CN102993163A - Synthesis method of 3-methylthiophene-2-aldehyde - Google Patents
Synthesis method of 3-methylthiophene-2-aldehyde Download PDFInfo
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- CN102993163A CN102993163A CN2012105205935A CN201210520593A CN102993163A CN 102993163 A CN102993163 A CN 102993163A CN 2012105205935 A CN2012105205935 A CN 2012105205935A CN 201210520593 A CN201210520593 A CN 201210520593A CN 102993163 A CN102993163 A CN 102993163A
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- methyl
- formaldehyde
- methyl thiophene
- bromothiophene
- aqueous solution
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- BSQKBHXYEKVKMN-UHFFFAOYSA-N 3-methylthiophene-2-carbaldehyde Chemical compound CC=1C=CSC=1C=O BSQKBHXYEKVKMN-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title abstract 4
- QENGPZGAWFQWCZ-UHFFFAOYSA-N 3-Methylthiophene Chemical compound CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000006243 chemical reaction Methods 0.000 claims abstract description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- YYJBWYBULYUKMR-UHFFFAOYSA-N 2-bromo-3-methylthiophene Chemical compound CC=1C=CSC=1Br YYJBWYBULYUKMR-UHFFFAOYSA-N 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 238000010189 synthetic method Methods 0.000 claims description 15
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 10
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000012044 organic layer Substances 0.000 claims description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 238000009413 insulation Methods 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 238000010907 mechanical stirring Methods 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000003747 Grignard reaction Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 230000031709 bromination Effects 0.000 abstract 1
- 238000005893 bromination reaction Methods 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000000575 pesticide Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000002351 wastewater Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of 3-methylthiophene-2-aldehyde. The 3-methylthiophene-2-aldehyde is a compound intermediate with great value and can be widely used for synthesis in the fields of medicines, pesticides and the like. According to the synthesis method disclosed by the invention, 3-methylthiophene is taken as a raw material, bromination and Grignard reaction are performed, and then the reaction with N,N-dimethylformamide is performed, so that 3-methylthiophene-2-aldehyde is synthesized. The problems of poor selectivity, low yield, low purity, a large quantity of three wastes and the like in the existing synthesis method can be overcome, and the method disclosed by the invention is the method for synthesizing high-purity 3-methylthiophene-2-aldehyde under mild reaction conditions, which has the advantages of high selectivity and high yield.
Description
Technical field
The invention belongs to pharmaceutical intermediate synthetic method technical field, be specifically related to the synthetic method of a kind of 3 methyl thiophene-2-formaldehyde.
Background technology
3 methyl thiophene-2-formaldehyde is a kind of compound intermediate, has very high practical value, is widely used in the fields such as medicine, agricultural chemicals.Existing document US 2008/21026 and WO2007/19884 propose to be processed through butyllithium by 3 methyl thiophene, obtain 3 methyl thiophene-2-formaldehyde with the DMF reaction again.This method can produce a kind of isomer 4-thiotolene-2-formaldehyde, has about 20 percent, and the boiling point of itself and 3 methyl thiophene-2-formaldehyde is close, and separating difficulty is large.And ether and butyllithium that reaction is used all are the materials that very easily fires, and safety in utilization is low.Also has document (Tetrahedron Letters; Vol.41; Nb.15; (2000); P.2749 – 2752) propose can obtain 3 methyl thiophene-2-formaldehyde by 3 methyl thiophene and Vilsmeier reagent react.There are equally separation and the lower problem of yield of isomer, and produce a large amount of waste water.Also have the synthetic method raw material of the proposition such as US4471139 to be not easy to obtain, yield is low, and practical value is extremely low especially.
Summary of the invention
The defects that exists in order to overcome the prior art field the object of the invention is to, and the synthetic method of a kind of 3 methyl thiophene-2-formaldehyde is provided, solving the prior art Raw is not easy to obtain, separating isomerism body difficulty is large, and yield is low, produces the problems such as a large amount of waste water and practical value are low.
