Methyl isocyanate synthesis

Long term, it will even be possible to manufacture many hazardous materials in plants as small as a silicon chip, using large numbers of plants on a chip in parallel to produce the quantity of material required [61, 62]. It is unlikely that the large, world-scale petrochemical plant vdll ever completely disappear. However, distributed manufacture of chemicals in small plants will become an important part of the industry, in particular for the improved safety through distributed manufacturing of hazardous chemicals. There are many relevant examples besides those cited previously of phosgene and methyl isocyanate synthesis, for example HCN [63] and aqueous peracetic acid [64] on-demand syntheses. 

More recently, a commercial process has been introduced for the manufacture of methyl isocyanate (MIC) which involves the dehydrogenation of /V-m ethyl form am i de [123-39-7] in the presence of palladium, platinum [7440-06-4], or mthenium [7440-18-8], at temperatures between 50—300°C (31). Aprotic solvents, such as ben2ene [71-43-2], xylenes, or toluene [108-88-3], may optionally be used. A variation of this synthesis employs stoichiometric amounts of palladium chloride [7647-10-1], PdCl2. 

A convenient method for the synthesis of these low boiling materials consists of the reaction of /V,/V-dimethy1iirea [96-31-1] with toluene diisocyanate to yield an aUphatic—aromatic urea (84). Alternatively, an appropriate aUphatic—aromatic urea can be prepared by the reaction of diphenylcarbamoyl chloride [83-01-2] with methylamine. Thermolysis of either of the mixed ureas produces methyl isocyanate ia high yield (3,85). 

X5lenol is an important starting material for insecticides, xylenol—formaldehyde resins, disinfectants, wood preservatives, and for synthesis of a-tocopherol (vitamin E) (258) and i7/-a-tocopherol acetate (USP 34-50/kg, October 1994). The Bayer insecticide Methiocarb is manufactured by reaction of 3,5-x5lenol with methylsulfenyl chloride to yield 4-methylmercapto-3,5-xylenol, followed by reaction with methyl isocyanate (257). Disinfectants and preservatives are produced by chlorination to 4-chloro- and 2,4-dich1oro-3,5-dimethylpheno1 (251). 

In many pyrimidine ring syntheses, it is possible or even desirable to isolate an intermediate ripe for ring-closure by the formation of just one bond. For example, ethyl 3-aminocrotonate (502) reacts with methyl isocyanate to give the ureido ester (503) which may be isolated and subsequently converted into 3,6-dimethyluracil (504) by the completion of one bond. However, viewed pragmatically, the whole synthesis involves the formation of two bonds and therefore is so classified. On such criteria, only two pyrimidine/quinazoline syntheses involve the formation of only one bond. 

Among the hazardous chemical weapons scheduled class 1-3, methyl isocyanate becoming more and more important as a precursor [83]. This is just one among a number of substances which could be made via micro-reactor synthesis. Especially in the case of so-called binary weapons, where two relatively harmless substances are mixed to give a weapon, on-site mixing is demanded this can be accomplished with high performance by micro reactors. Pocket-sized miniature plants can neither be monitored nor detected. 

Another reaction with hazardous potential is the synthesis of methyl isocyanate from mefhylformamide, which was investigated using a micro reactor in industry [74],... 

Beneficial Micro Reactor Properties for the Synthesis of Methyl Isocyanate... 

GP 12] [R 15] For the synthesis of methyl isocyanate from methylformamide similar conversions as for the conventional synthesis could be determined at low selectivities [71]. One reason for this is seen in the non-ideal temperature profiles within the reaction zone of the microstructured reactor packing. 

