CN102617442A - Preparation method and use of 3,3'-methylenebis(1H-Indole) - Google Patents
Preparation method and use of 3,3'-methylenebis(1H-Indole) Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- VFTRKSBEFQDZKX-UHFFFAOYSA-N 3,3'-diindolylmethane Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4NC=3)=CNC2=C1 VFTRKSBEFQDZKX-UHFFFAOYSA-N 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 79
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000002904 solvent Substances 0.000 claims abstract description 28
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- 150000001875 compounds Chemical class 0.000 claims abstract description 13
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- 238000001953 recrystallisation Methods 0.000 claims abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims description 63
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- 239000000758 substrate Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
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- RTNUTCOTGVKVBR-UHFFFAOYSA-N 4-chlorotriazine Chemical class ClC1=CC=NN=N1 RTNUTCOTGVKVBR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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- 229910013684 LiClO 4 Inorganic materials 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229910010413 TiO 2 Inorganic materials 0.000 description 1
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- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
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- 150000002576 ketones Chemical class 0.000 description 1
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- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
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- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a preparation method of 3,3'-methylenebis(1H-Indole). The preparation method comprises the following steps that 1, indole and p-toluenesulfonic acid are dissolved in a solvent comprising water and 95wt% of ethanol and a formaldehyde aqueous solution is added into the mixed solution in a nitrogen protective atmosphere; 2, the mixture obtained by the step 1 undergoes a reaction at a room temperature in dark for 20 to 30 hours, preferably, for 24 hours; 3, reaction products are filtered so that solids precipitated by the step 2 are obtained; and 4, the solids obtained by the step 3 are subjected to recrystallization purification. In addition, the invention also provides a use of the prepared 3,3'-methylenebis(1H-Indole) which is a high purity compound in preparation of drugs.
Description
Invention field
The invention belongs to field of medicaments, particularly, the present invention relates to 3, the working method and the medicinal application of the two indoles of 3 '-methene.
Background technology
3, the two indoles of 3 '-methene (3,3 '-methylenebis (1H-Indole)) (the CAS registration number: 1968-05-4) structure is as follows, is Lu Sheng or halobiontic meta-bolites at occurring in nature, possesses certain pharmaceutical use:
There has been certain methods to synthesize 3 now, two indoles of 3 '-methene and analogue thereof.For example, (Bandgar, B.P. such as B.P.Bandgar; Shaikh, K.A.Tetrahedron Lett.2003,44,1959-1961.) reported that a kind of is the method (reaction formula is as follows) of the efficient fast synthetic bisindole derivatives of catalyzer with the iodine.But blemish in an otherwise perfect thing is that post-reaction treatment must be used a large amount of Na
2S
2O
3, environment is had certain pollution, and has used deleterious acetonitrile also not meet the theory of environmental protection as solvent in the reaction.
(Ji, S.-J. such as Shun-Jun Ji; Wang, S.-Y.; Zhang, Y.; Loh, T.-P.Tetrahedron 2004,60,2051-2055.) under condition of no solvent, are catalyzer with the iodine, are that substrate has synthesized bisindole derivatives (reaction formula is as follows) efficiently with aromatic aldehyde and indoles.Although this method reaction conditions is gentle, the reaction times is of short duration, easy to operation, product yield is high; But this method only is applicable to the reaction of aromatic aldehyde and indoles; Alkanoic and ketone compounds are not appeared in the newspapers at present as yet, and visible this method has certain limitation to the application of substrate.
(Sharma, G.V.M. such as G.V.M.Sharma; Janardhan Reddy, J.; Sree Lakshmi, P.; Radha Krishna, P.Tetrahedron Lett.2004,45,7729-7732.) report uses 1,3, and 5-three chlorotriazines (TCT) are the synthetic bisindole compound (reaction formula is as follows) of catalyzer.But used deleterious acetonitrile as solvent in the reaction, do not met the synthetic theory of current environmental protection, economic actual effect.
(Tabatabaeian, K. such as Khalil Tabatabaeian; Mamaghani, M.; Mahmoodi, N.; Khorshidi, A.Can.J.Chem.2006,84,1541-1545.) reported with RuCl
3NH
2O is a catalyzer, is that solvent reacted 25 minutes to 3 hours at ambient temperature with methyl alcohol, is that substrate has synthesized bisindole derivatives (reaction formula is as follows) with aldehyde and indoles.But the catalyzer that this method is used is prone to cause heavy metal contamination, does not meet requirements of green environmental protection.
