CN1970548A - Medicinal methylene blue synthesis method - Google Patents
Medicinal methylene blue synthesis method Download PDFInfo
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- CN1970548A CN1970548A CNA2006102013069A CN200610201306A CN1970548A CN 1970548 A CN1970548 A CN 1970548A CN A2006102013069 A CNA2006102013069 A CN A2006102013069A CN 200610201306 A CN200610201306 A CN 200610201306A CN 1970548 A CN1970548 A CN 1970548A
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Abstract
The invention discloses a synthesizing method of medicinal methylen blue, which is characterized by the following: adopting N, N-dimethyl p-phenylene diamine hydrochlorate as raw material; obtaining 2-amino-5-dimethyl amino phenyl thiosulfonic acid oxidized by sodium dichromate and substituted by natrium thiosulfuricum; condensing with N, N-dimethyl p-phenylene diamine to obtain methylen blue zinc chloride salt oxidized by magnesium dioxide; neutralizing methylen blue zinc chloride salt through sodium carbonate to obtain methylen blue.
Description
Technical field: the present invention relates to a kind of synthetic method of medicinal methylene blue, belong to the pharmaceutical chemistry synthesis technical field.
Background technology: (Methylene blue MB) also claims methylene blue, methylene blue, methylene blue to methylenum coeruleum.Methylenum coeruleum is synthesized in 1876 with the chlorination zinc salt the earliest, is mainly used in thereafter: (1) methemoglobinemia: the lower concentration methylenum coeruleum is used for the treatment of nitrite, oxymuriate, quinones, quinone imides, aniline and oil of mirbane etc. and causes methemoglobinemia; (2) cyanide poisoning: the high density methylenum coeruleum can be used for cyanide poisoning; (3) share and be used for local analgesia with local anaesthetics; (4) clinical in recent years also trying out in treatment infectivity and traumatic shock, cancer, zoster etc.Pharmacological research shows that methylenum coeruleum has detoxification, analgesic activity, anti-microbial effect, antivirus action, antitumor action and can correct the haemodynamics disorder of patients with septic shock, treatment priapism.
At present, the synthetic route of the relevant methylenum coeruleum of bibliographical information mainly contains following two kinds of methods:
Method one: with N, the N-dimethyl-p-phenylenediamine is a raw material, through the Manganse Dioxide oxidation, Sulfothiorine replaces, and obtains 2 amino-5-dimethylamino phenyl thiosulfonic acid, the latter and N, after the accelerine condensation,, obtain methylenum coeruleum chlorination zinc salt again through Manganse Dioxide and copper sulfate dioxide giving.The latter with yellow soda ash neutralize the target compound methylenum coeruleum.Synthesis route is as follows
Method two: with N, accelerine is a raw material, and through nitrosification, iron powder reducing obtains N, the N-dimethyl-p-phenylenediamine.The latter is through the sodium dichromate 99 oxidation, and Sulfothiorine replaces, and obtains 2-amino-5-dimethylamino phenyl thiosulfonic acid.Itself and N after the accelerine condensation, again through sodium dichromate 99 and copper sulfate dioxide giving, obtain methylenum coeruleum chlorination zinc salt.The latter with yellow soda ash neutralize the target compound methylenum coeruleum.Synthesis route is as follows:
The reaction scheme of above-mentioned two kinds of methods is multiple basically, and wherein difference mainly is the selection difference of oxygenant in the reaction process.Method one and method two are all reacting under cold condition before the cyclization, and the process that feeds intake is more loaded down with trivial details, is unfavorable for industrial production; Its reaction process is the hydrosulfate that obtains methylenum coeruleum earlier, and then handles and to obtain methylenum coeruleum, makes the reaction times longer relatively.
Summary of the invention:
The objective of the invention is to: the synthetic method that a kind of medicinal methylene blue is provided.The present invention is directed to the deficiencies in the prior art, with N, N-dimethyl-p-phenylenediamine hydrochloride is a raw material, through the sodium dichromate 99 oxidation, Sulfothiorine replaces, and obtains 2-amino-5-dimethylamino phenyl thiosulfonic acid, then with N, after the N-dimethyl-p-phenylenediamine condensation,, in the presence of zinc chloride, obtain methylenum coeruleum chlorination zinc salt through the Manganse Dioxide dioxide giving; Methylenum coeruleum chlorination zinc salt again with in the yellow soda ash and after obtain methylenum coeruleum.This synthetic method is simple, and cost is lower, invests for a short time, and raw material is easy to get, and is suitable for suitability for industrialized production, and the product purity that obtains is higher, and environmental pollution is less.
The present invention is achieved in that the synthetic method of medicinal methylene blue is: with the P-aminodimethylaniline hydrochloride is starting raw material, makes methylenum coeruleum according to following circuit reaction:
Concrete synthetic method is: calculate according to the molar mass ratio, take by weighing 2 parts of P-aminodimethylaniline hydrochlorides, drop in the reactor of band thermometer, be dissolved in water, stir and drip 0.41 part of the vitriol oil down, add zinc chloride content under the room temperature successively and be 4.95 parts solution, Tai-Ace S 150 content is 1.00 parts solution, sodium thiosulfate content is 2.12 parts a solution, and adding sodium dichromate 99 content is 0.72 part solution, stir down reaction solution is heated to 30～50 ℃ rapidly, with N, accelerine content is that 1.65 parts hydrochloric acid soln drops into reactor, immediately add sodium dichromate 99 content and be 1.45 parts solution, be heated to 60～80 ℃ rapidly, 2.87 parts of Manganse Dioxide are dropped into reactor, be heated to 80～90 ℃, holding temperature reaction 20～40 minutes, be cooled to 40～60 ℃, stir and slowly add 7.14 parts of the vitriol oils down, emit reaction solution after stirring evenly, placed 4～6 hours down in 4 ℃ of environment, separate out precipitation, suction filtration, filter cake washs with 10% sodium chloride aqueous solution, filter cake is transferred in the beaker, adds entry, on electric mantle, be heated with stirring to boiling, suction filtration while hot, 25.64 parts in 1.84 parts of filtrate adding zinc chloride and sodium-chlor stir and make dissolving, again this solution are placed 22～26h down in 4 ℃ of environment, suction filtration, 45～55 ℃ of dry methylene blue chlorination zinc salts that get; Gained chlorination zinc salt is dissolved in the water, add 0.52 part in yellow soda ash, be chilled to room temperature, suction filtration, less water filter wash cake adds 17.09 parts in sodium-chlor, placed 10～14 hours down in 4 ℃ of environment after the stirring and dissolving, suction filtration, filter cake got the methylenum coeruleum crude product in 11～13 hours in 40-45 ℃ of drying, and the water recrystallization is promptly for several times then.
