CN105130926B - A kind of preparation method of methylene blue - Google Patents
A kind of preparation method of methylene blue Download PDFInfo
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- CN105130926B CN105130926B CN201510465840.XA CN201510465840A CN105130926B CN 105130926 B CN105130926 B CN 105130926B CN 201510465840 A CN201510465840 A CN 201510465840A CN 105130926 B CN105130926 B CN 105130926B
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- CMEWLCATCRTSGF-UHFFFAOYSA-N CN(C)c(cc1)ccc1N=O Chemical compound CN(C)c(cc1)ccc1N=O CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 1
- RYLHMUMBQAJPPS-UHFFFAOYSA-N CNC(C=C1Sc2c3)=CCC1=Nc2ccc3N(C)C Chemical compound CNC(C=C1Sc2c3)=CCC1=Nc2ccc3N(C)C RYLHMUMBQAJPPS-UHFFFAOYSA-N 0.000 description 1
- 0 CNc(ccc(N(C)C)c1)c1S* Chemical compound CNc(ccc(N(C)C)c1)c1S* 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
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Abstract
The invention discloses a kind of preparation method of methylene blue, belong to fine-chemical intermediate synthesis technical field.Concretely comprise the following steps in concentrated hydrochloric acid solution, with natrium nitrosum and N, N dimethylanilines carry out nitrosation reaction, and intermediate is made to nitroso N, N dimethylanilines；Nitroso N, N dimethylanilines will be carried out hydro-reduction, be prepared into amino N, N dimethylanilines；Amino N, N dimethylanilines will be aoxidized, then addition is carried out with sodium thiosulfate, and be prepared into 2- amino -5- dimethylamino phenyl thiosulfonic acids；2- amino -5- dimethylamino phenyl thiosulfonic acids, double (4 dimethylamino phenyl) thiosulfonic acids are generated with DMA oxidative condensation；Double (4 dimethylamino phenyl) thiosulfonic acids are subjected to ring closure reaction, obtain methylene blue.Preparation method product purity provided by the present invention is high, and technological process is simple, and manufacturing cost is low, and raw materials used to be easy to get suitable for industrialized production, environmental pollution is smaller.
Description
Technical field：
The invention belongs to fine-chemical intermediate synthesis technical field, and in particular to a kind of preparation method of methylene blue.
Background technology：
Methylene blue (as shown in formula (1)), molecular weight 319.86, English name are methylene blue, chemical name
Double (dimethylamino) phenthazine -5- chlorides of referred to as 3,7-, are a kind of phenthazine salt.It is earliest by Germanization scholar
Heinrich Caro were synthesized in 1876 in the form of chlorination zinc salt.Methylene blue is widely used in chemical indicator, dye
Material, biological stain and medicine etc..
At present, the preparation of the relevant methylene blue of document report mainly has following four method：
Method one：The synthetic method provided in CN200610201306.9 patent is, using DMA as original
Material, through manganese dioxide, sodium thiosulfate substitution, obtain 2- amino -5- dimethylamino phenyl thiosulfonic acids, the latter and N, N-
After dimethylaniline condensation, then through manganese dioxide and copper sulphate dioxide giving, obtain methylenum careuleum chlorination zinc salt.The latter's sodium carbonate
Target compound methylene blue crude product is neutralized to obtain, the crude product obtains methylene blue finished product for several times with water recrystallization again.Synthesis technique
Route is as follows：
Method two：The synthetic method provided in CN200610201306.9 patent is, using DMA as original
Material, through nitrosation, iron powder reducing, obtains N, N- dimethyl-p-phenylenediamines.The latter aoxidizes through sodium dichromate, and sodium thiosulfate takes
In generation, obtain 2- amino -5- dimethylamino phenyl thiosulfonic acids.After it is condensed with DMA, then through sodium dichromate and
Copper sulphate dioxide giving, obtain methylenum careuleum chlorination zinc salt.The latter neutralizes to obtain target compound methylenum careuleum crude product with sodium carbonate, and this is thick
Product obtain methylene blue finished product for several times with water recrystallization again.Synthesis route is as follows：
Method three：The synthetic method provided in CN200610201306.9 patent is, with N, N- dimethyl-p-phenylenediamines
Hydrochloride is raw material, is aoxidized through sodium dichromate, sodium thiosulfate substitution, obtains 2- amino -5- dimethylamino phenyl thiosulfonic acids,
Then with N, after N- dimethyl-p-phenylenediamines condensation, through manganese dioxide cyclization, methylenum careuleum chlorine is obtained in the presence of zinc chloride
Change zinc salt；Methylenum careuleum chlorination zinc salt obtains methylene blue crude product after being neutralized again with sodium carbonate, and the crude product is recrystallized for several times with water again
Obtain methylene blue finished product.Synthesis route is as follows：
Method four：J.Am.Chem.Soc, 1940,62 (1), 204-211 document reports are used to amino-N, N- dimethyl
Aniline (4) is initiation material, in the presence of the ferric trichloride of excess, oxidation addition occurs with the hydrochloric acid solution of hydrogen sulfide, then pass through
Superchlorination sodium salt analyses to obtain methylene blue crude product, after with water recrystallization obtain methylene blue product twice, this method synthesizes to obtain
Methylene blue product yield only has 8%, and yield is too low, does not possess commercialization value.Synthesis route is as follows：
The reaction scheme of above-mentioned four kinds of methods is substantially what is repeated, wherein primary difference is that oxidant in course of reaction
Selection it is different.It is required to enter using the serious manganese dioxide of environmental pollution and sodium dichromate or hydrogen sulfide in course of reaction
Row oxidation, and the process that feeds intake is cumbersome, is unfavorable for industrial production.
