CN112876409A - Synthesis method of 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and derivatives thereof - Google Patents
Synthesis method of 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and derivatives thereof Download PDFInfo
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- CN112876409A CN112876409A CN202110073833.0A CN202110073833A CN112876409A CN 112876409 A CN112876409 A CN 112876409A CN 202110073833 A CN202110073833 A CN 202110073833A CN 112876409 A CN112876409 A CN 112876409A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Abstract
The invention discloses a synthesis method of 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and derivatives thereof, which comprises the steps of taking 3-bromo-2-chloro-6-methylpyridine as a raw material, carrying out substitution reaction on the 3-bromo-2-chloro-6-methylpyridine to generate a compound 2, brominating the compound 2 to generate a compound 3, cyanating the compound 3 to obtain the 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile, then hydrolyzing the 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile to obtain a target compound 2- (5-bromo-6-methoxypyridine-2-yl) acetic acid. The synthetic method has the advantages of simple reaction route operation, various derivatization ways, rich product process route and great economic value.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and derivatives thereof.
Background
The nitrogen-containing heterocycle is commonly found in natural products such as nucleoside, amino acid, sugar, vitamin, alkaloid and the like, and the heterocycle structure is introduced into a medicine molecule, so that the nitrogen-containing heterocycle has great effects on improving the selectivity and the utilization rate of the medicine, fat solubility and water solubility and molecular polarity. From 2015, in small molecule drugs approved by FDA, the nitrogen heterocyclic ring is contained in a large proportion, pyridine ranks three in all nitrogen heterocyclic rings, so that the derivative of pyridine fragment compounds is of great significance for the design of small molecule drugs, and 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile is a product, wherein the pyridine ring of the compound is provided with a halogen atom, a new fragment can be connected through coupling reaction of Suzuki, Ullman and the like, and a cyano group can be hydrolyzed into acid, such as 2- (5-bromo-6-methoxypyridin-2-yl) acetic acid, esterified or amidated to obtain various products.
Disclosure of Invention
The invention provides a synthetic method of 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and derivatives thereof, aiming at overcoming the defects in the prior art.
The invention is realized by the following technical scheme: the invention discloses a synthesis method of 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and derivatives thereof, which comprises the steps of taking a compound 1 as a raw material, taking the compound 1 as 3-bromo-2-chloro-6-methylpyridine, carrying out substitution reaction on the compound 1 to generate a compound 2, carrying out bromination on the compound 2 to generate a compound 3, carrying out cyanation on the compound 3 to obtain a compound 4, taking the compound 4 as 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile, carrying out hydrolysis on the 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile to obtain a target compound 2- (5-bromo-6-methoxypyridine-2-yl) acetic acid, the synthetic reaction route is as follows:
the synthesis method of the 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and the derivatives thereof specifically comprises the following steps:
step 1: and (3) substitution reaction:
adding 10g of compound 1 into a 250mL round-bottom flask, wherein the compound 1 is 3-bromo-2-chloro-6-methylpyridine, pouring 100mL of methanol to dissolve the compound 1 into a clear solution, then adding 10.5g of sodium methoxide with 4.0 equivalents, stirring the mixture at the temperature of 40-65 ℃ for 16 hours, after the reaction is finished, concentrating the mixture under reduced pressure to remove most of the methanol, adding 100mL of water into the rest reaction solution to quench the reaction solution, extracting the reaction solution for 3 times by using 100mL of ethyl acetate, combining organic phases, concentrating and drying the mixture to obtain 8.4g of white solid compound 2, wherein the yield is 80.6%;