(Firouzabadi, H. such as Habib Firouzabadi; Iranpoor, N.; Jafarpour, M.; Ghaderi, A.J.Mol.Catal.A:Chem.2006,253,249-251.) report is a kind of under condition of no solvent, with ZrOCl
28H
2O/ silica gel is the method (reaction formula is as follows) of the synthetic bisindole derivatives of catalyzer.But for industrialized mass production, reaction substrate reaches sufficient contact and is difficult to control.
(Mehrazma, S. such as Shokoufeh Mehrazma; Azizi, N.; Saidi, M.R.Lett.Org.Chem.2006,3,161-164.) to have reported a kind ofly under condition of no solvent, the reaction of indoles and carbonyl compound generates the method (reaction formula is as follows) of bisindole derivatives.But LiClO
4Thermally labile at high temperature is prone to decompose blast.Because the thermolability of perchlorate makes its preparation and use all to exist certain risk, so it is promoted the use of and has received certain restriction.
(Zeng, X.-F. such as Zeng Xiao-Fei; Ji, S.-J.Lett.Org.Chem.2006,3,374-378.) reported a kind of under condition of no solvent, with solid superacid SO
4 2-/ TiO
2Method (reaction formula is as follows) for the synthetic bisindole derivatives of catalyzer.But the making of catalyzer is quite loaded down with trivial details, and the selection of reaction substrate is had certain limitation, and therefore, this method only possesses certain theoretical significance, lacks practicality.
An, (An, L.-T. such as Li-Tao; Ding, F.-Q.; Zou, J.-P.; Lu, X.-H.; Zhang, L.-L.Chin.J.Chem.2007,25,822-827) reported a kind ofly under condition of no solvent, with the amidosulfonic acid the efficiently method (reaction formula is as follows) of synthetic bisindole derivatives of catalyzer.Although this method high-efficiency environment friendly, economic actual effect, for industrialized production, the solid phase operation is difficult to control.
(Azizian, J. such as Javad Azizian; Teimouri, F.; Mohammadizadeh, M.R.Catal.Commun.2007,8,1117-1121.) reported a kind ofly under condition of no solvent, with ammonium chloride the method (reaction formula is as follows) of the synthetic bisindole derivatives of catalyzer.Although this method actual effect easy and simple to handle, efficient, a large amount of ammonium chlorides that use cause certain pollution to environment undoubtedly.
(Hasaninej ad, A. such as Alireza Hasaninejad; Zare, A.; Sharghi, H.; Shekouhy, M.; Khalifeh, R.; Beni, A.S.; Zare, A.R.M.Can.J.Chem.2007,85,416-420.) reported a kind ofly under condition of no solvent, with the silicon chloride method (reaction formula is as follows) of the efficient fast synthetic bisindole derivatives of catalyzer.This method rapidly and efficiently, easy handling, be suitable at short notice synthetic bis (indolyl) methane verivate, but for industrialized production, the solid phase operation is difficult to control.
(Kamble, V.T. such as Vinod T.Kamble; Kadam, K.R.; Joshi, N.S.; Muley, D.B.Catal.Commun.2007,8,498-502.) report is a kind of with HClO
4-SiO
2Be catalyzer, the method (reaction formula is as follows) of efficient fast synthetic bisindole derivatives.
WANG, (Wang, S.-Y. such as Shun-Yi; Ji, S.-J.; Su; X.-M.Chin.J.Chem.2008,26,22-24.) reported that with Meldrum ' s acid be catalyzer; Making solvent with water at ambient temperature and under ultrasonic radiation, reacted 3-8 hour, is that substrate has synthesized bisindole derivatives (reaction formula is as follows) with aldehyde (ketone) and indoles.Though this method avoids the use of deleterious organic solvent, the catalyzer of use is more cheap, and reaction conditions is gentle, and thick product just can obtain through filtering, and need under the UW radiation, just can obtain the higher product of yield, the unsuitable suitability for industrialized production of this method.