The content of the invention：
The present invention is directed to problems of the prior art, there is provided a kind of preparation method of methylene blue, it is therefore an objective to provide
A kind of technological design is reasonable, high income, reaction condition are gentle, low in raw material price, environment-friendly, suitable industrialized methylene
Blue preparation method.
The implementation steps of the present invention are as follows：DMA is used as initiation material, according to following route reaction system
Standby methylene blue：
Step 1：Accelerine, accelerine (3)
In concentrated hydrochloric acid medium, nitrosation reaction is carried out with natrium nitrosum and the DMA as shown in formula (2)
The intermediate accelerine as shown in formula (3) is prepared, accelerine, separation will be such as the intermediate shown in formula (3)
Accelerine, accelerine are tuned into free state with alkali, extract, and decolourize,
Obtain accelerine, accelerine toluene solution；
Described alkali is the one or two of sodium hydroxide or sodium acid carbonate.
Step 2：To amino-DMA (4)
Existing technology is reduced using iron powder, zinc powder or akali sulphide, and it is produced largely in reduction process
Solid waste and liquid waste, environmental pollution is serious.We are using the accelerine for obtaining step 1, N- dimethyl
Aniline toluene solution, the mode directly hydrogenated with raney ni catalysis are reduced, and reach green requirement.Route describes such as
Under：
The organic solvent can be toluene, benzene, monochlor-benzene, chloroform, dichloromethane, ethyl acetate etc., be most preferably
Toluene；Described reaction temperature is 10~80 DEG C, and preferred reaction temperature is 20~40 DEG C；
Described reaction pressure is 0.5~5.0Mpa, and preferred reaction pressure is 2.0~4.0Mpa；
Step 3：2- amino -5- dimethylamino phenyls thiosulfonic acids (5)
Existing technology is aoxidized using sodium dichromate and manganese dioxide, sodium thiosulfate addition, and it is being aoxidized
During produce substantial amounts of solid waste and liquid waste, environmental pollution is very serious.In reaction system, addition is urged for we
Agent sodium dichromate, is then aoxidized with ferric trichloride, then carries out addition with sodium thiosulfate, is prepared into 2- amino -5- two
Methylaminophenyl thiosulfonic acid (5), reaches green requirement.Route is described as follows：
Amino-DMA (4) in the presence of catalyst sodium dichromate, will be aoxidized with ferric trichloride,
Addition is carried out with sodium thiosulfate again, is prepared into 2- amino -5- dimethylamino phenyls thiosulfonic acids (5)；The catalyst weight chromium
Sour sodium with to amino-N, N- dimethyl benzenes mol ratio is 0.001~0.10；Preferred mol ratio is 0.005~0.05；It is described
Reaction temperature be -10~60 DEG C, preferred reaction temperature be 0~20 DEG C.
Step 4：Double (4- dimethylamino phenyls) thiosulfonic acids (6)
Existing technology is all double using sodium dichromate and manganese dioxide and the generation of DMA (2) oxidative condensation
(4- dimethylamino phenyls) thiosulfonic acid (6), it produces substantial amounts of solid waste and liquid waste during the course of the reaction, to environment
Pollution is very serious.We carry out oxidation using ferric trichloride and generate double (4- diformazans with DMA (2) oxidative condensation
Aminophenyl) thiosulfonic acid (6), the compound be not required to it is to be separated, directly carry out step 5 reaction；Reach green to want
Ask.Route is described as follows：
Described reaction temperature is -10~60 DEG C, and preferred reaction temperature is 0~20 DEG C；
Step 5：Methylene blue (1)
Existing technology is all after methylene blue cyclization, adds zinc chloride, is translated into the chlorine of methylene blue
Change zinc salt, separated out from mother liquor, Crystallization Separation.Obtained methylene blue chlorination zinc salt reuses sodium carbonate and neutralized, release
Go out methylene blue product.We are after methylene blue cyclization, direct heat filtering, obtained filtrate with salt acid for adjusting pH value,
Stirred crystallization, separation, the methylene blue finished product of drying i.e., reduce intermediary operation process, it is easier to realize industrialized production.Road
Line is described as follows：
By catalysis of cupric sulphate, double (4- dimethylamino phenyls) thiosulfonic acids that will be as shown in formula (6) carry out ring closure reaction,
Obtain the methylene blue as shown in formula (1).
