CN103193776A - Synthetic method of novel naphthyridine derivative with anti-tumor curative effect - Google Patents
Synthetic method of novel naphthyridine derivative with anti-tumor curative effect Download PDFInfo
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- CN103193776A CN103193776A CN2013101302610A CN201310130261A CN103193776A CN 103193776 A CN103193776 A CN 103193776A CN 2013101302610 A CN2013101302610 A CN 2013101302610A CN 201310130261 A CN201310130261 A CN 201310130261A CN 103193776 A CN103193776 A CN 103193776A
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Abstract
The invention discloses a synthetic method of a novel naphthyridine derivative with an anti-tumor curative effect. The synthetic method comprises the following steps of: adding materials to reactants including a DMF (Dimethyl Formamide) solution and phosphorus oxychloride for reacting to obtain 5-methoxyindole-3-formaldehyde white solid; adding materials for further reacting to obtain 5-methoxy-3-(2-nitryl- vinyl)-1H-indolue; adding lithium aluminium hydride for reducing to obtain 5-methoxy tryptamine; and adding materials to the reactants including dimethylsuccinate and methyl formate for reacting to obtain final products. The synthetic method of the novel naphthyridine derivative with the anti-tumor curative effect is simple in synthesis process, convenient for obtaining materials, good in medicine effect, capable of lowering the cost, capable of reducing a recurrence rate of the cancer and good in anti-tumor curative effect.
Description
Technical field
The present invention relates to a kind of synthetic method of antitumor curative effect biology, be specifically related to a kind of synthetic method with novel naphthyridine derivatives of antitumor curative effect.
Background technology
Cancer is the human second largest killer after cardiovascular disorder.The medicine that comes from plant plays an important role in the cancer clinical chemotherapy.In recent years, along with the successful identification of a plurality of biological targets in the tumour cell, the some organic molecule medicines that can attack these target spots go on the market in succession, and wherein naphthyridines class medicine has become one of modal antineoplastic chemotherapy medicine classification clinically.
In organic micromolecule compound, quinazoline is one of the most successful antineoplastic chemotherapy medicine classification, and Gefitinib, dust Lip river all belong to this compounds for Buddhist nun and Ka Nai for Buddhist nun etc.Based on this, the Pharmaceutical Chemist pair naphthyridines close with the quinazoline chemical structure compares research widely in recent years, a large amount of compounds have been synthesized in design, and therefrom filter out some compounds that the symptom of a trend is arranged, and wherein some compound has entered the clinical phase experimental stage of I/II at present.
Summary of the invention
For addressing the above problem, the purpose of this invention is to provide a kind of synthetic method with novel naphthyridine derivatives of antitumor curative effect, improved antitumor curative effect.
For realizing above-mentioned technical purpose, reach above-mentioned technique effect, the present invention is achieved through the following technical solutions:
A kind of synthetic method with novel naphthyridine derivatives of antitumor curative effect may further comprise the steps:
Step 1) is in 25 milliliters round-bottomed flask, add 7 milliliters of DMF solution, in 0.5 hour, drip 2 milliliters of phosphorus oxychloride after solution being cooled to-3 ℃, 5-methoxyl group-1H-indoles 2.94 grams are dissolved among 5 milliliters of DMF, this solution is added in the colourless above-mentioned reaction soln, get mixture, temperature of reaction is lower than 5 ℃ in this process, and said mixture is heated to 40 ℃, and keeps 2 hours in this temperature, thin-layer chromatography EA: PE=1: 3 show that starting raw material disappears, said mixture is cooled to room temperature, and pours 30 gram trash ice and 40 ml waters into, 18% NaOH drips until solution PH=12 in the solution that cools off under stirring, the pressure reducing and steaming organic solvent, water was placed in the refrigerator 1 hour, solid filtering is collected water washing, after the drying, obtain 2 gram 5-methoxyl group indole-3-formaldehyde white solids;
