CN102167679B - Method of synthesizing styryl indole compounds - Google Patents
Method of synthesizing styryl indole compounds Download PDFInfo
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- CN102167679B CN102167679B CN201110023991A CN201110023991A CN102167679B CN 102167679 B CN102167679 B CN 102167679B CN 201110023991 A CN201110023991 A CN 201110023991A CN 201110023991 A CN201110023991 A CN 201110023991A CN 102167679 B CN102167679 B CN 102167679B
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Abstract
The present invention provides a method of synthesizing styryl indole compounds. Substituted indole methanol, nitrogen atom of which is protected by methyl, is mixed with triethyl phosphite and iodine to be reacted, and then without treatments, the reaction product is directly subjected to Wittig-Horner reaction with substituted benzaldehyde under the effect of aprotic solvent and strong base to generate the styryl indole compounds with a one-step method. Compared with the prior art, the most prominent advantage of the method is that target products are synthesized with the one-step method after the substituted indole-3-methanol compound is obtained, reaction steps are simplified, and whole productivity is enhanced. Moreover, cost is reduced since materials which are relatively easily obtained are adopted.
Description
Technical field
It is raw material that the present invention relates generally to 5-cyanic acid-indole-3-formaldehyde; Through obtaining 5-cyanic acid-indole-3-carbinol behind the sodium borohydride reduction, its with triethyl-phosphite and Iod R after directly react single stage method generation styryl Benzazole compounds with substituted benzaldehyde generation Wittig-Horner.
Background technology
Two aromatic groups link to each other through the π key and obtain a conjugated system, form intramolecular stream of electrons, and like N-methyl-5-cyanic acid-indoles-3-substituted phenylethylene, its structure is seen formula (1).This compounds can show the excellent photoelectric effect; Can be applied to all respects such as sensitization equipment, white dyes, laserable material, light data storage, photo-conductor; Also can be used as research and wish that Huang is mould, the model of carrotenoid isoline type compound, the research photobiology is very helpful.
At present, keeping only changing the substituting group on the phenyl ring under the constant situation of indole ring structure, its synthetic route mainly contains following several kinds:
(1) " Acta Pharmaceutica Sinica "; 1999; 34 (12): the 908-912 report is a raw material with 5-cyanic acid-3-methyl-indoles, obtains N-methyl-5-cyanic acid-3-brooethyl indoles through the NBS bromination with after methylating; With triethyl-phosphite the Michaelis-Arbuzov reaction takes place then and generate important intermediate N-methyl-5-cyanic acid-diethyl phosphonate skatole, the Wittig-Horner reaction takes place and makes trans-N-methyl-5-cyanic acid-3-substituted phenylethylene base indoles in last and various substituted benzaldehydes.Synthetic route is as follows:
This route is a more common method for preparing the styryl indoles, obtains but its raw material 5-cyanic acid-3-methyl-indoles is difficult, and price is higher.In addition, occur the not exclusively perhaps problem of dibrominated product generation of raw material reaction during employing NBS bromination is everlasting often and is reacted, cause purification difficult.
(2) " Journal of Medicinal Chemistry "; 2007; The 50:1727-1730 report; With 5-cyanic acid-indole-3-formaldehyde is raw material, obtain N-methyl-5-cyanic acid-indole-3-formaldehyde with methylating reagent reaction after, aldehyde radical obtains N-methyl-5-cyanic acid-indole-3-carbinol through sodium borohydride reduction; Generate N-methyl-5-cyanic acid-3-brooethyl indoles with bromide reagent reaction back again, make trans-N-methyl-5-cyanic acid-3-substituted phenylethylene base indoles under identical with the method 1 then condition.Synthetic route is as follows:
After this route is used 5-cyanic acid-indole-3-formaldehyde instead and is raw material, reduced production cost.But its route steps is longer, and N-methyl-5-cyanic acid-indole-3-carbinol and bromide reagent prepared in reaction N-methyl-5-cyanic acid-this step productivity ratio of 3-brooethyl indoles are lower, and is in practical application, very impracticable.
Summary of the invention
Technical problem:The object of the invention is to provide a kind of styryl Benzazole compounds compound method, and after obtaining substituted indole-3-methyl alcohol compounds, single stage method is synthesized title product, has simplified reactions step, carries
High overall productivity.
