CN112898200A - Synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester - Google Patents
Synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester Download PDFInfo
- Publication number
- CN112898200A CN112898200A CN202110074298.0A CN202110074298A CN112898200A CN 112898200 A CN112898200 A CN 112898200A CN 202110074298 A CN202110074298 A CN 202110074298A CN 112898200 A CN112898200 A CN 112898200A
- Authority
- CN
- China
- Prior art keywords
- bromo
- methoxypyridine
- compound
- mixture
- carboxylate
- 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.)
- Pending
Links
Classifications
-
- 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 5-bromo-6-methoxypyridine-2-carboxylate, which develops two methods for synthesizing 5-bromo-6-methoxypyridine-2-carboxylate by taking 3-bromo-2-chloro-6-methylpyridine as a raw material, wherein the two methods are respectively a method for attacking carbonate by withdrawing hydrogen after substitution or a method for attacking carbonate by withdrawing hydrogen before substitution, and a target product 5-bromo-6-methoxypyridine-2-carboxylate is obtained only by two-step reaction. The synthetic method of the 5-bromo-6-methoxypyridine-2-carboxylic ester has the advantages of convenient and rapid reaction route, economy, environmental protection and huge potential economic value.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester.
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, and belongs to good heart of medicinal chemists. From 2015, FDA approved small molecule drugs contain a large proportion of nitrogen heterocyclic molecules, pyridine ranks three in all nitrogen heterocyclic rings, so that the derivative of pyridine fragment compounds is of great significance for small molecule drug design, and 5-bromo-6-methoxypyridine-2-methyl acetate is a product of which the pyridine ring contains a halogen atom, and can be connected with a new fragment through coupling reaction such as Suzuki, Ullman and the like, and methyl ester can be subjected to more derivatization through amine ester exchange or amidation after hydrolysis, so that 5-bromo-6-methoxypyridine-2-methyl acetate (cas: 1206777-11-8) is a very practical drug intermediate.
Disclosure of Invention
The invention provides a synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester, 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 5-bromo-6-methoxypyridine-2-carboxylate, which develops two methods for synthesizing 5-bromo-6-methoxypyridine-2-carboxylate by taking 3-bromo-2-chloro-6-methylpyridine as a raw material, wherein the two methods are respectively a method for attacking carbonate by withdrawing hydrogen after substitution or a method for attacking carbonate by withdrawing hydrogen before substitution, and a target product 5-bromo-6-methoxypyridine-2-carboxylate is obtained only by two-step reaction; the synthetic route is as follows:
r1, R2 include C1-C6 fatty carbon chains.
The invention relates to a synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester, which comprises the following steps:
step 1:
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:
adding 0.4g of compound 2 and 0.09g of compound 4 in an amount of 5.0 equivalents into a 100mL round-bottom flask, pouring 20mL of tetrahydrofuran to dissolve the compound 4 into a clear solution, dropwise adding 1mL of LDA in an amount of 1.0 equivalent under a dry ice acetone bath, and stirring at room temperature for 2 hours after dropwise adding; adding 40mL of water into the reaction solution, quenching, extracting for 3 times by using 60mL of ethyl acetate, combining organic phases, concentrating, drying and carrying out column chromatography to obtain 0.28g of yellow solid 5-bromo-6-methoxypyridine-2-methyl acetate with the yield of 55%.
