CN111961047A - 6-ethoxy-3, 4-dihydro-2, 7-naphthyridine-1 (2H) -ketone and synthetic method thereof - Google Patents
6-ethoxy-3, 4-dihydro-2, 7-naphthyridine-1 (2H) -ketone and synthetic method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of organic synthesis, and relates to 6-ethoxy-3, 4-dihydro-2, 7-naphthyridine-1 (2H) -ketone and a synthesis method thereof. The method of the compound comprises the following steps: the 6-ethoxy-3, 4-dihydro-2, 7-naphthyridine-1 (2H) -ketone is prepared by using 2, 5-dibromo-4-methylpyridine as a raw material through five-step reactions of substitution, Suzuki coupling, carbonyl insertion reaction, amidation and dehydration reaction, the synthetic route is simple, the cost is low, the efficiency is high, and the obtained pyridine derivative 6-ethoxy-3, 4-dihydro-2, 7-naphthyridine-1 (2H) -ketone can be used as a medical intermediate.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to 6-ethoxy-3, 4-dihydro-2, 7-naphthyridine-1 (2H) -ketone and a synthesis method thereof.
Background
Naphthyridine derivatives are an important class of nitrogen heterocyclic compounds, widely exist in the whole natural world, and often have important physiological and pharmacological activities. For example, naphthyridine derivatives are important pharmaceutical intermediates useful in the synthesis of many drugs. In addition, pyridine is used as an intermediate of fine chemical products, and has wide application in the fields of catalysts, medicines, pesticides and the like. Therefore, the synthesis of naphthyridine derivatives is of great importance.
Disclosure of Invention
The invention aims to provide a synthetic method of the compound which is 6-ethoxy-3, 4-dihydro-2, 7-naphthyridin-1 (2H) -ketone, the compound can be used as a compound of a medical intermediate, and the synthetic method is simple and has high yield.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a compound is 6-ethoxy-3, 4-dihydro-2, 7-naphthyridin-1 (2H) -ketone, and the molecular structure is shown as formula 1:
the invention also provides a synthesis method of the compound, which takes 2, 5-dibromo-4-methylpyridine as a raw material to synthesize the compound through five-step reaction, wherein the synthesis route is shown as the following formula:
the synthesis method comprises the following steps:
s1, adding 2, 5-dibromo-4-methylpyridine into NMP, adding sodium ethoxide, heating to 40 ℃, stopping heating, naturally heating to 70 ℃ for reaction, reducing the temperature to 50-60 ℃, and reacting for 3 hours to obtain 5-bromo-2-ethoxy-4-methylpyridine;
s2, adding the 5-bromo-2-ethoxy-4-methylpyridine obtained in the step S1 into ethanol, adding an organic base, and adding a catalyst Pd (dpf) cl2Controlling the reaction temperature at 110-;
s3, adding the 6-ethoxy-4-methylnicotinate obtained in the step S2 into DMF, adding pyrrolidine and DMF-DMA, controlling the reaction temperature to be 100-115 ℃, and reacting for 12h to obtain (E) 6-ethoxy-4- (2- (pyrrolidine-1-yl) vinyl) nicotinate;
s4, adding the (E) 6-ethoxy-4- (2- (pyrrolidine-1-yl) vinyl) nicotinate obtained in the step S3 into isopropyl ether, adding hydroxylamine hydrochloride, reacting for 12h, and reacting to obtain (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate;
s5, adding the (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate obtained in the step S4 into ethanol, adding raney nickel, introducing hydrogen, and reacting at room temperature for 12H to obtain 6-ethoxy-3, 4-dihydro-2, 7-naphthyridine-1 (2H) -ketone.
Further, the organic base is one of triethylamine, pyridine and triethanolamine.
Further, the reaction temperature in the step S4 is 20 to 35 ℃.
The invention has the beneficial effects that: compared with the prior art, the invention provides a new medical intermediate, and the synthesis method provided by the invention has the advantages of simple synthesis path, low cost and high efficiency.
Detailed description of the invention
The following detailed description will provide specific embodiments of the present invention. These embodiments are merely illustrative and not intended to limit the scope or the principles of the invention, which is defined by the claims and includes obvious modifications and variations based thereon.
Example 1
S1, synthesis of 5-bromo-2-ethoxy-4-methylpyridine:
573g of 2, 5-dibromo-4-methylpyridine is dissolved in 2.2L of NMP in a 3L four-necked flask, 282g of sodium ethoxide is added under mechanical stirring, the temperature is raised to 40 ℃, then the heating is stopped, the temperature is naturally raised to 70 ℃ for reaction, and the temperature is lowered to about 55 ℃ for reaction for 1 h. After the reaction of the starting materials was completed by TLC analysis, 3L of water and 1L of ethyl acetate were added to the system, the aqueous phase was extracted 2 times (2X 2L) with ethyl acetate, and the ethyl acetate phases were combined, dried and concentrated to dryness to obtain 455g of 5-bromo-2-ethoxy-4-methylpyridine as a solid in a yield of 92%.
