CN102285914B - Synthesis method of 2-(1-methyl-6-carboxy-1,6-dihydropyridine)-acetic acid - Google Patents
Synthesis method of 2-(1-methyl-6-carboxy-1,6-dihydropyridine)-acetic acid Download PDFInfo
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- CN102285914B CN102285914B CN 201010205020 CN201010205020A CN102285914B CN 102285914 B CN102285914 B CN 102285914B CN 201010205020 CN201010205020 CN 201010205020 CN 201010205020 A CN201010205020 A CN 201010205020A CN 102285914 B CN102285914 B CN 102285914B
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Abstract
The invention relates to a synthesis method of 2-(1-methyl-6-carboxy-1,6-dihydropyridine)-acetic acid, wherein problems that the current synthesis route is lacked, the reaction route is long, the post-treatment is complex, the amplification is difficult, the applicability is not wide and the like are solved by a fast efficient acetic acid group introducing method mainly. The synthesis method comprises the following steps of: reacting 6- chloro-1-hydrogen-pyridine-2-ketone 1 with a methylating reagent in the presence of an alkalization reagent to obtain 1-methyl-6-chloro-1-hydrogen-pyridine-2-ketone 2; reacting the compound 2 with acetonitrile in a solvent in the presence of the alkalization reagent, n-butyl lithium, at low temperature to generate 2-(1- methyl-6-carboxy-1,6-dihydropyridine)-acetonitrile 3; and hydrolyzing the compound 3 under the acidic condition to obtain the final product, 2-(1- methyl-6-carboxy-1,6-dihydropyridine)-acetic acid 4. A large amount of 2-(1- methyl-6-carboxy-1,6-dihydropyridine)-acetic acid can be quickly and conveniently prepared through the synthesis route disclosed by the invention.
Description
Technical field
The present invention relates to the synthetic method of a kind of important medicine intermediate 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid.
Background technology
2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid is a kind of important medicine intermediate, owing to having hydrogen bond donor and hydrogen bond receptor on its molecule simultaneously, can be widely used in the design of drug molecule; Its carboxyl, can synthesize from other a lot of drug template molecular reactions the drug molecule of various different demands.6-carbonyl-1, the derivative of 6-dihydro-pyridine-formic acid has more bibliographical information, and US20050245530 and US20070259862 have reported that respectively this compounds has certain anticancer and anti-gastroesophageal reflux effect.Therefore 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid has wide Research Prospects.But the synthetic report for this intermediate is few, the synthetic route of 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid of having only had at present one piece of bibliographical information, but these synthetic routes are very long, raw material costliness, and aftertreatment complexity, be difficult to the synthetic of the scale of being amplified.
Summary of the invention
The object of the present invention is to provide a kind of 2-(1-methyl-6-carbonyl-1, the new synthetic method of 6-dihydro-pyridine)-acetic acid, the reaction scheme that mainly by a kind of method of rapidly and efficiently introducing aceticoceptor, solves existing synthetic route shortage and exist is long, the technical problems such as aftertreatment is complicated, the amplification difficulty, and suitability is wideless.
The synthetic method of technical scheme of the present invention: 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid comprises the following steps:
It is raw material that the chloro-1-hydrogen-pyridin-2-ones of 6-is take in the first step reaction, with methylating reagent, under alkalizing agent exists, reacts and obtains the chloro-1-hydrogen-pyridin-2-ones of 1-methyl-6-;
The second step reaction under the chloro-1-hydrogen of 1-methyl-6--pyridin-2-ones cold condition, in solvent, generates 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetonitrile with acetonitrile reaction under the alkalizing agent n-Butyl Lithium exists;
Three-step reaction, 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetonitrile is hydrolyzed and obtains 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid under acidic conditions;
Chemical equation is as follows:
The first step reaction is carried out in solvent, and solvent is a kind of in methyl alcohol, ethanol or DMF; Alkalizing agent is salt of wormwood or cesium carbonate, and its consumption molar weight is 2.0 equivalents; A kind of with in methyl iodide or methyl-sulfate of methylating reagent; ; Temperature of reaction is 0～80 ℃; Reaction times is 3～18 hours.
The second step reaction, solvent is anhydrous tetrahydro furan or dry toluene; Described cold condition is: temperature of reaction is-40～-78 ℃; Reaction times is 3～4 hours.