In step 2, described reaction temperature is 10~80 DEG C, and preferable reaction temperature is 20~50 DEG C；Described reaction pressure
Power is 0.5~5.0Mpa, and preferably reaction pressure is 2.0~4.0Mpa；The organic solvent is toluene, benzene, dichloromethane, a chlorine
For benzene, chloroform, ethyl acetate, preferable organic solvent is toluene.
In step 3, the sodium dichromate for adding catalytic amount is reacted, sodium dichromate used with to amino-N, N- dimethyl
Aniline mol ratio is 0.005~0.05；Described reaction temperature is 0~20 DEG C.
In step 3 and step 4, oxidant used is ferric trichloride, preferably sodium peroxydisulfate, ferric trichloride.
In step 4, described reaction temperature is -10~60 DEG C, and preferable reaction temperature is 0~20 DEG C.
In step 5, described reaction temperature is 10~100 DEG C, and preferable reaction temperature is 60~90 DEG C；Described reaction
Liquid, it is 0~3 with hydrochloric acid solution regulation pH value, preferable ph is 0.5~2.0 after filtering.
In implementation process of the present invention, demethylation methylene can be brought into the building-up process of methylene blue according to the literature
Base indigo plant (impurity A in European Pharmacopoeia), structure is as follows：
Its chemistry is entitled：Chlorination 3- dimethylaminos -7- (methylamino) phenthazine -5- salt.
The methylene blue product being prepared with this patent method, is detected through HPLC, and the methylene blue area of demethylation contains
Amount is less than 5%.
The chemical equation that the present invention uses is as follows：
The technical scheme is that：In concentrated hydrochloric acid solution, nitrous is carried out with natrium nitrosum and DMA
Change reaction, intermediate accelerine, accelerine is made；By accelerine, accelerine hydrogenate also
Original, it is prepared into amino-DMA；Amino-DMA will be aoxidized, then use sodium thiosulfate
Addition is carried out, is prepared into 2- amino -5- dimethylamino phenyl thiosulfonic acids；2- amino -5- dimethylamino phenyl thiosulfonic acids, with
Double (4- dimethylamino phenyls) thiosulfonic acids of DMA oxidative condensation generation；Double (4- dimethylamino phenyls) is thio
Sulfonic acid carries out ring closure reaction, obtains methylene blue.Compared with prior art, preparation method provided by the present invention, product purity
Height, technological process is simple, and manufacturing cost is low, and raw materials used to be easy to get suitable for industrialized production, environmental pollution is smaller.
Beneficial effect：
1st, prior art is reduced to accelerine, the reduction of accelerine using iron powder or akali sulphide,
There is substantial amounts of useless solid and waste liquid to produce, than more serious, patent of the present invention is entered using the method for raney ni catalysis hydrogenation for environmental pollution
Row reduction, reaches green requirement.
2nd, the synthesis of 2- amino -5- dimethylamino phenyls thiosulfonic acid (4) and double (4- dimethylamino phenyls) thiosulfonic acids
(5) synthesis step, prior art are aoxidized using sodium dichromate and manganese dioxide, and effect on environment is very big, this hair
Bright patent is aoxidized using environment amenable ferric trichloride, reaches green requirement.
3rd, the methylene blue obtained by patent of the present invention, the methylene blue zinc chloride obtained using conventional method is avoided
Salt, the step of also carrying out alkali tune release free methylene blue with sodium carbonate liquor, the direct crystallization of patent of the present invention, suction filtration, baking
It is dry to obtain the product of high-purity high-quality, it is simple to operate, more suitable for industrialized production.
