Description:FIELD OF THE INVENTION
The present disclosure relates to a process for the preparation of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (Toluenesulfonylmethyl isocyanide or TosMIC).
BACKGROUND OF THE INVENTION
The background information herein below relates to the present disclosure but is not necessarily prior art.
1-((isocyanomethyl)sulfonyl)-4-methylbenzene (Tosylmethyl Isocyanide or TosMIC) is a highly versatile isocyanide compound. TosMIC reagent is a crucial building block in synthetic chemistry and has been greatly engaged as an undeniable synthon for the preparation of a heterocycles. The majority of the synthetic applications of TosMIC derive from the following fundamental properties including TosMIC contains an activated methylene group and readily forms a stablized, nucleophilic carbanion, which will react with a variety of electrophiles; the divalent isocyano carbon usually acts as an electrophilic center, which can participate in ring closing reactions; the activating tosyl group frequently operates as a moderately good leaving group in a 1,2-elimination step to produce sulphur-free products; the geminal isocyano and tosyl groups in TosMIC can be looked upon as a special type of N,S-acetal, and in fact can be made to react accordingly.
US4958030 and Wolf P. Fehlhammer et al (Tetrhedron letters, 23, 1972, pg-2367-2368) disclosed process of preparing TosMIC by dehydration of N-(tosylmethyl)formamide with phosphoroxy chloride in presence of triethylamine in 1,2-dimethoxyethane.
Ming-Jun Yi et al also disclosed process of preparing TosMIC by dehydration of N-(tosylmethyl)formamide with phosphoroxy chloride (1.1 equivalents) in presence of triethylamine (3.3 equivalents) in dichloromethane (ACS Catalysis 2021, 11, pg-3466-3472).
J. Armando Lujan-Montelongo et al disclosed synthesis of TosMIC from methyl p-tosyl sulfinate, which comprises following steps: (1) reacting methyl p-tosyl sulfinate with paraformaldehyde (5 equivalents), formamide (6 equivalents) and formic acid (5 equivalents) and toulene (5 equivalents) in a microwave at 100? for 3 hours to yield N-(tosylmethyl)formamide; (2) reacting N-(tosylmethyl)formamide obtained in step-(1) with isopropyl amine (9.3 equivalents) and phosphorous oxychloride (3.3 equivalents) in a solvent mixture of THF:Acetonitrile (2:1) to obtain TosMIC at yield of 71% (Eur. J. Org. Chem., 7, 1602-1605 (2015)).
Roland Obrecht el at disclosed a process of preparation of TosMIC from N-(tosylmethyl)formamide by using diisopropylamine and phosphoryl chloride, and also mentioned that diisopropyl amine enhances the average yield of the end product in comparison with triethyl amine (Communications, Synthesis Apr. 1985, pg-400-402).
WO2015127175 disclosed synthesis of TosMIC from methyl p-tosyl sulfinate which comprises following steps: (1) reacting methyl p-tosyl sulfinate with paraformaldehyde (4 or 5 equivalents), formamide (6 or 7.5 equivalents) and formic acid (5 equivalents) in a flask at 90-100? for 2-3 hours or in a microwave in toulene (5 equivalents) at 100? for 3 hours to yield N-(tosylmethyl) formamide; (2) dehydration of N-(tosylmethyl) formamide obtained in step-(1) with diisopropyl amine (9.3 equivalents) in a solvent mixture of THF:Acetonitrile (2:1) to obtain TosMIC.