Technical scheme:A kind of styryl Benzazole compounds of the object of the invention compound method under polar solvent and the alkaline condition and after the methylating reagent reaction, makes the nitrogen hydrogen of its indole ring replaced by methyl from substituted indole formaldehyde; Under the effect of reductive agent, make aldehyde radical be reduced into hydroxyl then; After last substituted indole methyl alcohol and triethyl-phosphite and the iodine hybrid reaction, Wittig-Horner reaction single stage method takes place and generates the styryl Benzazole compounds in direct and substituted benzaldehyde under aprotic solvent and alkaline effect.
Triethyl-phosphite be reactant be again solvent.
Said polar solvent is: N, dinethylformamide, methylene dichloride, trichloromethane, acetone, THF, acetonitrile or DMF.
Said methylating reagent is: methylcarbonate, methyl-sulfate or Soiodin.
Said reductive agent is Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN.
Beneficial effect:The compound method of styryl Benzazole compounds of the present invention; With respect to prior art; Owing to adopted so new synthetic route, that is: from substituted indole-3-formaldehyde, under polar solvent and the alkaline condition and after the methylating reagent reaction; The nitrogen hydrogen of its indole ring is replaced by methyl, obtain corresponding N-methyl-indole-3-formaldehyde.Under the effect of reductive agent, make aldehyde radical be reduced into hydroxyl then.Need not to handle after last N-methyl-5-cyanic acid-indole-3-carbinol and triethyl-phosphite and the iodine hybrid reaction, Wittig-Horner reaction single stage method takes place and generates the styryl Benzazole compounds in direct and substituted benzaldehyde under aprotic solvent and alkaline effect.The present invention overcomes the deficiency of above-mentioned prior art, and a kind of novel method for preparing the styryl Benzazole compounds is provided.The most outstanding advantage of the present invention is that single stage method is synthesized title product, has simplified reactions step, has improved overall productivity after obtaining substituted indole-3-methyl alcohol compounds.
Embodiment
The object of the invention realizes, has mainly designed a kind of new synthetic route, promptly from substituted indole-3-formaldehyde, under polar solvent and the alkaline condition and after the methylating reagent reaction, the nitrogen hydrogen of its indole ring is replaced by methyl.Under the effect of reductive agent, make aldehyde radical be reduced into hydroxyl then.Untreated after last N-methyl-5-cyanic acid-indole-3-carbinol and triethyl-phosphite and the iodine hybrid reaction, Wittig-Horner reaction single stage method takes place and generates the styryl Benzazole compounds in direct and substituted benzaldehyde under aprotic solvent and alkaline effect.
Synthetic route of the present invention is as follows:
R representes group arbitrarily such as fluorine, chlorine, bromine, alkyl, methoxyl group, benzyl, cyanic acid, nitro, ethanoyl and ester group in the formula.
Among the present invention:
This route indoles raw material is not limited to 5-cyanic acid-indole-3-formaldehyde, also can be indole ring 4,5,6 and 7 on contain various substituting groups, comprising fluorine, chlorine, bromine, alkyl, methoxyl group, benzyl, cyanic acid, nitro, ethanoyl and ester group etc.In addition, aldehyde radical also can be at each the position of substitution of indole ring.
Polar solvent plays dissolving raw material, helps strengthening the reaction contact surface, makes to be reflected in the homogeneous phase as far as possible and carries out, and reduces the reaction required time.It can be the polar solvent of using always such as but not limited to methylene dichloride, trichloromethane, acetone, THF, acetonitrile, DMF etc.Test is preferably DMF, and its solvability to substituted indole-3-formaldehyde is better, and what more help reacting is thorough.
Alkaline condition during methylation reaction is meant the general alkali that uses in laboratory, for example sodium hydroxide, Pottasium Hydroxide, salt of wormwood, yellow soda ash etc., but be not limited only to these several kinds.
Methylating reagent is meant the reagent of introducing a methyl on can the nitrogen-atoms at indoles.The main purpose of introducing methyl is because the nitrogen hydrogen on the indole ring is more active; Under the strong alkali environment of next step Wittig-Honor reaction; Nitrogen hydrogen is replaced by the electrophilic reagent in the reaction system easily and introduces impurity, and this also is often to mention but open question in the top bibliographical information.Methylating reagent used in the present invention is methylcarbonate, methyl-sulfate and Soiodin.Test is preferably methylcarbonate, and it is much smaller than other two kinds of toxicity, and low price.
