CN115260037A - Preparation method of 2-methyl-3-nitrobenzyl ether - Google Patents
Preparation method of 2-methyl-3-nitrobenzyl ether Download PDFInfo
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- CN115260037A CN115260037A CN202210958403.1A CN202210958403A CN115260037A CN 115260037 A CN115260037 A CN 115260037A CN 202210958403 A CN202210958403 A CN 202210958403A CN 115260037 A CN115260037 A CN 115260037A
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- methyl
- nitrobenzyl ether
- fluoro
- preparation
- nitrobenzene
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- MGJZLOLPKIULST-UHFFFAOYSA-N [N+](=O)([O-])C1=CC=CC(=C1C)COCC1=C(C(=CC=C1)[N+](=O)[O-])C Chemical compound [N+](=O)([O-])C1=CC=CC(=C1C)COCC1=C(C(=CC=C1)[N+](=O)[O-])C MGJZLOLPKIULST-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 16
- GXPIVRKDWZKIKZ-UHFFFAOYSA-N 1-fluoro-2-methyl-3-nitrobenzene Chemical compound CC1=C(F)C=CC=C1[N+]([O-])=O GXPIVRKDWZKIKZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 7
- 238000006266 etherification reaction Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 239000007787 solid Substances 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000003208 petroleum Chemical group 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 238000001035 drying Methods 0.000 abstract description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- GAKLFAZBKQGUBO-UHFFFAOYSA-N 2-methyl-3-nitrophenol Chemical compound CC1=C(O)C=CC=C1[N+]([O-])=O GAKLFAZBKQGUBO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- XTRDKALNCIHHNI-UHFFFAOYSA-N 2,6-dinitrotoluene Chemical compound CC1=C([N+]([O-])=O)C=CC=C1[N+]([O-])=O XTRDKALNCIHHNI-UHFFFAOYSA-N 0.000 description 1
- XCSNRORTQRKCHB-UHFFFAOYSA-N 2-chloro-6-nitrotoluene Chemical compound CC1=C(Cl)C=CC=C1[N+]([O-])=O XCSNRORTQRKCHB-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of 2-methyl-3-nitrobenzyl ether, which comprises the steps of synthesizing 2-methyl-3-nitrobenzyl ether by taking 3-fluoro-2-methyl nitrobenzene as a raw material, dimethyl sulfoxide as a solvent, methanol as an etherification reagent and anhydrous potassium carbonate as alkali, reacting for 24 hours, extracting a reaction solution by using an organic solvent, washing with water, drying, concentrating to remove the solvent, and distilling to obtain solid 2-methyl-3-nitrobenzyl ether. The invention takes 3-fluoro-2-methyl nitrobenzene as raw material to obtain a target product through nucleophilic substitution reaction of methanol. The reaction raw materials are easy to obtain, the route is short, and the yield is high.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a preparation method of 2-methyl-3-nitrobenzyl ether.
Background
2-methyl-3-nitrobenzyl ether is an important medical intermediate. Is mainly applied to the synthesis of pharmaceutical raw materials. At present, a world patent report (WO 2011/69951) uses 2, 6-dinitrotoluene for selective reduction and diazotization to prepare 2-methyl-3-nitrophenol, and finally, the 2-methyl-3-nitrophenol is generated by etherification reaction with methyl iodide, the three-step reaction is realized, the route has dangerous raw materials, expensive auxiliary materials and long route; CN112552224.2021, which uses expensive catalyst Pd complex, reports that 2-methyl-nitrochlorobenzene is used to prepare products through Pd catalyzed reaction; in addition to the methods, no other methods are reported at present, so that a method for preparing 2-methyl-3-nitrobenzyl ether with easily available raw materials, short route and high yield is lacking at present.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a preparation method of 2-methyl-3-nitrobenzyl ether, which has the advantages of easily obtained raw materials, short route and high yield.
In order to solve the above technical problem, the present invention provides a first technical solution as follows:
the invention relates to a preparation method of 2-methyl-3-nitrobenzyl ether, which comprises the following steps:
the first step, the synthesis of 2-methyl-3-nitrobenzyl ether takes 3-fluoro-2-methyl nitrobenzene as a raw material, dimethyl sulfoxide as a solvent, methanol as an etherification reagent and anhydrous potassium carbonate as alkali to react for 24 hours, reaction liquid is extracted by an organic solvent, washed by water, dried, concentrated to remove the solvent, and distilled to obtain solid 2-methyl-3-nitrobenzyl ether;
the mass ratio of dimethyl sulfoxide to 3-fluoro-2-methyl nitrobenzene is 5-10, the molar ratio of methanol to 3-fluoro-2-methyl nitrobenzene is 3-3.5, and the molar ratio of anhydrous potassium carbonate to 3-fluoro-2-methyl nitrobenzene is 2-2.5.