Synthesis of S2, 6-ethoxy-4-methylnicotinate:
451g of 5-bromo-2-ethoxy-4-methylpyridine were dissolved in 2.5L of ethanol in a 5L autoclave, and 531.2g of triethylamine and then 40g of Pd (dpff) cl were added with mechanical stirring2In the presence of oxygenPressurizing 15kg in carbon environment, raising the temperature to 120 ℃ and reacting for 12 h. The reaction of the raw materials was completed by TLC analysis, and the product was filtered through celite, ethanol was distilled off, and dissolved in dichloromethane, and column chromatography (PE: EA: 100:1-50:1) was carried out to obtain 275g of 6-ethoxy-4-methylnicotinate solid in a yield of 67.1%.
S3, (E) Synthesis of 6-ethoxy-4- (2- (pyrrolidin-1-yl) vinyl) nicotinate:
273g of 6-ethoxy-4-methylnicotinate was dissolved in 1.5L of DMF in a 3L reaction flask, and 150g of pyrrolidine and 250g of DMF-DMA were added with mechanical stirring and reacted at 105 ℃ for 12 hours. TLC analysis of the reaction of the starting materials was complete, 1.2L of water was added and extracted with 5L of methyl tert-butyl ether, the aqueous phase was also extracted once, the organic phases were combined and washed with saturated brine and evaporated to dryness to give 367g of 6-ethoxy-4- (2- (pyrrolidin-1-yl) vinyl) nicotinate solid in 95% yield.
Synthesis of S4, (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate:
54g of 6-ethoxy-4- (2- (pyrrolidin-1-yl) vinyl) nicotinate was dissolved in 1.8L of isopropyl ether in a 5L four-necked flask, and 120g of hydroxylamine hydrochloride was added thereto under mechanical stirring, and the temperature was maintained at 30 ℃ for 12 hours. The reaction of the raw materials was completed by TLC analysis, and 350ml and 200ml of methyl t-butyl ether were added thereto, stirred and filtered, and once washed with water, and dried to obtain 283g of (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate as a solid in 89.3% yield.
Synthesis of S5, 6-ethoxy-3, 4-dihydro-2, 7-naphthyridin-1 (2H) -one:
281g of (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate was added to 4L hydrogenation bottles of 1L, and 50g of Raney nickel was added thereto with mechanical stirring and reacted at room temperature overnight. The raw materials are analyzed by thin layer chromatography to react completely, and then the raw materials are filtered and subjected to column chromatography (PE: EA is 10:1-1:1) to obtain 143g of 6-ethoxy-3, 4-dihydro-2, 7-naphthyridin-1 (2H) -one solid with the yield of 63 percent.
Example 2
S1, synthesis of 5-bromo-2-ethoxy-4-methylpyridine:
573g of 2, 5-dibromo-4-methylpyridine is dissolved in 2.2L of NMP in a 3L four-necked flask, 282g of sodium ethoxide is added under mechanical stirring, the temperature is raised to 40 ℃, then the heating is stopped, the temperature is naturally raised to 70 ℃ for reaction, and the temperature is lowered to about 50 ℃ for reaction for 1.5 h. After the reaction of the raw materials was completed by TLC analysis, 3L of water and 1L of ethyl acetate were added to the system, the aqueous phase was extracted with ethyl acetate 2 times (2X 2L), and the ethyl acetate phases were combined, dried and concentrated to dryness to obtain 440g of 5-bromo-2-ethoxy-4-methylpyridine solid in a yield of 89%.
Synthesis of S2, 6-ethoxy-4-methylnicotinate:
451g of 5-bromo-2-ethoxy-4-methylpyridine were dissolved in 2.5L of ethanol in a 5L autoclave, and 531.2g of pyridine and then 40g of Pd (dpff) cl were added with mechanical stirring2And pressurizing 15kg in a carbon monoxide environment, and heating to 110 ℃ for reaction for 24 hours. The raw materials are analyzed by thin layer chromatography to react completely, the raw materials are filtered by diatomite, ethanol is distilled out, dichloromethane is used for dissolving, and column chromatography (PE: EA is 100:1-50:1) is carried out to obtain 292g of 6-ethoxy-4-methyl nicotinate solid, wherein the yield is 71.2%.
