CN107805204A - A kind of method for synthesizing 2,4,5 trimethoxy-anilines - Google Patents
A kind of method for synthesizing 2,4,5 trimethoxy-anilines Download PDFInfo
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- CN107805204A CN107805204A CN201610808898.4A CN201610808898A CN107805204A CN 107805204 A CN107805204 A CN 107805204A CN 201610808898 A CN201610808898 A CN 201610808898A CN 107805204 A CN107805204 A CN 107805204A
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- trimethoxy
- anilines
- nitrobenzene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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Abstract
The invention discloses a kind of method of 2,4,5 trimethoxy-anilines of synthesis, and 2,4,5 trimethoxy-anilines are synthesized especially with palladium-carbon catalyst.It includes contacting reactant mixture with hydrogen, to form 2,4,5 trimethoxy-anilines；Wherein, the reactant mixture includes solvent, the nitrobenzene of 1,2,4 trimethoxy 5 and catalyst, or after 2,4,5 trimethoxy-anilines are formed, in addition to 2,4,5 trimethoxy-anilines.The method of the present invention not only substantially increases reaction yield compared to prior art, it is often more important that the potential safety hazard in course of reaction is reduced, and the palladium-carbon catalyst that the present invention uses can recycle, and avoid the generation of inorganic salts, thus it is environmentally friendly.
Description
Technical field
The present invention relates to the method for 2,4,5- trimethoxy-anilines of synthesis, especially with palladium-carbon catalyst synthesis 2,4,5-
Trimethoxy-aniline.
Background technology
According to the literature, the hydrogenation of reduction reaction raney ni catalysis or tin grain add hydrochloric acid, and yield is no more than 63%, and (whole nation is former
Expect medicine technique compilation [M] .1980.1050-1054；Chapter thinks rule, the 1st edition of Fine Organic Chemical product technical manual (first volume) [M]
Beijing Science Press, 1991.427~429).Add hydrochloric acid, yield 92% according to another document report reduction reaction stannous chloride
(Hebei the 1st phases of chemical industry .2000. .32~34).Stannous chloride adds the hydrogenation of hydrochloric acid to produce substantial amounts of inorganic salts.
In addition, existing plant production processes are largely for raw material with 1,2,4- trimethoxy -5- nitrobenzene, active nickel is
Hydrogenation catalyst, reduce 2,4,5- trimethoxy-anilines are made under an atmosphere of hydrogen.Catalyst activity nickel in the reaction from
It can be burnt in the case of boiling water, it is very big to carry out hydrogenation hidden danger with it.And this catalyst inactivation recycles relatively tired
Difficulty, inorganic salts can be produced in course of reaction, environmental pollution is larger.
The content of the invention
According to problems of the prior art, the invention provides a kind of new work of 2,4,5- trimethoxy-anilines of synthesis
Skill.The new technology of the present invention, such as can be using palladium carbon as hydrogenation catalyst, compared to prior art, new technology of the invention
Not only substantially increase reaction yield, it is often more important that reduce the middle potential safety hazard of course of reaction, can large-scale production, peace
Full property is good.And the palladium-carbon catalyst that the present invention uses can be recycled, while avoid the generation of inorganic salts, therefore
It is environmentally friendly.
Specifically, the method for the trimethoxy-aniline of synthesis 2,4,5- of the invention is to connect reactant mixture and hydrogen
Touch, to form 2,4,5- trimethoxy-anilines；Wherein, the reactant mixture includes solvent, 1,2,4- trimethoxy -5- nitros
Benzene and catalyst, or after 2,4,5- trimethoxy-anilines are formed, the reactant mixture also includes 2,4,5- trimethoxies
Aniline.The present invention is not required particularly the charging sequence of each material, as long as by each material in reactant mixture anti-
Answer in kettle and mix.
Due to that can greatly improve yield using palladium carbon as hydrogenation catalyst, the middle safety that can reduce course of reaction is hidden
Suffer from, and the palladium-carbon catalyst used can recycle, and avoid the generation of inorganic salts, therefore it is environmentally friendly, so, this
The catalyst of invention is palladium carbon.It is preferred that the content of the butt palladium in the palladium carbon is 5% to 10%.