Synthetic method is more specifically: take by weighing P-aminodimethylaniline hydrochloride 2mol, be 418g, drop in the reactor of band thermometer, add the 6L water dissolution, stir and drip vitriol oil 0.41mol down, be 40g, add liquor zinci chloridi 500mL under the room temperature successively, alum liquor 600mL, hypo solution 500mL, and add the 300mL sodium dichromate solution rapidly, stir down reaction solution in 10 minutes internal heating to 40 ℃, with N, the hydrochloric acid soln 227ml of accelerine drops into reactor, immediately add remaining 600mL sodium dichromate solution, in 10 minutes internal heating to 70 ℃; When temperature reaches 70 ℃, with 2.87mol, be that 250g Manganse Dioxide drops into reactor, be heated to 85 ℃, holding temperature reaction 30 minutes is cooled to 50 ℃ naturally, stirs down slowly adding vitriol oil 7.14mol, is 700g; Emit reaction solution after stirring evenly, placed 5 hours down in 4 ℃ of environment, separate out precipitation, suction filtration, filter cake wash with 10% sodium chloride aqueous solution 600mL; Filter cake is transferred in the 20L beaker, add 10L water, on electric mantle, be heated with stirring to boiling, suction filtration while hot, filtrate adds 1.84mol, is 250g zinc chloride and 25.64mol, is 1500g sodium-chlor, stirs and makes dissolving, again this solution is placed 24h down in 4 ℃ of environment, suction filtration, 50 ℃ of dry methylene blue chlorination zinc salts that get; Gained chlorination zinc salt is dissolved in the 10L water, add yellow soda ash 0.52mol, be 55.2g, be chilled to room temperature, suction filtration, less water filter wash cake adds sodium-chlor 17.09mol, is 1000g, placed 12 hours down in 4 ℃ of environment after the stirring and dissolving, suction filtration, filter cake in 40-45 ℃ of drying 12 hours the methylenum coeruleum crude product, then promptly with the water recrystallization several of 4 times of weight.
More than used liquor zinci chloridi concentration be 9.9mol/l, wherein also contain the sodium dichromate 99 of 0.016mol/l.
Used alum liquor concentration is 1.67mol/l.
Used hypo solution concentration is 4.24mol/l.
Used sodium dichromate solution concentration is 2.41mol/l.
Used N, the concentration of hydrochloric acid solution of accelerine are 7.27mol/l.
The used main raw material of the present invention, reagent source and specification:
| Raw material reagent | Reagent source | Specification |
| The P-aminodimethylaniline hydrochloride | Shanghai San'aisi Reagent Co., Ltd. | CP |
| N, accelerine | Shenyang City's reagent three factories | CP |
| Hydrochloric acid | Chemical reagent factory of Zun Yi college of education | AR |
| Sulfuric acid | Chuanjiang River, Chongqing chemical reagent factory | AR |
| Five water Sulfothiorine | Tianjin strive forward Te Jier green technology institute | AR |
| Zinc chloride | Tianjin section close europeanized reagent development centre | AR |
| 18 water Tai-Ace S 150 | South Platform China prosperous chemical industry company limited | AR |
| Sodium dichromate dehydrate | Shen, Tianjin safe chemical reagent company limited | CP |
| Manganse Dioxide | Tianjin chemical reagent three factories | CP |
| Anhydrous sodium carbonate | State-run Chongqing inorganic chemical reagent factory | CP |
| Sodium-chlor | Kingsoft, Chengdu chemical reagent factory | CP |
Chemical equation of the present invention and reaction conditions are as follows:
Product of the present invention has several quality control key points in process of production: the one, the reaction in several times heat-up rate should be strict controlled in the time of process stipulation; The 2nd, the related substance in the purified product needs to check to be controlled in the specialized range with HPLC; The 3rd, temperature need be controlled at 40-45 ℃ in the product drying process, and too high meeting causes weight loss on drying unusual, and it is longer to spend low then time of drying.
The crude product quality control: bibliographical information in the methylenum coeruleum building-up process, can bring into the demethylation methylenum coeruleum (impurity A in the European Pharmacopoeia, chemistry is by name: chlorination 3-dimethylamino-7-(methylamino-) thiodiphenylamine-5-), its structure is:
Detect through HPLC, the content of demethylation methylenum coeruleum is lower than 7% in the crude product.
Elaboration quality control: HPLC area normalization method: demethylation methylenum coeruleum＜5.0%, other single impurity peak area must not be greater than 0.5%, and other impurity peak area sums except that the demethylation methylenum coeruleum must not be greater than 1%.If any process for purification water that exceeds standard then by crude product continues recrystallization to qualified.
The inventive method is from N, and the N-dimethyl-p-phenylenediamine rises to all operations that obtains methylenum coeruleum chlorination zinc salt synthetic for " one kettle way ", and the applicant arrives pilot scale again and produces with amplifying through the preparation of laboratory lab scale, and this synthesis technique is more suitable in suitability for industrialized production.Through experimental verification, the designed chemical synthesis route of the present invention is feasible.
