CN104130143A - Method for preparing 3-methylamino-4-nitrophenoxyethanol - Google Patents
Method for preparing 3-methylamino-4-nitrophenoxyethanol Download PDFInfo
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- CN104130143A CN104130143A CN201410382762.2A CN201410382762A CN104130143A CN 104130143 A CN104130143 A CN 104130143A CN 201410382762 A CN201410382762 A CN 201410382762A CN 104130143 A CN104130143 A CN 104130143A
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Abstract
The invention relates to a method for preparing 3-methylamino-4-nitrophenoxyethanol. The method comprises the steps of performing methylamination reaction by using 2,4-dichloronitrobenzene as a raw material and using methanol as a solvent to obtain 3-methylamino-4-nitrochlorobenzene, performing nucleophilic substitution with a sodium hydroxide (or other alkaline matter) solution of ethylene glycol to substitute the remaining other chlorine group so as to obtain crude 3-methylamino-4-nitrophenoxyethanol, and performing re-crystallization to obtain high-purity 3-methylamino-4-nitrophenoxyethanol. The process of preparing the 3-methylamino-4-nitrochlorobenzene intermediate through a one-step method replaces a two-step method process of preparing the intermediate through high pressure ammonolysis of 2,4-dichloronitrobenzene and N-methylation reaction; in addition, methanol is adopted in the one-step method to replace a tetrahydrofuran solution, so that the purposes of reducing the recovery cost and reducing the cost of the solvent are achieved; the method has the characteristics of conventional equipment, simplicity in operation, cheap and readily available raw materials, low cost, high yield and the like.
Description
Technical field
The present invention relates to a kind of preparation method of nitro class dyestuff, especially relate to a kind of preparation method of 3-methylamino--4-oil of mirbane oxyethanol.
Background technology
In recent years, along with the pursuit of people to fashionable life, the ratio day by day of hair dyeing.And direct color development composition in traditional hair dye is Ursol D, Ursol D is a kind of carcinogenic substance, and easily occurs during with skin contact irritatedly etc., is not suitable for long-term frequent use, therefore in the urgent need to developing low toxicity, hypoallergenic chromogenic reagent.
3-methylamino--4-oil of mirbane oxyethanol, a kind of nitro class dyestuff, CAS No.59820-63-2, it is a kind of direct hair coloring agents, can be used in 21 kinds of different colours hair dyes, working concentration is up to 0.15%.While being applied to the dyeing of keratin fiber, wherein by cuticle contact and remaining color, be attached to hair, rather than normal skin.Therefore without allergic or stimulation and toxicity, the problem such as leave over, can be used as hair dyed agent for the cosmetics of super quality.Existing directed foreign trader's active demand, the international and domestic product innovation that all belongs to, industrialization demand is large, and market and development prospect are wide.Yet the technique that directly obtains 3-methylamino--4-oil of mirbane oxyethanol have not been reported, what research was reported is only the synthetic of its intermediate 3-methylamino--4-nitro-chlorobenzene.
Chinese patent CN 102531923 A disclose a kind of production method of 3-methylamino--4-nitro-chlorobenzene, after being adopted to mixed acid nitrification, Meta Dichlorobenzene makes 2,4-dichloronitrobenzene, again by 2,4-dichloronitrobenzene adds high pressure amination still, pass into liquefied ammonia, 140～150 ℃, 7.0～8.5MPa insulation 5～6 hours, then make product 5-chloro-2-nitroaniline through washing, suction filtration.This method needs High Temperature High Pressure, the higher and complicated operation to equipment requirements.
Sergei Voskresensky etc. (Synthetic Communications, 2000,30 (19), 3523-3526) adopting 5-chloro-2-nitroaniline is raw material, toluene is solvent, Bu
4n+HSO
4 -or Bu
4n+Br
-for catalyzer, through methyl-sulfate, methylate and make product 3-methylamino--4-nitro-chlorobenzene, its preparation process is as follows:
The method exists that step is many, high pressure ammonia solution and the problem such as methylating reagent methyl-sulfate toxicity is large, yield is low.