(Nadkarni, S.V. such as Sharmin V; Gawande, M.B.; Jayaram, R.V.; Nagarkar, J.M.Catal.Commun.2008,9,1728-1733.) reported a kind of with PO
4 3-/ ZrO
2Be catalyzer, under condition of no solvent, the method (reaction formula is as follows) of the synthetic bisindole derivatives of high-level efficiency.But the making processes of catalyzer is more loaded down with trivial details.
(Satam, J.R. such as Jitendra R; Parghi, K.D.; Jayaram, R.V.Catal.Commun.2008,9,1071-1078.) reported a kind ofly under condition of no solvent, use the efficiently method (reaction formula is as follows) of synthetic bisindole derivatives of heterogeneous catalyst.But catalyzer making processes is more loaded down with trivial details, and price is high relatively.
Through a large amount of research, the inventor has obtained a kind of new 3, the working method of the two indoles of 3 '-methene; Can at room temperature carry out, use industrial alcohol, and not use complicated catalyst system as solvent; Reduce production cost, alleviated environmental pollution; And through the ratio through water and industrial alcohol in the control solvent effectively; Reduced the generation of by product; Reduced the solid product of separating out parcel ability, be very easy to purge process, only used the purity level that can purify to pharmaceutical grade through simple measures such as recrystallizations impurity.In addition, it is highly purified 3 that the inventor has obtained, the two indoles of 3 '-methene, and it can be safely uses as the active compound of pharmaceutical grade, all have significant lethal effect to kinds of tumors.
Summary of the invention
The object of the present invention is to provide 3, the working method of the two indoles of 3 '-methene, its cost is low, environmentally friendly, by product is few, convenient purification, safety simple to operate.In addition, it is highly purified 3 that the present invention also provides, the two indoles of 3 '-methene with and medicinal application.
Aspect first, the invention provides 3, the working method of the two indoles of 3 '-methene, it comprises:
(1) indoles and tosic acid are dissolved in the solvent of being made up of 95% (weight) second alcohol and water, under the condition of nitrogen protection, add formalin;
(2) lucifuge reaction at room temperature is 20-30 hour, is preferably 24 hours;
(3) filter the solid that acquisition step (2) reaction is separated out; With
(4) solid of recrystallization purifying step (3) acquisition.
In this article, as do not add explanation, " room temperature " refers to 20-30 ℃, like 20-25 ℃, 25-30 ℃, most preferably is 25 ℃.
Discover that through the inventor other alcohols impurity that is mixed with in alcoholic acid purity, the especially ethanol (mainly being methyl alcohol), heavy metallic salt etc. can not cause remarkably influenced for the productive rate and the purity of final product of the present invention.So; Although can adopt in the method for first aspect of the preferred the present invention of more highly purified ethanol (like, analytically pure ethanol) dilution, 95% (weight) ethanol be 95% (weight) industrial alcohol (promptly; Industrial spirit), promptly on the label be 95% ethanol of " technical pure ".Like this, the source of using industrial alcohol to widen raw material has greatly reduced the use cost of raw material.
In the method for preferred first aspect of the present invention, in solvent, water and 95% (weight) alcoholic acid volume ratio is 1: 1-6, excellent is 1: 1-3 most preferably is 1: 1.5.Discover that through the inventor such ratio can effectively be dissolved the indoles raw material, effectively reduce the kind and the quantity of by product simultaneously.
More complete for more expensive raw material indole reaction is got, preferably formaldehyde is excessive in actual production.So in the method for preferred first aspect of the present invention, the mol ratio of indoles and formaldehyde is 1-2: 1, be preferably 1.5-1.95: 1,1.85-1.92 more preferably: 1.
Discover through the inventor; Use the reaction effect of tosic acid will be far superior to use common agents such as glacial acetic acid; And inventor's discovery, even the tosic acid consumption is seldom, still can produce 3 effectively; The two indoles of 3 '-methene, the benefit to cost and environment is self-evident like this.So in the method for preferred first aspect of the present invention, the mol ratio of indoles and tosic acid is 50-200: 1, be preferably 80-120: 1,95-100 more preferably: 1.