Christian Schumacher et al describes a process of preparation of TosMIC which comprises following steps: (1) N-(Tosylmethyl)formamide preparation by reacting sodium p-toluenesulfinate monohydrate (1.0 equivalent), paraformaldehyde (3.0 equivalents), formamide (4.0 equivalents), and formic acid (5.0 equivalents) at 90°C for 2 hours; (2) reacting N-(tosylmethyl)formamide (1 equivalent) with diisopropylamine (1.2 equivalents) and phosphoryl chloride (3.2 equivalents) in THF. It also discloses that the obtained crude TosMIC was purified by recrystallization using methanol and by column chromatography (J. Org. Chem. 2021, 86, 20, pg-14213-14222).
WO2016073889 describes synthesis of TosMIC from sodium 4-methylbenzene-1-sulfinate which comprises following steps: (1) reacting sodium 4-methylbenzene-1-sulfinate (1 equivalent), formic acid (5 equivalents), paraformaldehyde (3 equivalents) and formamide (4 equivalents) at 90ºC for 16 hours; (2) reacting N-[(4-methylbenzenesulfonyl)methyl] formamide (1 equivalent) obtained in step (1) with triethylamine (4 equivalents) and phosphoryl chloride (2 equivalents) in anhydrous THF. It also discloses that the purity of the obtained TosMIC is >97%.
CN103497180 describes synthesis of TosMIC from sodium 4-methylbenzene-1-sulfinate which comprises following steps (1) reacting formamide (1.5 equivalents), paraformaldehyde (1.5 equivalents), Sodium p-toluene sulfinate (1 equivalents) at 100°C for 4 hours; (2) reacting p-toluenesulfonylmethylformamide (1 equivalent) and POCl3 (1.1 equivalent) in dichloromethane at -5°C to 0°C. It also discloses that the obtained crude TosMIC was purified by recrystallization using petroleum ether.
CN104387301 describes synthesis of TosMIC from sodium 4-methylbenzene-1-sulfinate which comprises following steps (1) reacting formamide, paraformaldehyde, formic acid Sodium p-toluene sulfinate at 90°C for 2 hours; (2) reacting p-toluenesulfonylmethylformamide obatained in step-1, triethylamine and phosphorus oxychloride in dichloromethane at -4°C to -2°C. It also discloses that the obtained crude TosMIC was purified by recrystallization using petroleum ether. .
CN107501140 describes synthesis of TosMIC from p-toluenesulfonylmethyl formamide using activated carbon.
CN111393348 describes synthesis of TosMIC from anhydrous sodium sulfite as starting material, which comprises following steps: (1) reacting anhydrous sodium sulfite, sodium bicarbonate and p-toluene sulfonyl chloride in water at 80°C for 1 hour to yield sodium p-toluenesulfinate with a purity of 99% and a yield of 96%; (2) reacting the sodium p-toluenesulfinate with paraformaldehyde, formamide and anhydrous formic acid at 90°C to obtain p-toluenesulfonylmethylformamide with purity of 98% and yield 78.1%; (3) reacting p-toluenesulfonylmethylformamide, triethylamine, phosphorusoxychloride in dichloromethane at the temperature below 0°C for 1 hour, then added 7% sodium hydroxide solution and stirred for 0.5 hour, the separated organic layer was washed once with water, dried with anhydrous sodium sulfate, and the filtrate obtained by filtration was distilled in dichloromethane under normal pressure and then under reduced pressure until solids appeared on the bottle wall, and then petroleum ether was added to the distillation bottle standing under ice-water cooling for 1 hour, the precipitated crystals were suction filtered, dried, and recrystallized from petroleum ether to yield light brown p-toluenesulfonylmethyl isonitrile with a purity of 98% and a yield of 80%.
AIM OF THE INVENTION
The aim of the present invention is to find new processes for preparing TosMIC in a commercial scale with high purity, low technical expenditure and a high yield.
SUMMARY OF THE INVENTION
