CN102060670A - Preparation method of 2-bromine-6-fluorophenyl methanol - Google Patents
Preparation method of 2-bromine-6-fluorophenyl methanol Download PDFInfo
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- CN102060670A CN102060670A CN2011100005622A CN201110000562A CN102060670A CN 102060670 A CN102060670 A CN 102060670A CN 2011100005622 A CN2011100005622 A CN 2011100005622A CN 201110000562 A CN201110000562 A CN 201110000562A CN 102060670 A CN102060670 A CN 102060670A
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Abstract
The invention relates to the field of organic synthesis, in particular to a preparation method of 2-bromine-6-fluorophenyl methanol. The preparation method comprises the following steps of: (1) adding 2-bromine-6-fluorotoluene in the presence of an organic solvent, slowly dropping bromine under an illumination condition, reacting for 5 to 12 hours, washing the reaction solution by using saturated sodium sulfite, washing the reaction solution by using water, drying with anhydrous sodium sulfate and then depressurizing to evaporate the solvent to obtain 2-bromine-6-fluorine benzyl bromine; and (2) in the presence of the organic solution, adding the 2-bromine-6-fluorine benzyl bromine obtained by the step (1), a certain amount of water and an inorganic compound, controlling the reaction temperature to be 85 DEG, reacting for 3 to 8 hours, then adding a certain amount of inorganic acid into the reaction solution, extracting the mixture by using dichloromethane, washing an organic layer by using water; drying with the anhydrous sodium sulfate, then depressurizing to evaporate the solvent, and performing silica gel column chromatography to obtain the 2-bromine-6-fluorophenyl methanol. The preparation method is simple in operation, is low in cost, and is simple in after-treatment. The product purity is more than or equal to 99.0 percent, and the yield is over 85 percent.
Description
Technical field
The present invention relates to the organic synthesis field, relate to the method that bromo and hydrolysis reaction prepare 2-bromo-6-fluorophenyl methanol particularly.The invention provides a kind of simple to operate, method for preparing 2-bromo-6-fluorophenyl methanol that yield is high.
Background technology
2-bromo-6-fluorophenyl methanol is a kind of important medicine intermediate, is that raw material synthetic carbadipimidine can be used for prevention and diseases such as treatment manic depressive illness, anti-arrhythmia with 2-bromo-6-fluorophenyl methanol among the patent US2009270369A1; Zhi q G etc. are (referring to document: Zhi q G, Dong p W, Yun-F, Bioorg.Med.Chem.Lett.2005,15:3685 – 3690) be raw material synthetic 1,3,5-triazines-2 with 2-bromo-6-fluorophenyl methanol, 4, the 6-3 ketone is the inhibitor of a kind of gonadotropin releasing hormone (GnRH) acceptor; Patent CN101160124A is that raw material synthetic boron-containing small molecules compound can be used for treating diseases such as onychomycosis or dermatophytid infection with 2-bromo-6-fluorophenyl methanol among the CN101420854A; Be raw material synthetic bicyclic amino derivative with 2-bromo-6-fluorophenyl methanol among the patent US2009270369A1, can be used for treating neurodynia, epilepsy, insomnia diseases such as (diseases).
At present the preparation method of the 2-bromo-6-fluorophenyl methanol of report has two kinds, and a kind of method is to be raw material with 2-bromo-6-fluorobenzaldehyde, and methyl alcohol is solvent, makes this compound through sodium borohydride reduction.(referring to document: WO2009144391A, 2009-03-12).Another kind method is to be raw material to contain fluorobenzonitrile and derivative thereof, makes fluorine-containing benzene methanamine through the sodium amide reduction, makes this compound by the diazotization hydrolysis again.(participate in document: US6452056B, 2002-09-17).
There are problems such as the reagent price is more expensive, seriously polluted respectively in above two kinds of methods.
Summary of the invention
The present invention has overcome that reagent costs an arm and a leg in the aforesaid method, with serious pollution problem.A kind of preparation method of simple to operate, 2-bromo-6-fluorophenyl methanol that yield is high is provided.
The liquid bromine is captured methyl hydrogen and is produced benzyl radicals at the light-initiated bromine free radical that produces down, generates bromobenzyl with the bromine reaction again, and the bromine free radical of generation can participate in reaction again.Its reaction mechanism is as follows:
The nucleophilic substitution reaction of 2-bromo-6-fluorine bromobenzyl is undertaken by two kinds of courses.Be bimolecular nucleophilic substitution (S
N2 react) and unimolecular nucleophilic substitution (S
N1 reaction).Reaction mechanism is as follows:
S
NThe first step of 1 reaction is that halohydrocarbon ionization generates the active intermediate carbonium ion, and carbonium ion carries out the reaction of second step with alkali again and generates product.So S
NIn 1 reaction active intermediate being arranged---carbonium ion generates.