Patent WO2005080388 A1 adopts 2,4-dichloronitrobenzene is raw material, tetrahydrofuran (THF) is solvent, first add triethylamine and methylamine in the lower 40 ℃ of reactions of argon gas atmosphere 6 hours, continue to add 40 ℃ of reactions of methylamine-tetrahydrofuran solution of two equivalents within 16 hours, to make product 3-methylamino--4-nitro-chlorobenzene, its preparation process is as follows again:
There is the problems such as solvents tetrahydrofurane valency is high, recovery difficult is large, yield is low in the method.
Therefore, improve intermediate 3-methylamino--4-nitro-chlorobenzene synthesis technique, make its reach produce feasible, especially develop 3-methylamino--4-nitro-chlorobenzene and under alkaline condition, carry out nucleophilic substitution with ethylene glycol and prepare 3-methylamino--4-oil of mirbane oxyethanol to obtain the novel process of high-quality product, extremely urgent.
Summary of the invention
In order to overcome the deficiencies in the prior art, the invention provides a kind of low toxicity, hypoallergenic chromogenic reagent of can be used as, and can be in order to prepare the preparation method of 3-methylamino--4-oil of mirbane oxyethanol of safety non-toxic hair dye.
A preparation method for 3-methylamino--4-oil of mirbane oxyethanol, comprises the steps:
The aqueous methylamine solution that (1) 2,4-dichloronitrobenzene is 30～45% with mass concentration reacts and makes 3-methylamino--4-nitro chlorobenzene through methylamine in methanol solvate; Wherein, the weight ratio of 2,4-dichloronitrobenzene, aqueous methylamine solution, methyl alcohol is: 1:095～1.25:2.12～3.02;
(2) 3-methylamino--4-nitro chlorobenzene and ethylene glycol carry out nucleophilic substitution reaction and obtain 3-methylamino--4-oil of mirbane oxyethanol crude product under alkali effect; Wherein, the weight ratio of 3-methylamino--4-nitro chlorobenzene, ethylene glycol, alkali is: 1:4.2～6.0:0.34～0.40;
(3) 3-methylamino--4-oil of mirbane oxyethanol crude product carries out purification process and obtains 3-methylamino--4-oil of mirbane oxyethanol sterling.
The present invention adopts 2 shown in formula (II), 4-dichloronitrobenzene is raw material, methyl alcohol is made solvent, through methylamine, make formula (III) 3-methylamino--4-nitro chlorobenzene, carry out again another chlorine of nucleophilic substitution remainder with sodium hydroxide (or other alkaline matters) solution of ethylene glycol, make the 3-methylamino--4-oil of mirbane oxyethanol crude product shown in formula (I), finally by recrystallization, prepare high purity 3-methylamino--4-oil of mirbane oxyethanol.Synthetic route is as follows:
Preferably, in step (1), the time for adding of aqueous methylamine solution is controlled at 0.75～1.5h, and methylamine reaction is carried out under reflux temperature, and the reaction times is 15～21h.
Preferably, methylamine reaction finish by crystallization, filtration, after dry 3-methylamino--4-nitro chlorobenzene crude product, gained crude product is again through washed with methanol, after filtering drying intermediate 3-methylamino--4-nitro chlorobenzene.
Preferably, in step (2), described alkali is KOH, NaOH, K
2cO
3, Na
2cO
3in a kind of.
Preferably, described alkali adopts and adds in batches, and the weight ratio of first alkali and second batch alkali is 1.5～2:1.
Preferably, the concrete operations of step (2) are: first first alkali is heated to 90～100 ℃, after making it be dissolved in ethylene glycol, control temperature at 100～105 ℃, add 3-methylamino--4-nitro chlorobenzene, after being warming up to again 110～115 ℃ of reaction 1～3h, add again second batch alkali, be controlled in 15～30min and add, then continue reaction 0.5～2.5h, after being cooled to 70 ℃, add deionized water stirred crystallization 30min, be cooled to 40 ℃ of filtrations, gained filter cake obtains 3-methylamino--4-oil of mirbane oxyethanol crude product after deionized water rinsing again.