The palladium carbon wherein used in the present invention can be prepared by any method of the prior art, and typically be come
Say, the commercially available acquisition of palladium carbon.
In research process, inventor has found that solvent has an impact to whole reaction system, is obtained using different solvents
The yield of 2,4,5- trimethoxy-anilines is significantly different.Reaction is had a great influence in view of it, therefore, in the present invention molten
Agent preferably is selected from least one of benzene, toluene and Isosorbide-5-Nitrae-dioxane, particularly preferred Isosorbide-5-Nitrae-dioxane.
In addition, inventor is also found surprisingly that, during the course of the reaction, the speed of stirring reaction mixture is influence 2,4,5-
One factor of the yield of trimethoxy-aniline.Specifically, stirring the speed of the reactant mixture typically can be
1200r/min to 2800r/min, preferably described speed be 1400r/min to 2000r/min, or preferably the speed be
2200r/min to 2800r/min.In addition, the speed can be 1600r/min to 1900r/min, or 2000r/
Min to 2500r/min, can also be 2400r/min to 2800r/min.
During the course of the reaction, reaction temperature is also a factor.According to the result of study of inventor, reaction temperature is 60 DEG C
During to 101 DEG C (such as 60 DEG C to 100 DEG C), preferable effect can be obtained, preferably described reaction temperature is 75 DEG C to 95 DEG C.
In an embodiment of the invention, the reaction time is 0.5h to 2.5h, and the preferably described reaction time is 0.5h
To 1h.
In yet another embodiment of the present invention, hydrogenation pressure therein is 1.0MPa to 4.0MPa, preferably described to add
Hydrogen pressure is 2.0MPa to 3.0MPa.
In the preferred embodiment of the present invention, 2,4- trimethoxy -5- nitrobenzene rub with the catalyst
You are than being 1:0.001 to 1:The mol ratio of 0.01, preferably 2,4- trimethoxy -5- nitrobenzene and the catalyst is 1:0.002
To 1:0.004, or the mol ratio of preferably 2,4- trimethoxy -5- nitrobenzene and the catalyst is 1:0.005 to 1:0.01.
In the preferred embodiment of the present invention, 1,2,4- trimethoxy -5- nitrobenzene rubs with the solvent
You are than being 1:15 to 1:The mol ratio of 22, preferably 1,2,4- trimethoxy -5- nitrobenzene and the solvent is 1:18 to 1:20.
Because product 2,4,5- trimethoxy-anilines are more stable in alkaline environment, and this just needs to provide a conjunction for it
Suitable alkaline environment.Therefore, in an embodiment of the invention, the pH of the reactant mixture is 7.5 to 14, preferably
7.5 to 9.5；It is preferred that adjusting the pH by adding alkalescent material into the reactant mixture, the alkalescent is more selected
Material is selected from least one of potassium carbonate, saleratus, sodium carbonate and sodium acid carbonate.Added into the reactant mixture
After alkalescent material, the alkalescent material also becomes a part for above-mentioned reactant mixture.1,2,4- trimethoxy -5- nitre
The mol ratio of base benzene and alkalescent material (such as potassium carbonate) is 1:0.01 to 1:0.02.
Embodiment
The application is described in detail with reference to embodiment, but the invention is not limited in these embodiments.
Unless otherwise instructed, the raw material in embodiments of the invention and catalyst are bought by commercial sources.Wherein 1,
2,4- trimethoxy -5- nitrobenzene is made by oneself by routine techniques；Palladium carbon is purchased from Xi'an Kai Li new materials limited company, palladium carbon
In butt palladium content be 5% to 10%；Solvent 1,4- dioxane, toluene, benzene are purchased from the limited public affairs of Chinese medicines group chemical reagent
Department；The alkalescent such as potassium carbonate material is purchased from Chemical Reagent Co., Ltd., Sinopharm Group.
