CN102408414B - Indole derivative with pyrrolidone structure and preparation method thereof - Google Patents
Indole derivative with pyrrolidone structure and preparation method thereof Download PDFInfo
- Publication number
- CN102408414B CN102408414B CN 201110250986 CN201110250986A CN102408414B CN 102408414 B CN102408414 B CN 102408414B CN 201110250986 CN201110250986 CN 201110250986 CN 201110250986 A CN201110250986 A CN 201110250986A CN 102408414 B CN102408414 B CN 102408414B
- Authority
- CN
- China
- Prior art keywords
- formula
- preparation
- methyl
- pyrrolidones
- hydrogen
- 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.)
- Active
Links
- CRDFJOLQWSUPLM-OUUTVGKISA-N CC/C=C1/NC=C(CCN(C)C)/C1=C/CCS(CNC)(=O)=O Chemical compound CC/C=C1/NC=C(CCN(C)C)/C1=C/CCS(CNC)(=O)=O CRDFJOLQWSUPLM-OUUTVGKISA-N 0.000 description 1
- ULFRLSNUDGIQQP-UHFFFAOYSA-N CN(C)CCc1c[nH]c2ccc(C[n]3ncnc3)cc12 Chemical compound CN(C)CCc1c[nH]c2ccc(C[n]3ncnc3)cc12 ULFRLSNUDGIQQP-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides indole derivatives with a pyrrolidone structure, which have a structure as shown in formula (IV), wherein R is hydrogen, alkyl, alkyloxy, nitro, halogen, cyan or sulfonyl; R2 is hydrogen, alkyl, aryl, nitro, halogen, alkyloxy or benzyloxy. The invention also provides a preparation method of the indole derivatives with a pyrrolidone structure, which comprises the following steps: allowing indole compounds with a structure shown in formula (V) to react with pyrrolidone compounds with a structure shown in formula (VI) with the catalysis of simple substance iodine so as to obtain the indole derivatives with a pyrrolidone structure which have a structure as shown in formula (IV). The invention adopts simple substance iodine as a catalyst, and no metal participates in the reaction process; therefore the obtained product has no metal residues, which thus avoids complicated subsequent processing of the reaction product.
Description
Technical field
The invention belongs to the indole derivatives technical field, relate in particular to indole derivatives of a kind of pyrrolidone containing structure and preparation method thereof.
Background technology
Indoles is the compound of pyrroles and benzo connection, claims again benzopyrrole, has formula (I) structure:
Indoles and homologue thereof and derivative are that occurring in nature exists the most general heterocycle, mainly be present in the natural flower oil, such as Flower of Arabian Jasmine, bigarabe flower, flower of Chinese Narcissus, fragrant rowland etc., contain indoles or its homologue and derivative in coal tar and the ight soil, vat pigment, tryptophane, alkaloid and plant hormone etc. all are indoles or its homologue and derivative.The compound that contains indole ring has widely biological activity, as has the effects such as antimycotic, antiviral, antitumor, anxiety.As has a vinpocetine of formula (I-a) mechanism, this medicine is not only effective to the high blood viscosity that prevents and treat cerebral arteriosclerosis, cerebral ischemia and hemorrhagic stroke sequela and hypertension, coronary heart disease, and the pathologic, physiologic of research cerebrovascular disease is also had important value; Have the risatriptan (Rizatriptan) of formula (I-b) structure, the core texture with Sumatriptan succinate (Sumatriptan Succinate) of formula (I-c) structure is indole ring, these two kinds of medicines can be used for the treatment of migraine; Melatonin with formula (I-d) structure is the chemical substance of pineal gland secretion, contain the indole ring structure, and have widely physiological action, such as hormone secretion, deep-well-internal secretion-immunomodulatory, biorhythm, delay senility, Green Tea Extract damage, calmness, analgesia, hypnosis, the effect such as anticonvulsion.
