CN101712603B - Method for preparing halogenated methyl-benzaldehyde by Grignard reaction - Google Patents
Method for preparing halogenated methyl-benzaldehyde by Grignard reaction Download PDFInfo
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Abstract
The invention relates to a method for preparing halogenated methyl-benzaldehyde by Grignard reaction. The reaction is carried out according to the following reaction formula and the following steps: (1) adding magnesium chips, an organic solvent and an initiating agent into a dry reaction flask with nitrogen protection for stirring to obtain a mixed solution A, then dropwise adding 1/10 volume of mixed solution B of halogenated benzene and the organic solvent into the mixed solution A for initiating the reaction, and dropwise adding residual 9/10 volume of the mixed solution B of the halogenated benzene and the organic solvent for reacting for 1h to prepare a Grignard reagent, wherein the reaction temperature is 10-80 DEG C, and iodine particles or 1,2-dibromoethane can be used as the initiating agent; and (2) cooling the Grignard reagent to -40-10 DEG C, dropwise adding a mixed solution of N,N-dimethyl formamide and the organic solvent into the Grignard reagent, then slowly heating the mixed solution to 10-45 DEG C for reacting for 0.5-5h, lowering the temperature below 20 DEG C, regulating the pH value to be less than or equal to 2, extracting with CH2Cl2, washing, removing the solvent, and distilling with water vapor to obtain the product. The invention has the advantages of easy acquisition of raw materials and simple processes, the product purity is greater than or equal to 99%, and the product yield is greater than 50%.
Description
Technical field
The present invention relates to the preparation method of halogenated benzaldehyde, more specifically, relate to halogeno-benzene and the DMF method through the synthetic Chlorobenzaldehyde of Bouveault aldehyde.Method of the present invention provide a kind of raw material be easy to get, simple to operate, be beneficial to the industrialized method for preparing halogenated benzaldehyde.
Background technology
Halogenated benzaldehyde is important organic intermediate, in fields such as medicine, agricultural chemicals and dyestuffs, has purposes widely.5-tolyl aldehyde as chloro-as 3-is synthetic tachykinin antagenists 1,2, and the raw material of 4-tri-substituted piperazine derivatives, be used for the treatment of the disease that tachykinin mediates, and comprises asthma, bronchitis, rhinitis, cough, expectoration etc.; The chloro-4-tolyl aldehyde of 2-is the raw material of the pyrazoline of synthetic important biomolecule war agent different substituents and derivative thereof etc., it can be used as the medicament of antitumor, antiviral medicament, antiparasitic medicament, tuberculosis etc., and some of them are compositions of anti-diabetic, narcotic, anodyne etc.
The preparation method of bibliographical information mainly contains Gattermann Koch reaction, Stephen reduction, oxidation etc.In US6300525 and US6297405, report be take ortho-chlorotolu'ene as raw material; under existing, catalyzer hydrogenchloride-aluminum chloride reacts yield 23% and 77% with the formylation generation chloro-4-tolyl aldehyde of 3-of carbon monoxide and the Gattermann Koch of the chloro-3-tolyl aldehyde of 4-.Yet this reaction only could be carried out during by electron donating group-substituted smoothly at aromatic hydrocarbons, and aromatic hydrocarbons while being replaced by electron-withdrawing group reaction carry out slow, therefore the industrial application difficulty.
In EP1544189, report be take ortho-chlorotolu'ene as raw material, under catalyzer hydrogen fluoride-boron trifluoride exists, with the formylation of carbon monoxide, produces 4-chloro-2-methyl phenyl aldehyde and the chloro-4-tolyl aldehyde of 2-, yield 76% and 23.9%.This reaction need under high pressure be carried out, and uses hydrogen fluoride.
It is raw material that the Stephen reduction reaction of reporting in WO2006004903 be take the chloro-6-methyl benzonitrile of 2-, in the tetrahydrofuran solution of tin protochloride, passes into hydrogen chloride gas to saturated, reaction 13h, and hydrolysis makes the chloro-6-tolyl aldehyde of 2-, yield 23%.
In 293 pages of 1989 " Synthesis " the 4th phases report with 3,4-dimethylated chlorobenzene for raw material, synthetic 5-chloro-2-methyl phenyl aldehyde and 4-chloro-2-methyl phenyl aldehyde under the effect of potassium permanganate-triethylamine.
" Indian Journal of Chemistry in 1989, Section B " 28B volume the 6th interim report is with 2-methyl-2-amylene-4-ketone and N, dinethylformamide is that raw material generates 2-chloro-4-methyl m-terephthal aldehyde and the chloro-4-tolyl aldehyde of 2-, the chloro-4-tolyl aldehyde of 2-yield 11% under the effect of phosphoryl chloride.