The first step: generate carbonium ion
Second step: nucleophilic attack
。
S
N2 reactions are a step to finish (formation of new key and the fracture of old key are carried out synchronously), and no intermediate generates, through one unsettled " transition state ".
。
The preparation method of the 2-bromo-6-fluorophenyl methanol that the present invention relates to is to be raw material with 2-bromo-6-toluene fluoride, makes 2-bromo-6-fluorine bromobenzyl through bromo-reaction, makes 2-bromo-6-fluorophenyl methanol through hydrolysis reaction again.Reaction formula is as follows:
It is characterized in that comprising the steps:
(1) in the presence of organic solvent, add 2-bromo-6-toluene fluoride, slow dropping liquid bromine under the illumination, reaction 2～30h, reaction solution washs through saturated sodium sulfite, washing, pressure reducing and steaming solvent behind the anhydrous sodium sulfate drying gets 2-bromo-6-fluorine bromobenzyl;
(2) in the presence of organic solvent, add gained 2-bromo-6-fluorine bromobenzyl in the step (1), a certain amount of water and mineral compound; Reaction is controlled at 85 ℃, behind reaction 2～15h, adds a certain amount of mineral acid in reaction solution, extracts with methylene dichloride again; Organic layer is through washing, and saturated common salt is washed, and pressure reducing and steaming solvent behind the anhydrous sodium sulfate drying, silica gel column chromatography get 2-bromo-6-fluorophenyl methanol.
Organic solvent described in the above-mentioned steps (1) is meant methylene dichloride, chloroform, tetracol phenixin, hexanaphthene or ethyl acetate; The add-on of wherein said liquid bromine is in 2-bromo-6-toluene fluoride, n (2-bromo-6-toluene fluoride): n (liquid bromine)=1:1～15; The 1000W tungsten-iodine lamp is adopted in wherein said illumination.
Organic solvent described in the above-mentioned steps (2) is meant 1,4-dioxane, dehydrated alcohol, anhydrous methanol or methyl-sulphoxide; Wherein said mineral compound is meant sodium hydroxide, lime carbonate, yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus; The consumption of wherein said mineral compound is in 2-bromo-6-fluorine bromobenzyl, n (2-bromo-6-fluorine bromobenzyl): n (mineral compound)=1:3～30; Wherein said mineral acid is meant that massfraction is that 10% hydrochloric acid or massfraction are 10% sulfuric acid, and its consumption is in mineral compound, n (mineral compound): n (HCl)=1:1～20, n (mineral compound): n (H
2SO
4)=1:0.5～10; Wherein said water, its consumption is in 2-bromo-6-fluorine bromobenzyl, n (2-bromo-6-fluorine bromobenzyl): n (water)=1:100～800; Wherein said silica gel column chromatography, the eluent of employing: V (ethyl acetate): V (sherwood oil)=1:5～30.
Advantage of the present invention: with 2-bromo-6-toluene fluoride is raw material, and the liquid bromine is a bromide reagent, makes 2-bromo-6-fluorine bromobenzyl under the illumination condition, makes 2-bromo-6-fluorophenyl methanol through hydrolysis reaction again.This method is simple to operate, cost is lower, aftertreatment is simple.Product purity 〉=99.0%, yield〉85%.
Embodiment
Embodiment 1
Stirring is housed, temperature is taken into account in the 250ml four-hole boiling flask of reflux condensate device, adds 1.89g (0.01mol) 2-bromo-6-toluene fluoride, the 80ml methylene dichloride is warming up to backflow under the irradiation of 1000W tungsten-iodine lamp, slowly drips 8.0g (0.05mol) liquid bromine.Dropwise and continue reaction 10h, it is complete that gas-chromatography (GC analysis) detects raw material reaction.Reaction solution cooling back is washed with the washing of 50ml saturated sodium bisulfite solution, and the organic layer anhydrous sodium sulfate drying filters, and filtrate decompression boils off solvent.Get 2.51g2-bromo-6-fluorine bromobenzyl, purity 95.4% (GC), yield 89.3%.Be directly used in next step reaction.