As a preferable technical scheme of the invention, the etherification reagent used in the step (A) is methanol.
As a preferred technical scheme of the invention, the organic solvent used in the first step is one or a combination of DMSO, DMAc and NMP.
As a preferable technical scheme of the invention, the alkali used in the first step is one or a combination of anhydrous potassium carbonate, anhydrous sodium carbonate and anhydrous potassium phosphate.
As a preferred technical scheme of the invention, the organic solvent used in the first step comprises one or more of dichloromethane, methyl tertiary ether, ethyl acetate and petroleum ether.
The specific synthetic route is as follows:
compared with the prior art, the invention has the following beneficial effects:
the invention takes 3-fluoro-2-methyl nitrobenzene as raw material to obtain the target product through nucleophilic substitution reaction of methanol. The reaction raw materials are easy to obtain, the route is short, and the yield is high.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention.
Wherein like reference numerals refer to like parts throughout.
In addition, if a detailed description of known technologies is not necessary to illustrate the features of the present invention, it is omitted. It should be noted that as used in the following description, the terms "front," "back," "left," "right," "upper" and "lower" refer to directions in the drawings, and the terms "inner" and "outer" refer to directions toward and away from, respectively, the geometric center of a particular component.
In the drawings:
FIG. 1 is a reaction diagram of the present invention;
fig. 2 is a graph of peak results.
Detailed Description
The preferred embodiments of the present invention will be described in conjunction with the accompanying drawings, and it will be understood that they are described herein for the purpose of illustration and explanation and not limitation.
Example 1
The invention provides a using method of a preparation method of 2-methyl-3-nitrobenzyl ether, which comprises the following steps:
under the protection of argon, 600ml of DMSO, 40g of 3-fluoro-2-methyl nitrobenzene, 60g of methanol and 120g of anhydrous potassium carbonate are added into a 1L three-necked bottle, the system is heated to 120 ℃ and is kept warm for 24h, 500ml of water is added to quench the reaction, 500ml of dichloromethane is used for extraction, the saturated saline solution is washed with water, and the anhydrous sodium sulfate is dried, concentrated and distilled to obtain 22g of white solid (GC = 98.4%).
Example 2
Synthesis of 2-methyl-3-nitrobenzyl ether:
under the protection of argon, 6L of tetrahydrofuran, 400g of 3-fluoro-2-methyl nitrobenzene, 60g of methanol and 120g of anhydrous potassium carbonate are added into a 10L three-necked bottle, the mixture is kept warm for 24h, 1L of quenching reaction is added, 5L of dichloromethane is used for extraction, saturated saline is washed, anhydrous sodium sulfate is added for drying and concentration, and distillation is carried out to obtain 240g of white solid (GC = 98.4%).
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the invention as defined by the appended claims. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. A preparation method of 2-methyl-3-nitrobenzyl ether comprises the following specific steps:
the first step, the synthesis of 2-methyl-3-nitrobenzyl ether takes 3-fluoro-2-methyl nitrobenzene as a raw material, dimethyl sulfoxide as a solvent, methanol as an etherification reagent and anhydrous potassium carbonate as alkali, the reaction is carried out for 24 hours, reaction liquid is extracted by an organic solvent, washed by water, dried, concentrated to remove the solvent, and distilled to obtain solid 2-methyl-3-nitrobenzyl ether;
the mass ratio of dimethyl sulfoxide to 3-fluoro-2-methyl nitrobenzene is 5-10, the molar ratio of methanol to 3-fluoro-2-methyl nitrobenzene is 3-3.5, and the molar ratio of anhydrous potassium carbonate to 3-fluoro-2-methyl nitrobenzene is 2-2.5.
2. A process for the preparation of 2-methyl-3-nitrobenzyl ether according to claim 1 wherein the etherification reagent used in the first step is methanol.
3. The method for preparing 2-methyl-3-nitrobenzyl ether according to claim 1, wherein the organic solvent used in the first step is one or a combination of DMSO, DMAc and NMP.