Reductive agent is meant the reagent that can be reduced into aldehyde radical hydroxyl, can be Peng Qinghuana, POTASSIUM BOROHYDRIDE 97MIN etc., but be not limited only to these several kinds.
Phosphorus ylide reagent in the Wittig-Honor reaction is relatively more responsive to protic solvents such as water, and solvent need dewater in advance when therefore reacting, and generally will use aprotic polar solvent.They are difficult for providing proton; But specific inductivity and molecular polarity are all very big; The negative charge end of molecule is exposed to the outside mostly, and the positive charge end wraps in inside, to negative charge solvation seldom; Therefore reaction is very favorable to aprotic polar solvent to Wittig-Honor, and is suitable for the alkaline reaction system.These solvents can be use always such as but not limited to the inferior maple of THF, dimethyl-, DMF etc.
The highly basic of using in the Wittig-Honor reaction is potassium amide, sodium amide, sodium hydride, potassium tert.-butoxide, potassium ethylate and sodium ethylate by alkaline power successively.It is generally acknowledged that used alkalescence is strong more, the stereoselectivity of reaction is good more.The used alkali of the present invention is 60% sodium hydride, and its alkalescence is stronger relatively, but inflammable and explosive danger is less relatively when being to use.
After single stage method is meant indole-alcohol and triethyl-phosphite and iodine hybrid reaction; Need not the diethyl phosphonate skatole of producing; Obtain through methods of purification such as recrystallization or column chromatographies, Wittig-Horner reaction of styrene base Benzazole compounds can directly take place with various phenyl aldehydes in reaction solution.
Substituted benzaldehyde is meant that ortho position, a position and the contraposition on phenyl ring contains various substituting groups, comprising fluorine, chlorine, bromine, alkyl, methoxyl group, benzyl, cyanic acid, nitro, ethanoyl and ester group etc.
In addition:
On the amount of using solvent and reagent, during the first step methylation reaction, the add-on of polar solvent satisfies gets final product its dissolving, and for example the 1g reactant is dissolved in 10ml to the 40ml polar solvent.The consumption of alkali is roughly at 1.1 to 2 equivalents, and little excessive getting final product is too much unnecessary.Methylating reagent in addition, like methylcarbonate, methyl-sulfate or Soiodin, consumption keeps identical with alkali, and promptly 1.1 to 2 equivalents are too much unnecessary.Second step, the consumption of reductive agent was roughly at 1.1 to 2 equivalents, and was too much unnecessary during reduction reaction.In the 3rd step Wittig-Honor when reaction, triethyl-phosphite is that reactant has the effect of playing solvent again, so consumption is controlled at more than 1.1 equivalents, but the dissolving fully that only need satisfy reactant gets final product, and is too much unnecessary.The consumption of iodine is roughly at 1.1 to 1.5 equivalents.The consumption of aprotic polar solvent is also to be advisable in right amount, and for example the 1g reactant needs among the 10ml to 40ml, and is too much unnecessary, but solvent must dewater before using.The consumption of highly basic and substituted benzaldehyde all is 1.1 to 5 equivalents, and is too much unnecessary.
In temperature of reaction with on the reaction times, during the first step methylation reaction, controlled temperature generally about the reflux temperature of solvent for use, if use methylene dichloride, then at 30 to 40 ℃, is used acetone, then at 45 to 57 ℃, uses DMF, then at 120 to 145 ℃.Also difference is very big according to the difference with alkali reaction times in addition, and alkalescence is strong more, and the time is short more, if use Pottasium Hydroxide, then at 1 to 2 hour, uses salt of wormwood, then at 8 to 12 hours.Can pass through thin-layer chromatography (TLC) and detect, judge whether reaction finishes fully.Second step, temperature of reaction was unsuitable too high, was controlled at 0 to 5 ℃ and was advisable during reduction reaction, and the reaction times is generally between 0.5 to 2 hour.Can pass through thin-layer chromatography (TLC) and detect, judge whether reaction finishes fully.Before the 3rd step Wittig-Honor reaction, should control about 0 ℃ when iodine adds reaction solution,, be warming up to 150 to 170 ℃ of reactions 2 to 4 hours until finishing.Temperature of reaction was generally in room temperature or lower temperature when ensuing Wittig-Honor reacted; Because at high temperature can generate the by product of cis for thermodynamic control; Yet then be that kinetic control is main with trans product when low temperature, be advisable so will be controlled at 0 to 25 ℃.Reaction times changes along with the difference of reaction conditions, generally at 1 to 8 hour.Can pass through thin-layer chromatography (TLC) and detect, judge whether reaction finishes fully.
