentrate, purifying obtains compound, and productive rate is excellent.
Claims (11)
1. the sharp C of two class 2-trifluoro methyl indole derivative B is characterized in that the structural formula of this compound is as follows:
Wherein, compd A is a reaction raw materials, and X can be Cl, any one among the Br etc.R in compd B and the Compound C in the compound
1Group can be hydrogen atom, halogen or other alkyl.R in B and the Compound C
2Group can be in aliphatic group or the aryl radical any one.
The preparation method of compd B according to claim 1 is characterized in that, is raw material with A, through obtaining compd B with primary amine reaction.
2. according to the reaction conditions of the described preparation compd B of claim 1, it is characterized in that, in the reaction of A and primary amine, make catalyzer with Pd, nitrogen phosphorus part and highly basic participate in down, and toluene is solvent.
3. the preparation method of compd B according to claim 2 is characterized in that, with Pd
2(dba)
3, Pd (OAc)
2, PdCl
2Deng being catalyzer.
4. according to the reaction conditions of the described preparation compd B of claim 2, it is characterized in that, participate in reaction with nitrogen phosphorus part, phosphorus part.
5. according to the reaction conditions of the described preparation compd B of claim 2, it is characterized in that with A: the ratio of components of primary amine is 1: 1.2.
6. according to the reaction conditions of the described preparation compd B of claim 2, it is characterized in that with organic bases, mineral alkali participates in reaction.
7. according to the reaction conditions of the described preparation compd B of claim 2, it is characterized in that temperature of reaction is the refluxing toluene temperature.
8. the preparation method of Compound C according to claim 3 is characterized in that, suitably B is reduced method with suitable 1-4-piperidone reaction that replaces and the tetrahydropyridine based compound that obtains subsequently.
9. the reaction conditions of described according to Claim 8 preparation Compound C is characterized in that, with Pd
2(dba)
3, Pd (OAc)
2Deng being catalyzer.
10. the reaction conditions of described according to Claim 8 preparation Compound C is characterized in that, participates in reaction with nitrogen phosphorus part, phosphorus part.
11. the reaction conditions of described according to Claim 8 preparation Compound C is characterized in that, reductive agent is lithium aluminum hydride, Zn powder etc.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200910165814XA CN101987832A (en) | 2009-08-02 | 2009-08-02 | Preparation method of 2-trifluoromethyl indole derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200910165814XA CN101987832A (en) | 2009-08-02 | 2009-08-02 | Preparation method of 2-trifluoromethyl indole derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101987832A true CN101987832A (en) | 2011-03-23 |
Family
ID=43744647
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200910165814XA Pending CN101987832A (en) | 2009-08-02 | 2009-08-02 | Preparation method of 2-trifluoromethyl indole derivatives |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101987832A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105130872A (en) * | 2015-08-25 | 2015-12-09 | 江西师范大学 | Preparation method for 3-substituted trifluoromethyl indole |
CN107619385A (en) * | 2017-10-13 | 2018-01-23 | 温州大学 | A kind of method that palladium chtalyst aryl enamine intramolecular amination synthesizes 2 trifluoro methyl indoles |
-
2009
- 2009-08-02 CN CN200910165814XA patent/CN101987832A/en active Pending
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105130872A (en) * | 2015-08-25 | 2015-12-09 | 江西师范大学 | Preparation method for 3-substituted trifluoromethyl indole |
CN105130872B (en) * | 2015-08-25 | 2018-01-30 | 江西师范大学 | A kind of preparation method of 3 position trifluoromethyl substituted indole |
CN107619385A (en) * | 2017-10-13 | 2018-01-23 | 温州大学 | A kind of method that palladium chtalyst aryl enamine intramolecular amination synthesizes 2 trifluoro methyl indoles |
CN107619385B (en) * | 2017-10-13 | 2020-02-21 | 温州大学 | Method for synthesizing 2-trifluoromethyl indole by palladium-catalyzed aryl enamine intramolecular amine |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Loach et al. | C7-derivatization of C3-alkylindoles including tryptophans and tryptamines | |
Cheng et al. | Palladium catalyzed acetoxylation of benzylic C–H bonds using a bidentate picolinamide directing group | |
Kim et al. | Rh (iii)-catalyzed 7-azaindole synthesis via C–H activation/annulative coupling of aminopyridines with alkynes | |
CN102516151B (en) | 3-substituted-3-hydroxyindazolone derivatives, and preparation method and application thereof | |
Xu et al. | Rhodium (III)-catalyzed selective access to isoindolinones via formal [4+ 1] annulation of arylamides and propargyl alcohols | |
Zhang et al. | Organocatalytic asymmetric [3+ 2]-cycloaddition of 3-isothiocyanato oxindoles with 1, 3, 5-trisubstituted-hexahydro-1, 3, 5-triazines to access spiro-imidazolidinethione-oxindoles | |
Feng et al. | Palladium catalyzed direct C-2 arylation of indoles | |
Ren et al. | Rhodium (III)-catalyzed [4+ 2] annulation of N-arylbenzamidines with 1, 4, 2-dioxazol-5-ones: Easy access to 4-aminoquinazolines via highly selective CH bond activation | |
Bao et al. | Palladium-catalyzed tandem cyclization of fluorinated imidoyl chlorides with 2-bromophenylboronic acid: Synthesis of 6-fluoroalkyl-phenanthridines | |
CN109232363B (en) | Synthetic method of 3-selenocyanoindole compound | |
Liu et al. | Highly regioselective synthesis of 3-alkylthio-2-oxindoles via DABCO-catalyzed allylic α-substitution of Morita–Baylis–Hillman carbonates of isatins with various thiols | |
CN111960997A (en) | Method for synthesizing hydroxyalkyl substituted quinoline derivatives | |
CN103420921A (en) | Method for synthesizing optically-active 2,3-dihydro quinazolinone derivative by using chiral spiro phosphoric acid as catalyst | |
CN114105978A (en) | Oxindole compound and preparation method and application thereof | |
CN106243105A (en) | Methylene-bridged 1,8 naphthyridines part and copper (I) coordination compound, preparation method and application | |
Xu et al. | Copper (II)-catalyzed direct C–H (hetero) arylation at the C3 position of indoles assisted by a removable N, N-bidentate auxiliary moiety | |
CN102977017B (en) | Method for catalytically preparing 6(5H)-phenanthridine ketone by copper component | |
Song et al. | Rhodium‐Catalyzed Direct Vinylene Annulation of Sulfoxonium Ylides and N‐carbamoylindoles with Vinylene Carbonate | |
CN102659494A (en) | Method for asymmetric synthesis of 3,3-disubstituted-2-oxindole compound | |
CN104557663B (en) | A kind of synthetic method of dicarbapentaborane substituent indole pharmaceutical intermediate compound | |
CN101987832A (en) | Preparation method of 2-trifluoromethyl indole derivatives | |
KR102207333B1 (en) | Novel Production Method for Quadruple Cyclic Compounds | |
CN105481867A (en) | Chiral spiro-oxindole constructed by three-step relay catalysis, as well as synthesizing method and application thereof | |
Zhang et al. | Construction of 2-alkynyl aza-spiro [4, 5] indole scaffolds via sequential C–H activations for modular click chemistry libraries | |
CN106892826A (en) | A kind of preparation method and application of amine and imines N-methyl |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110323 |