CN101987832A - Preparation method of 2-trifluoromethyl indole derivatives - Google Patents

Preparation method of 2-trifluoromethyl indole derivatives Download PDF

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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
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张兴国
董淑祥
李金恒
汤日元
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Wenzhou University
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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

The preparation method of 2-trifluoro methyl indole derivative
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.
Figure B200910165814XD0000011
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.
Figure B200910165814XD0000012
Figure B200910165814XD0000021
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:
Figure B200910165814XD0000022
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:
Figure B200910165814XD0000023
X=Br,Cl
R 1=H,Cl,F... R 2=Aryl,Alkyl
The following many category-B compounds that synthesized
Figure B200910165814XD0000031
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:
Figure B200910165814XD0000041
Figure B200910165814XD0000051
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:
Figure F200910165814XC0000011
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.
CN200910165814XA 2009-08-02 2009-08-02 Preparation method of 2-trifluoromethyl indole derivatives Pending CN101987832A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
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

Cited By (4)

* Cited by examiner, † Cited by third party
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

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