S3, (E) Synthesis of 6-ethoxy-4- (2- (pyrrolidin-1-yl) vinyl) nicotinate:
273g of 6-ethoxy-4-methylnicotinate was dissolved in 1.5L of DMF in a 3L reaction flask, and 150g of pyrrolidine and 250g of DMF-DMA were added with mechanical stirring and reacted at 115 ℃ for 8 hours. After the reaction of the starting materials was completed by TLC analysis, 1.2L of water was added, extraction was performed with 5L of methyl t-butyl ether, the aqueous phase was also extracted once, the organic phases were combined and washed with saturated brine, and evaporation and concentration were performed until dryness to obtain 348g of 6-ethoxy-4- (2- (pyrrolidin-1-yl) vinyl) nicotinate as a solid in 90% yield.
Synthesis of S4, (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate:
54g of 6-ethoxy-4- (2- (pyrrolidin-1-yl) vinyl) nicotinate are dissolved in 1.8L of isopropyl ether in a 5L four-necked flask, 120g of hydroxylamine hydrochloride are added with mechanical stirring and the temperature is maintained at 35 ℃ for reaction for 8 h. After the reaction of the starting materials was completed by TLC analysis, 350ml and 200ml of methyl t-butyl ether were added thereto, and the mixture was stirred, filtered and washed once with water, and dried to obtain 292g of (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate as a solid in a yield of 92.1%.
Synthesis of S5, 6-ethoxy-3, 4-dihydro-2, 7-naphthyridin-1 (2H) -one:
281g of (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate dissolved in 4L of ethanol are added to 4 hydrogenation bottles of 1L, and 50g of Raney nickel are added with mechanical stirring and reacted at room temperature for 18 h. The raw materials are analyzed by thin layer chromatography to react completely, and then the raw materials are filtered and subjected to column chromatography (PE: EA is 10:1-1:1) to obtain 152g of 6-ethoxy-3, 4-dihydro-2, 7-naphthyridin-1 (2H) -one solid, wherein the yield is 67%.
Example 3
S1, synthesis of 5-bromo-2-ethoxy-4-methylpyridine:
573g of 2, 5-dibromo-4-methylpyridine is dissolved in 2.2L of NMP in a 3L four-necked flask, 282g of sodium ethoxide is added under mechanical stirring, the temperature is raised to 40 ℃, then the heating is stopped, the temperature is naturally raised to 70 ℃ for reaction, and the temperature is lowered to about 60 ℃ for reaction for 2 hours. After the reaction of the raw materials was completed by TLC analysis, 3L of water and 1L of ethyl acetate were added to the system, the aqueous phase was extracted with ethyl acetate 2 times (2X 2L), the ethyl acetate phases were combined, dried and concentrated to dryness to obtain 470g of 5-bromo-2-ethoxy-4-methylpyridine as a solid in a yield of 95%.
Synthesis of S2, 6-ethoxy-4-methylnicotinate:
451g of 5-bromo-2-ethoxy-4-methylpyridine were dissolved in 2.5L of ethanol in a 5L autoclave, and 531.2g of triethanolamine and then 40g of Pd (dpff) cl were added with mechanical stirring2The reaction was carried out under a pressure of 15kg and a temperature of 130 ℃ for 8 hours in an atmosphere of carbon monoxide. The raw materials are analyzed by thin layer chromatography to react completely, the raw materials are filtered by diatomite, ethanol is distilled out, dichloromethane is used for dissolving, and column chromatography (PE: EA is 100:1-50:1) is carried out to obtain 248g of 6-ethoxy-4-methyl nicotinate solid with the yield of 60.4 percent.
S3, (E) Synthesis of 6-ethoxy-4- (2- (pyrrolidin-1-yl) vinyl) nicotinate:
273g of 6-ethoxy-4-methylnicotinate was dissolved in 1.5L of DMF in a 3L reaction flask, and 150g of pyrrolidine and 250g of DMF-DMA were added with mechanical stirring and reacted at 100 ℃ for 15 hours. After the reaction of the starting materials was completed by TLC analysis, 1.2L of water was added, extraction was performed with 5L of methyl t-butyl ether, the aqueous phase was also extracted once, the organic phases were combined and washed with saturated brine, and evaporation and concentration were performed until dried to obtain 375g of 6-ethoxy-4- (2- (pyrrolidin-1-yl) vinyl) nicotinate solid in 97% yield.
Synthesis of S4, (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate:
54g of 6-ethoxy-4- (2- (pyrrolidin-1-yl) vinyl) nicotinate are dissolved in 1.8L of isopropyl ether in a 5L four-necked flask, 120g of hydroxylamine hydrochloride are added with mechanical stirring and the temperature is maintained at 20 ℃ for reaction for 15 h. After completion of the reaction of the starting materials was analyzed by thin layer chromatography, 350ml and 200ml of methyl t-butyl ether were added thereto, and the mixture was stirred, filtered, washed once with water, and dried to obtain 277g of (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate as a solid in 87.5% yield.