Formaldehyde highly volatile under the normal temperature, and after sucking human body, have powerful damaging effect, therefore use formalin to replace usually, but the aqueous solution has increased the water in the solvent in fact.For this reason,, find to take the water in a certain proportion of formalin and the solvent, still can make method of the present invention effectively carry out through inventor's research.So in the method for preferred first aspect of the present invention, the volume ratio of the water in formalin and the solvent is 1: 8-15 is preferably 1: 9-12 most preferably is 1: 10.
In the method for preferred first aspect of the present invention, in step (3), said solid is through methyl alcohol drip washing.Although in fact use the effect of formaldehyde drip washing best; But formaldehyde highly volatile under the normal temperature; And the damaging effect that has brute force behind the suction human body; And through comparing with other organic solvents, the effect of methanol wash (comprising except that surface impurity and minimizing loss of yield) is best, the drip washing of therefore preferred use methyl alcohol.The solid of drip washing preferably needn't be through super-dry.
In the method for preferred first aspect of the present invention, in step (4), the solvent that recrystallization uses is an ETHYLE ACETATE.In embodiment of the present invention, the number of times of recrystallization is twice.
In the method for preferred first aspect of the present invention, the solid purity that step (3) obtains is preferably greater than 98% greater than 97%, and more preferably 98.5%.Like this 3 of purity, the two indoles of 3 '-methene are quite pure, practiced thrift cost for being further purified.When in the not too high application of purity requirement, using, the solid that can directly adopt step (3) to obtain, and needn't be further purified, this also is encompassed in protection scope of the present invention.
In the method for preferred first aspect of the present invention, produce obtain 3, the purity of the two indoles of 3 '-methene is preferably greater than 99.3% greater than 99%, more preferably 99.5%.Like this 3 of purity, the two indoles of 3 '-methene be medicinal levels other, can directly be formulated into medicine.
Aspect second; The invention provides the compound (3 of the method preparation of first aspect present invention; The two indoles of 3 '-methene) preparation anticancer (as, colorectal carcinoma, cancer of the stomach, prostate cancer and liver cancer) or anticancer (as; Colon cancer cell, stomach cancer cell, prostate cancer cell and liver cancer cell) application in the medicine.The high-purity compound of the method preparation that preferred wherein compound is a first aspect present invention (3, the two indoles of 3 '-methene), its purity is preferably greater than 99.3%, more preferably greater than 99.5% greater than 99%.
In an exemplary embodiment, the application of second aspect of the present invention that the present invention preferably provides comprises,
(1) method of embodiment of the present invention first aspect, make to produce obtain 3, the purity of the two indoles of 3 '-methene is preferably greater than 99.3%, more preferably greater than 99.5% greater than 99%; With
(2) high-purity compound and the pharmaceutically acceptable pharmaceutical carrier step (1) produced are mixed with medicine.
In this article, pharmaceutically acceptable carrier refers to nontoxic solid-state, semi-solid state or liquid weighting agent, thinner, adjuvant, lapping or other pharmaceutical adjuncts.Known technology according to this area; Can pharmaceutical composition be processed various formulations according to the needs of therapeutic purpose, route of administration; Preferred said composition is a unit dosage form, firmly penetrates with solution or suspension-s, aerosol or liquid spray, drops, injection, automated injection device or suppository like tablet, film, pill, capsule (comprise and continue release or postpone to release the form of establishing), pulvis, granule, tincture, syrup and emulsion agent, disinfectant.For example, with tablet or capsular clothes administration, above-mentioned active medicine component can be combined with a kind of oral acceptable inert support of nontoxic pharmacology, as ethanol, etc. ooze glucose solution, glycerine, saline water or its combination.
The present invention has obtained following beneficial effect:
(1) make solvent with water and industrial spirit (95%), low price, more expensive, the deleterious organic solvent of use price has been avoided in the safety material benefit;
(2) use tosic acid to make the catalyzer low price, less to the pollution of environment;
(3) react on room temperature and carry out, heating and condensing works need be provided, promptly practiced thrift water power, also do not have potential safety hazard;
(4) the product bis (indolyl) methane is insoluble in water and ethanol, and principal product is just separated out from system in the reaction process, and the thick product that contains the minute quantity by product only need filter just and can obtain, but further just purifying of recrystallization, and operation is simple and easy to do;
(5) lessivation of purifying only need use methyl alcohol, has avoided formaldehyde to use the suction that human body is caused to injure, and has further simplified operation steps, has more brought security;
(6) 3 of the present invention's acquisition, the two indoles purity of 3 '-methene are high, can directly be mixed with drug use, and can all have significant kill capability to kinds of tumors.
