CN1740126A - Prepn process of 2,3-halogeno toluene - Google Patents
Prepn process of 2,3-halogeno toluene Download PDFInfo
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- CN1740126A CN1740126A CN 200410057244 CN200410057244A CN1740126A CN 1740126 A CN1740126 A CN 1740126A CN 200410057244 CN200410057244 CN 200410057244 CN 200410057244 A CN200410057244 A CN 200410057244A CN 1740126 A CN1740126 A CN 1740126A
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- lithium
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- toluene
- methyl
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Abstract
The preparation process of 2, 3-dihalogeno toluene includes the reaction of metal lithium and alkyl halide inside the first solvent to produce organic metal lithium compound; and the reaction of o-benzene dihalide and methylating reagent inside the second solvent in the presence of the produced organic metal lithium compound. The prepared 2, 3-dihalogeno toluene is important intermediate for preparing active medicine molecule.
Description
Technical field
The present invention relates to 2, the preparation method of 3-two toluene halides particularly utilizes adjacent two halobenzenes to prepare 2 as raw material, the method for 3-two toluene halides.
Background technology
2,3-two toluene halides and derivative thereof are very important intermediate in Chemicals in the synthetic and medication preparation.Prior art is such as disclosing multiple Synthetic 2, the method for 3-difluoro toluene and derivative thereof among the patent RU2147569.Yet existing synthetic method need be carried out under hot conditions basically, thereby energy consumption of reaction is big, and the product productive rate is relatively low.
Summary of the invention
The purpose of this invention is to provide 2 shown in a kind of high yield, the following general formula of low-energy consumption preparing (I), the method for 3-two toluene halides:
X wherein
1, X
2Be selected from F, Cl, Br or I respectively.
For achieving the above object, the present invention prepares 2, the method of 3-two toluene halides comprises that metallic lithium and haloalkane are reacted generates the metallic lithium organic compound in first solvent, and in the presence of the metallic lithium organic compound that generates, neighbour's two halobenzenes shown in the following general formula (II) are reacted in second solvent with methylating reagent
X wherein
1, X
2Be selected from F, Cl, Br or I respectively.
First solvent is selected from normal hexane, cyclohexane, toluene, dimethylbenzene or its mixture in the inventive method, is preferably normal hexane.
The metallic lithium organic compound is selected from propyl lithium, sec.-propyl lithium, n-Butyl Lithium, isobutyl-lithium, s-butyl lithium, tert-butyl lithium, lithium diisopropylamine, phenyl lithium or its mixture in the inventive method, preferred n-Butyl Lithium.
Methylating reagent is selected from methyl chloride, monobromethane, methyl iodide, methylcarbonate, methyl-sulfate or its mixture in the inventive method, is preferably methyl chloride.
Second solvent is selected from THF, DMSO, methyl tertiary butyl ether, Di Iso Propyl Ether, DMF, N-Methyl pyrrolidone, toluene or its mixture in the inventive method, is preferably THF.
Methylation reaction preferably carries out under-40～-50 ℃ temperature in the inventive method.
In the preferred embodiment of the invention, X
1, X
2Be fluorine simultaneously.
Method of the present invention also comprises the step of methylate being separated purification, as uses extraction well known in the art, distillation or chromatographic technique that methylate is separated purification.
Compared with prior art, product 2 of the present invention, 3-two toluene halides can obtain through methylating by making adjacent two halobenzenes, and its product purity and reaction yield all are greatly improved.Product 2 of the present invention, 3-two toluene halides are important intermediate of preparation pharmaceutical activity molecule.
Embodiment
The present invention will be described in more detail below in conjunction with embodiment.
With the air argon replaces that is equipped with in the four-hole boiling flask of agitator, thermometer, reflux exchanger and dropping funnel, and under argon shield, add normal hexane 495g, metallic lithium 13.8g.Be heated to backflow under stirring.Refluxing drips chlorobutane 123.2g down, drips off in about 60 minutes, continues back flow reaction 2 hours.Be cooled to below 40 ℃, in 1 hour, drip THF 570g, and drip the solution of forming by 114g 1,2-Difluorobenzene and 114g THF down in-40～-50 ℃, under this temperature, continue reaction 2 hours, in about 1.5 hours, feed methyl chloride 75g, after continuing to react 1 hour under this temperature, be warming up to room temperature, add 500g water, extremely neutral with the salt acid for adjusting pH value, layering is analyzed through GC, contains 2 in the organic phase, 3-difluoro toluene 102.5g, yield 80%.Crude product through concentrate, to obtain purity be 99.5% product in rectifying.
MS(m/z，M
+)：128；
IR(KBr，cm
-1)：3053，2960，2862，1921，1842，1763，1597，1502，1471，1452，1383，1082，1022，767，709。
Those skilled in the art are appreciated that the argon gas among the embodiment also can replace with rare gas elementes such as helium.