The synthetic method of 3 methyl thiophene provided by the invention-2-formaldehyde in turn includes the following steps:
The first step is synthesized 3-methyl-2-bromothiophene: add 3 methyl thiophene, Hydrogen bromide or the bromine ion-containing aqueous solution in there-necked flask, be cooled to 0 ℃, then temperature is controlled at 5～10 ℃ and drips hydrogen peroxide, dropwise and be warming up to 20 ℃, stir and leave standstill after 2 hours, separatory, organic layer washs with sodium sulfite aqueous solution and aqueous sodium carbonate, obtain 3-methyl-2-bromothiophene after the rectification under vacuum, the ratio of the amount of substance of used 3 methyl thiophene, Hydrogen bromide or the bromine ion-containing aqueous solution, hydrogen peroxide is 1: 1～2: 0.7～1.5;
The chemical equation of the first step is:
Second step synthesizes 3 methyl thiophene-2-formaldehyde: add magnesium chips in there-necked flask, tetrahydrofuran (THF) and 3-methyl-2-bromothiophene, add thermal booster reaction, after reaction causes, change cooling into, then at 20～30 ℃ of lower mixed solutions that drip 3-methyl-2-bromothiophene and tetrahydrofuran (THF), dropwise, 30 ℃ of lower insulations 2 hours, be cooled to again 5 ℃, drip DMF, dropwise, be warming up to 20～30 ℃, be incubated 4 hours, after the hydrolysis, methylbenzene extraction, organic layer washs with sodium bicarbonate aqueous solution, decompression steams toluene, and high vacuum rectification obtains 3 methyl thiophene-2-formaldehyde, used 3-methyl-2-bromothiophene, MAGNESIUM METAL, N, the ratio of the amount of substance of dinethylformamide is 1: 1～1.2: 1～3, and the ratio of solvent for use volume and 3-methyl-2-bromothiophene quality is 4～10: 1;
The chemical equation of second step is:
The described bromine ion-containing aqueous solution is gained behind the methylbenzene extraction in the synthetic 3 methyl thiophene of second step-2-formaldehyde; It is tetrahydrofuran (THF) or 2-methyltetrahydrofuran that described second step synthesizes 3 methyl thiophene-2-formaldehyde solvent for use; Described hydrobromic concentration is 46%～50%, and the concentration of described hydrogen peroxide is 10%～40%; Described there-necked flask is equipped with mechanical stirring, thermometer, dropping funnel.
The synthetic method of 3 methyl thiophene provided by the invention-2-formaldehyde, its beneficial effect is, because the bromo-reaction selectivity is high, the isomer of final product is effectively controlled, product is purified become easily, yield is high, and bromine ion-containing aqueous solution reusable edible, reduced cost, greatly reduced discharge of wastewater, significant advantage and practical value have been arranged.
Embodiment
Below in conjunction with two embodiment, the synthetic method of 3 methyl thiophene provided by the invention-2-formaldehyde is described in detail.
Embodiment one
The synthetic method of the 3 methyl thiophene of present embodiment-2-formaldehyde in turn includes the following steps:
The first step is synthesized 3-methyl-2-bromothiophene: there-necked flask is equipped with mechanical stirring, thermometer, dropping funnel, in there-necked flask, add 3 methyl thiophene 98.17g(1mole), concentration is 48% Hydrogen bromide 202g(1.2mole), be cooled to 0 ℃, then temperature being controlled at 5～10 ℃, to drip concentration be 30% hydrogen peroxide 113.4g(1mole), dropwise and be warming up to 20 ℃, stir and leave standstill after 2 hours, separatory, organic layer washs with sodium sulfite aqueous solution and aqueous sodium carbonate, rectification under vacuum obtains 3-methyl-2-bromothiophene 165g, purity is 99.3%, and yield is 93.1%;
Second step synthesizes 3 methyl thiophene-2-formaldehyde: add magnesium chips 25.5g(1.05mole in there-necked flask), tetrahydrofuran (THF) 20ml and 3-methyl-2-bromothiophene 5g(0.03mole), add thermal booster reaction, after reaction causes, change cooling into, then at 20～30 ℃ of lower 172g(0.97mole that drip) mixed solution of 3-methyl-2-bromothiophene and 1000ml tetrahydrofuran (THF), dropwise, 30 ℃ of lower insulations 2 hours, be cooled to again 5 ℃, drip DMF 146g(2mole), dropwise, be warming up to 20～30 ℃, be incubated 4 hours, after the hydrolysis, methylbenzene extraction, organic layer washs with sodium bicarbonate aqueous solution, and decompression steams toluene, and high vacuum rectification obtains 3 methyl thiophene-2-formaldehyde 117g, purity is 99.1%, and yield is 92.7%.