The present invention discloses a process for preparing 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC). The process comprises the following steps: (i) reacting sodium metabisulphite in water with toluene sulfonyl chloride in presence of sodium carbonate and sodium bicarbonate at a first predetermined temperature for a first predetermined time period to provide sodium 4-methylbenzenesulfinate; (ii) reacting sodium 4-methylbenzenesulfinate with formic acid and formamide in paraformaldehyde at a second predetermined temperature for a second predetermined time period to provide N-(tosylmethyl) formamide; (iii) reacting N-(tosylmethyl) formamide with phosphorous oxychloride in presence of triethyl amine in a solvent mixture of dichloromethane and toluene at a third predetermined temperature for a third predetermined time period to obtain crude 1-((isocyanomethyl)sulfonyl)-4-methylbenzene and purifying the crude 1-((isocyanomethyl)sulfonyl)-4-methylbenzene by using crystallization in purification solvents; wherein the purity of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene is 99% and above.
DESCRIPTION OF THE DRAWINGS
For a more complete understanding of the invention, reference should now be made to the embodiments illustrated in greater detail in the accompanying drawings and described by way of embodiments of the invention.
Figure 1: Illustrates chromatogram for sodium 4-methylbenzenesulfinate (Example 1a).
Figure 2: Illustrates chromatogram for sodium 4-methylbenzenesulfinate (Example 1b).
Figure 3: Illustrates chromatogram for N-(tosylmethyl)formamide (Example 2a).
Figure 4: Illustrates chromatogram for N-(tosylmethyl)formamide (Example 2b).
Figure 5: Illustrates chromatogram for 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (Example 3a).
Figure 6: Illustrates chromatogram for 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (Example 3b).
Figure 7: Illustrates for 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (Example 3c).
DETAILED DESCRIPTION OF THE INVENTION
The present disclosure relates to a process for the synthesis of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC).
Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
TosMIC is synthesized by many conventional methods. The disadvantages of these methods are low purity, non-commercial scale and high expenditures. The present disclosure provides a simple, economical and commercially scalable process for the synthesis of TosMIC.
The process for preparing 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC), comprises the following steps:
i)reacting sodium metabisulphite in water with toluene sulfonyl chloride in presence of sodium carbonate and sodium bicarbonate at a first predetermined temperature for a first predetermined time period to provide sodium 4-methylbenzenesulfinate;
ii)reacting sodium 4-methylbenzenesulfinate with formic acid and formamide in paraformaldehyde at a second predetermined temperature for a second predetermined time period to provide N-(tosylmethyl) formamide;
iii)reacting N-(tosylmethyl) formamide, triethylamine and phosphorous oxychloride in a solvent mixture of dichloromethane and toluene at a third predetermined temperature for a third predetermined time period to obtain crude 1-((isocyanomethyl) sulfonyl)-4-methylbenzene and purifying the crude 1-((isocyanomethyl)sulfonyl)-4-methylbenzene by using crystallization in purification solvents;
wherein the purity of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene is 99% and above.
The preparation of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC), in accordance with an exemplary embodiment of the present disclosure, is represented as scheme 1 given below.