Alpha-pyrrolidone claims again 2-Pyrrolidone, 2-oxo-1-crassitude, butyrolactam, has formula (II) structure:
Alpha-pyrrolidone is not only a kind of important industrial chemicals, the amides that contains the alpha-pyrrolidone group also can be used as drug use, as have formula (II-a) structure, trade name is the compound of nefiracetam (Nefiracetam), can be used for the treatment of cerebro-vascular diseases; Levetiracetam (Levetiracetam) with formula (II-b) structure is a kind of antiepileptic drug commonly used; Have the Phenchlobenpyrrone (Phenchlobenpyrrone) identical with anti senile dementia drug Clausenamide commonly used (Clausenamide) core skeleton recently also by Kunming Inst. of Botany, Chinese Academy of Sciences's research and development and by the I clinical trial phase, its core texture has formula (II-c) structure:
This shows, indole ring and pyrrolidone ring all have biological activity, the compound that had not only had the indoles skeleton but also had a pyrrolidone skeleton can have both biological activitys simultaneously, sometimes can also show unique performance, a kind of 2-oxo that contains simultaneously indole ring and pyrrolidone ring-1-methylpyrrole alkane derivatives is disclosed such as world patent wo 2006128693, this 2-oxo-1-methylpyrrole alkane derivatives has formula (III) structure, can be used as anticonvulsion class medicinal application.This derivative can prepare by the following method: nucleophilic addition occurs in (replacement) pyrrolidone and aldehyde under the katalysis of potassium hydroxide, generates alcohol; Alcohol obtains final product by the Catalyzed by p-Toluenesulfonic Acid reaction with (replacement) indoles in toluene; Perhaps by indoles, (replacement) pyrrolidone, aromatic aldehyde under the katalysis of amido carbonic ether, make solvent with acetonitrile and in microwave reactor, obtain in 130 degrees centigrade of reactions.But these two kinds of method productive rates are lower, and the final product yield is all below 50%:
Prior art also discloses take indoles and NVP as raw material, in water or organic solvent, synthesizing compound (the Jiang R. with formula (III) structure under the katalysis of iron catalyst, Xu X.-P., Ji S.-J., et al.Eur.J.Org.Chem.2010,5946-5950; Niu T, Zhang Y, et al.Org.Biomol.Chem.2011,9,273-277).But the method is used the iron catalyst of 5mol%～10mol%, and meeting is so that exist metal residual in the product, and synthesizing of this oral disposition medicine is very disadvantageous, because the removal of metal ion will increase production cost; Moreover R in the compound structure
2Can only be methyl, if the Seeking Truth aryl, then this method have feasibility.
Summary of the invention
In view of this, indole derivatives that provides a kind of pyrrolidone containing structure and preparation method thereof is provided the technical problem to be solved in the present invention, and preparation method provided by the invention need not to carry out complicated aftertreatment, and the product that obtains is without metal residual.
The invention provides a kind of indole derivatives of pyrrolidone containing structure, have formula (IV) structure:
Wherein, R is hydrogen, alkyl, alkoxyl group, nitro, halogen, cyano group or methylsulfonyl; R
2Be hydrogen, alkyl, aromatic base, nitro, halogen, alkoxyl group or benzyloxy.
The present invention also provides a kind of preparation method of indole derivatives of pyrrolidone containing structure, may further comprise the steps:
The pyrrolidones that has the Benzazole compounds of formula (V) structure and have formula (VI) structure reacts in organic solvent under the katalysis of iodine, the indole derivatives of the pyrrolidone containing structure of (IV) structure that obtains having formula;
Wherein, R is hydrogen, alkyl, alkoxyl group, nitro, halogen, cyano group or methylsulfonyl; R
1Be methyl, ethyl, n-propyl or sec.-propyl; R
2Be hydrogen, alkyl, aromatic base, nitro, halogen, alkoxyl group or benzyloxy.
Preferably, described iodine and described mol ratio with pyrrolidones of formula (VI) structure are (0.01～0.5): 1.
Preferably, described iodine and described mol ratio with pyrrolidones of formula (VI) structure are (0.05～0.3): 1.
Preferably, described Benzazole compounds with formula (V) structure and mol ratio with pyrrolidones of formula (VI) structure are (1～5): (1～5).
Preferably, described Benzazole compounds with formula (V) structure and mol ratio with pyrrolidones of formula (VI) structure are (2～4): (2～4).
Preferably, the temperature of described reaction is 10 ℃～50 ℃.
Preferably, described organic solvent is methylene dichloride, DMF, N,N-dimethylacetamide or dimethyl sulfoxide (DMSO).
Preferably, described reaction is carried out under the condition that stirs.
Preferably, described pyrrolidones with formula (VI) structure prepares in accordance with the following methods:
2-Pyrrolidone, alcohol compound and have phenyl aldehyde back flow reaction under the katalysis of hydrogenchloride of formula (VII) structure, the pyrrolidones of (VI) structure that obtains having formula, described alcohol compound is methyl alcohol, ethanol, n-propyl alcohol or Virahol:
Wherein, R is hydrogen, alkyl, alkoxyl group, nitro, halogen, cyano group or methylsulfonyl.
Compared with prior art, the present invention is take Benzazole compounds with formula (V) structure and have the pyrrolidones of formula (VI) structure as raw material, take iodine as catalyzer, single step reaction can obtain having the indole derivatives that contains the pyrrolidone structure of formula (IV) structure in organic solvent.Described indole derivatives not only contains the indole ring structure but also contains the pyrrolidone structure, can be used as potential anticonvulsion class medicinal application.Preparation method provided by the invention is simple, and the productive rate of indole derivatives that contains the pyrrolidone structure is higher.The present invention participates in without metal in the reaction process take iodine as catalyzer, metal residual can not occur in the product that therefore obtains, thereby avoid reaction product is carried out numerous and diverse subsequent disposal.Preparation method's reaction conditions provided by the invention is gentle, raw material sources are extensive, cheap, can reduce production costs.Experiment shows, adopt method preparation provided by the invention have formula (IV) structure contain the indole derivatives of pyrrolidone structure the time, its productive rate is up to 87%～99%.