Synthesis of S5, 6-ethoxy-3, 4-dihydro-2, 7-naphthyridin-1 (2H) -one:
281g of (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate dissolved in 4L of ethanol are added to 4 hydrogenation bottles of 1L, and 50g of Raney nickel are added with mechanical stirring and reacted at room temperature for 8 h. The raw materials are analyzed by thin layer chromatography to react completely, and then the raw materials are filtered and subjected to column chromatography (PE: EA is 10:1-1:1) to obtain 125g of 6-ethoxy-3, 4-dihydro-2, 7-naphthyridin-1 (2H) -one solid, wherein the yield is 55%.
While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (4)
1. A compound is 6-ethoxy-3, 4-dihydro-2, 7-naphthyridin-1 (2H) -one, and the molecular structure is shown as formula 1:
2. the method for synthesizing the compound according to claim 1, wherein 2, 5-dibromo-4-methylpyridine is used as a raw material, and the compound is synthesized through five-step reaction, wherein the synthetic route is shown as a formula 2:
the synthesis method comprises the following steps:
s1, adding 2, 5-dibromo-4-methylpyridine into NMP, adding sodium ethoxide, heating to 40 ℃, stopping heating, naturally heating to 70 ℃ for reaction, reducing the temperature to 50-60 ℃, and reacting for 3 hours to obtain 5-bromo-2-ethoxy-4-methylpyridine;
s2, adding the 5-bromo-2-ethoxy-4-methylpyridine obtained in the step S1 into ethanol, adding an organic base, and adding a catalyst Pd (dpf) cl2Controlling the reaction temperature at 110-;
s3, adding the 6-ethoxy-4-methylnicotinate obtained in the step S2 into DMF, adding pyrrolidine and DMF-DMA, controlling the reaction temperature to be 100-115 ℃, and reacting for 12h to obtain (E) 6-ethoxy-4- (2- (pyrrolidine-1-yl) vinyl) nicotinate;
s4, adding the (E) 6-ethoxy-4- (2- (pyrrolidine-1-yl) vinyl) nicotinate obtained in the step S3 into isopropyl ether, adding hydroxylamine hydrochloride, reacting for 12h, and reacting to obtain (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate;
s5, adding the (Z) -methyl 6-ethoxy-4- (2- (hydroxyimino) ethyl) nicotinate obtained in the step S4 into ethanol, adding raney nickel, introducing hydrogen, and reacting at room temperature for 12H to obtain 6-ethoxy-3, 4-dihydro-2, 7-naphthyridine-1 (2H) -ketone.
3. The method of synthesis of claim 2, wherein: the organic base is one of triethylamine, pyridine and triethanolamine.
4. The method of synthesis of claim 2, wherein: the reaction temperature in the step S4 is 20-35 ℃.
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| WO2014019186A1 (en) * | 2012-08-02 | 2014-02-06 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
| WO2020022237A1 (en) * | 2018-07-23 | 2020-01-30 | 大日本住友製薬株式会社 | Fused ring lactam derivatives |
| WO2020086857A1 (en) * | 2018-10-24 | 2020-04-30 | Vanderbilt University | Wdr5 inhibitors and modulators |
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- 2020-08-19 CN CN202010836060.2A patent/CN111961047A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1342161A (en) * | 1999-01-11 | 2002-03-27 | 阿古龙制药公司 | Tricyclic inhibitors of poly(ADP-ribose) polymerases |
| WO2005087775A1 (en) * | 2004-03-15 | 2005-09-22 | Ono Pharmaceutical Co., Ltd. | Tricyclic heterocyclic compound and medicinal composition containing the compound as active ingredient |
| CN101405267A (en) * | 2006-03-22 | 2009-04-08 | Ucb医药有限公司 | Process for preparing l-halo-2,7-naphthyridinyl derivatives |
| CN101631787A (en) * | 2007-03-13 | 2010-01-20 | 比奥维特罗姆上市公司 | The tricyclic isoquinoline derivatives that is used for obesity treatment |
| WO2014019186A1 (en) * | 2012-08-02 | 2014-02-06 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
| WO2020022237A1 (en) * | 2018-07-23 | 2020-01-30 | 大日本住友製薬株式会社 | Fused ring lactam derivatives |
| WO2020086857A1 (en) * | 2018-10-24 | 2020-04-30 | Vanderbilt University | Wdr5 inhibitors and modulators |
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