In order to verify product of the present invention, the applicant has carried out confirmatory test to the chemical structure of methylenum coeruleum, and is specific as follows:
1. the structural formula of methylenum coeruleum, molecular formula and molecular weight
Chemical name: chlorination 3, two (dimethylamino) thiodiphenylamine of 7--5-trihydrate
Structural formula:
Molecular formula: C
16H
18ClN
3S3H
2O
Molecular weight: 373.90
2. structural identification is with methylenum coeruleum bulk drug sample and import reference substance
2.1 bulk drug sample source and lot number
(lot number: 060407), be moving phase with anhydrous formic acid-n-propyl alcohol, 200-300 order silica gel column chromatography is collected methylenum coeruleum component stream fluid to self-control methylenum coeruleum raw material, removes solvent under reduced pressure, residue twice in (4 times of weight water) recrystallization in water.Crystallization got highly finished product in 12 hours in 43-45 ℃ of constant pressure and dry.This product drying weightlessness is 16.4%.
2.1.1 bulk drug sample purity inspection method
Adopt high performance liquid chromatography (HPLC) peak area normalization method to survey purity.
Instrument: Aglient 1100, ChemStation chromatographic working station
Chromatographic column: octadecylsilane chemically bonded silica is the chromatographic column of weighting agent, i.e. C
18Chromatographic column (250mm * 4.6mm, 5 μ m).
Moving phase: be moving phase with 0.34% phosphoric acid solution (get phosphoric acid 3.4ml, be dissolved in water, add triethylamine and transfer pH to 3.0)-acetonitrile (73: 27) to 1000ml
Detect wavelength: 246nm
Flow velocity: 1.0ml/min
2.1.2 bulk drug sample purity check result
By above condition and method sample has been carried out purity test, its purity reaches 99.52% as a result, meets the requirement of structural confirmation with sample.
3. methylenum coeruleum bulk drug chemical structure is proved conclusively
The chemical structure of synthetic methylenum coeruleum bulk drug in order to prove conclusively, the applicant has carried out ultimate analysis, UV spectrum, infrared spectra, nucleus magnetic resonance, mass spectrum, differential thermal analysis and thermogravimetric analysis, powder x-ray diffraction to it.
Differential thermal analysis and thermogravimetric analysis are measured by Guizhou Normal University; Ultimate analysis, nucleus magnetic resonance, mass spectrum are measured by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences, Guizhou natural product chemistry key lab of Chinese Academy of Sciences institute of materia medica; Infrared spectra, UV spectrum are measured by Guiyang Medical College Institute of Analysis; Powder x-ray diffraction is measured by Chinese Academy of Sciences's Kweiyang geochemical investigation.
3.1 ultimate analysis
3.1.1 determining instrument
Vario EL elemental analyser; Kratos MS80 high-resolution mass spectrometer
3.1.2 measurement result
Table 1 results of elemental analyses
| C％ | H％ | N％ | ||
| Measured value | For the first time | 50.03 | 6.47 | 11.23 |
| For the second time | 50.05 | 6.46 | 11.42 | |
| Theoretical value | Anhydride | 60.08 | 5.67 | 13.14 |
| 3.5 water thing | 50.19 | 6.58 | 10.97 | |
High resolution mass spectrum analytical results: 284.1208[C
16H
18N
3S
+, calculated value: 284.1221].
3.1.3 conclusion
The weight loss on drying of this sample is 16.4%, shows to contain recrystallisation solvent water in the sample.The ultimate analysis experimental value of sample conforms to the calculated value that methylenum coeruleum a part contains 3.5 molecular waters.Thermogravimetric analysis shows that methylenum coeruleum is one to contain the compound of 3 crystal water, is that drying is not introduced fully so infer other 0.5 water molecules.
For further measuring the elementary composition of methylenum coeruleum molecule, carried out the high resolution mass spectrum analysis of methylenum coeruleum sample.High resolution mass spectrum shows the elementary composition C of being of the salt base section of institute's synthetic molecules
16H
18N
3S.
According to ultimate analysis and high resolution mass spectrum analytical results, the molecular formula of linkage heat weight analysis decidable institute synthetic compound is C
16H
18ClN
3S3H
2O.
3.2 ultra-violet absorption spectrum
3.2.1 determining instrument, condition and method:
Use Tianjin, island UV-2401PC ultraviolet spectrophotometer; According to pharmacopeia regulation, the methylenum coeruleum sample is made into the certain density aqueous solution, 0.1mol/L HCl solution and 0.1mol/L NaOH solution, with making blank with batch solvent, and respectively with standard control, employing 1cm cuvette is in the interscan of 190-900nm scope.
3.2.2 measurement result
The ultra-violet absorption spectrum data of table 2 methylenum coeruleum
| λ max(nm) | A | |||
| Sample | Standard substance | Sample | Standard substance | |
| The aqueous solution (10 μ g/ml) | 664.00 | 664.00 | 2.1641 | 2.0098 |
| 615.50 | 615.50 | 1.2528 | 1.1560 | |
| 292.00 | 292.00 | 1.2041 | 1.1207 | |
| 0.1mol/L HCl solution (10 μ g/ml) | 665.00 | 664.00 | 1.9463 | 1.9133 |
| 613.50 | 614.00 | 1.2437 | 1.2249 | |
| 292.00 | 292.00 | 1.1682 | 1.1553 | |
| 0.1mol/L NaOH solution (10 μ g/ml) | 663.00 | 663.00 | 0.9947 | 0.9720 |
| 614.50 | 614.50 | 0.9897 | 0.9804 | |
| 286.50 | 287.00 | 0.9603 | 0.9621 | |
3.2.3 resolve
This product 292.00nm absorption peak in neutral (water) solution is aromatic ring B band, and because of it moves to the long wave direction, illustrating to have in the molecule has electron donating group group on aromatic ring structure and the aromatic ring; Acidic solution and basic solution B band absorb mobile not obvious, illustrate that compound is stable under acid and alkaline condition.In addition from the contrast of standard substance as can be seen institute's synthetic compound be methylenum coeruleum.