Acid in three-step reaction is concentrated hydrochloric acid (the quality percentage composition is 38%) or the vitriol oil (the quality percentage composition is for being more than or equal to 50%); Temperature of reaction is 100～150 ℃, preferably 100～130 ℃; Reaction times is 2～6 hours.
The invention has the beneficial effects as follows: the invention provides a kind of synthetic route of novelty, can be from starting compound cheap, that be easy to get
1prepare quickly and easily a kind of important medicine intermediate 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid.This technique is three-step reaction altogether, and total recovery can reach 60%.
Embodiment
Following instance contributes to understand content of the present invention, the present invention includes but be not limited to following related content:
1.1-the chloro-1-hydrogen-pyridin-2-ones of methyl-6-
2synthetic
embodiment 1
By the chloro-1-hydrogen-pyridin-2-ones of 6-
1(60 g, 0.46 mol), salt of wormwood (128 g, 0.92 mol), methyl iodide (130 g, 0.92 mol) join respectively in ethanol (800 mL), this mixture is warming up to 50 ℃, react and after 16 hours, the solvent in system is spin-dried for, add 1L water in the solid mixture after being spin-dried for, with dichloromethane extraction (500 mL*2), merge organic phase and use again the saturated common salt water washing, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain the chloro-1-hydrogen-pyridin-2-ones of 1-methyl-6-
2(55g, 82.6%).
[0018] proton nmr spectra (DMSO, 400 MHz),
δppm:7.18-7.22 (m, 1H), 6.45-6.48 (m, 1H), 6.26-6.28 (m, 1H), 3.65 (s, 3H).
embodiment 2
By the chloro-1-hydrogen-pyridin-2-ones of 6-
1(60 g, 0.46 mol), cesium carbonate (300 g, 0.92 mol), methyl iodide (130 g, 0.92 mol) add respectively in methyl alcohol (800 mL), this mixture is spin-dried for the solvent in system after 16 hours in the lower reaction of room temperature (20～30 ℃), add 1L water in the solid mixture after being spin-dried for, with dichloromethane extraction (500 mL*2), merge organic phase and use again the saturated common salt water washing, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain the chloro-1-hydrogen-pyridin-2-ones of 1-methyl-6-
2(45 g, 69.2%).
embodiment 3
By the chloro-1-hydrogen-pyridin-2-ones of 6-
1(60 g, 0.46 mol), salt of wormwood (128 g, 0.92 mol), methyl-sulfate (86 g, 0.92 mol) add respectively N, in dinethylformamide (800 mL), this mixture is warmed up to 80 ℃, reacts after 4 hours the solvent in system is spin-dried for, in the solid mixture after being spin-dried for, add 1L water, with dichloromethane extraction (500 mL*2), merge organic phase and use again the saturated common salt water washing, anhydrous sodium sulfate drying, remove by filter siccative after concentrated filtrate obtain the chloro-1-hydrogen-pyridin-2-ones of 1-methyl-6-
2(35 g, 53.8%).
(2.2-1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetonitrile
embodiment 4
Add n-Butyl Lithium (480 mL in the 1.5L anhydrous tetrahydro furan under-78 ℃, 1.2 mol), slowly splash into again acetonitrile (49.2 g, 1.2 mol), in whole dropping process, temperature is controlled at-40～-78 ℃, stir adularescent solid after 45 minutes and produce, by the chloro-1-hydrogen-pyridin-2-ones of 1-methyl-6-
2the tetrahydrofuran solution of (55 g, 0.38 mol) splashes into above-mentioned white reaction system at-40～-78 ℃, stirs after two hours and slowly is raised to room temperature, continues to stir reaction system after 30 minutes and becomes sorrel, adds the 1L frozen water will react cancellation.By the 1L ethyl acetate, the ester solubility impurity in reaction system is washed away to concentrated 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetonitrile that obtains of rear water
3(50 g, 89%).
embodiment 5
Add n-Butyl Lithium (480 mL in the 1.5L dry toluene under-78 ℃, 1.2 mol), slowly splash into again acetonitrile (49.2 g, 1.2 mol), in whole dropping process, temperature is controlled at-40～-78 ℃, stir adularescent solid after 45 minutes and produce, by the chloro-1-hydrogen-pyridin-2-ones of 1-methyl-6-
2the tetrahydrofuran solution of (55 g, 0.38 mol) splashes into above-mentioned white reaction system at-40～-78 ℃, stirs after two hours and slowly is raised to room temperature, continues to stir reaction system after 30 minutes and becomes sorrel, adds the 1L frozen water will react cancellation.By the 1L ethyl acetate, the ester solubility impurity in reaction system is washed away to concentrated 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetonitrile that obtains of rear water
3(35 g, 62%).