Description of drawings
The TLC collection of illustrative plates of Fig. 1 comparative example 1.
The TLC collection of illustrative plates of Fig. 2 comparative example 2.
The TLC collection of illustrative plates of Fig. 3 comparative example 3.
The TLC collection of illustrative plates of Fig. 4 comparative example 4.
The TLC collection of illustrative plates of Fig. 5 embodiment 1.
The proton nmr spectra of Fig. 6 embodiment 2.
The present invention has quoted open source literature, and these documents are in order more clearly to describe the present invention, and their full text content is all included this paper in and carried out reference, just looks like that repeated description is the same excessively in this article for their full text.
For the ease of understanding, below will the present invention be described in detail through concrete embodiment.What need particularly point out is that these descriptions only are exemplary descriptions, do not constitute limitation of the scope of the invention.According to the argumentation of this specification sheets, many variations of the present invention, to change all be conspicuous concerning one of ordinary skill in the art, like water to the alcoholic acid dilution etc.
Embodiment
The high temperature of the two indoles of the methene that comparative example 1 glacial acetic acid is participated in is synthetic
The building-up reactions equation is following:
Building-up process is following:
After mechanical stirrer, TM being installed on the four-hole round bottom glass flask and being fed nitrogen, add 11.7 gram indoles, 3.0 gram glacial acetic acid and 250ml water.Under agitation, under room temperature condition, begin to drip 4mL 40% (weight) formalin, the limit heating edge drips, and after dropwising, heat temperature raising to 90 ℃ in 90 ℃ of lucifuges reactions 5 hours, can be separated out solid product in the reaction process.
The evaluation of product:
Get that the liquid stock of remaining reaction solution and sampling carries out thin-layer chromatography (TLC) monitoring in the above-mentioned reaction process, wherein, developping agent: normal hexane (V): ETHYLE ACETATE (V)=2: 1.TLC result (as shown in Figure 1) shows: reaction substrate indoles primitive reaction finishes, and removes main product object point 3 in the reaction solution, beyond the two indoles of 3 '-methene, also has three by-product object points.
Can find out that from the TLC detected result by product that produces in the reaction is many, influence productive rate largely.Temperature of reaction is too high possibly to be the major cause that causes by product too much.The normal temperature of the two indoles of the methene that comparative example 2 glacial acetic acids are participated in is synthetic
The building-up reactions equation is following:
Building-up process is following:
After mechanical stirrer, TM being installed on the four-hole round bottom glass flask and being fed nitrogen, add 11.7 gram indoles, 3.0 gram glacial acetic acid and 250ml water.Under the mechanical stirring, under room temperature (25-30 ℃) condition, drip 4mL 40% (weight) formalin, after dropwising,, can separate out solid product in the reaction process in 25-30 ℃ of lucifuge reaction 24 hours.
The evaluation of product:
Get that the liquid stock of remaining reaction solution and sampling carries out thin-layer chromatography (TLC) monitoring in the above-mentioned reaction process, wherein, developping agent: normal hexane (V): ETHYLE ACETATE (V)=2: 1.TLC result (as shown in Figure 2) shows: the reaction substrate indoles remains in a large number, but the product point has only two, and by-product object point relative proportion is minimum.Even continue to prolong the reaction times, TLC result shows that the reaction substrate indoles remained in a large number when reaction tended to balance.
Can find out that from the TLC detected result temperature of reaction is reduced to room temperature, though by product kind and quantity reduce to some extent, reaction is carried out quite not exclusively, and the reaction substrate indoles remains in a large number, is difficult to apply on the industry.
The room temperature of the two indoles of the methene that comparative example 3 tosic acid and water are participated in is synthetic
The building-up reactions equation is following:
Building-up process is following:
After adding 11.7 gram indoles, 0.25 gram tosic acid in the four-hole bottle, add 250ml water, mechanical stirring under nitrogen protection drips 4ml 40% (weight) formalin.Dropwise the back in room temperature (25-30 ℃) reaction 24 hours, can separate out solid product in the reaction process.
