CN103772080B - The benzoic synthetic method of polyhalo - Google Patents
The benzoic synthetic method of polyhalo Download PDFInfo
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- CN103772080B CN103772080B CN201210424664.1A CN201210424664A CN103772080B CN 103772080 B CN103772080 B CN 103772080B CN 201210424664 A CN201210424664 A CN 201210424664A CN 103772080 B CN103772080 B CN 103772080B
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Abstract
A kind of benzoic synthetic method of synthetic method polyhalo, is dissolved in polar solvent intensification by substituted benzoic acid, halogen, organic acid, after then aoxidizing in 50 70 DEG C, is incubated 26 hours at 60 80 DEG C, adds suitable quantity of water, be cooled to room temperature and get final product.Synthetic reaction of the present invention is carried out in alcohols solvent, with halogen simple substance as halide reagent, and add a small amount of organic acid and make catalyst, its effect is the catalysis halide ion electrophilic substitution reaction to phenyl ring, the effect instilling hydrogen peroxide in reaction is to make the halogen simple substance in reaction system be oxidized to halide ion, to improve the utilization rate of halogen, reach the effect of atom economy.
Description
Technical field
The present invention relates to chemical field, particularly relate to a kind of benzoic synthetic method of polyhalo, with neighbour cheap and easy to get
The substituted benzoic acid of bit strip electron-donating group is waste.
Background technology
Phenyl polyhalide formic acid compound is the important intermediate in pharmaceutical chemistry.With therein 3,5-diiodosalicylic acid is
Example, its global demand amount, can be directly as the propiodal in animal food more than 20,000 tons；Or synthetic pesticide, medicine, veterinary drug,
The important intermediate of the chemical industry fine product such as essence, spice, is especially applicable to veterinary drug iodine ether thiamine and the weight of closantel
Want raw material.It is applied to field, such as: 1) iodine ether thiamine, its structure is as follows:
Structural formula 1
Iodo-ether salicylamine is that halogenation Salicylanilide kills trematodiasis medicine, is a kind of strong oxidative phosphorylation uncoupler, permissible
The suppression mitochondrial Phosphorylation events of polypide, thus the synthesis of adenosine triphosphate (ATP) in stoping polypide, cause polypide energy generation
The vigor thanked weakens rapidly and death finally.It has the strongest affinity, so drug effect has longer in blood with blood protein
Persistent period.Iodo-ether salicylamine is mainly used in the treatment adult to horse cattle and sheep Fasciola hepatica；Additionally, it is to gastrointestinal nematode parasites bag
Include haemonchus (Haemonchus), Oesophagostomum dentatum (Oesophagostomum), Geiger nematicide (Gaigeria) etc. with
And sheep nose fly such as Oestrus ovis (Oestrus ovis) all has preferable curative effect.
CLOSANTEL BASE Tech .98min, its structure is as follows, is a kind of broad-spectrum de-worming medicine, dynamic to multiple trematode, nematode and segmental appendage
The larva class polypide of thing all has good efficacy；It is dynamic mainly for distoma hepaticum, nematicide and anti-segmental appendage that its anti-trematodiasis kills activity
Killing of thing larva is active then mainly for the various polypides sucking blood or blood plasma.This product is widely used in the above-mentioned parasitism of cattle and sheep
All kinds of infection of parasitosis, oral or parenteral (subcutaneous and intramuscular injection) is administered, has treatment and prevention effect simultaneously.City
Injection, pill and soaking agent etc. are had on Chang.General make to be combined with mebendazole and other benzimidazole series products compatibilities soak
Infusion, for sheep body；Compound pill is made, for cattle body with levamisole compatibility.
Structural formula 2
As the intermediate of other pesticide veterinary drug, such as:
Structural formula 3 structural formula 4
Wherein, pesticide shown in structural formula 3 can cure the insect pest of Anemone hepatica platymiscium, veterinary drug medicine pair shown in structural formula 4
Anti-liver anomalies has good curative effect.
Phenyl polyhalide formic acid compound is to prepare the intermediate of above-mentioned pesticide or veterinary drug, and its chemical structural formula is illustrated such as
Under:
The formula of above-mentioned phenyl polyhalide formic acid compound is:
Wherein R1For H, or hydroxyl, amino, sulfydryl, C1-C6Alkyl, C1-C6One in the electron-donating groups such as alkoxyl；R2For
H or and R3Identical halogen radical；R3Or halogen radical, especially bromine or iodine.