[0028](3.2-1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid
4synthetic
embodiment 6
By 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetonitrile
3(50 g) adds in 1L water, add again 500 mL concentrated hydrochloric acids, stir 2～6 hours after being heated to 100～130 ℃, reaction solution is concentrated except anhydrating and hydrogen chloride gas obtains thick product, obtain 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid by re-crystallizing in ethyl acetate
4(48 g, 86%).Proton nmr spectra (DMSO, 400 MHz),
δppm:7.32-7.36 (dd,
j1=8.8 Hz,
j2=6.8 Hz, 1H), 6.35 (d,
j=8.8 Hz, 1H), 6.22 (d,
j=6.4 Hz, 1H), 3.82 (s, 2H), 3.40 (s, 3H).
embodiment 7
By 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetonitrile
3(50 g) adds in 1L water, add again in 500 mL 50% vitriol oils, stir 2～6 hours after being heated to 100～130 ℃, obtain thick product except anhydrating by reaction solution is concentrated, obtain 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid by re-crystallizing in ethyl acetate
4(41.0 g, 73%).
Claims (5)
1.2-the synthetic method of (1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid comprises the following steps:
It is raw material that the chloro-1-hydrogen-pyridin-2-ones of 6-is take in the first step reaction, with methylating reagent, under alkalizing agent exists, reacts and obtains the chloro-1-hydrogen-pyridin-2-ones of 1-methyl-6-;
The second step reaction under the chloro-1-hydrogen of 1-methyl-6--pyridin-2-ones cold condition, in solvent, generates 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetonitrile with acetonitrile reaction under the alkalizing agent n-Butyl Lithium exists;
Three-step reaction, 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetonitrile is hydrolyzed and obtains 2-(1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid under acidic conditions.
2. the synthetic method of 2-according to claim 1 (1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid, is characterized in that, the first step reaction is carried out in solvent, and solvent is a kind of in methyl alcohol, ethanol or DMF; Alkalizing agent is salt of wormwood or cesium carbonate, methyl iodide or methyl-sulfate for methylating reagent; Temperature of reaction is 0～80 ℃; Reaction times is 3～18 hours.
3. the synthetic method of 2-according to claim 2 (1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid, is characterized in that, the alkalizing agent consumption is 2.0 equivalents.
4. the synthetic method of 2-according to claim 1 (1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid, is characterized in that, the second step reaction, and solvent is anhydrous tetrahydro furan or dry toluene; Described cold condition is: temperature of reaction is-40～-78 ℃; Reaction times is 3～4 hours.
5. the synthetic method of 2-according to claim 1 (1-methyl-6-carbonyl-1,6-dihydro-pyridine)-acetic acid, is characterized in that, the acid in three-step reaction is concentrated hydrochloric acid or the vitriol oil; Temperature of reaction is 100～130 ℃; Reaction times is 2～6 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4496542A (en) * | 1981-03-30 | 1985-01-29 | Usv Pharmaceutical Corporation | N-substituted-amido-amino acids |
| CN101128199A (en) * | 2004-04-23 | 2008-02-20 | 布里斯托尔-迈尔斯斯奎布公司 | Monocyclic heterocycles as kinase inhibitors |
| CN101506202A (en) * | 2006-05-05 | 2009-08-12 | 阿斯利康(瑞典)有限公司 | mGluR5 modulators I |
-
2010
- 2010-06-18 CN CN 201010205020 patent/CN102285914B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4496542A (en) * | 1981-03-30 | 1985-01-29 | Usv Pharmaceutical Corporation | N-substituted-amido-amino acids |
| CN101128199A (en) * | 2004-04-23 | 2008-02-20 | 布里斯托尔-迈尔斯斯奎布公司 | Monocyclic heterocycles as kinase inhibitors |
| CN101506202A (en) * | 2006-05-05 | 2009-08-12 | 阿斯利康(瑞典)有限公司 | mGluR5 modulators I |
Non-Patent Citations (4)
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Effective date of registration: 20170209 Address after: Jinshan District of Shanghai chemical industrial zone of Shanghai city Jinshan District 201507 (West) Yuegong Road No. 9 Patentee after: Shanghai SynTheAll Pharmaceutical Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Patentee before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Patentee before: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. |
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