Preferably, in step (3), described purification process is: 3-methylamino--4-oil of mirbane oxyethanol crude product first carries out activated carbon decolorizing processing in ethyl acetate solvent, then in deionized water, carries out recrystallization, obtains 3-methylamino--4-oil of mirbane oxyethanol; Wherein, the weight ratio of ethyl acetate, gac, 3-methylamino--4-oil of mirbane oxyethanol crude product is: 3.5～6.0:0.05～1:1, the weight ratio of deionized water and 3-methylamino--4-oil of mirbane oxyethanol crude product is: 5～7:1.
Preferably, the concrete operations of step (3) are: in reactor, add ethyl acetate, 3-methylamino--4-oil of mirbane oxyethanol crude product, pass into nitrogen and also stir and be warming up to 60～65 ℃, after solid is entirely molten, drop into gac, after continuing to stir 1～2h, stop heating, filter and filtrate is poured in deionized water, being heated to 60～65 ℃, then being cooled to 10～15 ℃, filter, filter cake obtains 3-methylamino--4-oil of mirbane oxyethanol after drying.
Preferably, the preparation method of described 3-methylamino--4-oil of mirbane oxyethanol comprises the steps:
(1) in four-hole boiling flask, add 50g 2,4-dichloronitrobenzene, 150g methyl alcohol, stir and be warming up to after backflow, drips the aqueous methylamine solution that 47.6g mass concentration is 40%, after dropwising in 1h, keep after reflux temperature reaction 15h, passing into icy salt solution and being cooled to 10 ℃, insulation crystallization 30min, after drying after filtration again, obtain 3-methylamino--4-nitro chlorobenzene crude product, gained crude product with the making beating of 60g methyl alcohol, filters again, 70 ℃ after dry 3-methylamino--4-nitro chlorobenzene;
(2) in four-hole boiling flask, add 5.5gNaOH, 105g ethylene glycol, stirring is warming up to 100 ℃, after dissolving completely to NaOH, add 25g 3-methylamino--4-nitro chlorobenzene, be warming up to after 110 ℃ of reaction 2h, add 3g NaOH, continue to be cooled to 70 ℃ after reaction 2.5h, add 105g deionized water, stirred crystallization 30min at 70 ℃, be cooled to 40 ℃ of filtrations, gained filter cake again filters to obtain 3-methylamino--4-oil of mirbane oxyethanol crude product after deionized water rinsing again;
(3) in four-hole boiling flask, add 100g ethyl acetate, 20g 3-methylamino--4-oil of mirbane oxyethanol crude product, pass into nitrogen and stir and be warming up to 65 ℃, after solid is entirely molten, drop into 1.18g gac, continue to stop heating after stirring 1h, filter also filtrate is poured in 115g deionized water, be heated to 65 ℃, be cooled to 10 ℃ again, filter, filter cake obtains 3-methylamino--4-oil of mirbane oxyethanol after drying.
Beneficial effect of the present invention is:
(1) compound 3-methylamino--4-oil of mirbane oxyethanol that the present invention prepares, can be used as effective color development composition of hair dye, have toxicity low, to advantages such as skin adaptability are good, there are wide market outlook;
(2) the present invention adopts 2,4-dichloronitrobenzene is in methanol solvate, with methylamine, carry out the selection MMAization reaction of normal pressure, by single stage method, prepare the technique of intermediate 3-methylamino--4-nitro-chlorobenzene, after having replaced the first high pressure ammonia solution of 2,4-dichloronitrobenzene, carry out again the two-step process that N-methylation reaction is prepared intermediate; In addition, in single stage method, adopt methyl alcohol substituted tetrahydrofuran solvent, reach the object that reduces reclaimer operation expense and reduce solvent cost;
(3) 3-methylamino--4-oil of mirbane oxyethanol preparation method provided by the present invention has equipment routine, simple to operate, raw material is cheap and easy to get, cost is low, yield high.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention is not limited to this.