Description of drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the product for preparing of the embodiment of the invention 3;
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the product for preparing of the embodiment of the invention 4;
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the product for preparing of the embodiment of the invention 6;
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of the product for preparing of the embodiment of the invention 8.
Embodiment
The invention provides a kind of indole derivatives of pyrrolidone containing structure, have formula (IV) structure:
Wherein, R can be positioned at any the position of substitution on the phenyl ring, is hydrogen, alkyl, alkoxyl group, nitro, halogen, cyano group or methylsulfonyl, is preferably hydrogen, methyl, ethyl, nitro or chlorine, more preferably hydrogen or nitro; R
2Can be positioned at any the position of substitution on the phenyl ring, be hydrogen, alkyl, aromatic base, nitro, halogen, alkoxyl group or benzyloxy, be preferably hydrogen, methyl, ethyl, phenyl, nitro, chlorine, bromine, methoxyl group or benzyloxy, more preferably hydrogen, methyl, nitro, phenyl, bromine or benzyloxy.
In indole derivatives provided by the invention, R and R
2Between there is no the contact or the restriction, can be independently selected from above-mentioned each group.
The present invention also provides a kind of preparation method of indole derivatives of pyrrolidone containing structure, may further comprise the steps:
The pyrrolidones that has the Benzazole compounds of formula (V) structure and have formula (VI) structure reacts in organic solvent under the katalysis of iodine, the indole derivatives of the pyrrolidone containing structure of (IV) structure that obtains having formula;
Wherein, R is hydrogen, alkyl, alkoxyl group, nitro, halogen, cyano group or methylsulfonyl; R
1Be methyl, ethyl, n-propyl or sec.-propyl; R
2Be hydrogen, alkyl, aromatic base, nitro, halogen, alkoxyl group or benzyloxy.
The present invention is take Benzazole compounds with formula (V) structure and have the pyrrolidones of formula (VI) structure as raw material, take iodine as catalyzer, single step reaction can obtain having the indole derivatives that contains the pyrrolidone structure of formula (IV) structure in organic solvent, the preparation method is simple, and products collection efficiency is higher.
The present invention is take Benzazole compounds with formula (V) structure as raw material, in the formula (V), and R
2Any the position of substitution on phenyl ring or the pyrrole ring be can be positioned at, hydrogen, alkyl, aromatic base, nitro, halogen, alkoxyl group or benzyloxy are.
Work as R
2During for hydrogen, described Benzazole compounds is indoles;
Work as R
2During for alkyl, described Benzazole compounds is the indoles that alkyl replaces; Described alkyl can for alkyl such as methyl, ethyl, propyl group, be preferably methyl; Work as R
2During for methyl, described Benzazole compounds is skatole, can be 1-skatole, 2 methyl indole, 3-skatole, 5-skatole or 7-skatole etc.;
Work as R
2During for aromatic base, described Benzazole compounds is the indoles that aromatic base replaces, and described aromatic base is preferably phenyl, and at this moment, described Benzazole compounds is Phenylindole, can be for 2-phenylindone etc.;
Work as R
2During for nitro, described Benzazole compounds is nitroindoline, can be 4-nitroindoline, 5-nitroindoline or 6-nitroindoline etc.;
Work as R
2During for halogen, described Benzazole compounds is the indoles that halogen replaces, and described halogen is preferably Br, and at this moment, described Benzazole compounds is the bromo indoles, can be 5-bromo indole or 7-bromo indole etc.;
Work as R
2During for alkoxyl group, described Benzazole compounds is the indoles that alkoxyl group replaces, and described alkoxyl group is preferably methoxyl group, and at this moment, described Benzazole compounds is methoxy-Indole, can be the 5-methoxy-Indole;
Work as R
2During for benzyloxy, described Benzazole compounds is benzyloxy indole, can be 4-benzyloxy indole, 7-benzyloxy indole etc.
According to the present invention, described Benzazole compounds is preferably indoles, skatole, nitroindoline, Phenylindole, bromo indoles or benzyloxy indole, more preferably indoles, skatole or Phenylindole.
The present invention is take pyrrolidones with formula (VI) structure as raw material, in the formula (VI), R can be positioned at any the position of substitution on the phenyl ring, be hydrogen, alkyl, alkoxyl group, nitro, halogen, cyano group or methylsulfonyl, be preferably hydrogen, methyl, ethyl, nitro or chlorine, more preferably hydrogen or nitro; R
1Be alkyl, be preferably methyl, ethyl, n-propyl or sec.-propyl, more preferably ethyl.