The invention discloses another synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester, which comprises the following steps:
step 1:
adding 6.7g of compound 1 and 5.0 equivalents of compound 4 into a 500mL round-bottom flask, adding 3-bromo-2-chloro-6-methylpyridine as compound 1 and methyl carbonate as compound 4 into 150mL tetrahydrofuran, dissolving into a clear solution, adding 3.0 equivalents of lithium hexamethylsilazide, stirring at room temperature for 2 hours, adding 500mL of saturated NH4Cl solution into a reaction solution after the reaction is finished, quenching, extracting with 100mL of ethyl acetate for 3 times, drying, and concentrating to obtain 8.2g of yellow solid compound 5 with the yield of 95.5%;
step 2:
adding 8.0g of compound 5 into a 500mL round-bottom flask, pouring 100mL of methanol to dissolve the compound 5 into a clear solution, then adding 3.0 equivalents of sodium methoxide, stirring the mixture at the temperature of 40-65 ℃ for 16 hours, adding 200mL of saturated ammonium chloride solution into the reaction solution after the reaction is finished, quenching the mixture, extracting the mixture for 3 times by using 100mL of ethyl acetate, drying the mixture, concentrating the mixture, and performing column chromatography separation to obtain 2.9g of yellow solid 5-bromo-6-methoxypyridine-2-methyl acetate with the yield of 37.2%.
The concentration of the LDA is 2.0 mol/L.
The eluent for column chromatography separation is petroleum ether/ethyl acetate 10/1.
The invention has the beneficial effects that: the invention develops two novel methods for synthesizing 5-bromo-6-methoxypyridine-2-carboxylic ester by taking 3-bromo-2-chloro-6-methylpyridine as a raw material, and the method comprises the steps of replacing firstly and then drawing out hydrogen to attack carbonate or drawing out hydrogen to attack carbonate and then replacing, so that the target product 5-bromo-6-methoxypyridine-2-carboxylic ester is obtained through two-step reaction.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1: the invention relates to a synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester, which comprises the following steps:
step 1: 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: adding 0.4g of compound 2 and 0.09g of compound 4 in an amount of 5.0 equivalents into a 100mL round-bottom flask, pouring 20mL of tetrahydrofuran to dissolve the compound 4 into a clear solution, dropwise adding 1mL of LDA in an amount of 1.0 equivalent under a dry ice acetone bath, and stirring at room temperature for 2 hours after dropwise adding; adding 40mL of water into the reaction solution, quenching, extracting for 3 times by using 60mL of ethyl acetate, combining organic phases, concentrating, drying and carrying out column chromatography to obtain 0.28g of yellow solid 5-bromo-6-methoxypyridine-2-methyl acetate with the yield of 55%.
The synthetic route of example 1 is:
example 2: the invention discloses another synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester, which comprises the following steps:
step 1: adding 6.7g of compound 1 and 5.0 equivalents of compound 4 into a 500mL round-bottom flask, adding 3-bromo-2-chloro-6-methylpyridine as compound 1 and methyl carbonate as compound 4 into 150mL tetrahydrofuran, dissolving into a clear solution, adding 3.0 equivalents of lithium hexamethylsilazide, stirring at room temperature for 2 hours, adding 500mL of saturated NH4Cl solution into a reaction solution after the reaction is finished, quenching, extracting with 100mL of ethyl acetate for 3 times, drying, and concentrating to obtain 8.2g of yellow solid compound 5 with the yield of 95.5%;
step 2: adding 8.0g of compound 5 into a 500mL round-bottom flask, pouring 100mL of methanol to dissolve the compound 5 into a clear solution, then adding 3.0 equivalents of sodium methoxide, stirring the mixture at the temperature of 40-65 ℃ for 16 hours, adding 200mL of saturated ammonium chloride solution into the reaction solution after the reaction is finished, quenching the mixture, extracting the mixture for 3 times by using 100mL of ethyl acetate, drying the mixture, concentrating the mixture, and performing column chromatography separation to obtain 2.9g of yellow solid 5-bromo-6-methoxypyridine-2-methyl acetate with the yield of 37.2%.