Conclusion: the characteristic ultraviolet absorption of methylenum coeruleum samples met methylenum coeruleum structure, the sample UV spectrum in various conditions is all consistent with the UV spectrum of reference substance.
3.3 infrared absorption spectrum
3.3.1 condition determination:
Instrument:
Method: KCl pressed disc method (get the about 1mg of trial-product and place mortar, drip a small amount of anhydrous methanol dissolving, add an amount of KCl fine powder, mixing is put under the infrared lamp and toasted 5 minutes, grinds compressing tablet and measures)
3.3.2 measurement result
The ir data of table 3 methylenum coeruleum
| Absorption peak wave number (cm -1) | Intensity | Group and oscillatory type | Resolve |
| 3367.2 | In (wide) | υ O-H | Crystal water O-H stretching vibration |
| 1598.2 1489.3 | Persistent erection | υ C＝C | The stretching vibration of phenyl ring skeleton |
| 1394.5 | By force | δCH 3 | The flexural vibration of methyl |
| 1352.7，1336.2 | By force | υC Alkane-N | The stretching vibration of fragrance C and amino N |
| 1249.1，1221.6 | In | υC Virtue-N | The C-N stretching vibration of the alkyl of fragrant tertiary amine |
| 1177.2，1140.1 | In | δ＝C-H | Phenyl ring=C-H in-plane bending vibration |
| 802.9，837.7，882.8 | In | δ＝C-H | Phenyl ring=C-H out-of-plane deformation vibration |
3.3.3 resolve:
3367.2cm
-1, the absorption peak of medium tenacity and broad illustrates to have intramolecular hydrogen bond in the compound, and O-H is arranged in the molecule.
1598.8,1541.9,1488.7,1447.7cm
-1Be the phenyl ring skeletal vibration, illustrate that containing phenyl ring in the compound exists.
882.3～615.2cm
-1Be the out-of-plane deformation vibration of fragrant hydrogen, further having proved has phenyl ring to exist in the compound.
1395.3,1249.1cm
-1Herein the strong peak of Chu Xianing and in strong peak be respectively the aryl and the alkyl C-N stretching vibration of fragrant tertiary amine, illustrate that compound is a fragrant tertiary amine structure.
1355.7 1339.5 is the symmetrical stretching vibration of methyl, two peak intensities are suitable, illustrate that two methyl are connected on the same atom.
3.3.4 conclusion
The ir data of prepared sample meets the methylenum coeruleum constitutional features, with " the infrared standard diagram of methylenum coeruleum is consistent in the Chinese pharmacopoeia.
3.4 nuclear magnetic resonance spectrum
3.4.1 condition determination
Instrument: the Inova of Varian company 400 nuclear magnetic resonance spectrometers
Solvent: D
2Mark: TMS in the O
3.4.2 measurement result
Table 4 methylenum coeruleum
1H-NMR data and ownership
| Sequence number | δ(ppm) | The H number | Multiplicity | Remarks |
| 1、2、 15、16 | 2.87 | 12 | s | |
| 8、14 | 6.48-6.52 | 2 | d，J＝1.6Hz | Relevant with the hydrogen of δ 6.71-6.76ppm |
| 4、12 | 6.71-6.76 | 2 | dd，J＝9.3Hz，J＝2.2Hz | Relevant with the hydrogen of δ 6.91-6.96ppm, 6.48-6.52 |
| 5、11 | 6.91-6.96 | 2 | d，J＝9.6Hz | Relevant with the hydrogen of δ 6.71-6.76ppm |
Table 5 methylenum coeruleum
13C-NMR data and ownership
| Sequence number | δ(ppm) | Carbon number | Carbon type | Remarks |
| 1、2、15、16 | 40.642 | 4 | Primary | Relevant with the H of δ 2.87ppm |
| 8、14 | 106.036 | 2 | Uncle | Relevant with the H of δ 6.48-6.52ppm, long-range relevant with the H of δ 6.7-6.76ppm |
| 4、12 | 118.267 | 2 | Uncle | Relevant with the H of δ 6.71-6.76ppm, long-range relevant with the H of δ 6.48-6.52ppm, δ 6.91-6.96ppm |
| 7、9 | 133.490 | 2 | Season | Long-range relevant with the H of δ 6.48-6.52ppm |
| 6、10 | 133.780 | 2 | Season | Long-range relevant with the H of δ 6.71-6.76ppm, δ 6.91-6.96ppm |
| 5、11 | 136.222 | 2 | Uncle | |
| 3、13 | 152.979 | 2 | Season | Long-range relevant with the H of δ 2.87ppm, δ 6.91-6.96ppm |
3.4.3 resolve
Four groups of proton signals in the hydrogen spectrum.In conjunction with ultimate analysis and high resolution mass spectrum analytical results, should be 3 groups of totally 6 unsaturated fragrant hydrogen, 1 group of 12 saturated mono hydrogen, and the deducibility sample molecule is a height symmetrical structure.Unimodal at δ 2.85ppm place, can extrapolate according to the result who calculates integral area is 12 saturated mono hydrogen herein, move to low field orientation owing to be subjected to the influence of electron-withdrawing group or atom, relevant from its C atom as can be seen of HMQC spectrum with δ 40.642ppm.Because this C atom shows as primary in DEPT spectrum-or the second month in a season-the C atom, so deducibility herein the H signal be four and be connected-CH with the N atom
3On H.Elementary composition, the degree of unsaturation of binding molecule and symmetry can infer substantially that so far sample molecule is the thiodiphenylamine structure that two (dimethylamino) replaces.According to raw material that uses in the chemosynthesis and reaction type (seeing declaration material 8), the position of substitution of inferring dimethylamino is at 3,13.The doublet of two H of δ 6.91-6.96ppm, J value 9.6Hz should be the coupling of simple phenyl ring ortho position and produces; In conjunction with H-H cosy spectrum and the deducibility of HMQC spectrum is 5 and 11 H.Two of δ 6.71-6.76ppm are bimodal, and integral area is two H, and the J value is respectively 9.3Hz and 2.2Hz, and position hydrogen between an ortho-hydrogens and one should be arranged; In conjunction with H-H cosy spectrum and the deducibility of HMQC spectrum is 4 and 12 H.δ 6.48-6.52ppm is the doublet of two H, and J value 1.6Hz should be between simple phenyl ring digit pair and closes generation; In conjunction with H-H cosy spectrum and the deducibility of HMQC spectrum is 8 and 14 H.