Embodiment 1
(1) preparation of 3-methylamino--4-nitro chlorobenzene
In four-hole boiling flask, add 50g(0.260mol) 2, 4-dichloronitrobenzene, 150g methyl alcohol, stirring is warming up to backflow, dropping 47.6g(0.613mol) aqueous methylamine solution that concentration is 40w%, time for adding is controlled at 1h, after dropwising, keep reflux temperature reaction 15h, reaction solution is orange transparent liquid, pass into icy salt solution slow cooling to 10 ℃, insulation crystallization 30min, after drying after filtration again, obtain orange 3-methylamino--4-nitro chlorobenzene crude product, gained crude product is again with the making beating of 60g methyl alcohol, filtration is dried to obtain the orange intermediate 3-methylamino--4-of 34.5g nitro chlorobenzene by 70 ℃, HPLC purity is 99.65%, yield is 71.00%.
(2) preparation of 3-methylamino--4-oil of mirbane oxyethanol crude product
In 250mL four-hole boiling flask, add first alkali of 5.5gNaOH(), 105g(1.692mol) ethylene glycol, stirring be warming up to 100 ℃ until NaOH dissolve completely, add 3-methylamino--4-nitro chlorobenzene that 25g (0.134mol) purity is 99.65%, be warming up to after 110 ℃ of reaction 2h, add 3g NaOH(second batch alkali), continue reaction 2.5h and be cooled to 70 ℃, slowly add 105g deionized water, stirred crystallization 30min at 70 ℃, be cooled to again 40 ℃ of filtrations, gained filter cake again filters to obtain 23.8g 3-methylamino--4-oil of mirbane oxyethanol crude product after deionized water rinsing, HPLC purity is 95.28%, yield is 83.31%.
(3) 3-methylamino--4-oil of mirbane oxyethanol is refining
In four-hole boiling flask, add 100g ethyl acetate, 20g 3-methylamino--4-oil of mirbane oxyethanol crude product (purity is 95.28%), pass into nitrogen and also stir and be warming up to 65 ℃, after solid is entirely molten, drop into 1.18g gac, after continuing to stir 1h, stop heating, filter and filtrate is poured in 115g deionized water, being heated to 65 ℃, then slow cooling to 10 ℃, filter, filter cake is 16.60g 3-methylamino--4-oil of mirbane oxyethanol after drying, and HPLC purity is 99.39%, and refining yield is 83.0%.
Embodiment 2～4
Adopt and the middle same operation of embodiment 1 step (1), different is methyl alcohol, aqueous methylamine solution, different concns aqueous methylamine solution and the differential responses time of selecting different amounts, and embodiment 1～4 the data obtained is as shown in table 1:
Table 1
According to table 1, can find out, adopt methyl alcohol, aqueous methylamine solution, different concns aqueous methylamine solution and the differential responses time of different amounts, all can there is significantly impact to the purity of 3-methylamino--4-nitro chlorobenzene and yield, thereby affect purity and the yield of final product 3-methylamino--4-oil of mirbane oxyethanol.
Embodiment 5～8
Adopt and the middle same operation of embodiment 1 step (2), different is ethylene glycol, NaOH and the differential responses time of selecting different amounts, and embodiment 1 and embodiment 5～8 the data obtaineds are as shown in table 2:
Table 2
Wherein, in embodiment 6, NaOH is disposable adding, and other embodiment are in batches and add.
According to table 2, can find out, adopt ethylene glycol, NaOH and the differential responses time of different amounts, all can there is significantly impact to the purity of 3-methylamino--4-oil of mirbane oxyethanol crude product and yield, thereby affect purity and the yield of final product 3-methylamino--4-oil of mirbane oxyethanol.