The synthetic route of example 2 is:
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 (5)
1. A synthetic method of 5-bromo-6-methoxypyridine-2-carboxylate is characterized by comprising the following steps: the synthesis method of the 5-bromo-6-methoxypyridine-2-carboxylate is characterized in that two methods for synthesizing the 5-bromo-6-methoxypyridine-2-carboxylate are developed by taking 3-bromo-2-chloro-6-methylpyridine as a raw material, wherein the two methods are respectively a method for attacking carbonate by hydrogen after substitution or a method for attacking carbonate by hydrogen before substitution, and the target product 5-bromo-6-methoxypyridine-2-carboxylate is obtained by only two-step reaction; the synthetic route is as follows:
r1, R2 include C1-C6 fatty carbon chains.
2. The method of synthesizing 5-bromo-6-methoxypyridine-2-carboxylate according to claim 1, wherein: the synthesis method of the 5-bromo-6-methoxypyridine-2-carboxylic ester specifically comprises the following steps:
step 1:
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:
adding 0.4g of compound 2 and 0.09g of compound 4 in an amount of 5.0 equivalents into a 100mL round-bottom flask, pouring 20mL of tetrahydrofuran to dissolve the compound 4 into a clear solution, dropwise adding 1mL of LDA in an amount of 1.0 equivalent under a dry ice acetone bath, and stirring at room temperature for 2 hours after dropwise adding; adding 40mL of water into the reaction solution, quenching, extracting for 3 times by using 60mL of ethyl acetate, combining organic phases, concentrating, drying and carrying out column chromatography to obtain 0.28g of yellow solid 5-bromo-6-methoxypyridine-2-methyl acetate with the yield of 55%.
3. The method of synthesizing 5-bromo-6-methoxypyridine-2-carboxylate according to claim 1, wherein: the synthesis method of the 5-bromo-6-methoxypyridine-2-carboxylic ester specifically comprises the following steps:
step 1:
adding 6.7g of compound 1 and 5.0 equivalents of compound 4 into a 500mL round-bottom flask, adding 3-bromo-2-chloro-6-methylpyridine as compound 1 and methyl carbonate as compound 4 into 150mL tetrahydrofuran, dissolving into a clear solution, adding 3.0 equivalents of lithium hexamethylsilazide, stirring at room temperature for 2 hours, adding 500mL of saturated NH4Cl solution into a reaction solution after the reaction is finished, quenching, extracting with 100mL of ethyl acetate for 3 times, drying, and concentrating to obtain 8.2g of yellow solid compound 5 with the yield of 95.5%;
step 2:
adding 8.0g of compound 5 into a 500mL round-bottom flask, pouring 100mL of methanol to dissolve the compound 5 into a clear solution, then adding 3.0 equivalents of sodium methoxide, stirring the mixture at the temperature of 40-65 ℃ for 16 hours, adding 200mL of saturated ammonium chloride solution into the reaction solution after the reaction is finished, quenching the mixture, extracting the mixture for 3 times by using 100mL of ethyl acetate, drying the mixture, concentrating the mixture, and performing column chromatography separation to obtain 2.9g of yellow solid 5-bromo-6-methoxypyridine-2-methyl acetate with the yield of 37.2%.
4. The method of synthesizing 5-bromo-6-methoxypyridine-2-carboxylate according to claim 2, wherein: the concentration of the LDA is 2.0 mol/L.