The present invention does not have particular restriction to described source with pyrrolidones of formula (VI) structure, preferably in accordance with the following methods preparation:
2-Pyrrolidone, alcohol compound and have phenyl aldehyde back flow reaction under the katalysis of hydrogenchloride of formula (VII) structure, the pyrrolidones of (VI) structure that obtains having formula, described alcohol compound is methyl alcohol, ethanol, n-propyl alcohol or Virahol:
Wherein, R is hydrogen, alkyl, alkoxyl group, nitro, halogen, cyano group or methylsulfonyl.
Phenyl aldehyde and the 2-Pyrrolidone that at first will have formula (VII) structure mix, and add the alcohol solution of hydrogenchloride, the pyrrolidones that obtains having formula (VI) structure after the back flow reaction.Wherein, have the phenyl aldehyde of formula (VII) structure and the mol ratio of 2-Pyrrolidone and be preferably 1: (1.5～2), more preferably 1: (1.7～1.8); The alcohol solution of hydrogenchloride is in situ preparation, and its pH value is preferably 1; 2-Pyrrolidone, alcohol compound and have the temperature that the phenyl aldehyde of formula (VII) structure reacts and be preferably 60 ℃～80 ℃, the time is preferably 20h～30h.Reaction finishes, with sodium bicarbonate with in the reaction product and after, extract with ethyl acetate, desolventize steaming after the extraction liquid drying, the pyrrolidones of (VI) structure of carrying out obtaining having formula after column chromatography is purified take ethyl acetate and sherwood oil as eluent.
The present invention is take iodine as catalyzer, and the present invention does not have particular restriction to the source of described iodine, buys from the market to get final product.
The present invention is take organic solvent as reaction medium, and described organic solvent is preferably methylene dichloride, trichloromethane, DMF, N,N-dimethylacetamide or dimethyl sulfoxide (DMSO), more preferably methylene dichloride.
Described Benzazole compounds with formula (V) structure reacts in organic solvent under the katalysis of iodine with the pyrrolidones with formula (VI) structure, generation has the indole derivatives of the pyrrolidone containing structure of formula (IV) structure, and reaction formula is as follows:
At first will have the Benzazole compounds of formula (V) structure, the pyrrolidones with formula (VI) structure, iodine and organic solvent mixes, preferably under the condition that stirs, react, preferably in reaction process, take thin plate chromatography (TLC) method to monitor, when disappearing, the pyrrolidone with formula (VI) structure finishes reaction, the indole derivatives of the pyrrolidone containing structure of (IV) structure that obtains having formula.
According to the present invention, described iodine and described mol ratio with pyrrolidones of formula (VI) structure are preferably (0.01～0.5): 1, more preferably (0.05～0.3): 1; During as catalyzer, less consumption can be brought into play effective katalysis with iodine, and simultaneously, because catalyst levels is few, the reaction product purity that obtains is higher.
According to the present invention, described Benzazole compounds with formula (V) structure is preferably (1～5) with the mol ratio with pyrrolidones of formula (VI) structure: (1～5), more preferably (2～4): (2～4);
According to the present invention, the temperature of described reaction is preferably 10 ℃～50 ℃, more preferably 30 ℃～40 ℃.
React complete after, the reaction product that obtains can be obtained having the indole derivatives of the pyrrolidone containing structure of formula (IV) structure after with the washing of glacial acetic acid ethyl ester, vacuum-drying.In order to improve the purity of the product that obtains, the present invention preferably carries out column chromatography operation well known to those skilled in the art to described reaction product.
The indole derivatives of the pyrrolidone containing structure by method provided by the invention preparation has formula (IV) structure, and according to the record of world patent wo2006128693, this compound can be used as anticonvulsion class medicinal application.In addition because this compound not only has indole structure but also have the pyrrolidone structure, in biorhythm, delay senility, Green Tea Extract damage, calmness, analgesia, hypnosis and treat the aspect such as cerebro-vascular diseases and have latent effect.
The present invention is take Benzazole compounds with formula (V) structure and have the pyrrolidones of formula (VI) structure as raw material, take iodine as catalyzer, single step reaction can obtain having the indole derivatives that contains the pyrrolidone structure of formula (IV) structure in organic solvent, the preparation method is simple, and reaction yield is higher.The present invention participates in without metal in the reaction process take iodine as catalyzer, metal residual can not occur in the product that therefore obtains, thereby avoid reaction product is carried out numerous and diverse subsequent disposal.Preparation method's reaction conditions provided by the invention is gentle, raw material sources are extensive, cheap, can reduce production costs.Experiment shows, adopt method preparation provided by the invention have formula (IV) structure contain the indole derivatives of pyrrolidone structure the time, its productive rate is up to 87%～99%.
In order to further specify the present invention, below in conjunction with embodiment indole derivatives of pyrrolidone containing structure provided by the invention and preparation method thereof is described in detail.