Embodiment two
The synthetic method of the 3 methyl thiophene of present embodiment-2-formaldehyde in turn includes the following steps:
The first step is synthesized 3-methyl-2-bromothiophene: there-necked flask is equipped with mechanical stirring, thermometer, dropping funnel, in flask, add 3 methyl thiophene 98.17g(1mole), bromine ion-containing aqueous solution 1.2mole(is in bromide anion), be cooled to 0 ℃, then temperature being controlled at 5～10 ℃, to drip concentration be 30% hydrogen peroxide 113.4g(1mole), dropwise and be warming up to 20 ℃, stir and leave standstill after 2 hours, separatory, organic layer washs with sodium sulfite aqueous solution and aqueous sodium carbonate, rectification under vacuum obtains 3-methyl-2-bromothiophene 162g, purity is 99.2%, and yield is 91.49%;
Second step synthesizes 3 methyl thiophene-2-formaldehyde: add magnesium chips 25.5g(1.05mole in there-necked flask), tetrahydrofuran (THF) 20ml and 3-methyl-2-bromothiophene 5g(0.03mole), add thermal booster reaction, after reaction causes, change cooling into, then at 20～30 ℃ of lower 172g(0.97mole that drip) mixed solution of 3-methyl-2-bromothiophene and 500ml tetrahydrofuran (THF), dropwise, 30 ℃ of lower insulations 2 hours, be cooled to again 5 ℃, drip DMF 80.4g(1.1mole), dropwise, be warming up to 20～30 ℃, be incubated 4 hours, after the hydrolysis, methylbenzene extraction, organic layer washs with sodium bicarbonate aqueous solution, and decompression steams toluene, and high vacuum rectification obtains 3 methyl thiophene-2-formaldehyde 112g, purity is 99.1%, and yield is 88.77%.
Claims (5)
1. the synthetic method of 3 methyl thiophene-2-formaldehyde is characterized in that: in turn include the following steps:
The first step is synthesized 3-methyl-2-bromothiophene: add 3 methyl thiophene, Hydrogen bromide or the bromine ion-containing aqueous solution in there-necked flask, be cooled to 0 ℃, then temperature is controlled at 5～10 ℃ and drips hydrogen peroxide, dropwise and be warming up to 20 ℃, stir and leave standstill after 2 hours, separatory, organic layer washs with sodium sulfite aqueous solution and aqueous sodium carbonate, obtain 3-methyl-2-bromothiophene after the rectification under vacuum, the ratio of the amount of substance of used 3 methyl thiophene, Hydrogen bromide or the bromine ion-containing aqueous solution, hydrogen peroxide is 1: 1～2: 0.7～1.5;
Second step synthesizes 3 methyl thiophene-2-formaldehyde: add magnesium chips in there-necked flask, tetrahydrofuran (THF) and 3-methyl-2-bromothiophene, add thermal booster reaction, after reaction causes, change cooling into, then at 20～30 ℃ of lower mixed solutions that drip 3-methyl-2-bromothiophene and tetrahydrofuran (THF), dropwise, 30 ℃ of lower insulations 2 hours, be cooled to again 5 ℃, drip N, dinethylformamide dropwises, and is warming up to 20～30 ℃, be incubated 4 hours, after the hydrolysis, methylbenzene extraction, organic layer washs with sodium bicarbonate aqueous solution, decompression steams toluene, high vacuum rectification obtains 3 methyl thiophene-2-formaldehyde, used 3-methyl-2-bromothiophene, MAGNESIUM METAL, the ratio of the amount of substance of DMF is that the ratio of 1: 1～1.2: 1～solvent for use volume and 3-methyl-2-bromothiophene quality is 4～10: 1.
2. the synthetic method of 3 methyl thiophene according to claim 1-2-formaldehyde is characterized in that: the described bromine ion-containing aqueous solution is gained behind the methylbenzene extraction in the synthetic 3 methyl thiophene of second step-2-formaldehyde.