The synthetic method of this compounds is it has been reported that US5013866 uses bromine and salicylic acid to react raw in methanol
One-tenth 3,5-dibromosalicylic acid, course of reaction has been used the bromine of 2 times of moles, relatively costly, and course of reaction has bromination
Hydrogen is released, and environment is had pollution；Li Hui in 2002 etc. use salicylic acid in " 3,5-diiodosalicylic acid new technique for synthesizing "
Being raw material with lodine chloride, hydrochloric acid is solvent synthesis 3, and 5-diiodosalicylic acid also has hydrogen chloride gas to produce, to environment also in reaction
There is pollution, separately owing to using more expensive lodine chloride, relatively costly；Guo in 2005 change precious its Master's thesis " medicine intermediate 3,
5-diiodosalicylic acid and the green syt of acyl chlorides " in use hydrogen peroxide and iodine to react generation 3 in ethanol, 5-diiodosalicylic acid,
Course of reaction have employed chlorobenzene or ethanol as solvent, and large usage quantity, amplify cost when producing the highest.
In the synthetic method reported, excess halogen is used to do halide reagent or the method using mineral acid to make solvent, all
There is the drawback discharging the toxic gas such as hydrogen bromide or hydrogen chloride in course of reaction, environment is caused bigger pollution；And use chlorine
Change iodine and do iodination reagent, or use the method that a large amount of organic solvent does reaction medium, there is also environmental pollution, relatively costly
Shortcoming；All it is unfavorable for industrialized production.
Summary of the invention
It is an object of the invention to provide a kind of benzoic synthetic method of polyhalo, with ortho position band supplied for electronic cheap and easy to get
The substituted benzoic acid of group is waste.
The phenyl polyhalide formic acid of present invention synthesis, its structure is as follows:
Formulas I
Wherein R1For H, hydroxyl, amino, sulfydryl, C1-C6Alkyl and C1-C6One in the electron-donating groups such as alkoxyl；R2For H
Or halogen；R3For halogen.R2With R3For identical halogen.The preferred bromine or iodine of halogen.
The present invention provides the synthetic method of a kind of phenyl polyhalide formic acid compound, and its operating procedure is as follows:
Substituted benzoic acid, halogen, organic acid are dissolved in polar solvent, are warming up to 40-60 DEG C, then control reaction
In system, temperature is when 50-70 DEG C, drips hydrogen peroxide, after dripping, is incubated 2-6 hour at 60-80 DEG C, adds suitable quantity of water, cooling
To room temperature, filter to obtain solid.
Reaction equation is as follows:
Substituted benzoic acid is the substituted benzoic acid in 2-ortho position (as above shown in reaction equation), and substituent group is H, hydroxyl, amino, mercapto
Base, C1-C6Alkyl and C1-C6One in the electron-donating groups such as alkoxyl.
In above-mentioned preparation method, described halogen (i.e. X in reaction equation2) preferably bromine or iodine, its consumption is for replacing
1.0-1.05 times of benzoic acid mole, preferably 1.03 times.
Described organic acid (i.e. H in reaction equation+) it is trichloroacetic acid, trifluoroacetic acid and tribromoacetic acid etc., preferably trichlorine
Acetic acid, its consumption is the 3.0-5.0wt% of substituted benzoic acid, preferably 4.0wt%.
Described polar solvent (i.e. ROH in reaction equation) is C1-C6Alkylol, preferably methanol.
Described add material after be warming up to 40-60 DEG C, be preferably warming up to 45-50 DEG C.
During described dropping hydrogen peroxide (such as: concentration 30wt%), control temperature is at 50-70 DEG C, and preferably temperature control is at 60-65 DEG C.
Described insulation 2-6 hour at 60-80 DEG C, preferably holding temperature is 65-70 DEG C, and preferably temperature retention time is that 3-5 is little
Time.
The synthetic method that the present invention provides, reaction is carried out in alcohols solvent, with halogen simple substance as halide reagent, and adds
A small amount of organic acid makees catalyst, and its effect is the catalysis halide ion electrophilic substitution reaction to phenyl ring, instills dioxygen in reaction
The effect of water is to make the halogen simple substance in reaction system be oxidized to halide ion, to improve the utilization rate of halogen, reaches atom warp
The effect of Ji.