Below in conjunction with two specific embodiments, essence of the present invention is further understood in exemplary illustration and help, but the embodiment detail only is for the present invention is described; Do not represent the present invention to conceive whole technical schemes down; Therefore should not be construed as the technical scheme qualification total to the present invention, some are In the view of the technician, and the unsubstantiality that does not depart from the present invention's design increases and/or change; For example simple the change or replacement of technical characterictic to have same or similar technique effect all belongs to protection domain of the present invention.
Embodiment 1:
N-methyl-5-cyanic acid-indole-3-formaldehyde
With 5-cyanic acid-indole-3-formaldehyde (1.17g, 6.90mmol) and salt of wormwood (1.87g 13.81mmol) joins among the 20ml DMF successively, stirs to drip methylcarbonate down (1.22g 13.81mmol), was warming up to back flow reaction 6 hours.Reaction finishes postcooling to room temperature, adds 30ml water, has solid to separate out, filter, and washing, oven dry, ethyl alcohol recrystallization gets yellow solid N-methyl-5-cyanic acid-indole-3-formaldehyde, productive rate 89.6%, HPLC>=98%, fusing point 182-183 ℃, IR (KBr, cm
-1) 3110,2840,2220,1660,1620,1530,1480,1460,1400,1360,1190,1060,880,820,790,
1H-NMR (300MHz, DMSO) δ 3.946 (s, 3H), 7.704-7.828 (m, 2H), 8.468-8.489 (m, 2H), 9.933 (s, 1H).
N-methyl-5-cyanic acid-indole-3-carbinol
Under the nitrogen protection, (0.92g 5mmol) is dissolved in the 20ml ethanol, is cooled to 0 ℃, and (0.38g 10mmol), stirs reaction down 1 hour to add Peng Qinghuana lentamente with N-methyl-5-cyanic acid-indole-3-formaldehyde.Reaction is poured in the 60ml frozen water after finishing, and has solid to separate out, filter, and washing, oven dry, ethyl alcohol recrystallization gets yellow solid N-methyl-5-cyanic acid-indole-3-carbinol, productive rate 90.1%, HPLC>=98%, fusing point 126-127 ℃, IR (KBr, cm
-1) 3280,2960,2240,1630,1500,1390,1370,1310,1190,1030,1000,810,710,
1H-NMR (300MHz, DMSO) δ 3.799 (s, 3H), 6.649 (d, 2H, J=5.4Hz), 4.966 (t, 1H, J=5.4Hz), 7.428-7.604 (m, 3H), 8.120 (s, 1H).
Trans-N-methyl-5-cyanic acid-3-is to benzonitrile vinyl base indoles
Under the nitrogen protection; With N-methyl-5-cyanic acid-indole-3-carbinol (0.56g; 3mmol) and triethyl-phosphite (0.1g, 6mmol) be cooled to 0 ℃ after, slowly add iodine (0.84g; 3.3mmol), finish and be warming up to 150 ℃ of reactions and obtained intermediate N methyl-5-cyanic acid-diethyl phosphonate skatole in 2 hours.In the reaction solution of reducing to room temperature, add 20ml DMF, be cooled to 0 ℃ then, slowly add sodium hydride (0.29g; 12mmol), reply stirring at room half a hour, and then be cooled to 0 ℃; (0.78g at room temperature reacted 2 hours after 6mmol) to cyanobenzaldehyde in adding.Reaction is poured in the 30ml frozen water after finishing, and uses ethyl acetate extraction, anhydrous sodium sulfate drying; Column chromatography purify yellow solid trans-N-methyl-5-cyanic acid-3-is to benzonitrile vinyl base indoles, productive rate 49.1%, HPLC>=98%; Fusing point 222-223 ℃, IR (KBr, cm
-1) 3150,2240,1640,1600,1490,1380,1270,1180,960,830,
1H-NMR (300MHz, CDCl
3) δ 3.864 (s, 3H), 7.011-7.036 (m, 1H), 7.316-7.416 (m, 3H), 7.514-7.649 (m, 5H), 8.286 (s, 1H).