Have 7 groups of peaks in the carbon spectrum, can find out from the DEPT-135 spectrum 3 groups of quaternary carbons are arranged, 4 groups of primary carbons or tertiary carbon, meet the symmetrical structure feature and the carbon atom type of methylenum coeruleum molecule.δ 40.642ppm carbon atom is primary carbon or tertiary carbon, in the HMQC spectrum with four N-CH
3On H relevant, should be four N-CH
3On the C atom; Three groups of carbon atoms of δ 106.036ppm, δ 118.267ppm, δ 136.222ppm are primary carbon or tertiary carbon, relevant with three groups of aromatic ring hydrogen respectively in the HMQC spectrum, can judge corresponding 8 and 14 C of δ 106.036ppm according to relevant hydrogen atom position, δ 118.267 corresponding 4 and 12 C, corresponding 5 and 11 C of δ 136.222ppm.Chemical shift is that one group of carbon atom of 152.979ppm is from HMBC visible itself and N-CH in three groups of quaternary carbons
3On H long-range relevant, should be 3 and 13 C; Other two groups of chemical shifts are nearer, and difficulty is distinguished from the HMBC, infer corresponding 6 and 10 C of δ 133.780ppm according to adjacent atom, corresponding 7 and 9 C of δ 133.490ppm.
So far, all 18 H and 16 C have all had more reasonably ownership, and
1H-NMR spectrum, BB+DEPT-135 compose all consistent with reference substance.
3.4.4 conclusion
Highly finished product
1H,
13C-NMR structure that spectrogram characterizes conforms to the methylenum coeruleum structure.
3.5 mass spectrum
3.5.1 condition determination
Determining instrument: Finnigan MAT 95 mass spectrometer
Mensuration mode: EI
3.5.2 MS determination data
| m/z | Relative abundance (%) |
| 285.2 | 0.16 |
| 284.2 | 0.29 |
| 269.2 | 0.93 |
| 268.2 | 5.61 |
The lytic pathway of methylenum coeruleum molecule is as follows:
The quasi-molecular ions of this product alkali is m/z 284.2 (M-Cl
-), the intensity maximum is decided to be base peak.This peak is elementary composition through the high resolution mass spectrum conclusive evidence to be: C
16H
18N
3S, hydrogen atom of this ion trap produces the quasi-molecular ions of m/z 285.2; Lose a CH
4Molecule then obtains the quasi-molecular ions of the m/z268.2 of a Schiff alkali structure, and the latter catches the quasi-molecular ions that a hydrogen atom produces m/z 269.2 again.The ion of m/z268.2 continues to lose a CH
4Molecule obtains the quasi-molecular ions of the m/z252.3 of the symmetric Schiff of containing alkali structure.
3.5.3 conclusion
Mass spectroscopy conforms to the methylenum coeruleum molecular structure.
3.6 thermogravimetric analysis and differential thermal analysis
3.6.1 condition determination
Instrument: NETZSCH STA409PC/PG; Sweep limit, 30 ℃～500 ℃; 10 ℃/min of temperature rise rate; Object of reference: Al
2O
3
3.6.2 result
The thermogravimetric analysis result of table 6 methylenum coeruleum
| X(℃) | Y(％) | ΔY(％) | ||
| Weightless for the first time | Beginning | 33.2 | 100 | 14.89 |
| Finish (℃) | 145.9 | 14.89 | ||
| Weightless for the second time | Beginning (℃) | 145.9 | 85.11 | ～16.66 |
| Finish (℃) | ～366.2 | 68.45 | ||
This product begins weightless for the first time when beginning to 33.2 ℃, until about 145.9 ℃, be total to weightless about 14.89%; Weightless for the second time beginning is more slow, about 132.5 ℃ of beginnings, and to about 366.2 ℃, weightless about 16.66%.
About for the first time weightlessness 14.89%, this process duration is short, the gradient is big, illustrates that this product may contain recrystallisation solvent.Again according to results of elemental analyses and recrystallizing technology, what can judge therefore that this process mainly loses is crystal water in the molecule, should be three molecular crystal water as calculated.For the second time weightless about 16.66%, it is comparatively mild to glide, and its lasting temperature is longer, can judge that therefore this weightlessness is to cause compound structure destruction to cause because temperature raises.
3.7 powder x-ray diffraction spectrum
Instrument: Japan's (Rigaku) D/max-rB of company type of science x-ray diffractometer
Measure the Cu target, 40KV, 60mA
3.7.1 X-ray diffraction data
| 2θ(°) | d(A°) | I/I0 | 2θ(°) | d(A°) | I/I 0 |
| 5.68 | 15.5465 | 38 | 25.00 | 3.5589 | 24 |
| 9.24 | 9.5631 | 68 | 25.60 | 3.4768 | 100 |
| 9.64 | 9.1672 | 34 | 26.24 | 3.3934 | 61 |
| 10.80 | 8.1850 | 28 | 27.08 | 3.2901 | 26 |
| 11.32 | 7.8102 | 21 | 28.08 | 3.1751 | 27 |
| 18.72 | 4.7362 | 25 | 28.48 | 3.1314 | 27 |
3.7.2 conclusion:
The powder x-ray diffraction stave is bright, and these highly finished product sample diffraction peak is sharp-pointed, and the well-crystallized of this product is described.