The evaluation of product:
Get that the liquid stock of remaining reaction solution and sampling carries out thin-layer chromatography (TLC) monitoring in the above-mentioned reaction process, wherein, developping agent: normal hexane (V): ETHYLE ACETATE (V)=2: 1.TLC result (as shown in Figure 3) shows: remove principal product and by product in the reaction solution, have neither part nor lot in a certain amount of indoles of reaction in addition, in addition, remove principal product and by product in the solid product of separating out, also be enclosed with a certain amount of indoles that has neither part nor lot in reaction.Even prolong the reaction times, accelerate churned mechanically speed, still have the indoles that has neither part nor lot in reaction to exist.
Reaction can't carry out completely that possible cause is, can parcel in the reaction product participates in the indoles of reaction, has influenced carrying out fully of reaction to a certain extent.
The room temperature of the two indoles of the methene that comparative example 4 tosic acid and industrial alcohol are participated in is synthetic
The building-up reactions equation is following:
Building-up process is following:
After adding 29.5 gram indoles, 0.45 gram tosic acid in the four-hole bottle; Adding the 100ml massfraction and be 95% industrial spirit dissolves the reaction substrate indoles fully; Mechanical stirring under nitrogen protection; Drip 10ml40% (weight) formalin, dropwise, can separate out solid product in the reaction process in room temperature (25-30 ℃) reaction 24 hours.
The evaluation of product:
Get that the liquid stock of remaining reaction solution and sampling carries out thin-layer chromatography (TLC) monitoring in the above-mentioned reaction process, wherein, developping agent: normal hexane (V): ETHYLE ACETATE (V)=2: 1.TLC result (as shown in Figure 4) shows: indoles is reacted completely basically, but has a kind of by product to generate, and by-product yields is relatively very high.
This shows, uses the relatively low solvent of this polarity of industrial alcohols of high density, can make that by-product yields improves greatly, is difficult to actual applying.
The room temperature of the two indoles of the methene that embodiment 1 tosic acid and a certain proportion of water and industrial alcohol are participated in is synthetic
The building-up reactions equation is following:
Building-up process is following:
After adding 29.5 gram indoles, 0.45 gram tosic acid in the four-hole bottle; Adding the 150mL massfraction and be 95% industrial spirit and 100mL water dissolves the reaction substrate indoles fully; Under nitrogen protection and mechanical stirring; Drip 10mL 40% formalin, dropwise, can separate out solid product in the reaction process in room temperature (25-30 ℃) reaction 24 hours.
The evaluation of product:
Get that the liquid stock of remaining reaction solution and sampling carries out thin-layer chromatography (TLC) monitoring in the above-mentioned reaction process, wherein, developping agent: normal hexane (V): ETHYLE ACETATE (V)=2: 1.TLC result (as shown in Figure 5) shows: indoles almost all transforms in the reaction solution, by product have only a kind of and also relative proportion very low.Almost do not wrap up indoles in the solid product simultaneously yet, obtain solid product 26.4g after the drying altogether, productive rate 85%, purity is 98.5%.Adopt analytical pure ethanol to be diluted with water to 95%, carry out, do not see the raising on product productive rate and the purity with reference to aforesaid method.From the result of Fig. 1-5, the product that adopts embodiment 1 to prepare obviously is superior to adopting the product of comparative example 1-4 preparation.
The result shows, adopts method for preparing, with respect to comparative example; Carry out the most completely during reaction, and the amount of by product is minimum, solved the problem of reaction product parcel indoles; This is very easy to the later stage purifying, wherein uses not impact effect of industrial alcohol.
The purifying of the two indoles of embodiment 2 methenes
The reaction system that embodiment 1 carries out is filtered, and isolates solid product, is thick product; Isolated reaction solution reclaims ethanol wherein through underpressure distillation.
Experiment finds that solid product directly carries out recrystallization, and moisture content wherein will greatly influence the yield and the purity of recrystallization purifying, therefore need carry out drip washing.Get embodiment 1 isolated wet solid product 31.7g (that is, needn't drying also do not influence crystalline rate), under decompress filter, thick product is carried out drip washing with 120mL methyl alcohol.