Brief description of the drawings
The methylene blue sample HPLC detection collection of illustrative plates that Fig. 1 embodiments 1 obtain
The methylene blue sample that Fig. 2 embodiments 1 obtain1H-NMR collection of illustrative plates
Embodiment：
Embodiment 1
1st, accelerine, the preparation of accelerine (3)
In 1000mL four-hole bottles, 116.5g 36%HCl, 81g water are added, stirs and is cooled to 0~5 DEG C, be slowly added dropwise
58g DMAs, heat release is added dropwise, is added dropwise below strict 5 DEG C of the temperature control of process palpus, completion of dropwise addition, stirs 15min, start
The solution of 36.33g natrium nitrosums and 113g water is added dropwise, it is violent to be added dropwise heat release, be added dropwise process must strict 0~5 DEG C of temperature control, during dropwise addition
Between be 4~5 hours, completion of dropwise addition, 0~5 DEG C of system temperature reaction 1h.Filtering, remove hydrochloric acid mother liquor, obtain solid to nitroso-
DMA hydrochloride.In 1000ml four-hole bottles, above-mentioned accelerine is added, accelerine hydrochloride,
150 toluene and 180g purified waters, mechanical agitation, start that the 45g aqueous solution of 15g sodium hydroxides is added dropwise, process control temp is added dropwise
20~30 DEG C；It is added dropwise, adds 15g solid sodium bicarbonates, stir 30min, split-phase, aqueous phase adds 35g toluene, stirring
30min, split-phase, combining methylbenzene phase, toluene are mutually decolourized 1 hour with 1g celluloses, 1g activated carbons, 1g diatomite, stirring, filtering,
Organic phase 253.79g is obtained, organic phase demarcation accelerine, accelerine content is 23.84%, and yield 84.14% is pure
Degree 94.98%.(accelerine, the detection method of accelerine, instrument high performance liquid chromatograph, pillar：Gemini
5u C18100A (250mm*4.6mm*5 μm), Detection wavelength：240nm, flow velocity：1.0mL/min；Mobile phase A：Weigh 3.85g vinegar
Sour ammonium to 1L water dissolves (50mM), and triethylamine adjusts pH=9, filters, degassing, Mobile phase B：Methanol, gradient elution).
The solid is directly used in react in next step.
2nd, to the preparation of amino-DMA (4)
253.79g accelerines are taken, the toluene phase of accelerine (3), are added in 1000mL hydriding reactors, are added simultaneously
Enter 20.0g methanol and 5.50g Raney's nickels, with nitrogen displacement three times, then again with hydrogen displacement three times, be forced into 2.0MPa, 20
Stirring reaction 6h samplings detection at DEG C, pressure release, three times, discharging, reacting liquid filtering, methanol washing filter cake, 60 DEG C subtract nitrogen displacement
Pressure-off is molten to without distillate, obtains grease, grease is evaporated under reduced pressure using oil pump (3mmHg), collects distillate
45.83g, 82~85 DEG C of top temperature control system are to amino-DMA (4), yield 83.43%, purity 99.72%.
(to the detection method of amino-DMA (4), instrument GC-2010, HP-5MS (30m*0.25mm*0.25 μm), post
Flow velocity：1.00mL/min clean flow velocity：3.0ml/min compensation currents speed：30ml/min hydrogen flow rates：40ml/min air streams
Speed：400ml/min)
3rd, the preparation of 2- amino -5- dimethylamino phenyls thiosulfonic acid (5)
In 1000ml four-hole bottles, 11.2g is added to amino-DMA (4) and 250g water, stirring ice-water bath
0 DEG C is cooled to, adds 21.2g Iron dichloride tetrahydrates, stirs 10 minutes with 36% salt acid for adjusting pH to 4.0, disposable addition
28.2g Patent alums, are finished, and stir 5min, are kept for 0 DEG C, and the 25g for adding 22.6g hypos is water-soluble
Liquid, finish, stir 5min, 0 DEG C of temperature, adding 0.12g, (0.5% mole, the mol ratio of sodium dichromate dihydrate is with to ammonia
Base-DMA meter) sodium dichromate dihydrate, the 40g aqueous solution of 26.8g ferric chloride hexahydrates is added dropwise, drips
Add process control temp between 0~1 DEG C.0.5h or so is added dropwise, and is added dropwise, and stirring reaction 1h, directly enters at 0 DEG C
Row reacts in next step.
4th, the preparation of double (4- dimethylamino phenyls) thiosulfonic acids (6)
10g DMAs (2), 10g water are added in 50ml single-necked flasks, ice-water bath is cooled to 0 DEG C, stirring
The 8g concentrated sulfuric acids are instilled under state, heat release, 0~2 DEG C of dropping temperature is controlled, is added dropwise, continue to stir 10min, by the reaction solution
Disposably pour into (preparing in reaction solution for 2- amino -5- dimethylamino phenyl thiosulfonic acids) above-mentioned reaction solution, 69.7g is added dropwise
The 70g aqueous solution of ferric chloride hexahydrate, process control temp is added dropwise between 0~2 DEG C, 0.5h or so is added dropwise, drop
Stirring keeps 4h at 0 DEG C after adding, and adds 10g celluloses, stirs 15min, directly carries out next step reaction.