Embodiment 2:
Trans-N-methyl-5-cyanic acid-3-is to methoxy styryl base indoles
Under the nitrogen protection; With N-methyl-5-cyanic acid-indole-3-carbinol (9.3kg; 50mol) and triethyl-phosphite (2.0kg, 120mol) be cooled to 0 ℃ after, slowly add iodine (16.8g; 66mol), finish and be warming up to 160 ℃ of reactions and obtained intermediate N methyl-5-cyanic acid-diethyl phosphonate skatole in 3 hours.In the reaction solution of reducing to room temperature, add 300L DMF, be cooled to 0 ℃ then, slowly add sodium hydride (3.6kg; 150mol), reply stirring at room half a hour, and then be cooled to 0 ℃; (7.8kg at room temperature reacted 2 hours after 60mol) to cyanobenzaldehyde in adding.Reaction is poured in the 500L frozen water after finishing, and uses ethyl acetate extraction, anhydrous sodium sulfate drying; Ethyl alcohol recrystallization gets yellow solid trans-N-methyl-5-cyanic acid-3-is to methoxy styryl base indoles, productive rate 44.5%, HPLC>=98%; Fusing point 156-157 ℃, IR (KBr, cm
-1) 3120,2240,1650,1520,1490,1380,1250,1190,1040,960,840,
1H-NMR (300MHz, CDCl
3) δ 3.826 (s, 3H), 3.841 (s, 3H), 6.917 (d, 2H, J=8.7Hz), 6.961-7.123 (m, 2H), 7.296-7.503 (m, 5H), 8.280 (s, 1H).
To those skilled in the art, under the enlightenment of design of the present invention and specific embodiment, some distortion that can directly derive or associate from this patent disclosure and general knowledge; Those of ordinary skills will recognize also can adopt additive method, or uses substituting of known technology in the prior art always, and the mutual various combination between characteristic; For example also to adopt two substituted indoles-3-formaldehyde, the substituted-phenyl diethyl phosphonate also can use and have two or more substituent phenyl-phosphonic acid diethyl ester substituted indole-3-formaldehyde, and reaction solvent also can substitute with the solvent that specification sheets is pointed out; Temperature of reaction, change of time, the variation of alkali, or the like unsubstantiality change; Can be employed equally; Can both realize this patent representation function and effect, launch for example no longer one by one to describe in detail, all belong to this patent protection domain.
Claims (5)
1. a styryl Benzazole compounds compound method is characterized in that from substituted indole formaldehyde, under polar solvent and the alkaline condition and after the methylating reagent reaction, the nitrogen hydrogen of its indole ring is replaced by methyl; Under the effect of reductive agent, make aldehyde radical be reduced into hydroxyl then; After last substituted indole methyl alcohol and triethyl-phosphite and the iodine hybrid reaction, Wittig-Horner reaction single stage method takes place and generates the styryl Benzazole compounds in direct and substituted benzaldehyde under the effect of aprotic solvent and potassium amide, sodium amide, sodium hydride, potassium tert.-butoxide, potassium ethylate or sodium ethylate.
2. according to the said styryl Benzazole compounds of claim 1 compound method, it is characterized in that triethyl-phosphite be reactant be again solvent.
3. according to the said styryl Benzazole compounds of claim 1 compound method, it is characterized in that said polar solvent is: N, dinethylformamide, methylene dichloride, trichloromethane, acetone, THF or acetonitrile.
4. according to the said styryl Benzazole compounds of claim 1 compound method, it is characterized in that said methylating reagent is: methylcarbonate or methyl-sulfate.
5. according to the said styryl Benzazole compounds of claim 1 compound method, it is characterized in that said reductive agent is Peng Qinghuana or POTASSIUM BOROHYDRIDE 97MIN.
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| CN108675951A (en) * | 2018-06-07 | 2018-10-19 | 河南师范大学 | A kind of synthetic method of 2- alkenyls indole -3-carboxylic acid ester type compound |
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| Michael N.Greco,et al.Discovery of Potent,Selective,Orally Active,Nonpeptide Inhibitors of Human Mast Cell Chymase.《Journal of Medicinal Chemistry》.2007,第50卷(第8期),1727-1730. * |
| 刘捷等.3-(取代苯基乙烯基)吲哚类衍生物的合成及抗肿瘤活性.《药学学报》.1999,第34卷(第12期),908-912. * |
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