The invention have the advantage that halogen or the lodine chloride that instead of 2 times with the halogen of 1 times, saved cost of material, subtracted
Lack environmental pollution；Select cheap methanol as reaction dissolvent, add a small amount of organic acid as catalyst, reduce reaction
Temperature, shortens the response time, decreases the consumption of solvent, reduces production cost, is suitable for industrialized production.
It is a further advantage of the invention that employing the method, by controlling the consumption of halogen, monohaloalkyl can be synthesized and produce
Thing, as with salicylic acid as raw material, uses the mole iodine less than 0.6 times, can prepare 5-iodo-salicylic acid.
Detailed description of the invention
Further illustrate the present invention below by embodiment, but embodiment is not intended to protection scope of the present invention.
Embodiment 1: toward a 2L equipped with in four mouthfuls of round-bottomed flasks of mechanical agitation, thermometer and condensing tube, add bigcatkin willow
Acid 138.1g (1.00mol), bromine 163.9g (1.03mol), trichloroacetic acid 7g (0.04mol) are dissolved in methanol (500ml),
Stirring is warming up to 45 DEG C, drips 30% hydrogen peroxide 175g (1.5mol), and when controlling to drip, temperature is at 55-60 DEG C, and time for adding is 1
Hour.It is incubated 4 hours at 65 DEG C after dripping.Being subsequently adding water 500g, room temperature is down in water-bath, filters, is drying to obtain product 3,
5-dibromosalicylic acid 277.6g, yield 93.8%.Fusing point 224-226 DEG C；1H NMR(DMSO-d6, 400MHz): δ 7.79 (d, J=
2.4Hz, 1H, ArH), 7.94 (d, J=2.4Hz, 1H, ArH), 10.36 (s, 1H, OH).
2: one 2L of embodiment, equipped with in four mouthfuls of round-bottomed flasks of mechanical agitation, thermometer and condensing tube, add salicylic acid
138.1g (1.00mol), iodine 261.4g (1.03mol), trichloroacetic acid 7g (0.04mol) are dissolved in methanol (500ml), stirring
It is warming up to 45 DEG C, dropping 30wt% hydrogen peroxide 175g (1.5mol), control during dropping that temperature is at 60-65 DEG C, time for adding is 1 little
Time.It is incubated 5 hours at 66 DEG C after dripping.Adding water 500g, water-bath is down to room temperature, is filtered, is drying to obtain product 3,5-diiodo-
Salicylic acid 374.1g, yield 95.9%.Fusing point 233-235 DEG C；1H NMR(DMSO-d6, 400MHz): δ 8.024 (d, J=
2.4Hz, 1H, ArH), 8.238 (d, J=2.4Hz, 1H, ArH).
3: one 2L of embodiment, equipped with in four mouthfuls of round-bottomed flasks of mechanical agitation, thermometer and condensing tube, add 2-amino
Benzoic acid 137.1g (1.00mol), iodine 261.4g (1.03mol), trichloroacetic acid 7g (0.04mol) are dissolved in methanol (500ml)
In, stirring is warming up to 45 DEG C, dropping 30wt% hydrogen peroxide 175g (1.5mol), and when controlling to drip, temperature is at 60-65 DEG C, during dropping
Between be 1 hour.It is incubated 5 hours at 68 DEG C after dripping.Adding water 500g, water-bath is down to room temperature, is filtered, is drying to obtain product 2-
Amino-3,5-diiodo acid 350.7g, yield 90.2%.Fusing point 232-234 DEG C；1H NMR(DMSO-d6, 400MHz): δ
6.31 (s, 2H, NH2), 7.87 (d, J=2.4Hz, 1H, ArM), 8.06 (d, J=2.4Hz, 1H, ArH).
4: one 2L of embodiment, equipped with in four mouthfuls of round-bottomed flasks of mechanical agitation, thermometer and condensing tube, add 2-sulfydryl
Benzoic acid 154.2g (1.00mol), bromine 163.9g (1.03mol), trichloroacetic acid 7g (0.04mol) are dissolved in methanol
(500ml) in, stirring is warming up to 45 DEG C, dropping 30wt% hydrogen peroxide 175g (1.5mol), and when controlling to drip, temperature is at 55-60
DEG C, time for adding is 1 hour.It is incubated 4 hours at 65 DEG C after dripping.Adding water 500g, room temperature is down in water-bath, filters, and is dried
Obtain product 2-sulfydryl-3,5-dibromobenzoic acid 269.2g, yield 86.3%.Fusing point 220-222 DEG C；1H NMR(DMSO-d6,
400MHz): δ 6.18 (s, 1H, SH), 7.60 (d, J=2.5Hz, 1H, ArH), 7.96 (d, J=2.5Hz, 1H, ArH).