Embodiment 1
In the 25mL round-bottomed flask, add 0.1056g (0.4mmol) 1-oxyethyl group (4-nitrophenyl) methyl) pyrroline-2-one, 0.0702g (0.6mmol) indoles, 0.0050g (0.02mmol) iodine and 2mL methylene dichloride, stirring and refluxing under 40 ℃ of conditions, TLC (thin plate chromatography) detects, until raw material 1-oxyethyl group (4-nitrophenyl) methyl) the rear stopped reaction of pyrroline-2-one disappearance, with reaction product behind column chromatography, obtain 120.6mg1-((1H-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one, productive rate is 90%.
Described 1-((1H-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one is carried out nuclear magnetic resonance spectroscopy, and the spectral data that obtains is as follows:
1H NMR (300MHz, CDCl
3): δ=8.36 (s, 1H), 8.21 (d, J=8.6Hz, 2H), (7.49 d, J=8.6Hz, 2H), 7.42 (d, J=8.1Hz, 1H), 7.31-7.22 (m, 3H), 7.11-7.06 (t, J=7.5Hz, 1H), 6.97 (s, 1H), 6.92 (s, 1H), (3.42-3.35 m, 1H), 3.16-3.07 (m, 1H), (2.56-2.45 m, 2H), 2.09-1.95 (m, 2H) ppm.By above-mentioned spectral data as can be known, described product is 1-((1H-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one.
In the 25mL round-bottomed flask, add 0.1056g (0.4mmol) 1-oxyethyl group (4-nitrophenyl) methyl) pyrroline-2-one, 0.0787g (0.6mmol) 2 methyl indole, 0.005g (0.02mmol) iodine and 2mL methylene dichloride, stirring and refluxing under 40 ℃ of conditions, TLC (thin plate chromatography) detects, until raw material 1-oxyethyl group (4-nitrophenyl) methyl) the rear end reaction of pyrroline-2-one disappearance, with reaction product behind column chromatography, obtain 138mg1-((2-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one, productive rate is 99%.
Described 1-((2-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one is carried out nuclear magnetic resonance spectroscopy, and the spectral data that obtains is as follows:
1H NMR (300MHz, CDCl
3): δ=8.18 (d, J=7.6Hz, 2H), 8.09 (s, 1H), (7.36 d, J=7.6Hz, 2H), 7.12 (s, 1H), (6.94-6.90 m, 3H), 6.80 (s, 1H), (6.78 s, 1H), 3.53-3.48 (m, 1H), (3.11-3.06 m, 1H), 2.47-2.45 (m, 2H), (2.44 s, 3H), 2.09-1.95 (m, 2H) ppm.By above-mentioned spectral data as can be known, described product is 1-((2-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one.
Embodiment 3
In the 25mL round-bottomed flask, add 0.1056g (0.4mmol) 1-oxyethyl group (4-nitrophenyl) methyl) pyrroline-2-one, 0.0787g (0.6mmol) N-skatole, 0.005g (0.02mmol) iodine and 2mL methylene dichloride, stirring and refluxing under 40 ℃ of conditions, TLC (thin plate chromatography) detects, until raw material 1-oxyethyl group (4-nitrophenyl) methyl) the rear end reaction of pyrroline-2-one disappearance, with reaction product behind column chromatography, obtain 142mg1-((1-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one, productive rate is 98%.
Described 1-((1-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one is carried out nuclear magnetic resonance spectroscopy, the result is referring to Fig. 1, Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the product for preparing of the embodiment of the invention 3, and its spectral data is as follows:
1H NMR (300MHz, CDCl
3): δ=8.25 (d, J=8.7Hz, 2H), 7.52 (d, J=8.8Hz, 2H), 7.40-7.26 (m, 4H), 7.10-7.05 (t, J=7.5Hz, 1H), 6.93 (s, 1H), (6.85 s, 1H), 3.80 (s, 3H), (3.42-3.35 m, 1H), 3.15-3.10 (m, 1H), (2.56-2.45 m, 2H), 2.09-1.95 (m, 2H) ppm.By above-mentioned spectrogram and spectral data as can be known, described product is 1-((1-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one.
Embodiment 4
In the 25mL round-bottomed flask, add 0.1056g (0.4mmol) 1-oxyethyl group (4-nitrophenyl) methyl) pyrroline-2-one, 0.0787g (0.6mmol) 5-skatole, 0.005g (0.02mmol) iodine and 2mL methylene dichloride, stirring and refluxing under 40 ℃ of conditions, TLC (thin plate chromatography) detects, until raw material 1-oxyethyl group (4-nitrophenyl) methyl) the rear end reaction of pyrroline-2-one disappearance, with reaction product behind column chromatography, obtain 105mg1-((5-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one, productive rate is 95%.