5th, the preparation (1) of methylene blue
Prepared to double (4- dimethylamino phenyls) thiosulfonic acid (6) in reaction solution, add 1.3g anhydrous cupric sulfates, will be anti-
Liquid is answered to be warming up to 60 DEG C, stirring keeps 1h, filters while hot, filter cake 4 × 100g, 60 DEG C of hot washes, collects filtrate, adds
0.4g activated carbons, heat up 60~65 DEG C, stir decolouring 30min, filter while hot, collect filtrate, filtrate is cooled to 15~20 DEG C, drop
Adding 36%HCl 18g, adjust pH=0.5, slow cooling filters, 0~5 DEG C of 2 × 20g of filter cake to crystallization 18h is stirred at room temperature,
The diluted hydrochloric acid aqueous solution that pH value is 1 washes twice, and then washed once with 0~5 DEG C of purified water of 20g, obtains wet product, wet product is 40
18h (vacuum 22mmHg) is dried under reduced pressure at DEG C.Methylene blue product 15.38g is obtained, yield 49.00% (for demarcation receive by yield
Rate), purity 96.24%.(detection method of methylene blue (1), high performance liquid chromatograph, Zorbax EclipseXDB
Phenyl (150mm*4.6mm*3.5 μm), Detection wavelength 284nm, flow velocity 1.5mL/min, mobile phase A：Accurately pipette
5.00mL trifluoroacetic acids are in 4995mL water, after fully mixing, ultrasound degassing, and Mobile phase B：Acetonitrile, ultrasound degassing, gradient are washed
It is de-, see Fig. 1).Fig. 2 is methylene blue sample1H-NMR collection of illustrative plates,1H NMR (400MHz, D2O) δ 2.91 (2N (CH3) 2,12H),
6.55 (Ar-H, 2H), 6.78 (Ar-H, 2H), 7.00 (Ar-H, 2H)
Embodiment 2
1st, accelerine, the preparation of accelerine (3)
In 1000mL four-hole bottles, 116.5g 36%HCl, 81g water are added, stirs and is cooled to 0~5 DEG C, be slowly added dropwise
58g DMAs, heat release is added dropwise, is added dropwise below strict 5 DEG C of the temperature control of process palpus, completion of dropwise addition, stirs 15min, start
The solution of 36.33g natrium nitrosums and 113g water is added dropwise, it is violent to be added dropwise heat release, be added dropwise process must strict 0~5 DEG C of temperature control, during dropwise addition
Between be 4~5 hours, completion of dropwise addition, 0~5 DEG C of system temperature reaction 1h.Filtering, remove hydrochloric acid mother liquor, obtain solid to nitroso-
DMA hydrochloride.In 1000ml four-hole bottles, above-mentioned accelerine is added, accelerine hydrochloride,
150g dichloromethane and 180g purified waters, mechanical agitation, start that the 45g aqueous solution of 15g sodium hydroxides is added dropwise, process control is added dropwise
20~30 DEG C of temperature；It is added dropwise, adds 15g solid sodium bicarbonates, stirs 30min, split-phase, aqueous phase adds 35g dichloromethane,
30min is stirred, split-phase, combined dichloromethane phase, dichloromethane is mutually with 1g celluloses, 1g activated carbons, 1g diatomite, stirring decolouring
1 hour, filtering, organic phase 255.74g is obtained, organic phase demarcation accelerine, accelerine content is 25.00%, is received
Rate 88.92%, purity 95.04%.(accelerine, the detection method of accelerine (3), instrument high performance liquid chromatography
Instrument, pillar：Gemini 5u C18 100A (250mm*4.6mm*5 μm), Detection wavelength：240nm, flow velocity：1.0mL/min；Stream
Dynamic phase A：Weigh 3.85g ammonium acetates to 1L water and dissolve (50mM), triethylamine adjusts PH=9, filters, degassing, Mobile phase B：Methanol, ladder
Degree elution).The solid is directly used in react in next step.