5: one 2L of embodiment, equipped with in four mouthfuls of round-bottomed flasks of mechanical agitation, thermometer and condensing tube, add salicylic acid
138.1g (1.00mol), iodine 129.4g (0.51mol), trichloroacetic acid 7g (0.04mol) are dissolved in methanol (500ml), stirring
Being warming up to 45 DEG C, dropping 30wt% hydrogen peroxide 116.7g (1.0mol), when controlling to drip, temperature is at 60-65 DEG C, and time for adding is 1
Hour.It is incubated 5 hours at 65 DEG C after dripping.Adding water 500g, water-bath is down to room temperature, is filtered to obtain crude product.Gained crude product second
Alcohol recrystallization i.e. obtains product 5-iodo-salicylic acid 202.8g, yield 76.8%.Fusing point 197-198 DEG C；1H NMR(DMSO-d6,
400MHz): δ 6.83 (dd, J1=8.4Hz, J2=2.5Hz, 1H, ArH), 7.79 (d, J=8.4Hz, 1H, ArH), 8.04 (d,
1H, J=8.4Hz, ArH).
Embodiment 6-11:
With identical method, available compound as shown in the table.
Claims (4)
1. the benzoic synthetic method of polyhalo, its operating procedure is as follows:
Substituted benzoic acid, halogen, organic acid are dissolved in methanol, are warming up to 45-50 DEG C, then control temperature in reaction system
When 60-65 DEG C, drip hydrogen peroxide, after dripping, be incubated 2-6 hour at 65-70 DEG C, add water, be cooled to room temperature, filter i.e.
Must as shown in following formula I phenyl polyhalide formic acid；
Wherein R1For hydroxyl, amino, sulfydryl, C1-C6Alkyl and C1-C6One in alkoxyl electron-donating group；R3For halogen, R2For H
Or and R3Identical halogen；
Described substituted benzoic acid is the substituted benzoic acid in 2-ortho position, and substituent group is hydroxyl, amino, sulfydryl, C1-C6Alkyl and C1-
C6One in alkoxyl；
Described organic acid is one or more in trichloroacetic acid, trifluoroacetic acid and tribromoacetic acid, and consumption is described replacement
Benzoic 3.0-5.0wt%；
Described 1.0-1.05 times that halogen consumption is substituted benzoic acid mole.
The benzoic synthetic method of polyhalo the most according to claim 1, is characterized in that described organic acid consumption is
The 4.0wt% of described substituted benzoic acid.
The benzoic synthetic method of polyhalo the most according to claim 1, is characterized in that described temperature retention time is that 3-5 is little
Time.
The benzoic synthetic method of polyhalo the most according to claim 1, is characterized in that described halogen is bromine or iodine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1812954A (en) * | 2003-07-03 | 2006-08-02 | 三菱瓦斯化学株式会社 | Process for producing 5-iodo-2-methylbenzoic acid |
| CN101001830A (en) * | 2004-08-10 | 2007-07-18 | 三菱瓦斯化学株式会社 | Method for producing 2-amino-5-iodobenzoic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1812954A (en) * | 2003-07-03 | 2006-08-02 | 三菱瓦斯化学株式会社 | Process for producing 5-iodo-2-methylbenzoic acid |
| CN101001830A (en) * | 2004-08-10 | 2007-07-18 | 三菱瓦斯化学株式会社 | Method for producing 2-amino-5-iodobenzoic acid |
Non-Patent Citations (1)
| Title |
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| 医药中间体3,5-二碘水杨酸及酰氯的绿色合成;郭改珍;《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》;20051115;第B016-22页 * |
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Address after: 314006 west side of bujiao Road, Daqiao Town, Nanhu District, Jiaxing City, Zhejiang Province Patentee after: Zhejiang Luoxing Chemical Co.,Ltd. Address before: 314006 west side of bujiao Road, Daqiao Town, Nanhu District, Jiaxing City, Zhejiang Province Patentee before: ZHEJIANG LUOXING INDUSTRIAL Co.,Ltd. |