4. the methylenum coeruleum chemical structure is proved conclusively conclusion
(1) being used for sample that structure identifies in this experiment is synthetic with reference to methylenum coeruleum of the present invention, begins synthetic and refining the obtaining according to the known response route from simple raw material.This product is that crystallization is separated out from water at last, and weight loss on drying is 16.4%.This product results of elemental analyses and methylenum coeruleum a part (C
16H
18ClN
3S) calculated value that contains 3.5 molecular waters conforms to.High resolution mass spectrum has also illustrated the elementary composition C of being of the salt base section of institute's synthetic molecules
16H
18N
3S.Thermogravimetric analysis shows that this product contains 3 crystal water.So elementary composition and methylenum coeruleum (C of this product of deducibility
16H
18ClN
3S3H
2O) unanimity.
(2) this products molecule formula is C
16H
18ClN
3S3H
2O, calculating degree of unsaturation is 9, therefore, should have aromatic ring to exist in the molecule.UV spectrum has shown the aromatic ring B band absorption peak in the molecule, and because of this peak moves to the long wave direction, illustrating has electron donating group group on the aromatic ring in the molecule.The phenyl ring skeletal vibration is also arranged among the IR, other 1395.3,1249.1cm
-1Absorption compound tool fragrant tertiary amine structure has been described.These constitutional featuress conform to methylenum coeruleum.
(3) in the hydrogen spectrum 18 H signals are arranged, 3 groups of totally 6 fragrant hydrogen, 1 group of 12 saturated hydrogen, and the deducibility sample molecule is a height symmetrical structure.Chemical shift and coupling constant according to these hydrogen, in conjunction with H-H cosy spectrum and HMQC spectrum, can judge identical 4 methyl of chemical environment are arranged, and the aromatic ring hydrogen of 1,3,4 types of two groups of symmetric phenyl ring, and can infer substantially that sample molecule is the thiodiphenylamine structure that two (dimethylamino) replaces.Be in contraposition according to two N atoms in the synthesis material, can determine substituting group position substantially.Have 7 groups of peaks in the carbon spectrum, can find out from the DEPT-135 spectrum 3 groups of quaternary carbons are arranged, 4 groups of primary carbons or tertiary carbon.In conjunction with HMBC spectrum and HMQC spectrum, the existence of two symmetric dimethylaminos and the position of substitution on aromatic ring thereof have further been proved conclusively.So far can determine that the sample molecule structure is exactly the molecular structure of methylenum coeruleum.
(4) obtain the base peak of a m/z 284.2 in the mass spectrum, be M-Cl
-Produce, further proved conclusively the composition of base cation; The M-Cl that two other abundance is bigger
--4 and M-Cl
--28 quasi-molecular ions has shown further that also the aromatic ring side chain has methyl substituted structure.
(5) the sample powder x-ray diffraction pattern shows, this sample diffraction peak is sharp-pointed, and the well-crystallized of this product is described; The full spectrum peak type of highly finished product and reference substance is consistent with main spectrum peak d value, is to be same crystal formation.
(6) in sum, through to the HPLC of sample, ultimate analysis, IR, UV,
1HNMR, H-HCOSY,
13CNMR, DEPT, HMQC, HMBC, EI-MS, TG, DTA, powder x-ray diffraction analysis, and with the comparative analysis of reference substance, the chemical structure of confirming this product is consistent with the chemical structure of methylenum coeruleum, and the sample macroscopic property is also identical with methylenum coeruleum, therefore confirms that this product is a methylenum coeruleum.
Compared with prior art, synthetic method cost provided by the present invention is lower, invests for a short time, and the reaction times is shorter, is suitable for suitability for industrialized production, raw materials used being easy to get, and product purity is higher, and environmental pollution is less.
Embodiment:
Embodiments of the invention 1:
The preparation of solution: take by weighing zinc chloride 500g (4.95mol) and be dissolved in 500mL water, add sodium dichromate dehydrate 2.5g and be mixed with liquor zinci chloridi; Taking by weighing 18 water Tai-Ace S 150 670g (1.00mol) is dissolved in 600mL water and is mixed with alum liquor; Taking by weighing five water Sulfothiorine 525g (2.12mol) is dissolved in 500mL water and is mixed with hypo solution; Taking by weighing sodium dichromate dehydrate 648g (2.17mol) is dissolved in 900mL water and is mixed with sodium dichromate solution; Take by weighing N, N xylidine 200g (1.65mol) is dissolved in 227ml concentrated hydrochloric acid (2.66mol) and is mixed with N, the hydrochloric acid soln of accelerine.
Synthesizing of medicinal methylene blue: take by weighing P-aminodimethylaniline hydrochloride 2mol (418g), drop in the reactor of band thermometer, add the 6L water dissolution, stir and drip vitriol oil 0.41mol (40g) down, make solution become acid, add liquor zinci chloridi under the room temperature successively, alum liquor, hypo solution, and adding 300mL sodium dichromate solution, stir down reaction solution in 10 minutes internal heating to 40 ℃, with N, the hydrochloric acid soln of accelerine drops into reactor, immediately adds remaining 600mL sodium dichromate solution, in 10 minutes internal heating to 70 ℃; When temperature reaches 70 ℃, 2.87mol (250g) Manganse Dioxide is dropped into reactor, be heated to 85 ℃, holding temperature reaction 30 minutes is cooled to 50 ℃ naturally, stirs slowly to add vitriol oil 7.14mol (700g) down; Emit reaction solution after stirring evenly, placed 5 hours down in 4 ℃ of environment, separate out precipitation, suction filtration, filter cake wash with 10% sodium chloride aqueous solution 600mL; Filter cake is transferred in the 20L beaker, add 10L water, on electric mantle, be heated with stirring to boiling, suction filtration while hot, filtrate adds 1.84mol (250g) zinc chloride and 25.64mol (1500g) sodium-chlor, stirs to make dissolving, again this solution is placed 24h down in 4 ℃ of environment, suction filtration, 50 ℃ of dry methylene blue chlorination zinc salt 460g that get; Gained chlorination zinc salt is dissolved in the 10L water, add yellow soda ash 0.52mol (55.2g), be chilled to room temperature, suction filtration, less water filter wash cake adds sodium-chlor 17.09mol (1000g), placed 12 hours down in 4 ℃ of environment after the stirring and dissolving, suction filtration, filter cake in 40-45 ℃ of drying 12 hours methylenum coeruleum crude product 320g (weight loss on drying about 15%, be 42.5%) with the anhydride calculated yield.The methylenum coeruleum crude product is dropped in the triangular flask, add 0.1mol/L hydrochloric acid 1280mL (1: 4), 60 ℃ of heating in water bath dissolvings are placed crystallization, suction filtration in room temperature, recrystallization is once in equal volume, concentration hydrochloric acid for filter cake, in the same volume ponding recrystallization once, filter cake obtains methylenum coeruleum 205g in 40-45 ℃ of drying 12 hours, weight loss on drying 14.6% is with anhydride calculated yield 64.3%.Calculating total recovery by raw material P-aminodimethylaniline hydrochloride is 27.4%.