In GB2126218, to take the chloro-4-phenylmethylamine of 2-be raw material to report, react the chloro-4-tolyl aldehyde of generation 3-with Sodium Nitrite and formic acid, yield 50%.
Summary of the invention
The object of the invention is to obtain that a kind of reaction yield is high, the preparation method of the simple halogenated benzaldehyde of technique.
The preparation method of halogenated benzaldehyde of the present invention, be that to take halogeno-benzene and DMF be raw material, makes through Bouveault aldehyde is synthetic.Technical scheme of the present invention is as follows:
R wherein
1=CH
3, O CH
3; R
2=Cl, F; X=Cl, Br;
Any phenyl-monohalide can be introduced the present invention; Described halogeno-benzene comprises the bromo-3-toluene(mono)chloride of 2-, the bromo-4-toluene(mono)chloride of 3-, the chloro-4-toluene bromide of 3-, the chloro-4-toluene bromide of 2-, the chloro-5-toluene bromide of 3-, the bromo-4-toluene(mono)chloride of 2-, 2-methoxyl group-4-bromofluorobenzene etc.;
Reaction conditions of the present invention is as follows:
(1) add magnesium chips, organic solvent, initiator in the dry reaction bottle of nitrogen protection, stir to obtain mixed liquor A, drip the halogeno-benzene of 1/10 volume and the mixed liquid B of organic solvent again in mixed liquor A, initiation reaction, 9/10 halogeno-benzene of the remaining volume of rear dropping and the mixed liquid B of organic solvent, reaction 1h makes Grignard reagent, and temperature of reaction is 10～80 ℃, preferably 10～30 ℃; In halogeno-benzene, with the mol ratio of magnesium chips be 1: 1～1: 1.5; With the mass ratio of organic solvent 1: 3～1: 10; With the mass ratio of initiator be 10: 1～51: 1; Wherein said initiator available iodine grain or glycol dibromide;
(2) Grignard reagent is cooled to-40～10 ℃, preferably-5～0 ℃, drips wherein the mixed solution of DMF and organic solvent, it slowly rises to 10～45 ℃ relief, preferably 25～35 ℃, reacts 0.5～5h, temperature is down to below 20 ℃, regulates pH≤2, uses CH
2cl
2extraction, washing, slough solvent, and wet distillation obtains product.In halogeno-benzene, with the molar ratio of material of DMF be 1: 1～1: 1.6; With the mass ratio of organic solvent be 1: 3～1: 10; Wherein said adjusting pH can be with ammonium chloride or hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid is a kind of or the mixing acid of above-mentioned several acid, preferably ammonium chloride or hydrochloric acid.
Wherein the organic solvent in above-mentioned steps (1), (2) can be used tetrahydrofuran (THF), propyl ether, isopropyl ether, methyl-phenoxide, preferably tetrahydrofuran (THF).
Advantage of the present invention: the present invention be take halogeno-benzene as raw material, through Bouveault aldehyde, synthesizes and makes.The method raw material is easy to get, technique is simple, product purity >=99%, yield>50%.
Embodiment
Embodiment 1:
Drop into 6.5g (0.27mol) magnesium silk in the device of 500mL dried and clean band drying tube, the 50mL tetrahydrofuran (THF), 1g iodine grain, stir, the chloro-4-toluene bromide of 51.4g (0.25mol) 3-that drips 1/10 volume is dissolved in the mixing solutions initiation reaction of 178g (200mL) anhydrous tetrahydro furan, be cooled to 25 ℃ of left and right, drip the anhydrous tetrahydrofuran solution of the chloro-4-toluene bromide of 3-of residue 9/10 volume, drip and finish, 20 ℃ of left and right reaction 1h obtain Grignard reagent, be cooled to-5 ℃, drip 50mL tetrahydrofuran (THF) and 20g (0.27mol) N in Grignard reagent, the mixed solution of dinethylformamide, drip and finish, allow it slowly rise to 20 ℃ of left and right, reaction 1h, below 20 ℃, regulate pH≤2, standing, separate organic phase, water C
2h
4cl
2extraction, merge organic phase, precipitation, and wet distillation obtains the chloro-4-tolyl aldehyde of 35.62g 2-, yield 69.3%.