Embodiment 9
Other steps are identical with embodiment 1, with the treating process difference of 3-methylamino--4-oil of mirbane oxyethanol crude product as a comparative example 1: add 330g methylene dichloride in four-hole boiling flask, 20g 3-methylamino--4-oil of mirbane oxyethanol crude product (purity 95.28%), pass into nitrogen and stir and be warming up to 65 ℃, solids cannot dissolve, filter and in backward filter cake, add 105g methyl alcohol, be heated to 70 ℃, after all dissolving, solids drops into 1g gac, after continuing to stir 1h, stop heating, filter and filtrate is poured in 100g deionized water, be heated to 65 ℃, slow cooling to 15 ℃ again, filter, filter cake is 3g 3-methylamino--4-oil of mirbane oxyethanol after drying, HPLC purity is 99.58%, refining yield is 15.64%.
Embodiment 10～12
Adopt and the middle same operation of embodiment 1 step (3), different is the organic solvent of selecting different sorts and consumption, and embodiment 1 and embodiment 10～12 the data obtaineds are as shown in table 3:
Table 3
Embodiment 9 and embodiment 10～12 in conjunction with the embodiments 1,, can know, the organic solvent of different sorts and consumption, for the very large impact of refining existence of 3-methylamino--4-oil of mirbane oxyethanol crude product, can affect purity and the yield of final product 3-methylamino--4-oil of mirbane oxyethanol.
Finally, it is also to be noted that, what more than enumerate is only several specific exampless of the present invention.Obviously, the invention is not restricted to above example, can also have many distortion.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention, all should think protection scope of the present invention.
Claims (9)
1. a preparation method for 3-methylamino--4-oil of mirbane oxyethanol, is characterized in that comprising the steps:
The aqueous methylamine solution that (1) 2,4-dichloronitrobenzene is 30～45% with mass concentration reacts and makes 3-methylamino--4-nitro chlorobenzene through methylamine in methanol solvate; Wherein, the weight ratio of 2,4-dichloronitrobenzene, aqueous methylamine solution, methyl alcohol is: 1:095～1.25:2.12～3.02;
(2) 3-methylamino--4-nitro chlorobenzene and ethylene glycol carry out nucleophilic substitution reaction and obtain 3-methylamino--4-oil of mirbane oxyethanol crude product under alkali effect; Wherein, the weight ratio of 3-methylamino--4-nitro chlorobenzene, ethylene glycol, alkali is: 1:4.2～6.0:0.34～0.40;
(3) 3-methylamino--4-oil of mirbane oxyethanol crude product carries out purification process and obtains 3-methylamino--4-oil of mirbane oxyethanol sterling.
2. the preparation method of 3-methylamino--4-oil of mirbane oxyethanol according to claim 1, it is characterized in that: in step (1), the time for adding of aqueous methylamine solution is controlled at 0.75～1.5h, and methylamine reaction is carried out under reflux temperature, and the reaction times is 15～21h.
3. the preparation method of 3-methylamino--4-oil of mirbane oxyethanol according to claim 2, it is characterized in that: methylamine reaction finish by crystallization, filtration, after dry 3-methylamino--4-nitro chlorobenzene crude product, gained crude product, again through washed with methanol, obtains intermediate 3-methylamino--4-nitro chlorobenzene after filtering drying.
4. the preparation method of 3-methylamino--4-oil of mirbane oxyethanol according to claim 1, is characterized in that: in step (2), described alkali is KOH, NaOH, K
2cO
3, Na
2cO
3in a kind of.
5. the preparation method of 3-methylamino--4-oil of mirbane oxyethanol according to claim 4, is characterized in that: described alkali adopts and adds in batches, and the weight ratio of first alkali and second batch alkali is 1.5～2:1.
