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[ CAS No. 1236208-20-0 ] {[proInfo.proName]}

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Chemical Structure| 1236208-20-0
Chemical Structure| 1236208-20-0
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Product Details of [ 1236208-20-0 ]

CAS No. :1236208-20-0 MDL No. :MFCD29764308
Formula : C18H27N3O6S3 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 477.62 Pubchem ID :-
Synonyms :
TRx0237 mesylate;Methylene blue leuco base mesylate;LMTM;Leukomethylthioninium dihydromesylate;Leucomethylene Blue;Hydromethylthionine;TRx0237 (mesylate);Hydromethylthionine mesylate
Chemical Name :N3,N3,N7,N7-Tetramethyl-10H-phenothiazine-3,7-diamine dimethanesulfonate

Safety of [ 1236208-20-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1236208-20-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 1236208-20-0 ]

[ 1236208-20-0 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 75-75-2 ]
  • [ 3763-06-2 ]
  • [ 1236208-20-0 ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: 1-[3,7-bis(dimethylamino)phenothiazin-10-yl]ethanone In toluene for 0.5h; Reflux; Stage #2: methanesulfonic acid In water; toluene at 85℃; for 3h; 1 Synthesis 1: Synthesis of N,N,N',N'-tetramethyl-10H-phenothiazine-3, 7-diaminium bis(methanesulphonate) (LMT.2MsOH)i. MSA, H20, toluene, 85 °Cii. EtOH10-Acetyl-A/,//,//'//-tetramethyl-10H-phenothiazine-3,7-diamine (AcMT) (150 g) was added to a 3-neck round bottomed flask. Toluene (1.8 I) was added and the mixture heated to reflux for 30 min. The solution was allowed to cool to 70 °C before being passed through an in-line 5 μ filter to a jacketed vessel fitted with distillation apparatus.1 Toluene (150 ml) was added to the round bottom flask. This was used to rinse the transfer line and filter. Approximately 1.4 I. of toluene was distilled off under reduced pressure.2 The temperature was lowered to 18 °C before water (42 ml) was added.3 This was followed by the addition of methanesulphonic acid (MSA) (65.5 ml, 99%, 2.2 equiv.) over a 5 min. period.4 A second portion of water (18 ml) was added. The mixture was heated to 85 °C for 3 h by which time the reaction was judged complete by tic analysis. The biphasic solution was allowed to cool to 50 °C before absolute EtOH (150 ml) was added over 20 min.5 The mixture was seeded using 150 mg of Λ/,Λ/,Λ/',/V'-tetramethyl- 10H-phenothiazine-3,7-diaminium bis(methanesulphonate).6"8 A second portion of EtOH (600 ml) was added over 90 min.9 and the reaction allowed to cool to 20 °C over 1 h.10 It was stirred at this temperature for 1 h. before the solid was collected by filtration. The cake was washed with 3 x 300 ml of MeCN,11 sucked dry for 5 min. and placed under vacuum overnight to give the product as a yellow crystalline solid (85-90 % yield). vmax (KBr)/crn 1; 3430 (NH), 3014 (=CH), 2649 (C-H), 1614 (C=C), 1487 (C-C), 1318 (S=0), 1 199 (S02-0), 1059 (S=0), 823 (ArC=-H)δΗ(600 MHz; CD3OD); 2.71 (6H, s, SCH3), 3.21 (12H, s, NCH3), 6.75 (2H, d, J 8.8 Hz,ArH), 7.22 (4H, d J 2.9 Hz, ArH), 7.24 (4H, dd J 2.9, 8.8 Hz, ArH),δο(100 MHz; CD3OD); 38.2 (SCH3), 45.9 (NCH3), 115.0 (CH), 1 18.2 (CH), 1 18.7 (QC),1 19.9 (QH), 137.1 (CH), 142.8 (QC)MP: 271 °Cm/z (EI+): Calculated 285.129970; Observed 285.131292 (100%, [M-2MSAD- m/z (ES-): Calculated 95; Observed 95 (100%, [M-LMT] ).Elemental analysis % (C18H27N306S3): Calculated C (45.26), N (8.80), S (20.14), H (5.70); Observed C (45.19), N (8.76), S (19.84), H (5.53)Notes1. Heating to reflux ensures complete dissolution of AcMT for transfer through 5 μ filter. Toluene is a good solvent and a 70 °C target is a compromise between ensuring the material stays in solution and minimising potential damage to plastic transfer hoses and filter.2. 500 ml of remaining toluene ensures reaction volume meets minimum stir depth of reactor.3. Volume of water is controlled to ensure product crystallises out as a free flowing precipitate. Seeding the reaction reduces the impact of small variations in water volume.4. 