3. the synthetic method of 3 methyl thiophene according to claim 1-2-formaldehyde, it is characterized in that: it is tetrahydrofuran (THF) or 2-methyltetrahydrofuran that described second step synthesizes 3 methyl thiophene-2-formaldehyde solvent for use.
4. the synthetic method of 3 methyl thiophene according to claim 1-2-formaldehyde, it is characterized in that: described hydrobromic concentration is 46%～50%, the concentration of described hydrogen peroxide is 10%～40%.
5. the synthetic method of 3 methyl thiophene according to claim 1-2-formaldehyde, it is characterized in that: described there-necked flask is equipped with mechanical stirring, thermometer, dropping funnel.
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| CN2012105205935A CN102993163A (en) | 2012-12-07 | 2012-12-07 | Synthesis method of 3-methylthiophene-2-aldehyde |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103819449A (en) * | 2014-02-20 | 2014-05-28 | 常州市正锋光电新材料有限公司 | Preparation method for 2-bromothiophene |
| CN103896909A (en) * | 2014-04-01 | 2014-07-02 | 安庆丰源化工有限公司 | Synthesis method of 2-thiopheneethanol |
| CN103965160A (en) * | 2014-05-16 | 2014-08-06 | 南通诚信氨基酸有限公司 | Synthesis method of hydrogen sulfate clopidogrel intermediate derivative |
| CN107188898A (en) * | 2012-10-10 | 2017-09-22 | 霍夫曼-拉罗奇有限公司 | Process for preparing thienopyrimidine compounds |
| CN109843862A (en) * | 2016-10-26 | 2019-06-04 | 石原产业株式会社 | 3- methyl -2-Thiophene Carboxylic Acid manufacturing method |
| CN112574169A (en) * | 2020-12-10 | 2021-03-30 | 武汉至精诚医药技术有限公司 | Preparation method of 5-methyl-2-thiophenecarboxaldehyde |
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| CN101045723A (en) * | 2007-04-30 | 2007-10-03 | 浙江大学宁波理工学院 | Synthetic method of 2-bromine-3-methylthiophene |
| US20110284082A1 (en) * | 2010-05-18 | 2011-11-24 | Gwangju Institute Of Science And Technology | Polymer containing thiophene unit and thienylenevinylene unit, and organic field effect transistor and organic solar cell containing the polymer |
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2012
- 2012-12-07 CN CN2012105205935A patent/CN102993163A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101045723A (en) * | 2007-04-30 | 2007-10-03 | 浙江大学宁波理工学院 | Synthetic method of 2-bromine-3-methylthiophene |
| US20110284082A1 (en) * | 2010-05-18 | 2011-11-24 | Gwangju Institute Of Science And Technology | Polymer containing thiophene unit and thienylenevinylene unit, and organic field effect transistor and organic solar cell containing the polymer |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107188898A (en) * | 2012-10-10 | 2017-09-22 | 霍夫曼-拉罗奇有限公司 | Process for preparing thienopyrimidine compounds |
| CN107188898B (en) * | 2012-10-10 | 2019-12-03 | 霍夫曼-拉罗奇有限公司 | Process for preparing thienopyrimidine compounds |
| CN103819449A (en) * | 2014-02-20 | 2014-05-28 | 常州市正锋光电新材料有限公司 | Preparation method for 2-bromothiophene |
| CN103896909A (en) * | 2014-04-01 | 2014-07-02 | 安庆丰源化工有限公司 | Synthesis method of 2-thiopheneethanol |
| CN103965160A (en) * | 2014-05-16 | 2014-08-06 | 南通诚信氨基酸有限公司 | Synthesis method of hydrogen sulfate clopidogrel intermediate derivative |
| CN109843862A (en) * | 2016-10-26 | 2019-06-04 | 石原产业株式会社 | 3- methyl -2-Thiophene Carboxylic Acid manufacturing method |
| CN109843862B (en) * | 2016-10-26 | 2021-10-29 | 石原产业株式会社 | Process for producing 3-methyl-2-thiophenecarboxylic acid |
| CN112574169A (en) * | 2020-12-10 | 2021-03-30 | 武汉至精诚医药技术有限公司 | Preparation method of 5-methyl-2-thiophenecarboxaldehyde |
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