Step 2) in 100 milliliters round-bottomed flask, 0.375 gram ammonium acetate is suspended in 20 milliliters of Nitromethane 99Min.s, 1.5 gram 5-methoxyl group indole-3-formaldehydes are added in the above-mentioned solution and are heated to reflux temperature then, this temperature 2 hours, reaction soln is stirred, TLC shows that raw material disappears, after being cooled to room temperature, add 200 milliliters of ethyl acetate in the solution, organic phase washes twice with water, and uses the salt water washing, dry in anhydrous sodium sulphate, the vaporising under vacuum solvent, and with resistates by chromatography EA: PE=1: purifying in 3 obtains 1.207 gram orange solids product 5-methoxyl group-3-(2-nitro-vinyl)-1H-indoles;
Step 3) is in 100 milliliters round-bottomed flask, 0.455 gram LiAlH4 is suspended in 20 milliliters of anhydrous THF and mixture is stirred, solution is cooled to 2-3 ℃, then 0.436 gram 5-methoxyl group-3-(2-nitro-vinyl)-1H-indoles is dissolved in 20 milliliters of anhydrous THF solutions, drip as reaction system, at room temperature stirred 5 hours, TLC is cooled to 0 ℃ after showing that starting raw material disappears, after water dropping collection is gone out, mixture is filtered, and filtrate is concentrated under vacuum, add ethyl acetate in the resistates, with organic layer salt water washing, anhydrous sodium sulfate drying, and under reduced pressure concentrate, required product 5-methoxytryptamine 0.37 gram into orange obtained;
Step 4) is in 500 milliliters round-bottomed flask, 12.15 the gram sodium methylate is suspended in 250 milliliters of anhydrous diethyl ethers, and under nitrogen, stir, be cooled to 0 ℃, 21.9 gram Succinic acid dimethylester and 36 gram methyl-formiates mix, in 20 minutes, dropwise be added to then in the reaction flask, reaction mixture stirred 2 hours down at 0 ℃, then in ambient temperature overnight; Solvent evaporated obtains brown residue, and it is dissolved in 3M hydrochloric acid, transfers to slightly acidic with hydrochloric acid, PH ≈ 5 uses dichloromethane extraction then, with the organic phase anhydrous sodium sulfate drying, filter also and under reduced pressure remove solvent, get output 27 gram 2-formyl radical Succinic acid dimethylesters;
Step 5) is in 100 milliliters three neck round-bottomed flasks; 0.57 the tryptamines of gram is dissolved in 15 milliliters the anhydrous methanol; under the room temperature; stir and dropwise add 15 milliliters of absolute methanol solutions of 0.56 gram 2-formyl radical Succinic acid dimethylester; continue to stir 1 hour; solution is cooled to 0 ℃, remain in the vitriol oil that adds 1.6 milliliters in 0 ℃ the mixture, with reaction mixture 100 ℃ of heating 1 hour; reaction terminating; with the reaction mixture cooling, pour in the 50g frozen water, and filter; with disgorging; with the ammoniacal liquor neutralization of filtrate with 28% concentration, use dichloromethane extraction, and the organic extract liquid that merges washes with water; use anhydrous sodium sulfate drying; extraction liquid filters, evaporating solvent, and resistates separates at the mixture of silica gel with methylene dichloride-acetone; obtain 30 milligrams the finished product indoles also [3; 2,1-de]-[1,5] 7-naphthyridine derivatives.
The invention has the beneficial effects as follows:
Synthesis technique of the present invention is simple, and starting material obtain conveniently, and effect of drugs is good, has reduced cost, has reduced the recurrence rate of cancer, to antitumor better curative effect is arranged.
Above-mentioned explanation only is the general introduction of technical solution of the present invention, for can clearer understanding technique means of the present invention, and can be implemented according to the content of specification sheets, below with preferred embodiment of the present invention and conjunction with figs. describe in detail as after.The specific embodiment of the present invention is provided in detail by following examples and accompanying drawing thereof.