step 2: bromination reaction:
adding 5.4g of compound 2 into a 250mL round-bottom flask, pouring 100mL of carbon tetrachloride for dissolving, then adding 0.5 equivalent of BPO and 1.1 equivalent of NBS, stirring at 40-80 ℃ for 12 hours, after the reaction is finished, performing vacuum filtration to remove a solid part, directly concentrating the residual reaction solution, performing reverse phase silica gel column chromatography, combining, collecting, concentrating and freeze-drying to obtain 3.8g of yellow solid compound 3, wherein the yield is 50.8%;
and step 3: cyanation reaction:
adding 2.8g of the compound 3 into a 100mL round-bottom flask, adding 20mL of methanol and 10mL of water for dissolving, then adding 3 equivalents of sodium cyanide and 0.1 equivalent of sodium iodide, stirring at 40-65 ℃ for 4 hours, after the reaction is finished, concentrating under vacuum to remove most of methanol, then adding 50mL of water into the rest reaction liquid, extracting for 3 times by using 100mL of ethyl acetate, combining organic phases, concentrating, drying, and carrying out column chromatography to obtain 1.9g of a yellow solid compound 4, wherein the yellow solid compound 4 is 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile, and the yield is 84.0%;
and 4, step 4: and (3) hydrolysis reaction:
adding 15g of 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile into a 250mL round-bottom flask, adding 120mL of hydrochloric acid to dissolve the acetonitrile, stirring the mixture at 40-65 ℃ for 4 hours, concentrating a part of reaction solvent after the reaction is finished, adding 100mL of water into the rest reaction solution, extracting the mixture for 3 times by using 200mL of ethyl acetate, concentrating the mixture, drying the concentrated mixture, performing column chromatography, and obtaining 12.5g of a yellow solid product, namely 2- (5-bromo-6-methoxypyridin-2-yl) acetic acid with the yield of 77.1 percent (eluent is dichloromethane/methanol ═ 10/1).
In the bromination reaction of step 2, the acetonitrile/water content of the reverse phase silica gel column chromatography was 45%.
In the cyanation reaction of step 3, the column chromatography of petroleum ether/ethyl acetate is 4/1.
The concentration of hydrochloric acid in the hydrolysis reaction in the step 4 is 6.0 mol/L. The eluent for column chromatography in the hydrolysis reaction of step 4 was dichloromethane/methanol 10/1.
The invention has the beneficial effects that: the method takes 3-bromo-2-chloro-6-methylpyridine as a raw material, and obtains the target compound 2- (5-bromo-6-methoxypyridine-2-yl) acetic acid through substitution, bromination, cyanation and hydrolysis. The synthetic method has the advantages of simple reaction route operation, various derivatization ways, rich product process route and great economic value.
Detailed Description
The present invention will be described in detail with reference to specific embodiments.
The invention discloses a synthesis method of 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and derivatives thereof, which comprises the steps of taking a compound 1 as a raw material, taking the compound 1 as 3-bromo-2-chloro-6-methylpyridine, carrying out substitution reaction on the compound 1 to generate a compound 2, carrying out bromination on the compound 2 to generate a compound 3, carrying out cyanation on the compound 3 to obtain a compound 4, taking the compound 4 as 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile, carrying out hydrolysis on the 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile to obtain a target compound 2- (5-bromo-6-methoxypyridine-2-yl) acetic acid, the synthetic reaction route is as follows:
example (b): the synthesis method of the 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and the derivatives thereof specifically comprises the following steps:
step 1: and (3) substitution reaction:
adding 10g of compound 1 into a 250mL round-bottom flask, wherein the compound 1 is 3-bromo-2-chloro-6-methylpyridine, pouring 100mL of methanol to dissolve the compound 1 into a clear solution, then adding 10.5g of sodium methoxide with 4.0 equivalents, stirring the mixture at the temperature of 40-65 ℃ for 16 hours, after the reaction is finished, concentrating the mixture under reduced pressure to remove most of the methanol, adding 100mL of water into the rest reaction solution to quench the reaction solution, extracting the reaction solution for 3 times by using 100mL of ethyl acetate, combining organic phases, concentrating and drying the mixture to obtain 8.4g of white solid compound 2, wherein the yield is 80.6%;