Described 1-((5-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one is carried out nuclear magnetic resonance spectroscopy, the result is referring to Fig. 2, Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the product for preparing of the embodiment of the invention 4, and its spectral data is as follows:
1H NMR (300MHz, CDCl
3): δ=8.25 (s, 1H), 8.20 (d, J=8.6Hz, 2H), 7.47 (d, J=8.6Hz, 2H), (7.31-7.29 t, J=6.3Hz, 1H), 7.07-7.05 (m, 2H), 6.88 (s, 1H), 3.41-3.34 (m, 1H), 3.15-3.07 (m, 2H), 2.38 (s, 3H), 2.08-1.99 (m, 2H) ppm.By above-mentioned spectrogram and spectral data as can be known, described product is 1-((5-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one.
Embodiment 5
In the 25mL round-bottomed flask, add 0.1056g (0.4mmol) 1-oxyethyl group (4-nitrophenyl) methyl) pyrroline-2-one, 0.0787g (0.6mmol) 6-skatole, 0.005g (0.02mmol) iodine and 2mL methylene dichloride, stirring and refluxing under 40 ℃ of conditions, TLC (thin plate chromatography) detects, until raw material 1-oxyethyl group (4-nitrophenyl) methyl) the rear end reaction of pyrroline-2-one disappearance, with reaction product behind column chromatography, obtain 107mg1-((6-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one, productive rate is 79%.
Described 1-((6-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one is carried out nuclear magnetic resonance spectroscopy, and the spectral data that obtains is as follows:
1H NMR (300MHz, CDCl
3): δ=8.20 (d, J=8.0Hz, 2H), 7.26 (d, J=8.1Hz, 2H), 7.21 (s, 1H), 7.16 (d, J=8.3Hz, 2H), 7.39 (s, 1H), (6.89 s, 2H), 3.38-3.36 (m, 1H), (3.11-3.09 m, 1H), 2.54-2.46 (m, 2H), (2.48 s, 3H), 2.08-2.03 (m, 2H) ppm.By above-mentioned spectral data as can be known, described product is 1-((6-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one.
Embodiment 6
In the 25mL round-bottomed flask, add 0.1056g (0.4mmol) 1-oxyethyl group (4-nitrophenyl) methyl) pyrroline-2-one, 0.0882g (0.6mmol) 5-methoxy-Indole, 0.005g (0.02mmol) iodine and 2mL methylene dichloride, stirring and refluxing under 40 ℃ of conditions, TLC (thin plate chromatography) detects, until raw material 1-oxyethyl group (4-nitrophenyl) methyl) the rear end reaction of pyrroline-2-one disappearance, with reaction product behind column chromatography, obtain 144mgl-((5-methoxyl group-1 hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one, productive rate is 98%.
Described 1-((5-methoxyl group-1 hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one is carried out nuclear magnetic resonance spectroscopy, the result is referring to Fig. 3, Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of the product for preparing of the embodiment of the invention 6, and its spectral data is as follows:
1H NMR (300MHz, CDCl
3): δ=8.22 (d, J=8.2Hz, 2H), 8.21 (s, 1H), 7.50 (d, J=8.0Hz, 2H), (7.32-7.30 m, 2H), 6.90-6.88 (m, 3H), (6.77 s, 1H), 3.76 (s, 3H), (3.38-3.36 m, 1H), 3.11-3.09 (m, 1H), (2.54-2.52 m, 2H), 2.07-2.00 (m, 2H) ppm.By above-mentioned spectrogram and spectral data as can be known, described product is 1-((5-methoxyl group-1 hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one.
In the 25mL round-bottomed flask, add 0.1056g (0.4mmol) 1-oxyethyl group (4-nitrophenyl) methyl) pyrroline-2-one, 0.1176g (0.6mmol) 5-bromo indole, 0.005g (0.02mmol) iodine and 2mL methylene dichloride, stirring and refluxing under 40 ℃ of conditions, TLC (thin plate chromatography) detects, until raw material 1-oxyethyl group (4-nitrophenyl) methyl) the rear end reaction of pyrroline-2-one disappearance, with reaction product behind column chromatography, obtain 146mgl-((5-bromo-1 hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one, productive rate is 67%.
Described 1-((5-bromo-1 hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one is carried out nuclear magnetic resonance spectroscopy, and the spectral data that obtains is as follows:
1H NMR (300MHz, CDCl
3): δ=8.31 (s, 1H), 8.21 (d, J=8.8Hz, 2H), (7.45 d, J=9.1Hz, 2H), 7.41 (s, 1H), 7.31-7.30 (d, J=7.7Hz, 2H), (6.69 s, 1H), 6.84 (s, 1H), (3.36-3.34 m, 1H), 3.11-3.09 (m, 1H), (2.52-2.50 m, 2H), 2.06-2.03 (m, 2H) ppm.By above-mentioned spectral data as can be known, described product is 1-((5-bromo-1 hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one.