Metallic lithium organic compound among the present invention is except being the n-Butyl Lithium, can also be selected from propyl lithium, sec.-propyl lithium, isobutyl-lithium, s-butyl lithium, tert-butyl lithium, lithium diisopropylamine, phenyl lithium or its mixture, promptly used chlorobutane can use above-mentioned corresponding haloalkane to replace.
Generate the used solvent of metallic lithium organic compound among the present invention except being the normal hexane, can also use other organic solvent that is fit to, as cyclohexane, toluene, dimethylbenzene or its mixture etc.
Carry out the used solvent of methylation reaction among the present invention except THF, can also use DMSO, methyl tertiary butyl ether, Di Iso Propyl Ether, DMF, N-Methyl pyrrolidone, toluene or its mixture.
Methylating reagent among the present invention also can use monobromethane, methyl iodide, methylcarbonate, methyl-sulfate or its mixture except methyl chloride.
Should be appreciated that embodiments of the invention only are for understanding the indefiniteness explanation that the present invention makes the present invention better.Those skilled in the art are not departing from the spirit and scope of the present invention and can make various modifications, replacement and change to the present invention, and these modifications, replacement and change still belong to protection scope of the present invention.
Claims (9)
1. one kind is prepared as follows 2 shown in the general formula (I), the method for 3-two toluene halides,
Described method comprises:
Metallic lithium and haloalkane are reacted in first solvent generate the metallic lithium organic compound; And
Neighbour's two halobenzenes shown in the following general formula (II) are reacted with methylating reagent in second solvent,
X at general formula (I) and (II) wherein
1, X
2Be selected from F, Cl, Br or I respectively.
2. the method for claim 1, wherein said first solvent is selected from normal hexane, hexanaphthene, toluene, dimethylbenzene or its mixture.
3. the method for claim 1, wherein said metallic lithium organic compound is selected from propyl lithium, sec.-propyl lithium, n-Butyl Lithium, isobutyl-lithium, s-butyl lithium, tert-butyl lithium, lithium diisopropylamine, phenyl lithium or its mixture.
4. the method for claim 1, wherein said methylating reagent is selected from methyl chloride, monobromethane, methyl iodide, methylcarbonate, methyl-sulfate or its mixture.
5. the method for claim 1, wherein said second solvent is selected from THF, DMSO, methyl tertiary butyl ether, Di Iso Propyl Ether, DMF, N-Methyl pyrrolidone, toluene or its mixture.
6. the method for claim 1, wherein said methylation reaction carries out under-40～-50 ℃ temperature.
7. the method for claim 1 also comprises the step of methylate being separated purification.
8. the method for claim 1, wherein X
1, X
2Be fluorine simultaneously.
9. method as claimed in claim 8, wherein said first solvent is a normal hexane, and described metallic lithium organic compound is a n-Butyl Lithium, and described methylating reagent is a methyl chloride, and described second solvent is THF.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410057244 CN1301948C (en) | 2004-08-26 | 2004-08-26 | Prepn process of 2,3-halogeno toluene |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410057244 CN1301948C (en) | 2004-08-26 | 2004-08-26 | Prepn process of 2,3-halogeno toluene |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1740126A true CN1740126A (en) | 2006-03-01 |
| CN1301948C CN1301948C (en) | 2007-02-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410057244 Expired - Fee Related CN1301948C (en) | 2004-08-26 | 2004-08-26 | Prepn process of 2,3-halogeno toluene |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102976987A (en) * | 2012-12-17 | 2013-03-20 | 黄河三角洲京博化工研究院有限公司 | Method for co-producing sodium methyl mercaptide and dimethyl sulfide |
| CN113735670A (en) * | 2021-08-28 | 2021-12-03 | 江西赣锋锂业股份有限公司 | Method for industrially producing sec-butyl lithium |
-
2004
- 2004-08-26 CN CN 200410057244 patent/CN1301948C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102976987A (en) * | 2012-12-17 | 2013-03-20 | 黄河三角洲京博化工研究院有限公司 | Method for co-producing sodium methyl mercaptide and dimethyl sulfide |
| CN102976987B (en) * | 2012-12-17 | 2014-05-21 | 黄河三角洲京博化工研究院有限公司 | Method for co-producing sodium methyl mercaptide and dimethyl sulfide |
| CN113735670A (en) * | 2021-08-28 | 2021-12-03 | 江西赣锋锂业股份有限公司 | Method for industrially producing sec-butyl lithium |
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| Publication number | Publication date |
|---|---|
| CN1301948C (en) | 2007-02-28 |
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Granted publication date: 20070228 Termination date: 20120826 |