step 2: bromination reaction:
adding 5.4g of compound 2 into a 250mL round-bottom flask, pouring 100mL of carbon tetrachloride for dissolving, then adding 0.5 equivalent of BPO and 1.1 equivalent of NBS, stirring at 40-80 ℃ for 12 hours, after the reaction is finished, performing vacuum filtration to remove a solid part, directly concentrating the residual reaction solution, performing reverse phase silica gel column chromatography, combining, collecting, concentrating and freeze-drying to obtain 3.8g of yellow solid compound 3, wherein the yield is 50.8%;
and step 3: cyanation reaction:
adding 2.8g of the compound 3 into a 100mL round-bottom flask, adding 20mL of methanol and 10mL of water for dissolving, then adding 3 equivalents of sodium cyanide and 0.1 equivalent of sodium iodide, stirring at 40-65 ℃ for 4 hours, after the reaction is finished, concentrating under vacuum to remove most of methanol, then adding 50mL of water into the rest reaction liquid, extracting for 3 times by using 100mL of ethyl acetate, combining organic phases, concentrating, drying, and carrying out column chromatography to obtain 1.9g of a yellow solid compound 4, wherein the yellow solid compound 4 is 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile, and the yield is 84.0%;
and 4, step 4: and (3) hydrolysis reaction:
adding 15g of 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile into a 250mL round-bottom flask, adding 120mL of hydrochloric acid to dissolve the acetonitrile, stirring the mixture at 40-65 ℃ for 4 hours, concentrating a part of reaction solvent after the reaction is finished, adding 100mL of water into the rest reaction solution, extracting the mixture for 3 times by using 200mL of ethyl acetate, concentrating the mixture, drying the concentrated mixture, performing column chromatography, and obtaining 12.5g of a yellow solid product, namely 2- (5-bromo-6-methoxypyridin-2-yl) acetic acid with the yield of 77.1 percent (eluent is dichloromethane/methanol ═ 10/1).
The synthetic reaction route of the embodiment of the invention is as follows:
in the bromination reaction of step 2, the acetonitrile/water content of the reverse phase silica gel column chromatography was 45%. In the cyanation reaction of step 3, the column chromatography of petroleum ether/ethyl acetate is 4/1. The concentration of hydrochloric acid in the hydrolysis reaction in the step 4 is 6.0 mol/L. The eluent for column chromatography in the hydrolysis reaction of step 4 was dichloromethane/methanol 10/1.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (6)
1. A synthetic method of 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and derivatives thereof is characterized in that: the synthesis method comprises the following steps of taking a compound 1 as a raw material, taking the compound 1 as 3-bromo-2-chloro-6-methylpyridine, carrying out substitution reaction on the compound 1 to generate a compound 2, brominating the compound 2 to generate a compound 3, cyanating the compound 3 to obtain a compound 4, taking the compound 4 as 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile, and hydrolyzing the 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile to obtain a target compound 2- (5-bromo-6-methoxypyridin-2-yl) acetic acid, wherein the synthesis reaction route is as follows:
2. the method for synthesizing 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile and its derivatives as claimed in claim 1, wherein: the synthesis method specifically comprises the following steps:
step 1: and (3) substitution reaction:
adding 10g of compound 1 into a 250mL round-bottom flask, wherein the compound 1 is 3-bromo-2-chloro-6-methylpyridine, pouring 100mL of methanol to dissolve the compound 1 into a clear solution, then adding 10.5g of sodium methoxide with 4.0 equivalents, stirring the mixture at the temperature of 40-65 ℃ for 16 hours, after the reaction is finished, concentrating the mixture under reduced pressure to remove most of the methanol, adding 100mL of water into the rest reaction solution to quench the reaction solution, extracting the reaction solution for 3 times by using 100mL of ethyl acetate, combining organic phases, concentrating and drying the mixture to obtain 8.4g of white solid compound 2, wherein the yield is 80.6%;