Take into account in the 250ml there-necked flask of heating unit in that stirring, prolong, temperature are housed, add 1.41g (0.005mol) the 2-bromo-6-fluorine bromobenzyl of previous step preparation, 80ml dehydrated alcohol, 5.0g (0.05mol) lime carbonate, 9.0g (0.5mol) water.Be warming up to 85 ℃ under stirring, reaction 6h, it is complete that GC detects raw material reaction.After the question response liquid cooling but, to wherein adding 18g(0.05mol) massfraction is 10% hydrochloric acid.Extract (20ml * 3) with methylene dichloride again.Organic layer is through washing, and saturated common salt is washed, evaporated under reduced pressure solvent behind the anhydrous sodium sulfate drying, (eluent: V (ethyl acetate): V (sherwood oil)=1:5) gets 0.95g2-bromo-6-fluorophenyl methanol to silica gel column chromatography, 49 ~ 51 ℃ of fusing points, purity 99.6% (GC), yield 92.5%.IR(KBr)ν(cm
-1)3327，1604，1573，1452，1240，1012，778。
1H?NMR(500MHz，CDCl
3)δ：2.12(s，1H)，δ：4.85(s，2H)，δ：7.03~7.07(t，1H，J=20Hz)，δ：7.14~7.19(q，1H，J=25Hz)，δ：7.37~7.39(d，1H，J=10Hz)。
Embodiment 2
With the technological operation step of embodiment 1, different condition is:
The 80ml tetracol phenixin, 1.60g (0.01mol) liquid bromine, reaction 8h gets 2.71g2-bromo-6-fluorine bromobenzyl, purity 93.8%, yield 94.3%.
The 80ml anhydrous methanol, 1.59g (0.015mol) yellow soda ash, 18.0g (1mol) water, 147g(0.15mol) massfraction is 10% sulfuric acid, reaction 8h, eluent: V (ethyl acetate): V (sherwood oil)=1:10, get 0.93g2-bromo-6-fluorophenyl methanol, purity 99.5%, yield 90.5%.
Embodiment 3
With the technological operation step of embodiment 1, different condition is:
The 80ml tetracol phenixin, 16.0g (0.1mol) liquid bromine, reaction 2h gets 2.7g2-bromo-6-fluorine bromobenzyl, purity 92.5%, yield 93.5%.
The 80ml anhydrous methanol, 18.0g (0.15mol) sodium hydroxide, 54.0g (3mol) water, 73.5g(0.075mol) massfraction is 10% sulfuric acid, eluent: V (ethyl acetate): V (sherwood oil)=1:8,0.91g2-bromo-6-fluorophenyl methanol, purity 99.5%, yield 88.5%.
Embodiment 4
With the technological operation step of embodiment 1, different condition is:
The 80ml chloroform, 19.2g (0.12mol) liquid bromine, reaction 15h gets 2.8g2-bromo-6-fluorine bromobenzyl, purity 93.0%, yield 93.8%.
The 80ml methyl-sulphoxide, 13.8g (0.1mol) salt of wormwood, 72g (4mol) water, reaction 7h, eluent: V (ethyl acetate): V (sherwood oil)=1:15 gets 0.98g2-bromo-6-fluorophenyl methanol, purity 99.5%, yield 95.6%.
Embodiment 5
With the technological operation step of embodiment 1, different condition is:
The 80ml hexanaphthene, reaction 20h, 24.0g (0.15mol) liquid bromine gets 2.65g2-bromo-6-fluorine bromobenzyl, purity 90.5%, yield 89.8%.
12.6g (0.15mol) sodium bicarbonate, 18g (1mol) water, eluent: V (ethyl acetate): V (sherwood oil)=1:15 gets 0.93g2-bromo-6-fluorophenyl methanol, purity 99.6%, yield 90.2%.
Embodiment 6
With the technological operation step of embodiment 1, different condition is:
The 80ml ethyl acetate, reaction 30h gets 2.59g2-bromo-6-fluorine bromobenzyl, purity 91.3%, yield 88.5%.
5g (0.05mol) saleratus, reaction 15h, 36.5g(0.1mol) massfraction is 10% hydrochloric acid, eluent: V (ethyl acetate): V (sherwood oil)=1:20 gets 0.89g2-bromo-6-fluorophenyl methanol, purity 99.4%, yield 86.6%.
Embodiment 7
With the technological operation step of embodiment 1, different condition is:
The 80ml tetracol phenixin, reaction 12h gets 2.59g2-bromo-6-fluorine bromobenzyl, purity 95.5%, yield 94.7%.
80ml1, the 4-dioxane, 12.5g (0.125mol) lime carbonate, reaction 8h, eluent: V (ethyl acetate): V (sherwood oil)=1:30 gets 0.97g2-bromo-6-fluorophenyl methanol, purity 99.6%, yield 94.8%.