2nd, to the preparation of amino-DMA (4)
255.74g accelerines are taken, the dichloromethane phase of accelerine (3), are added in 1000mL hydriding reactors, together
When add 20.0g methanol and 5.50g Raney's nickels, with nitrogen displacement three times, then again with hydrogen displacement three times, be forced into
3.0MPa, stirring reaction 6h samplings detection at 35 DEG C, pressure release, nitrogen displacement three times, discharging, reacting liquid filtering, methanol washing filter
Cake, 60 DEG C of decompression precipitations obtain grease, grease is evaporated under reduced pressure using oil pump (3mmHg), and collection evaporates to without distillate
Go out liquid 47.66g, 82~85 DEG C of top temperature control system is to amino-DMA (4), yield 82.10%, purity
99.87%.(to the detection method of amino-DMA (4), instrument GC-2010, HP-5MS (30m*0.25mm*
0.25 μm), column flow rate：1.00mL/min clean flow velocity：3.0ml/min compensation currents speed：30ml/min hydrogen flow rates：
40ml/min air velocitys：400ml/min)
3rd, the preparation of 2- amino -5- dimethylamino phenyls thiosulfonic acid (5)
In 1000ml four-hole bottles, 11.2g is added to amino-DMA (4) and 250g water, stirring ice-water bath
10 DEG C are cooled to, adds 21.2g Iron dichloride tetrahydrates, stirs 10 minutes with 36% salt acid for adjusting pH to 4.0, disposable addition
28.2g Patent alums, are finished, and stir 5min, are kept for 10 DEG C, and the 25g for adding 22.6g hypos is water-soluble
Liquid, finish, stir 5min, 10 DEG C of temperature, add 0.25g (1% mole, the mol ratio of sodium dichromate dihydrate with to amino-
DMA meter) sodium dichromate dihydrate, the 40g aqueous solution of 26.8g ferric chloride hexahydrates is added dropwise, was added dropwise
Process control temperature is between 8~10 DEG C.0.5h or so is added dropwise, and is added dropwise, the stirring reaction 1h at 10 DEG C, directly carries out
React in next step.
4th, the preparation of double (4- dimethylamino phenyls) thiosulfonic acids (6)
10g DMAs (2), 10g water are added in 50ml single-necked flasks, ice-water bath is cooled to 10 DEG C, stirring
The 8g concentrated sulfuric acids are instilled under state, heat release, 10 DEG C of dropping temperature is controlled, is added dropwise, continue to stir 10min, by the reaction solution one
Secondary property is poured into (preparing in reaction solution for 2- amino -5- dimethylamino phenyl thiosulfonic acids) above-mentioned reaction solution, and 69.7g tri- is added dropwise
The 70g aqueous solution of ferric chloride hexahydrate, process control temp is added dropwise between 8~10 DEG C, 0.5h or so is added dropwise, and is added dropwise
After at 10 DEG C stirring keep 4h, add 10g celluloses, stir 15min, directly progress next step reaction.
5th, the preparation (1) of methylene blue
Prepared to double (4- dimethylamino phenyls) thiosulfonic acid (6) in reaction solution, add 1.3g anhydrous cupric sulfates, will be anti-
Liquid is answered to be warming up to 75 DEG C, stirring keeps 1h, filters while hot, filter cake 4 × 100g, 60 DEG C of hot washes, collects filtrate, adds
0.4g activated carbons, heat up 60~65 DEG C, stir decolouring 30min, filter while hot, collect filtrate, filtrate is cooled to 15~20 DEG C, drop
Adding 36%HCl 18g, adjust pH=1.0, slow cooling filters, 0~5 DEG C of 2 × 20g of filter cake to crystallization 18h is stirred at room temperature,
The diluted hydrochloric acid aqueous solution that pH value is 1 washes twice, and then washed once with 0~5 DEG C of purified water of 20g, obtains wet product, wet product is 40
18h (vacuum 22mmHg) is dried under reduced pressure at DEG C.Methylene blue product 15.20g is obtained, yield 48.92% (for demarcation receive by yield
Rate), purity 94.57%.(detection method of methylene blue (1), high performance liquid chromatograph, Zorbax Eclipse XDB
Phenyl (150mm*4.6mm*3.5 μm), Detection wavelength 284nm, flow velocity 1.5mL/min, mobile phase A：Accurately pipette
5.00mL trifluoroacetic acids are in 4995mL water, after fully mixing, ultrasound degassing, and Mobile phase B：Acetonitrile, ultrasound degassing, gradient are washed
It is de-).