2.2 equivalents of MSA are used to effect the hydrolysis and form the salt whilst leaving a sufficient quantity of excess acid (0.2 equiv.) to ensure the stability of the product in solution. Addition of MSA causes a slight exotherm, hence the 5 minute addition time. 5. EtOH is used as counter solvent to precipitate the product. A portion is added before the seed to ensure the seed does not dissolve. An extended addition time ensures controlled crystallisation of the product (see notes 7 and 8).6. It is possible to carry out the reaction without the use of a seed, however itsincorporation ensures the early precipitation of L T.2 sOH which in turn prevents formation of by-products (such as the alcohol ester EMS a potential genotoxic byproduct - not detected in the synthetic process) and encapsulation of EtOH.7. The seed is also useful as a means of controlling the particle size of the product.When the seed material was used which has been ground in a mortar and pestle to <100 μηι a significant reduction in the average particle size of the product is observed. When <100 μ seed which had not been ground was used no such effect was observed. Therefore, without wishing to be bound by theory, it appears that the ability of the seed to control the particle size is not a function of the seed particle size, it is linked to the proportion of internal or 'new' crystal faces that the crushing of the seed has exposed.8. Finally, when the seed material was relatively large and uncrushed a considerable amount of product (skin) may adhere to the side of the reactor vessel during the EtOH addition. This may be reduced by introducing a heat/cool cycle into the process after the EtOH addition. However, an unexpected bonus of the utilisation of the crushed seed was that the level of skinned materia) present after EtOH addition was reduced by -90%. Therefore it was no longer necessary to carry out the heat/cool cycle. It seems that this is linked to the small seed size rather than new faces because when the reaction was carried out using uncrushed <100 μ seed the same reduction in skinning was observed.9. The rate of EtOH addition has an effect on particle size and EtOH inclusion. Fast addition (<1 h) reduces particle size however EtOH inclusion increases. A slow addition (2 h) has the opposite effect hence a balance must be struck.0. Rate of cooling has a similar although reduced effect. Fast cool down (<1 h) leads to reduction in particle size with a concomitant increase in EtOH levels. A slow cool has the opposite effect.1 1. EtOH is equally effective as MeCN at removing the related substances, however its use is accompanied by a slight increase in the level of retained EtOH.
  • 2
  • [ 61-73-4 ]
  • [ 1236208-20-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: triethylamine; hydrazine hydrate / acetonitrile / 2 h / 15 - 70 °C / Industry scale 1.2: 2 h / 90 - 100 °C / Industry scale 2.1: toluene / 0.5 h / Reflux 2.2: 3 h / 85 °C
  • 3
  • [ 50-00-0 ]
  • [ 75-75-2 ]
  • [ 1747-90-6 ]
  • [ 1236208-20-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3,11-dinitro-10H-phenothiazine With 5%-palladium/activated carbon; hydrogen In water; N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: formaldehyd With hydrogen In water; N,N-dimethyl-formamide at 90℃; for 24h; Stage #3: methanesulfonic acid In methanol; ethanol; toluene at 5℃; for 2h; Inert atmosphere; 4 Method 4 Synthesis of ^/V^^-tetramethyl-I OH-phenothiazine-SJ-diaminium bis(methanesulfonate) ("LMTM") Method 4 Synthesis of ^/V^^-tetramethyl-I OH-phenothiazine-SJ-diaminium bis(methanesulfonate) ("LMTM") Part 1 : To a 450 ml pressure vessel, fitted with an entrainment stirrer, thermometer, pressure gauge and connected to a pressure burette, was added 3,7-dinitro-10H- phenothiazine (DNP, 5.00 g, 17.28 mmol, 1 equivalent), palladium on carbon (5% (w/w) Pd, 58% (w/w) water, 1 .15 g, 0.0131 equivalents), and /V,/V-dimethylformamide (150 ml). The pressure burette and vessel were then purged with hydrogen five times to 10 bar before the burette was pressurised with hydrogen to 20.4 bar and the vessel to 3.7 bar. The mixture was stirred (1500 rpm) at ambient temperature for 90 minutes (i.e., until the nitro group reduction was complete, as