Claims (7)
1.2-the preparation method of bromo-6-fluorophenyl methanol, it is characterized in that comprising the steps: that (1) is in the presence of organic solvent, add 2-bromo-6-toluene fluoride, slow dropping liquid bromine under the illumination, reaction 2～30h, reaction solution washs through saturated sodium sulfite, washing, pressure reducing and steaming solvent behind the anhydrous sodium sulfate drying gets 2-bromo-6-fluorine bromobenzyl; (2) in the presence of organic solvent, add gained 2-bromo-6-fluorine bromobenzyl in the step (1), a certain amount of water and mineral compound, reaction is controlled at 85 ℃, reaction 2～15h.
2. add a certain amount of mineral acid in reaction solution, use dichloromethane extraction again, organic layer is through washing, and saturated common salt is washed, and pressure reducing and steaming solvent behind the anhydrous sodium sulfate drying, silica gel column chromatography get 2-bromo-6-fluorophenyl methanol.
3. the preparation method of 2-bromo-6-fluorophenyl methanol according to claim 1 is characterized in that the organic solvent described in the above-mentioned steps (1) is meant methylene dichloride, chloroform, tetracol phenixin, hexanaphthene or ethyl acetate.
4. the preparation method of 2-bromo-6-fluorophenyl methanol according to claim 1, the add-on that it is characterized in that the liquid bromine described in the above-mentioned steps (1) be in 2-bromo-6-toluene fluoride, n (2-bromo-6-toluene fluoride): n (liquid bromine)=1:1～15; The 1000W tungsten-iodine lamp is adopted in wherein said illumination.
5. the preparation method of 2-bromo-6-fluorophenyl methanol according to claim 1 is characterized in that the organic solvent described in the above-mentioned steps (2) is meant 1,4-dioxane, dehydrated alcohol, anhydrous methanol or methyl-sulphoxide.
6. the preparation method of 2-bromo-6-fluorophenyl methanol according to claim 1 is characterized in that the mineral compound described in the above-mentioned steps (2) is meant sodium hydroxide, lime carbonate, yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus; The consumption of wherein said mineral compound is in 2-bromo-6-fluorine bromobenzyl, n (2-bromo-6-fluorine bromobenzyl): n (mineral compound)=1:3～30.
7. the preparation method of 2-bromo-6-fluorophenyl methanol according to claim 1, it is characterized in that the mineral acid described in the above-mentioned steps (2) is meant that massfraction is that 10% hydrochloric acid or massfraction are 10% sulfuric acid, its consumption is in mineral compound, n (mineral compound): n (HCl)=1:1～20, n (mineral compound): n (H
2SO
4)=1:0.5～10; The consumption of wherein said water is in 2-bromo-6-fluorine bromobenzyl, n (2-bromo-6-fluorine bromobenzyl): n (water)=1:100～400; Wherein said silica gel column chromatography, the eluent of employing: V (ethyl acetate): V (sherwood oil)=1:5～15.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187828A (en) * | 2016-07-19 | 2016-12-07 | 南通市晗泰化工有限公司 | Alkylbenzene methanol polyoxyethylene ether disodium succinate salt and preparation method thereof |
| CN107324971A (en) * | 2017-06-30 | 2017-11-07 | 长兴化学工业(中国)有限公司 | The method for preparing cyclohexanedimethanol and its pre-reaction material |
Citations (2)
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| CN1648114A (en) * | 2004-02-16 | 2005-08-03 | 青岛科技大学 | Method for preparing p-bromobenzyl bromine |
| CN101903377A (en) * | 2007-12-19 | 2010-12-01 | 伊莱利利公司 | 6H-dibenz0 [b, e] oxepine derived nonsteroidal mineralocorticoid receptor antagonists |
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2011
- 2011-01-04 CN CN2011100005622A patent/CN102060670A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1648114A (en) * | 2004-02-16 | 2005-08-03 | 青岛科技大学 | Method for preparing p-bromobenzyl bromine |
| CN101903377A (en) * | 2007-12-19 | 2010-12-01 | 伊莱利利公司 | 6H-dibenz0 [b, e] oxepine derived nonsteroidal mineralocorticoid receptor antagonists |
Non-Patent Citations (1)
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|---|
| 彭新华等: "催化溴化邻硝基甲苯合成邻硝基苯甲醇的研究", 《精细化工》, vol. 15, no. 5, 31 December 1998 (1998-12-31), pages 42 - 44 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187828A (en) * | 2016-07-19 | 2016-12-07 | 南通市晗泰化工有限公司 | Alkylbenzene methanol polyoxyethylene ether disodium succinate salt and preparation method thereof |
| CN107324971A (en) * | 2017-06-30 | 2017-11-07 | 长兴化学工业(中国)有限公司 | The method for preparing cyclohexanedimethanol and its pre-reaction material |
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Application publication date: 20110518 |