Embodiment 3
1st, accelerine, the preparation of accelerine (3)
In 1000mL four-hole bottles, 116.5g 36%HCl, 81g water are added, stirs and is cooled to 0~5 DEG C, be slowly added dropwise
58g DMAs, heat release is added dropwise, is added dropwise below strict 5 DEG C of the temperature control of process palpus, completion of dropwise addition, stirs 15min, start
The solution of 36.33g natrium nitrosums and 113g water is added dropwise, it is violent to be added dropwise heat release, be added dropwise process must strict 0~5 DEG C of temperature control, during dropwise addition
Between be 4~5 hours, completion of dropwise addition, 0~5 DEG C of system temperature reaction 1h.Filtering, remove hydrochloric acid mother liquor, obtain solid to nitroso-
DMA hydrochloride.In 1000ml four-hole bottles, above-mentioned accelerine is added, accelerine hydrochloride,
150g ethyl acetate and 180g purified waters, mechanical agitation, start that the 45g aqueous solution of 15g sodium hydroxides is added dropwise, process control is added dropwise
20~30 DEG C of temperature；It is added dropwise, adds 15g solid sodium bicarbonates, stirs 30min, split-phase, aqueous phase adds 35g ethyl acetate,
Stir 30min, split-phase, combined ethyl acetate phase, ethyl acetate phase 1g celluloses, 1g activated carbons, 1g diatomite, stirring decolouring
1 hour, filtering, organic phase 251.67g is obtained, organic phase demarcation accelerine, accelerine content is 24.64%, is received
Rate 86.25%, purity 93.97%.(accelerine, the detection method of accelerine (3), instrument high performance liquid chromatography
Instrument, pillar：The 100A (250mm*4.6mm*5 μm) of Gemini 5u C 18, Detection wavelength：240nm, flow velocity：1.0mL/min；Stream
Dynamic phase A：Weigh 3.85g ammonium acetates to 1L water and dissolve (50mM), triethylamine adjusts PH=9, filters, degassing, Mobile phase B：Methanol, ladder
Degree elution).The solid is directly used in react in next step.
2nd, to the preparation of amino-DMA (4)
251.67g accelerines are taken, the ethyl acetate phase of accelerine (3), are added in 1000mL hydriding reactors, together
When add 20.0g methanol and 5.50g Raney's nickels, with nitrogen displacement three times, then again with hydrogen displacement three times, be forced into
4.0MPa, stirring reaction 6h samplings detection at 50 DEG C, pressure release, nitrogen displacement three times, discharging, reacting liquid filtering, methanol washing filter
Cake, 60 DEG C of decompression precipitations obtain grease, grease is evaporated under reduced pressure using oil pump (3mmHg), and collection evaporates to without distillate
Go out liquid 46.32g, 82~85 DEG C of top temperature control system is to amino-DMA (4), yield 82.27%, purity
99.85%.(to the detection method of amino-DMA (4), instrument GC-2010, HP-5MS (30m*0.25mm*
0.25 μm), column flow rate：1.00mL/min clean flow velocity：3.0ml/min compensation currents speed：30ml/min hydrogen flow rates：
40ml/min air velocitys：400ml/min)
3rd, the preparation of 2- amino -5- dimethylamino phenyls thiosulfonic acid (5)
In 1000ml four-hole bottles, 11.2g is added to amino-DMA (4) and 250g water, stirring ice-water bath
20 DEG C are cooled to, adds 21.2g Iron dichloride tetrahydrates, stirs 10 minutes with 36% salt acid for adjusting pH to 4.0, disposable addition
28.2g Patent alums, are finished, and stir 5min, are kept for 20 DEG C, and the 25g for adding 22.6g hypos is water-soluble
Liquid, finish, stir 5min, 20 DEG C of temperature, adding 1.25g, (5.0% mole, the mol ratio of sodium dichromate dihydrate is with to ammonia
Base-DMA meter) sodium dichromate dihydrate, the 40g aqueous solution of 26.8g ferric chloride hexahydrates is added dropwise, drips
Add process control temp between 18~20 DEG C.0.5h or so is added dropwise, and is added dropwise, the stirring reaction 1h at 20 DEG C, directly
Row is tapped into react in next step.
4th, the preparation of double (4- dimethylamino phenyls) thiosulfonic acids (6)
10g DMAs (2), 10g water are added in 50ml single-necked flasks, ice-water bath is cooled to 20 DEG C, stirring
The 8g concentrated sulfuric acids are instilled under state, heat release, 18~20 DEG C of dropping temperature is controlled, is added dropwise, continues to stir 10min, this is reacted
Liquid is disposably poured into (preparing in reaction solution for 2- amino -5- dimethylamino phenyl thiosulfonic acids) above-mentioned reaction solution, is added dropwise
The 70g aqueous solution of 69.7g ferric chloride hexahydrates, process control temp is added dropwise between 18~20 DEG C, 0.5h or so is added dropwise
Finish, stirring keeps 4h at 20 DEG C after being added dropwise, and adds 10g celluloses, stirs 15min, directly carries out next step reaction.