Description of drawings
Fig. 1 is the block diagram of synthetic 5-methoxytryptamine;
Fig. 2 is the block diagram of synthetic 2-formyl radical Succinic acid dimethylester;
Fig. 3 is the also block diagram of [3,2,1-de]-[1,5] 7-naphthyridine derivatives of synthesis of indole.
Embodiment
Below with reference to the accompanying drawings and in conjunction with the embodiments, describe the present invention in detail.
A kind of synthetic method with novel naphthyridine derivatives of antitumor curative effect may further comprise the steps:
Step 1) is referring to shown in Figure 1, in 25 milliliters round-bottomed flask, add 7 milliliters of DMF solution, in 0.5 hour, drip 2 milliliters of phosphorus oxychloride after solution being cooled to-3 ℃, 5-methoxyl group-1H-indoles 2.94 grams are dissolved among 5 milliliters of DMF, this solution is added in the colourless above-mentioned reaction soln, gets mixture, temperature of reaction is lower than 5 ℃ in this process, said mixture is heated to 40 ℃, and this temperature maintenance 2 hours, thin-layer chromatography EA: PE=1: 3 showed that starting raw materials disappear, and are cooled to room temperature with said mixture, and pour 30 gram trash ice and 40 ml waters into, stir in the solution of cooling down 18% NaOH and drip until solution PH=12, the pressure reducing and steaming organic solvent was placed on water in the refrigerator 1 hour, solid filtering is collected, water washing after the drying, obtains 2 gram 5-methoxyl group indole-3-formaldehyde white solids;
Step 2) in 100 milliliters round-bottomed flask, 0.375 gram ammonium acetate is suspended in 20 milliliters of Nitromethane 99Min.s, 1.5 gram 5-methoxyl group indole-3-formaldehydes are added in the above-mentioned solution and are heated to reflux temperature then, this temperature 2 hours, reaction soln is stirred, TLC shows that raw material disappears, after being cooled to room temperature, add 200 milliliters of ethyl acetate in the solution, organic phase washes twice with water, and uses the salt water washing, dry in anhydrous sodium sulphate, the vaporising under vacuum solvent, and with resistates by chromatography EA: PE=1: purifying in 3 obtains 1.207 gram orange solids product 5-methoxyl group-3-(2-nitro-vinyl)-1H-indoles;
Step 3) is in 100 milliliters round-bottomed flask, 0.455 gram LiAlH4 is suspended in 20 milliliters of anhydrous THF and mixture is stirred, solution is cooled to 2-3 ℃, then 0.436 gram 5-methoxyl group-3-(2-nitro-vinyl)-1H-indoles is dissolved in 20 milliliters of anhydrous THF solutions, drip as reaction system, at room temperature stirred 5 hours, TLC is cooled to 0 ℃ after showing that starting raw material disappears, after water dropping collection is gone out, mixture is filtered, and filtrate is concentrated under vacuum, add ethyl acetate in the resistates, with organic layer salt water washing, anhydrous sodium sulfate drying, and under reduced pressure concentrate, required product 5-methoxytryptamine 0.37 gram into orange obtained;
Step 4) is referring to shown in Figure 2, in 500 milliliters round-bottomed flask, 12.15 the gram sodium methylate is suspended in 250 milliliters of anhydrous diethyl ethers, and under nitrogen, stir, be cooled to 0 ℃, 21.9 gram Succinic acid dimethylesters and 36 gram methyl-formiates mix, and dropwise are added in the reaction flask in 20 minutes then, reaction mixture was stirred 2 hours down at 0 ℃, then in ambient temperature overnight; Solvent evaporated obtains brown residue, and it is dissolved in 3M hydrochloric acid, transfers to slightly acidic with hydrochloric acid, PH ≈ 5 uses dichloromethane extraction then, with the organic phase anhydrous sodium sulfate drying, filter also and under reduced pressure remove solvent, get output 27 gram 2-formyl radical Succinic acid dimethylesters;
Step 5) is referring to shown in Figure 3; in 100 milliliters three neck round-bottomed flasks; 0.57 the tryptamines of gram is dissolved in 15 milliliters the anhydrous methanol; under the room temperature; stir and dropwise add 15 milliliters of absolute methanol solutions of 0.56 gram 2-formyl radical Succinic acid dimethylester, continue to stir 1 hour, solution is cooled to 0 ℃; remain in the vitriol oil that adds 1.6 milliliters in 0 ℃ the mixture; 100 ℃ of heating 1 hour, reaction terminating cooled off reaction mixture with reaction mixture; pour in the 50g frozen water; and filter, with disgorging, with the ammoniacal liquor neutralization of filtrate with 28% concentration; use dichloromethane extraction; reach the organic extract liquid that merges and wash with water, use anhydrous sodium sulfate drying, extraction liquid filters; evaporating solvent; resistates separates at the mixture of silica gel with methylene dichloride-acetone, obtains 30 milligrams the finished product indoles also [3,2; 1-de]-[1,5] 7-naphthyridine derivatives.