In the 25mL round-bottomed flask, add 0.1056g (0.4mmol) 1-oxyethyl group (4-nitrophenyl) methyl) pyrroline-2-one, 0.0787g (0.6mmol) 7-skatole, 0.005g (0.02mmol) iodine and 2mL methylene dichloride, stirring and refluxing under 40 ℃ of conditions, TLC (thin plate chromatography) detects, until raw material 1-oxyethyl group (4-nitrophenyl) methyl) the rear end reaction of pyrroline-2-one disappearance, reaction product behind column chromatography, is obtained 124mg1-((7-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one. productive rate is 84%.
Described 1-((7-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one is carried out nuclear magnetic resonance spectroscopy, the result is referring to Fig. 4, Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of the product for preparing of the embodiment of the invention 8, and its spectral data is as follows:
1H NMR (300MHz, CDCl
3): δ=11.21 (s, 1H), 8.22 (d, J=8.7Hz, 2H), (7.54 d, J=8.5Hz, 2H), 7.09 (s, 1H), (6.98 d, J=7.4Hz, 1H), 6.90-6.88 (m, 1H), (6.87 s, 1H), 6.69 (s, 1H), 3.35 (s, 1H), 2.99-2.94 (m, 1H), 2.46 (s, 3H), (2.35-2.27 m, 2H), 2.01-1.98 (m, 2H) ppm.By above-mentioned spectrogram and spectral data as can be known, described product is 1-((7-methyl isophthalic acid hydrogen-indol-3-yl) (4-nitrophenyl) methyl) pyrroline-2-one.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (9)
1. the preparation method of the indole derivatives of a pyrrolidone containing structure may further comprise the steps:
The pyrrolidones that has the Benzazole compounds of formula V structure and have formula (VI) structure reacts in organic solvent under the katalysis of iodine, the indole derivatives of the pyrrolidone containing structure of (IV) structure that obtains having formula;
Wherein, R is hydrogen, alkyl, alkoxyl group, nitro, halogen, cyano group or methylsulfonyl; R
1Be methyl, ethyl, n-propyl or sec.-propyl; R
2Be hydrogen, alkyl, aromatic base, nitro, halogen, alkoxyl group or benzyloxy.
2. preparation method according to claim 1 is characterized in that, described iodine and described mol ratio with pyrrolidones of formula (VI) structure are (0.01～0.5): 1.
3. preparation method according to claim 2 is characterized in that, described iodine and described mol ratio with pyrrolidones of formula (VI) structure are (0.05～0.3): 1.
4. preparation method according to claim 1 is characterized in that, described Benzazole compounds with formula V structure and the mol ratio with pyrrolidones of formula (VI) structure are (1～5): (1～5).
5. preparation method according to claim 4 is characterized in that, described Benzazole compounds with formula V structure and the mol ratio with pyrrolidones of formula (VI) structure are (2～4): (2～4).
6. preparation method according to claim 1 is characterized in that, the temperature of described reaction is 10 ℃～50 ℃.
7. preparation method according to claim 1 is characterized in that, described organic solvent is methylene dichloride, DMF, N,N-dimethylacetamide or dimethyl sulfoxide (DMSO).
8. preparation method according to claim 1 is characterized in that, described reaction is carried out under the condition that stirs.
9. preparation method according to claim 1 is characterized in that, described pyrrolidones with formula (VI) structure prepares in accordance with the following methods:
2-Pyrrolidone, alcohol compound and have substituted benzaldehyde back flow reaction under the katalysis of hydrogenchloride of formula (VII) structure, the pyrrolidones of (VI) structure that obtains having formula, described alcohol compound is methyl alcohol, ethanol, n-propyl alcohol or Virahol:
Wherein, R is hydrogen, alkyl, alkoxyl group, nitro, halogen, cyano group or methylsulfonyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110250986 CN102408414B (en) | 2011-08-29 | 2011-08-29 | Indole derivative with pyrrolidone structure and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110250986 CN102408414B (en) | 2011-08-29 | 2011-08-29 | Indole derivative with pyrrolidone structure and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102408414A CN102408414A (en) | 2012-04-11 |
| CN102408414B true CN102408414B (en) | 2013-03-27 |
Family
ID=45910801
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110250986 Active CN102408414B (en) | 2011-08-29 | 2011-08-29 | Indole derivative with pyrrolidone structure and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102408414B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2006254336B9 (en) * | 2005-06-01 | 2013-02-28 | Ucb Pharma, S.A. | 2 -oxo-I -pyrrolidine derivatives/ processes for preparing them and their therapeutic use on the central nervous system |
-
2011