Scheme-1
The process for preparing 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) is described in detail herein below.
Step (i): Preparation of sodium 4-methylbenzenesulfinate
In a first step, sodium metabisulphite is reacted with toluene sulfonyl chloride in presence of sodium carbonate and sodium bicarbonate in water at a first predetermined temperature for a first predetermined time period to obtain sodium 4-methylbenzenesulfinate.
In accordance with the present disclosure, the first predetermined temperature is in the range of 60°C to 85°C. In a preferred embodiment of the present disclosure, the first predetermined temperature is 65°C to 70°C. In another preferred embodiment of the present disclosure, the first predetermined temperature is 80°C to 85°C.
In accordance with the present disclosure, the first predetermined time period is in the range of 2 hours to 4 hours. In a preferred embodiment of the present disclosure, the first predetermined time period is in the range of 3 hours to 4 hours. In another preferred embodiment of the present disclosure, the first predetermined time period is in the range of 2 hours to 3 hours.
In accordance with the present disclosure, the molar ratio of reactants in step-(i), toluene sulfonyl chloride : sodium metabisulphite : sodium carbonate : sodium bicarbonate is 1: (0.55 to 0.60) :(0.56 to 0.58):(1.9 to 2.1).
In accordance with the present disclosure, the purity of sodium 4-methylbenzenesulfinate obtained in step-(i) is not less than 99%. In a preferred embodiment of the present disclosure, the purity of sodium 4-methylbenzenesulfinate obtained in step-(i) is 99.119%. In another preferred embodiment of the present disclosure, the purity of sodium 4-methylbenzenesulfinate obtained in step-(i) is 99.338%.
Step (ii): Preparation of N-(tosylmethyl) formamide
In a second step, sodium 4-methylbenzenesulfinate is reacted with formic acid and formamide in paraformaldehyde at a second predetermined temperature for a second predetermined time period to obtain N-(tosylmethyl) formamide.
In accordance with the present disclosure, the second predetermined temperature is in the range of 80°C to 95°C. In a preferred embodiment of the present disclosure, the second predetermined temperature is 90°C to 95°C. In another preferred embodiment of the present disclosure, the second predetermined temperature is 80°C to 85°C.
In accordance with the present disclosure, the second predetermined time period is in the range of 4 hours to 12 hours. In a preferred embodiment of the present disclosure, the second predetermined time period is in the range of 4 hours to 6 hours. In another preferred embodiment of the present disclosure, the second predetermined time period is in the range of 10 hours to 12 hours.
In accordance with the present disclosure, the molar ratio of reactants in step-(ii), sodium 4-methylbenzenesulfinate : formic acid : formamide : paraformaldehyde is 1: (5 to 5.1) : (7.0 to 7.5) : (3.9 to 4).
In accordance with the present disclosure, the purity of N-(tosylmethyl) formamide obtained in step-(ii) is not less than 99%. In a preferred embodiment of the present disclosure, the purity of N-(tosylmethyl) formamide obtained in step-(ii) is 99.082%. In another preferred embodiment of the present disclosure, the purity of N-(tosylmethyl) formamide obtained in step-(ii) is 99.53%.
Step (iii):Preparation of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC)
In a third step, triethylamine was added to N-(tosylmethyl) formamide in dichloromethane and toluene solvent mixture at a third predetermined temperature under nitrogen atmosphere, further added phosphorous oxychloride and maintained the reaction mixture at a third predetermined temperature for a third predetermined time period, after completion of the reaction the reaction mixture was quenched with a aqueous solution of inorganic base to obtain crude 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) and the obtained crude 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) was purified by crystallization in purification solvents.
In accordance with the present disclosure, the third predetermined temperature is in the range of -5°C to 15°C. In a preferred embodiment of the present disclosure, the third predetermined temperature is -5°C to 0°C. In another preferred embodiment of the present disclosure, the third predetermined temperature is 0°C to 10°C. In another preferred embodiment of the present disclosure, the third predetermined temperature is 10°C to 15°C.
In accordance with the present disclosure, the third predetermined time period is in the range of 1 hour to 2 hours.
In accordance with the present disclosure, the molar ratio of reactants in step-(iii), N-(tosylmethyl) formamide: phosphorous oxychloride: triethyl amine is 1: (0.6 to 0.7) : (3.7 to 3.8).
In accordance with the present disclosure, the addition of phosphorous oxychloride to the reaction mixture in step (iii) is over a period of 2 hours to 12 hours. In a preferred embodiment of the present disclosure, the addition of phosphorous oxychloride to the reaction mixture in step (iii) is over a period of 3 hours to 6 hours. In another preferred embodiment of the present disclosure, the addition of phosphorous oxychloride to the reaction mixture in step (iii) is over a period of 8 hours to 12 hours. In another preferred embodiment of the present disclosure, the addition of phosphorous oxychloride to the reaction mixture in step (iii) is over a period of 2 hours to 4 hours.