The method of the present invention 2,4,5- trimethoxy-anilines of synthesis, is with palladium carbon by 1,2,4- trimethoxy -5- nitrobenzene
For catalyst, 2,4,5- trimethoxy-anilines are obtained with catalytic hydrogenation method.Its synthetic route is as follows：
In embodiment, product 2,4, the analysis method of 5- trimethoxy-anilines is as follows：Utilize Dai An companies
Ultimate3000 high performance liquid chromatographs, using area normalization method, carry out composition analysis.Have using extremely big day hair science and technology
The YTR-3 drug melting point instrument of limit company, determine product fusing point.
Catalyst hydrogenation yield is based on product in embodiments of the invention and the respective molal quantity of raw material is calculated as follows：
The synthetic method of 2,4,5- trimethoxy-anilines comprises at least following steps：
(1) it is 1 in molar ratio by 1,2,4- trimethoxy -5- nitrobenzene and solvent:15 to 1:20 mix, by 1,2,4- tri-
The mol ratio 1 of methoxyl group -5- nitrobenzene and alkalescent material (such as potassium carbonate):0.001 to 1:0.02 adds alkalescent material.
In gained mixture input hydriding reactor.
(2) palladium carbon that butt palladium content is 5% to 10% is used as catalyst, and temperature control is at 60 to 101 DEG C, hydrogenation
Pressure is 1.0 to 4.0MPa, and the reaction time is 0.5 to 2.5h.It is 2,4,5- trimethoxy-anilines to obtain product.
Embodiment 1
By the trimethoxy -5- nitrobenzene of 33.0g (0.1548mol) 1,2,4-, 4.0g (0.0015mol) palladium carbon (butt palladium
Content is 10.0%), 0.32g (0.0023mol) potassium carbonate input hydriding reactor, to add 232g (2.6331mol) Isosorbide-5-Nitrae-dioxy six
Ring.Reaction temperature is controlled at 75 DEG C -85 DEG C, and hydriding reactor mixing speed is in 1400r/min-1500r/min.Hydrogen Vapor Pressure is maintained at
2.0MPa-2.2MPa after reacting 1h, terminate reaction.Filtering reacting liquid, palladium carbon recovery, filtrate have been concentrated into solid precipitation, added
50ml toluene, stirring are cooled to 5 DEG C, filter, and obtain violet solid, 25 DEG C of -30 DEG C of vacuum drying, obtain 26.9g violet solids.
Catalytic hydrogenation yield (abbreviation yield in the present invention) is 94.9%, and violet solid send HPLC, and collection of illustrative plates shows that liquid phase purity reaches
98.0%, it is 93.7 DEG C -94.3 DEG C to survey fusing point.Product is the 2,4,5- trimethoxy-anilines of high-purity.
With reference to the proportioning of embodiment 1, only change mixing speed, other conditions are constant, to determine that mixing speed is received to product
The influence of rate, is shown in Table one.
Table one：Influence of the mixing speed to yield
Comparative example 1
By the trimethoxy -5- nitrobenzene of 33.0g (0.1548mol) 1,2,4-, 4.0g (0.0015mol) palladium carbon (butt palladium
Content is 10.0%), 0.32g (0.0023mol) potassium carbonate input hydriding reactor, to add 232g (2.6331mol) Isosorbide-5-Nitrae-dioxy six
Ring.Reaction temperature is controlled at 75 DEG C -85 DEG C, and hydriding reactor mixing speed is in 800r/min-900r/min.Hydrogen Vapor Pressure is maintained at
2.0MPa-2.2MPa after reacting 1h, terminate reaction.Filtering reacting liquid, palladium carbon recovery, filtrate have been concentrated into solid precipitation, added
50ml toluene, stirring are cooled to 5 DEG C, filter, and obtain violet solid, 25 DEG C of -30 DEG C of vacuum drying, obtain 12.8g violet solids.