indicated by approximately 60% up-take of hydrogen). Part 2: The vessel was vented and paraformaldehyde (H2CO, 97%, 2.08 g, 67.39 mmol, 3.9 equivalents) was added to the reaction mixture in one aliquot. The vessel was re- pressurised with hydrogen to 3.6 bar and heated to 90 °C while stirring at 1500 rpm. Progress of the reaction was monitored via hydrogen uptake, temperature, and pressure (see Figure 3). The reaction reached completion after approximately 16 hours (i.e., when the hydrogen up-take had reached approximately 100%, or had plateaued). After a further 8 hours (24 hours in total), the reaction mixture (a green solution) was cooled to 23 °C, and the vessel vented. The catalyst was removed by filtration using a Buchner funnel (12 cm diameter) and the filtrate was collected in a round bottom flask. The catalyst was washed with /V,/V-dimethylformamide (2 x 15 ml) and the combined filtrate and washings were distilled to dryness under reduced pressure giving a purple solid. Figure 3 is a graph of hydrogen uptake (%), vessel temperature (°C), and vessel pressure (bar) versus time (hours) for the reaction in which the nitro groups of 3,7-dinitro-10H- phenothiazine (DNP) are reduced, and the resulting amino groups are selectively alkylated. Part 3: The round bottom flask containing the purple solid was purged with argon before toluene (3 ml), methanol (10 ml) and methane sulfonic acid (5.22 g, 38.02 mmol, 2.2 equivalents) were added. The resultant solution was cooled to 5 °C. Ethanol (30 ml) was added drop-wise as an anti-solvent, which caused the product to precipitate as a green crystalline solid. The slurry was stirred at 5 °C for 2 hours and then filtered to give green crystals, which were washed with ethanol (4 x 10 ml, cooled to 5 °C) giving the product as yellow crystals, which were dried to constant weight in a 50 °C vacuum oven at 10 mm Hg (1333 kPa) (6.59 g, yield 80%). The LMTM product was characterised as follows: The organic purity of the LMTM product was determined by HPLC analysis and the results are summarised in the following table. Again, the term "others" refers to all other compounds that are present, for which a specific value is not reported. The HPLC parameters are summarised in the following tables. Table 18 HPLC parameters for LMTM System Parametrs HPLC system Agilent 1200 with DAD and data handling capacity Column Agilent Zorbax SB-CN, 50 x 4.6 mm, 3 μηη particle size Column Temperature 10 °C Autosampler Temperature 5 °C A: Degassed 0.1 % v/v formic acid Mobile Phase B: Degassed acetonitrile Flow Rate 1 mL/min Injection volume 5 μ. Stop time 22.0 min Wavelength 255 nm, slit width 4 nm HPLC standards and samples were prepared as follows: • Fresh LMTM reference material was used when preparing standards (for determination of retention times and quantification of samples). • 50 mL amber-glass volumetric flasks used to prepare standards and samples. • Amber-glass vials filled as much as possible; using a volumetric pipette, the ideal volume was 1.85 mL (which allows for expansion upon chilling of solution). • All glassware pre-rinsed with 0.1 % formic acid, oven-dried, and degassed with argon prior to use. • All eluents and diluent (0.1 % formic acid) degassed thoroughly (at least 10 min of vigorous degassing), prior to use. For the diluent, degassed for 5 minutes once every hour during a sample run. • Samples were pre-weighed (about 42 mg) into flasks, and stoppered, prior to wetting. • Samples are not wetted more than 10 minutes prior to injection. • Ensure complete material dissolution prior to solution sampling. This was done by inverting the flask, rotating argon bubble around the bottom of the flask a number of times, checking for undissolved material, and then re-invert the solution to ensure thorough mixing. For reference, the chemical structures of LMTM and the related impurities are shown in the following table. Table 21 Chemical Structures of LMTM and Related Im urities Azure B Mesylate Λ ,Λ ,ΛΓ-trimethyl-I OH- phenothiazine-3,7-diaminium bis(methanesulphonate) (Leuco Azure B Mesylate)
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