The above only for the preferred embodiment of invention, is not limited to the present invention, and for a person skilled in the art, the present invention can have various changes and variation.Within the spirit and principles in the present invention all, any modification of doing, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (1)
1. the synthetic method with novel naphthyridine derivatives of antitumor curative effect is characterized in that, may further comprise the steps:
Step 1) is in 25 milliliters round-bottomed flask, add 7 milliliters of DMF solution, in 0.5 hour, drip 2 milliliters of phosphorus oxychloride after solution being cooled to-3 ℃, 5-methoxyl group-1H-indoles 2.94 grams are dissolved among 5 milliliters of DMF, this solution is added in the colourless above-mentioned reaction soln, get mixture, temperature of reaction is lower than 5 ℃ in this process, and said mixture is heated to 40 ℃, and keeps 2 hours in this temperature, thin-layer chromatography EA: PE=1: 3 show that starting raw material disappears, said mixture is cooled to room temperature, and pours 30 gram trash ice and 40 ml waters into, 18% NaOH drips until solution PH=12 in the solution that cools off under stirring, the pressure reducing and steaming organic solvent, water was placed in the refrigerator 1 hour, solid filtering is collected water washing, after the drying, obtain 2 gram 5-methoxyl group indole-3-formaldehyde white solids;
Step 2) in 100 milliliters round-bottomed flask, 0.375 gram ammonium acetate is suspended in 20 milliliters of Nitromethane 99Min.s, 1.5 gram 5-methoxyl group indole-3-formaldehydes are added in the above-mentioned solution and are heated to reflux temperature then, this temperature 2 hours, reaction soln is stirred, TLC shows that raw material disappears, after being cooled to room temperature, add 200 milliliters of ethyl acetate in the solution, organic phase washes twice with water, and uses the salt water washing, dry in anhydrous sodium sulphate, the vaporising under vacuum solvent, and with resistates by chromatography EA: PE=1: purifying in 3 obtains 1.207 gram orange solids product 5-methoxyl group-3-(2-nitro-vinyl)-1H-indoles;
Step 3) is in 100 milliliters round-bottomed flask, 0.455 gram LiAlH4 is suspended in 20 milliliters of anhydrous THF and mixture is stirred, solution is cooled to 2-3 ℃, then 0.436 gram 5-methoxyl group-3-(2-nitro-vinyl)-1H-indoles is dissolved in 20 milliliters of anhydrous THF solutions, drip as reaction system, at room temperature stirred 5 hours, TLC is cooled to 0 ℃ after showing that starting raw material disappears, after water dropping collection is gone out, mixture is filtered, and filtrate is concentrated under vacuum, add ethyl acetate in the resistates, with organic layer salt water washing, anhydrous sodium sulfate drying, and under reduced pressure concentrate, required product 5-methoxytryptamine 0.37 gram into orange obtained;
Step 4) is in 500 milliliters round-bottomed flask, 12.15 the gram sodium methylate is suspended in 250 milliliters of anhydrous diethyl ethers, and under nitrogen, stir, be cooled to 0 ℃, 21.9 gram Succinic acid dimethylester and 36 gram methyl-formiates mix, in 20 minutes, dropwise be added to then in the reaction flask, reaction mixture stirred 2 hours down at 0 ℃, then in ambient temperature overnight; Solvent evaporated obtains brown residue, and it is dissolved in 3M hydrochloric acid, transfers to slightly acidic with hydrochloric acid, PH ≈ 5 uses dichloromethane extraction then, with the organic phase anhydrous sodium sulfate drying, filter also and under reduced pressure remove solvent, get output 27 gram 2-formyl radical Succinic acid dimethylesters;