4. The preparation method of 2-methyl-3-nitrobenzyl ether according to claim 1, wherein the base used in the first step is one or more of anhydrous potassium carbonate, anhydrous sodium carbonate and anhydrous potassium phosphate.
5. The preparation method of 2-methyl-3-nitrobenzyl ether according to claim 1, wherein the organic solvent used in the first step comprises one or more of dichloromethane, methyl tertiary ether, ethyl acetate and petroleum ether.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210958403.1A CN115260037A (en) | 2022-08-09 | 2022-08-09 | Preparation method of 2-methyl-3-nitrobenzyl ether |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210958403.1A CN115260037A (en) | 2022-08-09 | 2022-08-09 | Preparation method of 2-methyl-3-nitrobenzyl ether |
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| CN115260037A true CN115260037A (en) | 2022-11-01 |
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| CN202210958403.1A Pending CN115260037A (en) | 2022-08-09 | 2022-08-09 | Preparation method of 2-methyl-3-nitrobenzyl ether |
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|---|---|---|---|---|
| US20080227784A1 (en) * | 2006-06-21 | 2008-09-18 | Institute Of Medicinal Molecular Design. Inc. | N-(3,4-disubstituted phenyl) salicylamide derivatives |
| WO2008110863A1 (en) * | 2007-03-15 | 2008-09-18 | Glenmark Pharmaceuticals S.A. | Indazole derivatives and their use as vanilloid receptor ligands |
| CN102320978A (en) * | 2011-09-22 | 2012-01-18 | 江苏康恒化工有限公司 | Preparation method of anhydrous system o-nitroanisole |
| CN104557557A (en) * | 2013-10-09 | 2015-04-29 | 中国石油化工股份有限公司 | Method for preparing nitroanisole from m-nitrochlorobenzene oil |
| CN104755465A (en) * | 2012-08-24 | 2015-07-01 | 武田药品工业株式会社 | Heterocycic compound |
| WO2020005935A1 (en) * | 2018-06-25 | 2020-01-02 | Kadmon Corporation, Llc | Glucose uptake inhibitors |
| CN111646904A (en) * | 2020-05-28 | 2020-09-11 | 浙江闰土研究院有限公司 | Method for synthesizing p-nitroanisole |
| CN112552224A (en) * | 2020-12-30 | 2021-03-26 | 爱斯特（成都）生物制药股份有限公司 | Synthesis method of 4-hydroxyindole |
| WO2021087112A1 (en) * | 2019-10-30 | 2021-05-06 | Biogen Ma Inc. | Condensed bi-heterocycles as inhibiting agents for bruton's tyrosine kinase |
-
2022
- 2022-08-09 CN CN202210958403.1A patent/CN115260037A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080227784A1 (en) * | 2006-06-21 | 2008-09-18 | Institute Of Medicinal Molecular Design. Inc. | N-(3,4-disubstituted phenyl) salicylamide derivatives |
| WO2008110863A1 (en) * | 2007-03-15 | 2008-09-18 | Glenmark Pharmaceuticals S.A. | Indazole derivatives and their use as vanilloid receptor ligands |
| CN102320978A (en) * | 2011-09-22 | 2012-01-18 | 江苏康恒化工有限公司 | Preparation method of anhydrous system o-nitroanisole |
| CN104755465A (en) * | 2012-08-24 | 2015-07-01 | 武田药品工业株式会社 | Heterocycic compound |
| CN104557557A (en) * | 2013-10-09 | 2015-04-29 | 中国石油化工股份有限公司 | Method for preparing nitroanisole from m-nitrochlorobenzene oil |
| WO2020005935A1 (en) * | 2018-06-25 | 2020-01-02 | Kadmon Corporation, Llc | Glucose uptake inhibitors |
| WO2021087112A1 (en) * | 2019-10-30 | 2021-05-06 | Biogen Ma Inc. | Condensed bi-heterocycles as inhibiting agents for bruton's tyrosine kinase |
| CN111646904A (en) * | 2020-05-28 | 2020-09-11 | 浙江闰土研究院有限公司 | Method for synthesizing p-nitroanisole |
| CN112552224A (en) * | 2020-12-30 | 2021-03-26 | 爱斯特（成都）生物制药股份有限公司 | Synthesis method of 4-hydroxyindole |
Non-Patent Citations (4)
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