In accordance with the present disclosure, the inorganic base used for the quenching of the reaction mixture in step (iii) is selected from sodium hydroxide, sodium bicarbonate sodium carbonate, potassium carbonate and potassium hydroxide.
In accordance with the present disclosure, the purification solvent used in step (iii) for the crystallization of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) is selected from alcohol, ketone, water or mixtures thereof.
In a preferred embodiment of the present disclosure, the purification solvent used in step (iii) for the crystallization of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) is an alcohol selected from methanol, ethanol, isopropyl alcohol, propanol, n-butanol or mixtures thereof.
In another preferred embodiment of the present disclosure, the purification solvent used in step (iii) for the crystallization of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) is water.
In another preferred embodiment of the present disclosure, the purification solvent used in step (iii) for the crystallization of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) is a mixture of water and alcohol; wherein alcohol is selected from methanol, ethanol, isopropyl alcohol, propanol, n-butanol or mixtures thereof.
In accordance with the present disclosure, the crystallization temperature in step (iii) for the crystallization of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) is in the range of 20°C to 55°C.
In a preferred embodiment the present disclosure, the purification solvent used in step (iii) for the crystallization of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) is selected from alcohol, ketone, water or mixtures thereof and the crystallization temperature is in the range of 20°C to 55°C.
In a preferred embodiment of the present disclosure, the purification solvent used in step (iii) for the crystallization of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) is an alcohol selected from methanol, ethanol, isopropyl alcohol, propanol, n-butanol or mixtures thereof and the crystallization temperature is in the range of 20°C to 55°C.
In another preferred embodiment of the present disclosure, the purification solvent used in step (iii) for the crystallization of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) is methanol and the crystallization temperature is in the range of 20°C to 50°C.
In another preferred embodiment of the present disclosure, the purification solvent used in step (iii) for the crystallization of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) is isopropyl alcohol and the crystallization temperature is in the range of 20°C to 50°C.
In accordance with the present disclosure, the purity of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC) obtained in step-(iii) is not less than 99%. In a preferred embodiment of the present disclosure, the purity of TosMIC obtained in step-(iii) is 99.147%. In another preferred embodiment of the present disclosure, the purity TosMIC obtained in step-(iii) is 99.536%. In another preferred embodiment of the present disclosure, the purity TosMIC obtained in step-(iii) is 99.649%.
EXPERIMENTAL DETAILS
Example-1: Preparation of sodium 4-methylbenzenesulfinate
Example-1a:
Sodium metabisulphite (298 g, 1.56 mole), sodium carbonate (157 g, 1.48 mole) and sodium bicarbonate (462 g, 5.5 mole) were dissolved in 3000 ml water, added Toluene sulfonyl chloride (500 g, 2.62 mole) at 30-40°C and heat the reaction mixture to 65-70°C and for 3-4 hours. Reaction mass was cooled to the temperature 0-5°C and filtered the obtained solid. Further, wet cake was washed with chilled water to give 480 g dry sodium 4-methylbenzenesulfinate as solid with purity NLT 99.119% (as depicted in Figure-1, detector A 230nm).
Table No 1: Chromatogram for sodium 4-methylbenzenesulfinate
Peak# Name Ret. Time Height Area Area% Ative Retention T
1 RT:1.704 1.704 11246 140000 0.603 0.795
2 RT:2.143 2.143 1680427 23029909 99.119 1.000
3 RT:4.711 4.711 3796 16269 0.070 2.198
4 RT:9.510 9.510 6604 33692 0.145 4.438
5 RT:10.698 10.698 2220 14832 0.064 4.992
Total 1704293 23234703 100.000
Example-1b:
Sodium metabisulphite (298 g, 1.56 mole), sodium carbonate (157 g, 1.48) and sodium bicarbonate (462 g, 5.5 mole) were dissolved in 3000 ml water, added Toluene sulfonyl chloride (500 g, 2.62 mole) at 30-40°C and heat the reaction mixture to 80-85°C and stir for 2-3 hours. Reaction mass was cooled to the room temperature 0-5°C and filtered the obtained solid. Further, wet cake was washed with chilled water to give 470 g dry sodium 4-methylbenzenesulfinate as solid with purity 99.338% (as depicted in Figure-2, Detector A230nm).
Table no 2 Chromatogram for sodium 4-methylbenzenesulfinate
Peak# Name Ret. Time Height Area Area% RRT
1 RT:1.512 1.512 4110 34643 0.243 0.709
2 RT:1.704 1.704 6027 44605 0.313 0.798
3 Sodium P-Toluenesulfininate 2.131 1040161 14151759 99.338 1.000
4 RT:9.501 9.501 3184 15121 0.106 4.458
Total 1053482 14246128 100.000