Embodiment 2:
With the technological operation step of embodiment 1, different condition is:
Temperature of reaction after 154.2g (173mL) anhydrous tetrahydrofuran solution of magnesium silk 6.0g (0.25mol), 3g iodine grain, the chloro-4-toluene bromide of 51.4g (0.25mol) 3-, initiation is 10 ℃ ,-10 ℃ and drips N, dinethylformamide, yield 55.2%.
Embodiment 3:
With the technological operation step of embodiment 1, different condition is:
Temperature of reaction after 514g (578mL) anhydrous tetrahydrofuran solution of 5g iodine grain, the chloro-4-toluene bromide of 51.4g (0.25mol) 3-, initiation is 30 ℃, 18g (0.25mol) DMF, yield 64.1%.
Embodiment 4:
With the technological operation step of embodiment 1, different condition is:
9.0g (0.375mo) magnesium silk, 1g1,148g (200mL) the propyl ether solution of 2-ethylene dibromide, the bromo-3-toluene(mono)chloride of 51.4g (0.25mol) 2-, 35 ℃ of reaction 0.5h, yield 51.2%.
Embodiment 5:
With the technological operation step of embodiment 1, different condition is:
51.4g (0.25mol) 514g (578mL) anhydrous tetrahydrofuran solution of the bromo-4-toluene(mono)chloride of 3-, 27.6g (0.38mol) N, dinethylformamide, 25 ℃ of 36% hydrochloric acid and adjustings of acetic acid mixed solution that reaction 3h, pH value are 2: 1 by volume ratio, yield is 64.9%.
Embodiment 6:
With the technological operation step of embodiment 1, different condition is:
9.0g (0.375mol) magnesium silk, 3g1,199g (200mL) the methyl-phenoxide solution of 2-ethylene dibromide, the chloro-4-toluene bromide of 51.4g (0.25mol) 2-, reaction 5h, 10 ℃ of dropping DMFs, yield 50.7%.
Embodiment 7:
With the technological operation step of embodiment 1, different condition is:
Temperature of reaction after 154.2g (173mL) anhydrous tetrahydrofuran solution of magnesium silk 6.5g (0.27mol), 3g iodine grain, the chloro-5-toluene bromide of 51.4g (0.25mol) 3-, initiation is 10 ℃ ,-10 ℃ and drips N, dinethylformamide, yield 65.2%.
Embodiment 8:
With the technological operation step of embodiment 1, different condition is:
9.0g (0.375mo) magnesium silk, 1g1,148g (200mL) the propyl ether solution of 2-ethylene dibromide, the bromo-4-toluene(mono)chloride of 51.4g (0.25mol) 2-, 35 ℃ of reaction 0.5h, yield 59.2%.
Embodiment 9:
With the technological operation step of embodiment 1, different condition is:
51.3g (0.25mol) 514g (578mL) anhydrous tetrahydrofuran solution of 2-methoxyl group-4-bromofluorobenzene, 27.6g (0.38mol) N, dinethylformamide, 25 ℃ of 36% hydrochloric acid and adjustings of acetic acid mixed solution that reaction 3h, pH value are 2: 1 by volume ratio, yield is 56%.
Claims (5)
1. preparing the method for halogenated methyl-benzaldehyde with grignard reaction, is that to take halogeno-benzene and DMF be raw material, it is characterized in that being reacted according to following reaction formula:
R wherein
1=CH
3or O CH
3; R
2=Cl or F; X=Cl or Br;
Reaction is carried out according to following step: (1) adds magnesium chips, organic solvent, initiator in the dry reaction bottle of nitrogen protection, stir to obtain mixed liquor A, drip the halogeno-benzene of 1/10 volume and the mixed liquid B of organic solvent again in mixed liquor A, initiation reaction, 9/10 halogeno-benzene of the remaining volume of rear dropping and the mixed liquid B of organic solvent, reaction 1h makes Grignard reagent, and temperature of reaction is 10～80 ℃; In halogeno-benzene, with the mol ratio of magnesium chips be 1: 1～1: 1.5; With the mass ratio of organic solvent 1: 3～1: 10; With the mass ratio of initiator be 10: 1～51: 1; Wherein said initiator available iodine grain or glycol dibromide;
(2) Grignard reagent is cooled to-40～10 ℃, drips wherein the mixed solution of DMF and organic solvent, and it slowly rises to 10～45 ℃ relief, reacts 0.5～5h, and temperature is down to below 20 ℃, regulates pH≤2, uses CH
2cl
2extraction, washing, slough solvent, and wet distillation obtains product; In halogeno-benzene, with the molar ratio of material of DMF be 1: 1～1: 1.6; With the mass ratio of organic solvent be 1: 3～1: 10;
Wherein the organic solvent in step (1), (2) is tetrahydrofuran (THF).