Embodiments of the invention 2:
The preparation of solution: take by weighing zinc chloride 50g (0.495mol) and be dissolved in 50ml water, and adding sodium dichromate dehydrate 0.25g is mixed with liquor zinci chloridi; Take by weighing AL
2(SO
4)
318H
2O 67g (0.1mol) is dissolved in 60ml water and is mixed with alum liquor; Take by weighing Na
2S
2O
35H
2O 52.5g (0.212mol) is dissolved in 50ml water and is mixed with hypo solution; Take by weighing Na
2Cr
2O
72H
2O 64.8g (0.217mol) is dissolved in 90ml water and is mixed with sodium dichromate solution; Take by weighing N, accelerine 20g (0.165mol) is dissolved in 22.7ml concentrated hydrochloric acid (0.266mol) and is mixed with N, the hydrochloric acid soln of accelerine.
Synthesizing of medicinal methylene blue: take by weighing P-aminodimethylaniline hydrochloride 41.8g, drop in the 2000ml reaction flask of band thermometer, add the 600ml water dissolution, stir and drip vitriol oil 4g down, make solution become acid, add liquor zinci chloridi, alum liquor, hypo solution under the room temperature successively, and in 2 seconds, add the 30ml sodium dichromate solution, stir down reaction solution at 1 minute internal heating to 30 ℃, with N, the hydrochloric acid soln of accelerine drops into reaction flask, immediately adds remaining 60ml sodium dichromate solution, in 3 minutes internal heating to 60 ℃.When temperature reaches 60 ℃, 25g Manganse Dioxide is dropped into reaction flask, be heated to 80 ℃, holding temperature reaction 20 minutes, naturally be cooled to 40 ℃, stir the slow down vitriol oil 70g that adds, emit reaction solution after stirring evenly, placed 4 hours down in 4 ℃ of environment, separate out precipitation, suction filtration, filter cake is transferred to filter cake in the 2000ml beaker with the washing of 60ml 10% sodium chloride aqueous solution, add 1000ml water, on electric mantle, be heated with stirring to boiling, suction filtration while hot, filtrate adds 25g zinc chloride and 150g sodium-chlor, stirring makes dissolving, again this solution is placed 22h down in 4 ℃ of environment, suction filtration, 45 ℃ of dry methylene blue chlorination zinc salt 24g that get; Gained chlorination zinc salt is dissolved in the 1000ml water, add yellow soda ash 5.52g, be chilled to room temperature, suction filtration, less water filter wash cake adds sodium-chlor 100g, placed 10 hours down in 4 ℃ of environment after the stirring and dissolving, suction filtration, filter cake in 40-45 ℃ of drying 11 hours methylenum coeruleum crude product 16g, then promptly with the water recrystallization several of 4 times of weight.
Embodiments of the invention 3:
The preparation of solution: take by weighing zinc chloride 250g (2.475mol) and be dissolved in 250mL water, add sodium dichromate dehydrate 1.25g and be mixed with liquor zinci chloridi; Taking by weighing 18 water Tai-Ace S 150 335g (0.50mol) is dissolved in 300mL water and is mixed with alum liquor; Taking by weighing five water Sulfothiorine 262.5g (1.06mol) is dissolved in 250mL water and is mixed with hypo solution; Taking by weighing sodium dichromate dehydrate 324g (1.09mol) is dissolved in 450mL water and is mixed with sodium dichromate solution; Take by weighing N, accelerine 100g (0.83mol) is dissolved in 114ml concentrated hydrochloric acid (1.33mol) and is mixed with N, the hydrochloric acid soln of accelerine.
Synthesizing of medicinal methylene blue: take by weighing P-aminodimethylaniline hydrochloride 1mol (209g), drop in the reactor of band thermometer, add the 3L water dissolution, stir and drip vitriol oil 0.21mol (20g) down, make solution become acid, add liquor zinci chloridi, alum liquor, hypo solution under the room temperature successively, and adding 150mL sodium dichromate solution, stir down reaction solution in 5 minutes internal heating to 50 ℃, with N, the hydrochloric acid soln of accelerine drops into reactor, immediately adds remaining 300mL sodium dichromate solution, in 7 minutes internal heating to 80 ℃; When temperature reaches 80 ℃, 1.44mol (125g) Manganse Dioxide is dropped into reactor, be heated to 90 ℃, holding temperature reaction 40 minutes is cooled to 60 ℃ naturally, stirs slowly to add vitriol oil 3.57mol (350g) down; Emit reaction solution after stirring evenly, placed 6 hours down in 4 ℃ of environment, separate out precipitation, suction filtration, filter cake wash with 10% sodium chloride aqueous solution 300mL; Filter cake is transferred in the 10L beaker, add 5L water, on electric mantle, be heated with stirring to boiling, suction filtration while hot, filtrate adds 0.92mol (1250g) zinc chloride and 12.82mol (750g) sodium-chlor, stirs to make dissolving, again this solution is placed 26h down in 4 ℃ of environment, suction filtration, 55 ℃ of dry methylene blue chlorination zinc salt 230g that get; Gained chlorination zinc salt is dissolved in the 5L water, add yellow soda ash 0.26mol (27.6g), be chilled to room temperature, suction filtration, less water filter wash cake adds sodium-chlor 8.55mol (500g), placed 14 hours down in 4 ℃ of environment after the stirring and dissolving, suction filtration, filter cake in 40-45 ℃ of drying 13 hours methylenum coeruleum crude product 160g, then promptly with the water recrystallization several of 4 times of weight.