Example-2: Preparation of N-(tosylmethyl)formamide

Example-2a:

Sodium 4-methylbenzenesulfinate (400 g, 2.25 mole), formic acid (520 g, 11.30 mole) and formamide (744 g, 16.53 mole) were dissolved in paraformaldehyde (268 g, 8.92 mole) at 25-30°C. The reaction mixture was heated to 90-95°C and stir the reaction mass for 4-6 hours, progress of the reaction was monitored by TLC. Once TLC complies, 150 g of water was added and the reaction mass was cooled to 10-15°C, and filtered the obtained solid. Further, wet cake was washed with chilled water to give 395 g dry N-(tosylmethyl) formamide as solid with purity 99.082% (as depicted in Figure-3).
Table no 3 Chromatogram for N-(tosylmethyl) formamide
Peak# Name Ret. Time Height Area Area% RRT
1 RT:2.229 2.229 1955 19822 0.087 0.575
2 STAGE-2 3.876 2675682 22584834 99.082 1.000
3 RT:4.523 4.523 3325 20885 0.092 1.167
4 RT:4.711 4.711 4163 18901 0.083 1.215
5 RT: 4.850 4.850 2326 13287 0.058 1.251
6 RT:10.698 10.698 2502 18833 0.083 2.760
7 RT:11.139 11.139 22464 111337 0.488 2.874
8 RT:15.111 15.111 663 6256 0.027 3.899
Total 2713080 22794154 100.000

Example-2b:

Sodium 4-methylbenzenesulfinate (400 g, 2.25 mole), formic acid (520 g, 11.30 mole) and formamide (744 g, 16.53 mole) were dissolved in paraformaldehyde (268 g, 8.92 mole) at 25-30°C. The reaction mixture was heated to 80-85°C and stir for 10-12 hours, progress of the reaction was monitored by TLC. Once TLC complies, 150 g water was added and the reaction mass was cooled to 10-15°C, and filtered the obtained solid. Further, wet cake was washed with chilled water to give 388 g dry N-(tosylmethyl) formamide as solid with purity 99.53% (as depicted in Figure-4).
Table no 4 Chromatogram for N-(tosylmethyl) formamide
Peak# Name Ret. Time Height Area Area% RRT
1 RT:1.739 1.739 1843 13320 0.071 0.452
2 RT:2.195 2.195 6812 59872 0.321 0.571
3 P-Toluenesulfonylmethyl Formamid 3.845 1857868 18558222 99.530 1.000
4 RT:6.646 6.646 3281 14533 0.078 1.728
Total 1869803 18645947 100.000

Example-3: Preparation of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TosMIC)

Example-3a:

To a suspension of N-(tosylmethyl) formamide (390 g, 1.82 mole) in 300 ml dichloromethane and 600 ml toluene under nitrogen atmosphere, triethylamine (700 g, 6.91 mole) was added at 0°C to 10°C. Further, phosphorous oxychloride (315 g, 1.13 mole) was added over a period of 3-6 hours at 0°C to 10°C and stirred the reaction mass for 1-2 hours. After completion of reaction, quench the reaction mass in to sodium hydroxide (150 g, 3.75 mole) in 3000 ml water at 0-10°C, filtered the obtained solid. Further, wet cake was washed with chilled water to give crude 1-((isocyanomethyl)sulfonyl)-4-methylbenzene 235 g dry as solid, further the crude solid was stirred in methanol at 45-50°C for 2 hours, then gradually cooled to room temperature, filtered the solid observed and washed with methanol to give pure 1-((isocyanomethyl)sulfonyl)-4-methylbenzene, with purity 99.147% (as depicted in Figure-5).