2. the method for preparing halogenated methyl-benzaldehyde with grignard reaction according to claim 1, is characterized in that wherein said halogeno-benzene is the bromo-3-toluene(mono)chloride of 2-, the bromo-4-toluene(mono)chloride of 3-, the chloro-4-toluene bromide of 3-, the chloro-4-toluene bromide of 2-, the chloro-5-toluene bromide of 3-, the bromo-4-toluene(mono)chloride of 2-or 2-methoxyl group-4-bromofluorobenzene.
3. the method for preparing halogenated methyl-benzaldehyde with grignard reaction according to claim 1, is characterized in that in above-mentioned steps (2) regulating ammonium chloride or hydrochloric acid, sulfuric acid, phosphoric acid for pH, acetic acid is a kind of or the mixing acid of above-mentioned several acid.
4. the method for preparing halogenated methyl-benzaldehyde with grignard reaction according to claim 3, is characterized in that in above-mentioned steps (2) regulating ammonium chloride or hydrochloric acid for pH.
5. the method for preparing halogenated methyl-benzaldehyde with grignard reaction according to claim 1, is characterized in that above-mentioned steps (1) temperature of reaction is 10～30 ℃; Step (2) Grignard reagent is cooled to-5～0 ℃, drips wherein the mixed solution of DMF and organic solvent, and it slowly rises to 25～35 ℃ relief, reacts 0.5～5h.
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| CN103172503B (en) * | 2011-12-26 | 2015-03-11 | 南京工业大学 | Preparation method of lycopene intermediate 3-methyl-4,4-dialkoxy-1-butyraldehyde |
| KR102085535B1 (en) * | 2012-04-26 | 2020-03-06 | 바이엘 크롭사이언스 악티엔게젤샤프트 | Process for preparing n-(5-chloro-2-isopropylbenzyl)cyclopropanamine |
| CN102964233A (en) * | 2012-11-18 | 2013-03-13 | 大连九信生物化工科技有限公司 | Synthetic method of 3,5-2-fluoro-(trifluoromethyl)benzophenone |
| CN105418436B (en) * | 2015-11-16 | 2017-08-25 | 成都倍特药业有限公司 | A kind of preparation method of melitracen hydrochloride |
| CN108358766A (en) * | 2018-03-08 | 2018-08-03 | 珠海奥博凯生物医药技术有限公司 | A kind of preparation method of bis- chloro- 4- fluorobenzaldehydes of 2,6- |
| CN108530293B (en) * | 2018-05-23 | 2021-02-19 | 王华平 | Preparation method of high-purity chloro 2-carboxyl benzophenone |
| CN111253223A (en) * | 2020-03-20 | 2020-06-09 | 重庆医科大学 | Triarylmethane derivatives with large steric hindrance and synthesis method thereof |
| CN115677464B (en) * | 2021-07-23 | 2024-04-16 | 新发药业有限公司 | Preparation method of high-yield beta-cyclic citral |
| CN114105743A (en) * | 2021-11-02 | 2022-03-01 | 阜阳欣奕华材料科技有限公司 | Method for synthesizing 3-bromo-5-chlorobenzaldehyde |
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| CN1616384A (en) * | 2003-09-09 | 2005-05-18 | 拜尔化学品股份公司 | Difluoroalkylaromatics |
| WO2009089310A1 (en) * | 2008-01-11 | 2009-07-16 | Dow Agrosciences Llc | Process for the selective deprotonation and functionalization of 1-fluoro-2-substituted-3-chlorobenzenes |
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| CN1616384A (en) * | 2003-09-09 | 2005-05-18 | 拜尔化学品股份公司 | Difluoroalkylaromatics |
| WO2009089310A1 (en) * | 2008-01-11 | 2009-07-16 | Dow Agrosciences Llc | Process for the selective deprotonation and functionalization of 1-fluoro-2-substituted-3-chlorobenzenes |
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Address after: Gehu Lake Road Wujin District 213164 Jiangsu city of Changzhou province No. 1 Patentee after: Jiangsu Polytechnic University Address before: 213016 Baiyun District, Changzhou, Jiangsu Patentee before: Jiangsu Polytechnic University |
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Effective date of registration: 20151026 Address after: Daitou town of Liyang City Ferry Street 213311 Jiangsu city of Changzhou province 8-2 No. 7 Patentee after: Liyang Chang Technology Transfer Center Co., Ltd. Address before: Gehu Lake Road Wujin District 213164 Jiangsu city of Changzhou province No. 1 Patentee before: Jiangsu Polytechnic University |