Catalytic hydrogenation yield (abbreviation yield in the present invention) is 20.1%, and violet solid send HPLC, and collection of illustrative plates shows that liquid phase purity reaches
98.0%, it is 93.7 DEG C -94.3 DEG C to survey fusing point.Product is the 2,4,5- trimethoxy-anilines of high-purity.
With reference to the proportioning of comparative example 1, only change mixing speed, other conditions are constant, to determine that mixing speed is received to product
The influence of rate, is shown in Table two.
Table two：Influence of the mixing speed to yield
Next, with reference to the proportioning of embodiment 1, change reaction temperature and/or hydrogenation pressure, other conditions are constant, with true
Determine the influence of reaction temperature and hydrogenation pressure respectively to reaction time and product yield, be shown in Table three.
Table three：Reaction temperature and/or the hydrogenation pressure influence to yield respectively
Embodiment 2
By the trimethoxy -5- nitrobenzene of 103.0g (0.4831mol) 1,2,4-, 7.5g (0.0014mol) palladium carbon (butt palladium
Content is 5.0%), 0.82g (0.0059mol) potassium carbonate input hydriding reactor, to add 723.6g (8.2125mol) Isosorbide-5-Nitrae-dioxy six
Ring.Reaction temperature is controlled at 75-85 DEG C, and hydriding reactor mixing speed is maintained in 1400r/min-1500r/min, Hydrogen Vapor Pressure
2.0MPa-2.2MPa, after reacting 1h, terminate reaction.Filtering reacting liquid, palladium carbon recovery, filtrate have been concentrated into solid precipitation, added
154.5ml toluene, stirring are cooled to 5 DEG C, filter, and obtain violet solid, 25 DEG C of -30 DEG C of vacuum drying, obtain 84.3g purples and consolidate
Body.Catalytic hydrogenation yield is 95.2%, and violet solid send HPLC, and collection of illustrative plates shows liquid phase purity up to 98.0%, and it is 94.2 to survey fusing point
℃-95.0℃.Product is the 2,4,5- trimethoxy-anilines of high-purity.
With reference to the reaction condition of embodiment 2, only change 1,2,4- trimethoxy -5- nitrobenzene (in table four abbreviation nitro
Benzene) with the proportioning of palladium carbon, other conditions are constant, to determine influence of the proportionate relationship between them to product yield, are shown in Table four.
Table four：Nitrobenzene and palladium carbon with the influence for comparing yield
Next, with reference to the reaction condition of embodiment 2, it is (simple in table four only to change 1,2,4- trimethoxy -5- nitrobenzene
Claim nitrobenzene) with the proportioning of solvent, other conditions are constant, to determine influence of the proportionate relationship between them to product yield,
It is shown in Table five.
Table five：Nitrobenzene and solvent with the influence for comparing yield
Next, with reference to the reaction condition of embodiment 2, only change the species of solvent, other conditions are constant, to determine solvent
Influence to product yield, is shown in Table six.
Table six：Influence of the species of solvent to yield
Next, with reference to the reaction condition of embodiment 2, the pH value of a change reactant mixture, other conditions are constant, with true
Determine influence of the pH value to product yield of reactant mixture, be shown in Table seven.
Table seven：Influence of the pH value of reactant mixture to yield
It is described above, only it is several embodiments of the application, any type of limitation is not done to the application, although this Shen
Please with preferred embodiment disclose as above, but and be not used to limit the application, any person skilled in the art, do not taking off
In the range of technical scheme, make a little variation using the technology contents of the disclosure above or modification is equal to
Case study on implementation is imitated, is belonged in the range of technical scheme.
Claims (10)
1. one kind synthesis 2,4,5- trimethoxy-anilines method, it is characterised in that methods described include by reactant mixture with
Hydrogen contacts, to form 2,4,5- trimethoxy-anilines；Wherein, the reactant mixture include solvent, 1,2,4- trimethoxies-
5- nitrobenzene and catalyst, or after 2,4,5- trimethoxy-anilines are formed, the reactant mixture also includes 2,4,5- tri-
Aminoanisole.