5th, the preparation (1) of methylene blue
Prepared to double (4- dimethylamino phenyls) thiosulfonic acid (6) in reaction solution, add 1.3g anhydrous cupric sulfates, will be anti-
Liquid is answered to be warming up to 90 DEG C, stirring keeps 1h, filters while hot, filter cake 4 × 100g, 60 DEG C of hot washes, collects filtrate, adds
0.4g activated carbons, heat up 60~65 DEG C, stir decolouring 30min, filter while hot, collect filtrate, filtrate is cooled to 15~20 DEG C, drop
Adding 36%HCl 18g, adjust pH=2.0, slow cooling filters, 0~5 DEG C of 2 × 20g of filter cake to crystallization 18h is stirred at room temperature,
The diluted hydrochloric acid aqueous solution that pH value is 1 washes twice, and then washed once with 0~5 DEG C of purified water of 20g, obtains wet product, wet product is 40
18h (vacuum 22mmHg) is dried under reduced pressure at DEG C.Methylene blue product 15.90g is obtained, yield 51.72% (for demarcation receive by yield
Rate), purity 94.36%.(detection method of methylene blue (1), high performance liquid chromatograph, Zorbax Eclipse XDB
Phenyl (150mm*4.6mm*3.5 μm), Detection wavelength 284nm, flow velocity 1.5mL/min, mobile phase A：Accurately pipette
5.00mL trifluoroacetic acids are in 4995mL water, after fully mixing, ultrasound degassing, and Mobile phase B：Acetonitrile, ultrasound degassing, gradient are washed
It is de-).
Claims (10)
1. a kind of preparation method of methylene blue as shown in formula (1), its step are as follows：
Step 1：In concentrated hydrochloric acid solution, it is anti-with the DMA as shown in formula (2) to carry out nitrosation with natrium nitrosum
The intermediate accelerine as shown in formula (3) should be prepared, accelerine, separation will be such as the centre shown in formula (3)
Body accelerine, accelerine are tuned into free state with alkali, extract, and decolourize, obtain accelerine, accelerine
Toluene solution；
Step 2：In toluene solvant, hydrogenated by raney ni catalysis, will be such as the accelerine shown in formula (3), N- dimethyl
Aniline toluene solution carry out hydro-reduction, be prepared into as shown in formula (4) to amino-DMA；
Step 3：Amino-DMA will be aoxidized as shown in formula (4), then used using ferric trichloride in water
Sodium thiosulfate is substituted, and is prepared into the 2- amino -5- dimethylamino phenyl thiosulfonic acids as shown in formula (5)；Using urging
Agent sodium dichromate participates in reaction, and sodium dichromate used is with being 0.001~0.1 to the mol ratio of amino-DMA；
Step 4：In the presence of ferric trichloride, 2- amino -5- dimethylamino phenyls thiosulfonic acid as shown in formula (5) with such as
DMA oxidative condensation shown in formula (2) generates double (4- dimethylamino phenyls) thio sulphurs as shown in formula (6)
Acid；
Step 5：It is anti-by catalysis of cupric sulphate, double (4- dimethylamino phenyls) thiosulfonic acids progress cyclizations that will be as shown in formula (6)
Should, obtain the methylene blue as shown in formula (1).
2. preparation method according to claim 1, it is characterized in that：In step 1, described alkali is sodium hydroxide or carbonic acid
The one or two of hydrogen sodium.
3. preparation method according to claim 1, it is characterized in that：In step 2, reaction temperature is 10~80 DEG C；Reaction pressure
Power is 0.5~5.0Mpa.
4. preparation method according to claim 3, it is characterized in that：In step 2, described reaction temperature is 20~40 DEG C；
Described reaction pressure is 2.0~4.0Mpa.
5. preparation method according to claim 1, it is characterized in that：In step 3, reaction temperature is 0~60 DEG C.
6. preparation method according to claim 1, it is characterized in that：In step 3, sodium dichromate used with to amino-N, N-
The mol ratio 0.005~0.05 of dimethylaniline；Reaction temperature is 0~20 DEG C.
7. preparation method according to claim 1, it is characterized in that：In step 4, reaction temperature is 0~60 DEG C.
8. preparation method according to claim 7, it is characterized in that：In step 4, reaction temperature is 0~20 DEG C.
9. preparation method according to claim 1, it is characterized in that：In step 5, reaction temperature is 10~100 DEG C；Described
The reaction solution of step (5), it is 0~3 with hydrochloric acid solution regulation pH value after filtering.
10. preparation method according to claim 9, it is characterized in that：In step 5, described reaction temperature is 60~90 DEG C；
The reaction solution of described step (5), it is 0.5~2.0 with hydrochloric acid solution regulation pH value after filtering.
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| CN111303076A (en) * | 2020-03-03 | 2020-06-19 | 中国水产科学研究院东海水产研究所 | Preparation method of methylene blue hapten and methylene blue immunogen |
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| Synthesis and properties of some 7-dimethylamino-1,4-benzoxazin-2-ones;Le Bris et al.;《Journal of Heterocyclic Chemistry》;19851231;第22卷(第5期);1275-1280 * |
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