Table no 5 Chromatogram of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene
Peak# Name Ret. Time Height Area Area% RRT
1 Tosylmethylformamide 4.372 4806 38788 0.259 0.613
2 TOSMIC 7.126 1891599 14859118 99.147 1.000
3 RT:7.783 7.783 12849 60553 0.404 1.092
4 RT: 8.299 8.299 387 1801 0.012 1.165
5 RT:8.854 8.854 5013 22781 0.152 1.242
6 RT:9.640 9.640 236 1106 0.007 1.353
7 RT:10.392 10.392 226 916 0.006 1.458
8 RT:11.791 11.791 198 1059 0.007 1.655
9 RT:12.051 12.051 197 825 0.006 1.691
Total 1915512 14986947 100.000

Example-3b:

To a suspension of N-(tosylmethyl) formamide (390 g, 1.82 mole) in 300 ml dichloromethane and 600 ml toluene under nitrogen atmosphere, triethyl ammine (700 g, 6.91 mole) was added at 0°C to -5°C. Further, phosphorous oxychloride (315 g, 1.13 mole) was added over a period of 8-12 hours and maintained the reaction mass for 1-2 hours at 0°C to -5°C. After completion of the reaction, quench the reaction mass in to sodium bicarbonate (150 g, 1.83 mole) in 3000 ml water at 10-15°C, filtered the obtained solid. Further, wet cake was washed with chilled water to give crude 1-((isocyanomethyl)sulfonyl)-4-methyl benzene 235 g dry as solid, further the crude solid was stirred in isopropyl alcohol at 45-50°C for 2 hours, then gradually cooled to room temperature, filtered the solid observed and washed with isopropyl alcohol to give pure 1-((isocyanomethyl)sulfonyl)-4-methylbenzene, with purity 99.536% (as depicted in Figure-6).
Table no 6 chromatogram of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene
Peak# Name Ret. Time Height Area Area% RRT
1 Tosylmethylformamide 4.367 7481 59308 0.380 0.613
2 TOSMIC 7.120 1935046 15518997 99.536 1.000
3 RT:8.288 8.288 337 2073 0.013 1.164
4 RT: 8.620 8.620 224 1606 0.010 1.211
5 RT:8.848 8.848 1600 7436 0.048 1.243
6 RT:9.639 9.639 173 771 0.005 1.354
7 RT:10.392 12.045 237 1113 0.007 1.692
Total 1945099 15591304 100.000

Example-3c:

To a suspension of N-(tosylmethyl) formamide (390 g, 1.82 mole) in 300 ml dichloromethane and 600 ml MDC under nitrogen atmosphere, triethyl ammine (700 g, 6.91 mole) was added at 10°C to 15°C. Further, phosphorous oxychloride (315 g 1.13 mole) was added over a period of 2-4 hours and maintained the reaction mass for 1-2 hours at 10°C to 15°C . After completion of the reaction, quench the reaction mass in to sodium carbonate (165 g, 1.55 mole) in 3000 ml water at 10-15°C, filtered the obtained solid. Further wet cake was washed with chilled water to give crude 1-((isocyanomethyl)sulfonyl)-4-methyl benzene 235 g dry as solid, further the crude solid was stirred in methanol at 45-50°C for 2 hours, then gradually cooled to room temperature, filtered the solid observed and washed with methanol to give pure 1-((isocyanomethyl)sulfonyl)-4-methylbenzene, with purity 99.649% (as depicted in Figure-7).
Table no 7 Chromatogram of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene
Peak# Name Ret. Time Height Area Area% RRT
1 Tosylmethylformamide 4.369 5983 46895 0.284 0.614
2 TOSMIC 7.121 1989582 16481391 99.649 1.000
3 RT:8.289 8.289 377 2089 0.013 1.164
4 RT:8.850 8.850 1410 6595 0.040 1.243
5 RT:9.638 9.638 177 810 0.005 1.353
6 RT:10.969 10.969 136 629 0.004 1.540
7 RT:12.047 12.047 199 956 0.006 1.692
Total 1997865 16539365 100.000 , Claims:WE CLAIM:
1.A process for preparing 1-((isocyanomethyl)sulfonyl)-4-methylbenzene, comprising the steps of:
(i)reacting sodium metabisulphite in water with toluene sulfonyl chloride in presence of sodium carbonate and sodium bicarbonate at a first predetermined temperature for a first predetermined time period to provide sodium 4-methylbenzenesulfinate;
(ii)reacting sodium 4-methylbenzenesulfinate with formic acid and formamide in paraformaldehyde at a second predetermined temperature for a second predetermined time period to provide N-(tosylmethyl) formamide;
(iii)reacting N-(tosylmethyl) formamide, triethyl amine and phosphorous oxychloride in a solvent mixture of dichloromethane and toluene at a third predetermined temperature for a third predetermined time period to obtain crude 1-((isocyanomethyl)sulfonyl)-4-methylbenzene and purifying the crude 1-((isocyanomethyl)sulfonyl)-4-methylbenzene by using crystallization in purification solvent;
wherein the purity of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene is 99% and above.
2.The process as claimed in claim-1 wherein in step (i) the first predetermined temperature is in the range of 60°C to 85°C and the first predetermined time period is in the range of 2 hours to 4 hours.
3.The process as claimed in claim-1 wherein in step (ii) the second predetermined temperature is in the range of 80°C to 95°C and the second predetermined time period is in the range of 4 hours to 12 hours.

4.The process as claimed in claim-1 wherein in step (iii) the third predetermined temperature is in the range of -5°C to 15°C and the third predetermined time period is in the range of 1 hour to 2 hours.
5.The process as claimed in claim-1 wherein in step (i) the molar ratio of toluene sulfonyl chloride : sodium metabisulphite : sodium carbonate : sodium bicarbonate is 1: (0.55 to 0.60) : (0.56 to 0.58) : (1.9 to 2.1).
6.The process as claimed in claim-1 wherein in step (ii) the molar ratio of sodium 4-methylbenzenesulfinate : formic acid : formamide : paraformaldehyde is 1: (5 to 5.1) : (7.0 to 7.5)) : (3.9 to 4).
7. The process as claimed in claim-1 wherein in step (iii) the molar ratio of N-(tosylmethyl) formamide: phosphorous oxychloride: triethyl amine is 1 : (0.6 to 0.7) : (3.7 to 3.8).
8.The process as claimed in claim-1 wherein in step (iii) the ratio of solvent mixture dichloromethane : toluene is 1:2.
9.The process as claimed in claim-2 wherein the percentage purity of obtained sodium 4-methylbenzenesulfinate is 99% and above.
10.The process as claimed in claim-3 wherein the percentage purity of obtained N-(tosylmethyl)formamide is 99% and above.
11.The process as claimed in claim-1, wherein in the purification solvent used in step (iii) for the crystallization of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene is selected from alcohol, ketone, water or mixtures thereof.
12. The process as claimed in claim-11, wherein the alcohol is selected from methanol, ethanol, isopropyl alcohol, propanol, n-butanol or mixtures thereof.

13.The process as claimed in claim-1 wherein in step (i):
the first predetermined temperature is in the range of 65°C to 70°C and the first predetermined time period is in the range of 3 hours to 4 hours; or
the first predetermined temperature is in the range of 80°C to 85°C and the first predetermined time period is in the range of 2 hours to 3 hours.
14.The process as claimed in claim-1 wherein in step (ii):
the second predetermined temperature is in the range of 90°C to 95°C and the second predetermined time period is in the range of 4 hours to 6 hours; or
the second predetermined temperature is in the range of 80°C to 85°C and the second predetermined time period is in the range of 10 hours to 12 hours.
15.The process as claimed in claim-1 wherein in step (iii) the third predetermined temperature is in the range of -5°C to 0°C or 0°C to 10°C or 10°C to 15°C.