2. according to the method for claim 1, it is characterised in that the catalyst is palladium carbon；It is it is preferred that dry in the palladium carbon
The content of base palladium is 5% to 10%.
3. method according to claim 1 or 2, it is characterised in that the solvent is selected from benzene, toluene and Isosorbide-5-Nitrae-dioxane
At least one of, particularly preferred Isosorbide-5-Nitrae-dioxane.
4. method as claimed in any of claims 1 to 3, it is characterised in that stir the speed of the reactant mixture
Rate is 1200r/min to 2800r/min, preferably described speed be 1400r/min to 2000r/min, or the preferably speed
For 2200r/min to 2800r/min.
5. method as claimed in any of claims 1 to 4, it is characterised in that reaction temperature is 60 DEG C to 101 DEG C,
It is preferred that the reaction temperature is 75 DEG C to 95 DEG C.
6. method as claimed in any of claims 1 to 5, it is characterised in that the reaction time is 0.5h to 2.5h, excellent
It is 0.5h to 1h to select the reaction time.
7. method as claimed in any of claims 1 to 6, it is characterised in that hydrogenation pressure therein is 1.0MPa
To 4.0MPa, preferably described hydrogenation pressure is 2.0MPa to 4.0MPa.
8. method as claimed in any of claims 1 to 7, it is characterised in that 2,4- trimethoxy -5- nitrobenzene with
The mol ratio of the catalyst is 1:0.001 to 1:0.01, preferably 2,4- trimethoxy -5- nitrobenzene rub with the catalyst
You are than being 1:0.002 to 1:0.004, or the mol ratio of preferably 2,4- trimethoxy -5- nitrobenzene and the catalyst is 1:
0.005 to 1:0.01.
9. method as claimed in any of claims 1 to 8, it is characterised in that 1,2,4- trimethoxy -5- nitrobenzene
Mol ratio with the solvent is 1:15 to 1:22, preferably 1, the mol ratio of 2,4- trimethoxy -5- nitrobenzene and the solvent
For 1:18 to 1:20.
10. method as claimed in any of claims 1 to 9, it is characterised in that the pH of the reactant mixture is
7.5 to 14, preferably 7.5 to 9.5；It is preferred that the pH is adjusted by adding alkalescent material into the reactant mixture, it is more excellent
The alkalescent material is selected to be selected from least one of potassium carbonate, saleratus, sodium carbonate and sodium acid carbonate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4457875A (en) * | 1981-04-23 | 1984-07-03 | Choay S.A. | Substituted 2,4 dialkoxy benzene sulfonyl chlorides |
| CN1738615A (en) * | 2002-11-15 | 2006-02-22 | 沃泰克斯药物股份有限公司 | Diaminotriazoles useful as inhibitors of protein kinases |
| CN1749250A (en) * | 2005-05-19 | 2006-03-22 | 杭州电化集团有限公司 | Chemical synthetic method for 2-chloro-4-amino-6,7-dimethoxy quinazoline |
-
2016
- 2016-09-08 CN CN201610808898.4A patent/CN107805204A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4457875A (en) * | 1981-04-23 | 1984-07-03 | Choay S.A. | Substituted 2,4 dialkoxy benzene sulfonyl chlorides |
| CN1738615A (en) * | 2002-11-15 | 2006-02-22 | 沃泰克斯药物股份有限公司 | Diaminotriazoles useful as inhibitors of protein kinases |
| CN1749250A (en) * | 2005-05-19 | 2006-03-22 | 杭州电化集团有限公司 | Chemical synthetic method for 2-chloro-4-amino-6,7-dimethoxy quinazoline |
Non-Patent Citations (2)
| Title |
|---|
| NADALE K. DOWNER等: "Synthesis of benzothiazoles via ipso substitution of orthomethoxythiobenzamides", 《ORG. BIOMOL. CHEM.》 * |
| 高兴文等: "3,4,5-三甲氧基苯胺的合成", 《化学试剂》 * |
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Application publication date: 20180316 |