5. The method of synthesizing 5-bromo-6-methoxypyridine-2-carboxylate according to claim 3, wherein: the eluent for column chromatography separation is petroleum ether/ethyl acetate 10/1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110074298.0A CN112898200A (en) | 2021-01-20 | 2021-01-20 | Synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110074298.0A CN112898200A (en) | 2021-01-20 | 2021-01-20 | Synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112898200A true CN112898200A (en) | 2021-06-04 |
Family
ID=76116482
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110074298.0A Pending CN112898200A (en) | 2021-01-20 | 2021-01-20 | Synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112898200A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102099335A (en) * | 2008-07-23 | 2011-06-15 | 弗·哈夫曼-拉罗切有限公司 | Heterocyclic antiviral compounds |
| 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 |
| CN104321325A (en) * | 2012-05-24 | 2015-01-28 | 诺华股份有限公司 | Pyrrolopyrrolidinone compounds |
| CN104936954A (en) * | 2012-11-22 | 2015-09-23 | 安吉奥斯医药品有限公司 | Compounds and their methods of use |
| US20170050980A1 (en) * | 2015-08-18 | 2017-02-23 | Forum Pharmaceuticals Inc. | Oxadiazine compounds and methods of use thereof |
-
2021
- 2021-01-20 CN CN202110074298.0A patent/CN112898200A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102099335A (en) * | 2008-07-23 | 2011-06-15 | 弗·哈夫曼-拉罗切有限公司 | Heterocyclic antiviral compounds |
| 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 |
| CN104321325A (en) * | 2012-05-24 | 2015-01-28 | 诺华股份有限公司 | Pyrrolopyrrolidinone compounds |
| CN104936954A (en) * | 2012-11-22 | 2015-09-23 | 安吉奥斯医药品有限公司 | Compounds and their methods of use |
| US20170050980A1 (en) * | 2015-08-18 | 2017-02-23 | Forum Pharmaceuticals Inc. | Oxadiazine compounds and methods of use thereof |
Non-Patent Citations (1)
| Title |
|---|
| VIKTOR BARAT ET AL.: ""Synthesis of (−)-Cytisine Using a 6-endo aza-Michael Addition"", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2017096996A1 (en) | Preparation method for cobimetinib | |
| CN107011321A (en) | A kind of preparation method of artificial synthesized raceme nicotine | |
| CN104910002B (en) | A kind of preparation method of dezocine key intermediate | |
| CN110183367A (en) | A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization | |
| CN111171027B (en) | Preparation method of (R) -praziquantel | |
| CN112898200A (en) | Synthesis method of 5-bromo-6-methoxypyridine-2-carboxylic ester | |
| CN110294748B (en) | Synthesis method of teneligliptin key intermediate | |
| CN104016867A (en) | Synthesis method of 1-nitro-3,4:9,10-perylene tetracarboxylate and 1,6(7)-binitro-3,4:9,10-perylene tetracarboxylate | |
| CN109369611B (en) | Synthetic method of 4-chlorothiophene-2-carbonyl derivative | |
| CN104771392B (en) | Class I histone deacetylase inhibitor and application | |
| CN104478974B (en) | A kind of 20, the synthetic method of 23-dipiperidino-5-O-mycamino syl-tylono lide | |
| CN114014773A (en) | Preparation method of N-acetyl-L-aspartic acid | |
| CN110803994B (en) | Synthetic method of pregabalin intermediate 3-nitromethylene-5-methyl-ethyl caproate | |
| CN106349145A (en) | Method for preparing intelligence-improving medicine (S)-oxiracetam | |
| CN105646284A (en) | Lacosamide synthesis method | |
| CN110804022A (en) | Preparation method of dexrazoxane | |
| CN105130972A (en) | Emtricitabine benzoate, preparation method thereof, and method of preparing emtricitabine from emtricitabine benzoate | |
| CN109280049B (en) | Synthetic method of medical compound avanafil | |
| CN112457235B (en) | Preparation method of 7-methylindole | |
| CN112876409A (en) | Synthesis method of 2- (5-bromo-6-methoxypyridine-2-yl) acetonitrile and derivatives thereof | |
| CN112759575B (en) | Preparation method of clopidogrel hydrogen sulfate and intermediate N- (2-thienylethyl) methylamine thereof | |
| CN115677456B (en) | Preparation method of cannabidiol | |
| WO2014106419A1 (en) | Process for synthesizing 1-methyl-2-oxo-3,6,7-trioxabicyclo[2,2,2]octane | |
| CN111087433B (en) | Preparation method of tulathromycin intermediate | |
| CN112661727B (en) | Purification method of 7- (2, 2-trichloroethyl oxycarbonyl) taxol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210604 |