Solid product after the drip washing is mixed in 60mL ETHYLE ACETATE, is heated to 70-78 ℃ of dissolving under stirring, be cooled to room temperature then naturally, filter and separate out solid.Then, solid adds 50mL ETHYLE ACETATE, is heated to 70-78 ℃ of dissolving, stirs the back then and is cooled to room temperature naturally; After solid product is separated out, discard liquid, with 10mL cold ethyl acetate wash solids, drying under reduced pressure solid product; Altogether 3, the two indoles product 18.6g of 3 '-methene, purity 99.5%.167 ℃ of this product fusing points, its proton nmr spectra is as shown in Figure 6, and nuclear magnetic data is following: 4.1322 (s, 2H), 6.8924 (t, 2H), 7.0025 (t, 2H), 7.1240 (s, 2H), 7.3206 (d, 2H), 7.5215 (d, 2H), 10.7153 (s, 2H).
The medicinal application test of the two indoles of embodiment 3 methenes
The all cells system of this test all can be available from the U.S. representative microbial preservation center (ATCC).
1, Colon38 cells in vitro killing experiments
The source: the Colon38 cell is a mouse colonic cell, is attached cell.
Substratum: 164090% (nutrient solution)+NCS (NBCS) 10%+1ml penicillin streptomycin mixed solution
Culture condition: at 5%CO
237 ℃ of incubators in cultivate.Went down to posterity once in per 3 days, and began test when 2-3 time the back cell that goes down to posterity gets into logarithmic phase.
Experimental procedure: (1) culturing cell in vegetative period of taking the logarithm dispels evenly the preparation single cell suspension;
(2) be 2 * 10 with the RPMI1640 nutrient solution adjustment cell concn that contains 10%FBS
5/ mL, in the inoculation of 96 porocyte culture plates, every hole 100 μ L place 37 ℃, 5%CO
2Incubator is cultivated 24h;
(3) get the compound of embodiment 2, be dissolved in DMSO 99.8MIN. (DMSO), compound concentration is respectively: 1 μ g/ml, 3 μ g/ml, 9 μ g/ml, 27 μ g/ml, 81 μ g/ml.
(4) dosing of dividing into groups behind the 24h;
(5) continue to cultivate 72 hours;
(6) wash plate with PBS, every hole adds 20ul MTS solution and adds the RPMI1640 of 100ul10%FBS, continues to cultivate 2 hours;
(7) with ELIASA A570nm colorimetric, measure the OD value, dosing holes and control wells OD value relatively draw 503nhibiting concentration (IC50).
2, SGC-7901 cells in vitro killing experiments
Process like above-mentioned method 1 is measured, and wherein uses SGC-7901 cell (gastric carcinoma cells is attached cell) replaced C olon38 cell.
3, H22 cells in vitro killing experiments
The source: the H22 cell is the rat liver cancer cell, is suspension cell.
Substratum: RPMI1640 substratum and 10% foetal calf serum, and add mycillin (1%)
Culture condition: at 5%CO
237 ℃ of incubators in cultivate.Went down to posterity once in per 3 days, and began test when 2-3 time the back cell that goes down to posterity gets into logarithmic phase.
Experimental procedure: (1) culturing cell in vegetative period of taking the logarithm dispels evenly the preparation single cell suspension;
(2) be 2 * 10 with the RPMI1640 nutrient solution adjustment cell concn that contains 10%FBS
5/ mL, in 96 porocyte culture plates inoculations, every hole 50 μ L place 37 ℃, 5%CO2 incubator to hatch;
(3) get the compound of embodiment 2, be dissolved in DMSO 99.8MIN. (DMSO), compound concentration is respectively: 1 μ g/ml, 3 μ g/ml, 9 μ g/ml, 27 μ g/ml, 81 μ g/ml
(3) dosing of dividing into groups next day complements to 100 μ L with nutrient solution in the hole;
(4) continue to cultivate 72 hours;
(5) every hole adds 5mg/mLMTT solution 10 μ L, continues to cultivate 3-4 hour;
(6) every hole adds 100 μ L10%HCl-SDS solution, 37 ℃ of incubated overnight;
(7) vibration 10min fully dissolves crystallization, and in Model 550 ELIASAs, the A570nm colorimetric is measured the OD value, and dosing holes and control wells OD value relatively draw 503nhibiting concentration (IC50).