- 2011-08-29 CN CN 201110250986 patent/CN102408414B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| Ferric(III) Nitrate: An Efficient Catalyst for the Regioselective Friedel–Crafts Reactions of Indoles and tert-Enamides in Water;Ran Jiang et al.;《Eur. J. Org. Chem.》;20101231;5946–5950 * |
| Ran Jiang et al..Ferric(III) Nitrate: An Efficient Catalyst for the Regioselective Friedel–Crafts Reactions of Indoles and tert-Enamides in Water.《Eur. J. Org. Chem.》.2010,5946–5950. |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102408414A (en) | 2012-04-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Oh et al. | Synthesis of (2 H)-indazoles through Rh (III)-catalyzed annulation reaction of azobenzenes with sulfoxonium ylides | |
| Gao et al. | Efficient organocatalytic asymmetric synthesis of 2-amino-4H-chromene-3-carbonitrile derivatives | |
| Chen et al. | An efficient, microwave-assisted, one-pot synthesis of indoles under Sonogashira conditions | |
| Li et al. | Iodine-Induced Regioselective C− C and C− N Bonds Formation of N-Protected Indoles | |
| Bandyopadhyay et al. | Novel synthesis of 3-pyrrole substituted β-lactams via microwave-induced bismuth nitrate-catalyzed reaction | |
| De Rosa et al. | A combination of water and microwave irradiation promotes the catalyst-free addition of pyrroles and indoles to nitroalkenes | |
| Srinivasulu et al. | Post-Ugi cascade transformations for accessing diverse chromenopyrrole collections | |
| Lu et al. | Stereoselective synthesis of spirooxindole amides through nitrile hydrozirconation | |
| Satyanarayana et al. | Ultrasound-assisted synthesis of 2, 5-dimethyl-N-substituted pyrroles catalyzed by uranyl nitrate hexahydrate | |
| Xu et al. | Divergent synthesis of quinolones and dihydroepindolidiones via Cu (I)-catalyzed cyclization of anilines with alkynes | |
| Dong et al. | Synthesis of Benzo-Fused Cyclic Compounds via Intramolecular Cyclization of Aryltriazenes | |
| Khan et al. | Lambert salt-initiated development of Friedel–crafts reaction on isatin to access distinct derivatives of oxindoles | |
| Kumar et al. | Novel three-component tandem reactions of cyclic mono ketones, isatin and sarcosine: formation of dispiropyrrolidines | |
| Moghaddam et al. | Diastereoselective construction of a functionalized dihydro-pyridazine-based spirooxindole scaffold via C-3 umpolung of isatin N, N′-cyclic azomethine imine | |
| Marchese et al. | A Modular Approach for the Palladium-Catalyzed Synthesis of Bis-heterocyclic Spirocycles | |
| Yang et al. | Brønsted-Acid-Promoted Selective C2–N1 Ring-Expansion Reaction of Indoles toward Cyclopenta [b] quinolines | |
| Zhang et al. | Acid-promoted bicyclization of diaryl alkynes: synthesis of 2 h-indazoles with in situ generated diazonium salt as nitrogen source | |
| Li et al. | Aymmetric Aza-Friedel–Crafts Reaction of Isatin-Derived Ketimines with Indoles Catalyzed by a Chiral Phase-Transfer Catalyst | |
| Chen et al. | Asymmetric Sequential Vinylogous Mannich/Annulation/Acylation Process of 2‐Ethylidene 1, 3‐Indandiones and Isatin N‐Boc Ketimines: Access to Chiral Spiro‐Oxindole Piperidine Derivatives | |
| Tran et al. | Iron-catalyzed reductive cyclization of nitroarenes: Synthesis of aza-heterocycles and DFT calculations | |
| Ma et al. | Access to Polycyclic Thienoindolines via Formal [2+ 2+ 1] Cyclization of Alkynyl Indoles with S8 and K2S | |
| Thakur et al. | Microwave assisted rapid, catalyst-free, and efficient synthesis of a new class of diversely functionalized 3-hydroxy-2-oxindole scaffolds under aqueous reaction media | |
| CN103755708B (en) | A kind of indoles or the preparation method of Pyrrolopyrimidine derivatives | |
| Warghude et al. | Direct access to spirooxindole dihydropyrrole fused pyrazolones and bis-spiropyrazolone derivatives | |
| CN102584860A (en) | Spiro-heterocyclic compound containing indole structures and preparation method of spiro-heterocyclic compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Free format text: FORMER OWNER: SUZHOU UNIVERSITY Effective date: 20140224 |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 215200 SUZHOU, JIANGSU PROVINCE TO: 215123 SUZHOU, JIANGSU PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20140224 Address after: 215123 building 14, science and Technology Pioneer Park, No. 2358, Changan Road, Wujiang Economic Development Zone, Suzhou, Jiangsu Patentee after: Suzhou Chukai Pharmaceutical Technology Co., Ltd. Address before: 215200 building 3, science and Technology Pioneer Park, No. 2358, Changan Road, Wujiang Economic Development Zone, Suzhou, Jiangsu Patentee before: Suzhou Chukai Pharmaceutical Technology Co., Ltd. Patentee before: Soochow University |
|
| TR01 | Transfer of patent right |