step 2: bromination reaction:
adding 5.4g of compound 2 into a 250mL round-bottom flask, pouring 100mL of carbon tetrachloride for dissolving, then adding 0.5 equivalent of BPO and 1.1 equivalent of NBS, stirring at 40-80 ℃ for 12 hours, after the reaction is finished, performing vacuum filtration to remove a solid part, directly concentrating the residual reaction solution, performing reverse phase silica gel column chromatography, combining, collecting, concentrating and freeze-drying to obtain 3.8g of yellow solid compound 3, wherein the yield is 50.8%;
and step 3: cyanation reaction:
adding 2.8g of the compound 3 into a 100mL round-bottom flask, adding 20mL of methanol and 10mL of water for dissolving, then adding 3 equivalents of sodium cyanide and 0.1 equivalent of sodium iodide, stirring at 40-65 ℃ for 4 hours, after the reaction is finished, concentrating under vacuum to remove most of methanol, then adding 50mL of water into the rest reaction liquid, extracting for 3 times by using 100mL of ethyl acetate, combining organic phases, concentrating, drying, and carrying out column chromatography to obtain 1.9g of a yellow solid compound 4, wherein the yellow solid compound 4 is 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile, and the yield is 84.0%;
and 4, step 4: and (3) hydrolysis reaction:
adding 15g of 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile into a 250mL round-bottom flask, adding 120mL of hydrochloric acid to dissolve the acetonitrile, stirring the mixture at 40-65 ℃ for 4 hours, concentrating a part of reaction solvent after the reaction is finished, adding 100mL of water into the rest reaction solution, extracting the mixture for 3 times by using 200mL of ethyl acetate, concentrating the mixture, drying the concentrated mixture, performing column chromatography, and obtaining 12.5g of a yellow solid product, namely 2- (5-bromo-6-methoxypyridin-2-yl) acetic acid with the yield of 77.1 percent (eluent is dichloromethane/methanol ═ 10/1).
3. The method for synthesizing 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile and its derivatives as claimed in claim 2, wherein: in the bromination reaction of step 2, the acetonitrile/water content of the reverse phase silica gel column chromatography was 45%.
4. The method for synthesizing 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile and its derivatives as claimed in claim 2, wherein: in the cyanation reaction of step 3, the column chromatography of petroleum ether/ethyl acetate is 4/1.
5. The method for synthesizing 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile and its derivatives as claimed in claim 2, wherein: the concentration of hydrochloric acid in the hydrolysis reaction in the step 4 is 6.0 mol/L.
6. The method for synthesizing 2- (5-bromo-6-methoxypyridin-2-yl) acetonitrile and its derivatives as claimed in claim 2, wherein: the eluent for column chromatography in the hydrolysis reaction of step 4 was dichloromethane/methanol 10/1.
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| US20140371269A1 (en) * | 2012-01-23 | 2014-12-18 | Eli Lilly And Company | Phenyl methanesulfonamide derivatives useful as mgat-2 inhibitors |
| CN104321325A (en) * | 2012-05-24 | 2015-01-28 | 诺华股份有限公司 | Pyrrolopyrrolidinone compounds |
| US20170050980A1 (en) * | 2015-08-18 | 2017-02-23 | Forum Pharmaceuticals Inc. | Oxadiazine compounds and methods of use thereof |
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2021
- 2021-01-20 CN CN202110073833.0A patent/CN112876409A/en active Pending
Patent Citations (8)
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| CN1675212A (en) * | 2002-08-21 | 2005-09-28 | 贝林格尔英格海姆法玛两合公司 | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| CN101952274A (en) * | 2007-11-20 | 2011-01-19 | 默沙东公司 | Non-nucleoside reverse transcriptase inhibitor |
| CN102099335A (en) * | 2008-07-23 | 2011-06-15 | 弗·哈夫曼-拉罗切有限公司 | Heterocyclic antiviral compounds |
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| US20120202787A1 (en) * | 2009-10-20 | 2012-08-09 | Pfizer Inc. | Novel Heteroaryl Imidazoles And Heteroaryl Triazoles As Gamma-Secretase Modulators |
| US20140371269A1 (en) * | 2012-01-23 | 2014-12-18 | Eli Lilly And Company | Phenyl methanesulfonamide derivatives useful as mgat-2 inhibitors |
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Application publication date: 20210601 |