6. the preparation method of 3-methylamino--4-oil of mirbane oxyethanol according to claim 5, it is characterized in that: the concrete operations of step (2) are: first first alkali is heated to 90～100 ℃, after making it be dissolved in ethylene glycol, control temperature at 100～105 ℃, add 3-methylamino--4-nitro chlorobenzene, after being warming up to again 110～115 ℃ of reaction 1～3h, add again second batch alkali, be controlled in 15～30min and add, then continue reaction 0.5～2.5h, after being cooled to 70 ℃, add deionized water stirred crystallization 30min, be cooled to again 40 ℃ of filtrations, gained filter cake obtains 3-methylamino--4-oil of mirbane oxyethanol crude product after deionized water rinsing.
7. the preparation method of 3-methylamino--4-oil of mirbane oxyethanol according to claim 1, it is characterized in that: in step (3), described purification process is: 3-methylamino--4-oil of mirbane oxyethanol crude product first carries out activated carbon decolorizing processing in ethyl acetate solvent, then in deionized water, carry out recrystallization, obtain 3-methylamino--4-oil of mirbane oxyethanol; Wherein, the weight ratio of ethyl acetate, gac, 3-methylamino--4-oil of mirbane oxyethanol crude product is: 3.5～6.0:0.05～1:1, the weight ratio of deionized water and 3-methylamino--4-oil of mirbane oxyethanol crude product is: 5～7:1.
8. the preparation method of 3-methylamino--4-oil of mirbane oxyethanol according to claim 7, it is characterized in that: the concrete operations of step (3) are: in reactor, add ethyl acetate, 3-methylamino--4-oil of mirbane oxyethanol crude product, pass into nitrogen and stir and be warming up to 60～65 ℃, after solid is entirely molten, drop into gac, after continuing to stir 1～2h, stop heating, filter and filtrate is poured in deionized water, be heated to 60～65 ℃, be cooled to again 10～15 ℃, filter, filter cake obtains 3-methylamino--4-oil of mirbane oxyethanol after drying.
9. the preparation method of 3-methylamino--4-oil of mirbane oxyethanol according to claim 1, is characterized in that comprising the steps:
(1) in four-hole boiling flask, add 50g 2,4-dichloronitrobenzene, 150g methyl alcohol, stir and be warming up to after backflow, drip the aqueous methylamine solution that 47.6g mass concentration is 40%, time for adding is controlled at 1h, after dropwising, keeps after reflux temperature reaction 15h, pass into icy salt solution and be cooled to 10 ℃, insulation crystallization 30min, then obtain 3-methylamino--4-nitro chlorobenzene crude product after drying after filtration, gained crude product is again with the making beating of 60g methyl alcohol, filter, after being dried, obtain 3-methylamino--4-nitro chlorobenzene;
(2) in four-hole boiling flask, add 5.5gNaOH, 105g ethylene glycol, stirring is warming up to 100 ℃, after dissolving completely to NaOH, add 25g 3-methylamino--4-nitro chlorobenzene, be warming up to after 110 ℃ of reaction 2h, add 3g NaOH, continue to be cooled to 70 ℃ after reaction 2.5h, add 105g deionized water, stirred crystallization 30min at 70 ℃, be cooled to 40 ℃ of filtrations, gained filter cake again filters to obtain 3-methylamino--4-oil of mirbane oxyethanol crude product after deionized water rinsing again;
(3) in four-hole boiling flask, add 100g ethyl acetate, 20g 3-methylamino--4-oil of mirbane oxyethanol crude product, pass into nitrogen and stir and be warming up to 65 ℃, after solid is entirely molten, drop into 1.18g gac, continue to stop heating after stirring 1h, filter also filtrate is poured in 115g deionized water, be heated to 65 ℃, be cooled to 10 ℃ again, filter, filter cake obtains 3-methylamino--4-oil of mirbane oxyethanol after drying.
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| CN105367567A (en) * | 2015-11-18 | 2016-03-02 | 浙江京新药业股份有限公司 | Compound and application thereof in preparation of riociguat |
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