4, PC-3 cells in vitro killing experiments
Process like above-mentioned method 1 is measured, and wherein uses PC-3 cell (prostate cancer cell is attached cell) replaced C olon38 cell.
The result of aforesaid method 1-4 is as shown in the table, shows that this medicine has great tumor cytotoxicity ability.
Claims (10)
1.3, the working method of the two indoles of 3 '-methene, it comprises:
(1) indoles and tosic acid are dissolved in the solvent of being made up of 95% (weight) second alcohol and water, under the condition of nitrogen protection, add formalin; Wherein in solvent; Water and 95% (weight) alcoholic acid volume ratio is 1: 1-6, and excellent is 1: 1-3 most preferably is 1: 1.5;
(2) lucifuge reaction at room temperature is 20-30 hour, is preferably 24 hours;
(3) filter the solid that acquisition step (2) reaction is separated out; With
(4) solid of recrystallization purifying step (3) acquisition.
2. the arbitrary described method of aforementioned claim, wherein 95% (weight) ethanol is 95% (weight) industrial alcohol.
3. the arbitrary described method of aforementioned claim, wherein the mol ratio of indoles and formaldehyde is 1-2: 1, be preferably 1.5-1.95: 1,1.85-1.92 more preferably: 1.
4. the arbitrary described method of aforementioned claim, wherein the mol ratio of indoles and tosic acid is 50-200: 1, be preferably 80-120: 1,95-100 more preferably: 1.
5. the arbitrary described method of aforementioned claim, wherein the volume ratio of the water in formalin and the solvent is 1: 8-15 is preferably 1: 9-12 most preferably is 1: 10.
6. the arbitrary described method of aforementioned claim, wherein in step (3), said solid is through methyl alcohol drip washing, and/or wherein in step (4), the solvent that recrystallization uses is an ETHYLE ACETATE.
7. the arbitrary described method of aforementioned claim, wherein the solid purity that obtains of step (3) is preferably greater than 98% greater than 97%, and more preferably 98.5%.
8. the arbitrary described method of aforementioned claim, wherein produce obtain 3, the purity of the two indoles of 3 '-methene is preferably greater than 99.3% greater than 99%, more preferably 99.5%.
The high-purity compound of the described method of claim 8 preparation preparation anticancer (as, colorectal carcinoma, cancer of the stomach, prostate cancer and liver cancer) or anticancer (as, colon cancer cell, stomach cancer cell, prostate cancer cell and liver cancer cell) application in the medicine.
10. the described application of claim 10, comprising,
(1) implements the described method of claim 8; With
(2) high-purity compound and the pharmaceutically acceptable pharmaceutical carrier step (1) produced are mixed with medicine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103214408A (en) * | 2013-05-07 | 2013-07-24 | 南京理工大学 | Method for synthesizing bisindole methane derivative |
| CN103214408B (en) * | 2013-05-07 | 2015-09-30 | 南京理工大学 | A kind of method of synthesizing bisindole methane derivative |
| CN103274987A (en) * | 2013-06-07 | 2013-09-04 | 华东师范大学 | 3,3-disubstituted oxoindole derivative, and synthetic method and application thereof |
| CN103936648A (en) * | 2014-04-17 | 2014-07-23 | 浙江工业大学 | 2,2-di(1H-indole-3-yl)-2H-acenaphthene-1-ketone compound and preparation method thereof |
| CN103936648B (en) * | 2014-04-17 | 2016-05-18 | 浙江工业大学 | Two (1H-indol-3-yl)-2H-acenaphthene-1-ketone compounds of 2,2-and preparation method thereof |
| CN104016900A (en) * | 2014-06-19 | 2014-09-03 | 罗田县新普生药业有限公司 | Preparation method of 3, 3'-diindolylmethane |
| CN104177283A (en) * | 2014-07-10 | 2014-12-03 | 陕西师范大学 | Method for preparing bis (indolyl) methane derivative in presence of amine salt |
| CN104177283B (en) * | 2014-07-10 | 2016-08-17 | 陕西师范大学 | The method preparing bisindole methane derivative in the presence of amine salt |
| CN110256325A (en) * | 2019-07-16 | 2019-09-20 | 杭州志源生物科技有限公司 | A kind of process synthesizing 3,3 '-di-indole methyl hydrides |
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