Step 5) is in 100 milliliters three neck round-bottomed flasks; 0.57 the tryptamines of gram is dissolved in 15 milliliters the anhydrous methanol; under the room temperature; stir and dropwise add 15 milliliters of absolute methanol solutions of 0.56 gram 2-formyl radical Succinic acid dimethylester; continue to stir 1 hour; solution is cooled to 0 ℃, remain in the vitriol oil that adds 1.6 milliliters in 0 ℃ the mixture, with reaction mixture 100 ℃ of heating 1 hour; reaction terminating; with the reaction mixture cooling, pour in the 50g frozen water, and filter; with disgorging; with the ammoniacal liquor neutralization of filtrate with 28% concentration, use dichloromethane extraction, and the organic extract liquid that merges washes with water; use anhydrous sodium sulfate drying; extraction liquid filters, evaporating solvent, and resistates separates at the mixture of silica gel with methylene dichloride-acetone; obtain 30 milligrams the finished product indoles also [3; 2,1-de]-[1,5] 7-naphthyridine derivatives.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104496882A (en) * | 2014-11-29 | 2015-04-08 | 湖北金赛药业有限公司 | Synthesis method of melatonin |
| CN114437092A (en) * | 2022-01-27 | 2022-05-06 | 贵州中医药大学 | Chiral tetrahydrocarbazole polycyclic derivative and preparation method and application thereof |
| CN114516826A (en) * | 2022-02-21 | 2022-05-20 | 八叶草健康产业研究院(厦门)有限公司 | Preparation method of melatonin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4190657A (en) * | 1976-03-11 | 1980-02-26 | Synthelabo | Naphthyridine derivatives |
| US5766855A (en) * | 1991-05-24 | 1998-06-16 | Buchardt, Deceased; Ole | Peptide nucleic acids having enhanced binding affinity and sequence specificity |
-
2013
- 2013-04-16 CN CN2013101302610A patent/CN103193776A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4190657A (en) * | 1976-03-11 | 1980-02-26 | Synthelabo | Naphthyridine derivatives |
| US5766855A (en) * | 1991-05-24 | 1998-06-16 | Buchardt, Deceased; Ole | Peptide nucleic acids having enhanced binding affinity and sequence specificity |
Non-Patent Citations (2)
| Title |
|---|
| A. SELEN GURKAN,ET AL.: "Syntheses of Novel Indole Lipoic Acid Derivativesand Their Antioxidant Effects on Lipid Peroxidation", 《ARCH. PHARM. CHEM. LIFE SCI.》 * |
| 冯连顺等: "喹啉和萘啶衍生物抗肿瘤活性及其构-效关系研究进展", 《国外医药抗生素分册》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104496882A (en) * | 2014-11-29 | 2015-04-08 | 湖北金赛药业有限公司 | Synthesis method of melatonin |
| CN114437092A (en) * | 2022-01-27 | 2022-05-06 | 贵州中医药大学 | Chiral tetrahydrocarbazole polycyclic derivative and preparation method and application thereof |
| CN114437092B (en) * | 2022-01-27 | 2024-02-06 | 贵州中医药大学 | Chiral tetrahydrocarbazole polycyclic derivative and preparation method and application thereof |
| CN114516826A (en) * | 2022-02-21 | 2022-05-20 | 八叶草健康产业研究院(厦门)有限公司 | Preparation method of melatonin |
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Application publication date: 20130710 |