Claims (8)
1. the synthetic method of a medicinal methylene blue, it is characterized in that: with the P-aminodimethylaniline hydrochloride is starting raw material, makes methylenum coeruleum according to following circuit reaction:
2. according to the synthetic method of the described medicinal methylene blue of claim 1, it is characterized in that: calculate according to the molar mass ratio, take by weighing 2 parts of P-aminodimethylaniline hydrochlorides, drop in the reactor of band thermometer, be dissolved in water, stir and drip 0.41 part of the vitriol oil down, add zinc chloride content under the room temperature successively and be 4.95 parts solution, Tai-Ace S 150 content is 1.00 parts solution, sodium thiosulfate content is 2.12 parts a solution, and adding sodium dichromate 99 content is 0.72 part solution, stir down reaction solution is heated to 30～50 ℃ rapidly, with N, accelerine content is that 1.65 parts hydrochloric acid soln drops into reactor, immediately add sodium dichromate 99 content and be 1.45 parts solution, be heated to 60～80 ℃ rapidly, 2.87 parts of Manganse Dioxide are dropped into reactor, be heated to 80～90 ℃, holding temperature reaction 20～40 minutes, be cooled to 40～60 ℃, stir slow down 7.14 parts of the vitriol oils that add, emit reaction solution after stirring evenly, placed 4～6 hours down in 4 ℃ of environment, separate out precipitation, suction filtration, filter cake washs with 10% sodium chloride aqueous solution, and filter cake is transferred in the beaker, add entry, on electric mantle, be heated with stirring to boiling, suction filtration while hot, filtrate adds 25.64 parts in 1.84 parts of zinc chloride and sodium-chlor, stirring makes dissolving, again this solution is placed 22～26h down in 4 ℃ of environment, suction filtration, 45～55 ℃ of dry methylene blue chlorination zinc salts that get; Gained chlorination zinc salt is dissolved in the water, add 0.52 part in yellow soda ash, be chilled to room temperature, suction filtration, less water filter wash cake adds 17.09 parts in sodium-chlor, placed 10～14 hours down in 4 ℃ of environment after the stirring and dissolving, suction filtration, filter cake got the methylenum coeruleum crude product in 11～13 hours in 40-45 ℃ of drying, and the water recrystallization is promptly for several times then.
3. according to the synthetic method of the described medicinal methylene blue of claim 2, it is characterized in that: take by weighing P-aminodimethylaniline hydrochloride 2mol, be 418g, drop in the reactor of band thermometer, add the 6L water dissolution, stir and drip vitriol oil 0.41mol down, be 40g, add liquor zinci chloridi 500mL under the room temperature successively, alum liquor 600mL, hypo solution 500mL, and add the 300mL sodium dichromate solution rapidly, stir down reaction solution in 10 minutes internal heating to 40 ℃, with N, the hydrochloric acid soln 227ml of accelerine drops into reactor, immediately adds remaining 600mL sodium dichromate solution, in 10 minutes internal heating to 70 ℃; When temperature reaches 70 ℃, with 2.87mol, be that 250g Manganse Dioxide drops into reactor, be heated to 85 ℃, holding temperature reaction 30 minutes is cooled to 50 ℃ naturally, stirs down slowly adding vitriol oil 7.14mol, is 700g; Emit reaction solution after stirring evenly, placed 5 hours down in 4 ℃ of environment, separate out precipitation, suction filtration, filter cake wash with 10% sodium chloride aqueous solution 600mL; Filter cake is transferred in the 20L beaker, add 10L water, on electric mantle, be heated with stirring to boiling, suction filtration while hot, filtrate adds 1.84mol, is 250g zinc chloride and 25.64mol, is 1500g sodium-chlor, stirs and makes dissolving, again this solution is placed 24h down in 4 ℃ of environment, suction filtration, 50 ℃ of dry methylene blue chlorination zinc salts that get; Gained chlorination zinc salt is dissolved in the 10L water, add yellow soda ash 0.52mol, be 55.2g, be chilled to room temperature, suction filtration, less water filter wash cake adds sodium-chlor 17.09mol, is 1000g, placed 12 hours down in 4 ℃ of environment after the stirring and dissolving, suction filtration, filter cake in 40-45 ℃ of drying 12 hours the methylenum coeruleum crude product, then promptly with the water recrystallization several of 4 times of weight.
4. according to the synthetic method of claim 2 or 3 described medicinal methylene blues, it is characterized in that: used liquor zinci chloridi concentration is 9.9mol/l, wherein also contains the sodium dichromate 99 of 0.016mol/l.
5. according to the synthetic method of claim 2 or 3 described medicinal methylene blues, it is characterized in that: used alum liquor concentration is 1.67mol/l.
6. according to the synthetic method of claim 2 or 3 described medicinal methylene blues, it is characterized in that: used hypo solution concentration is 4.24mol/l.
7. according to the synthetic method of claim 2 or 3 described medicinal methylene blues, it is characterized in that: used sodium dichromate solution concentration is 2.41mol/l.
8. according to the synthetic method of claim 2 or 3 described medicinal methylene blues, it is characterized in that: used N, the concentration of hydrochloric acid solution of accelerine are 7.27mol/l.
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| US4212971A (en) * | 1979-03-08 | 1980-07-15 | American Cyanamid Company | Process for preparing methylene blue |
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