As already described for the all-carbon-Diels-Alder reaction, a hetero-Diels-Alder reaction can also be followed by a retro-hetero-Diels-Alder reaction. This type of process, which has long been known, is especially useful for the synthesis of heterocyclic compounds. Sanchez and coworkers described the synthesis of 2-aminopyridines [48] and 2-glycosylaminopyridines 4-144 [49] by a hetero-Diels-Alder reaction of pyrimidines as 4-143 with dimethyl acetylenedicarboxylate followed by extrusion of methyl isocyanate to give the desired compounds (Scheme 4.30). This approach represents a new method for the synthesis of 2-aminopyridine nucleoside analogues. In addition to the pyridines 4-144, small amounts of pyrimidine derivatives are formed by a Michael-type addition. 

To this end, the diazoimidazole carboxamide compound 32 was transformed first by methylamine to the methyl-triazene derivative 39, which was reacted with 11 (". -phosgene to give the desired product 40 <2002JME5448>. In another approach, 32 was directly cyclized to the bicyclic product by using 1 C-labeled methyl isocyanate. This route allowed the synthesis of both the C-2-labeled 40 and the (7-methyl-labeled samples 41 <1997JLR371, 2002JME5448> (Scheme 13). 

The synthesis of pyrido[4,3-rf]pyrimidine-2,4-diones was carried out by thermal fusion of enamine 601 with A-methylurea at 180 °C to give the pyridopyrimidines 156 and 607 in addition to the unexpected a,/3-unsaturated esters 608, which were separated chromatographically in very poor yield (Equation 51). Alternatively, 156 was obtained in 59% yield by treatment of 601 with methyl isocyanate and EtsN to give the corresponding uriedo intermediate which was cyclized in situ with NaOH <1994JHC1569>. 

Cyclization of quinazolin-4(3//)-one with an excess of methyl isocyanate gave the 1,3,5-triazino[ 1,2-u]quinazoline-1,3,6-trione (643) (84H501). A one-pot synthesis of 1,3,5-triazino[ 1,2-u ]quinazolines (645) was carried out by reacting 2-amino-4-phenylquinazolines (644) with chlorocarbonyl isocyanate (85S892). 

Kantlehner et al. (78LA512) have reported a novel synthesis of triazine-2,4-diones from (170) and methyl isocyanate (equation 95). 

Low boiling isocyanates, such as methyl isocyanate, are difficult to prepare via conventional phosgenation due to Ihe fact that the /V-alkyl carhamovl chlorides are volatile below their decomposition point. A convenient method for the synthesis of these low boiling materials eonsisls of live reaction of JV. Al -dimeihylurea with toluene diisocyanate to yield an aliphatic -aromatic urea which is pymlyycd to yield the desired isocyanate. Alternatively, an appropriate aliphatic-aromatic urea can he prepared by the reaction of dipltenylcarbamoyl chloride with methylanune. 

Isocyanates are compounds with the general formula R-N=C=0. They have numerous uses in chemical synthesis, particularly in the manufacture of polymers with carefully tuned specialty properties. Methyl isocyanate is a raw material in the manufacture of carbaryl insecticide. Methyl isocyanate (like other isocyanates) can be synthesized by the reaction of a primary amine with phosgene in a moderately complex process, represented by reaction 15.8.1. Structures of three significant isocyanates are given in Figure 15.7. 

New Chemistry for the Preparation of Temozolomide. The three main disadvantages of the present synthesis (Scheme 14) were outlined earlier. Of these only the first two, the potential explosivity of the diazonium intermediate (XXIV) and the toxicity of methyl isocyanate, can be addressed. In the first, the handling of the potentially explosive intermediate is best accommodated by ensuring that this material remains wet at all times. Thus, avoiding the preparation and use of methyl isocyanate became the primary objective. 

The cycloaddition of isomiinchnones with acetylenic dipolarophiles followed by the extrusion of an alkyl or aryl isocyanate (RNCO) has proven to be an effective method for the synthesis of substituted furans. The Ibata group investigated the bimolecular 1,3-dipolar-cycloaddition of aryl-substituted isomiinchnones with a number of acetylenic dipolarophiles [50]. Aryl diazoimides of type 1 were heated in the presence of a catalytic amount of Cu(acac)2 and the appropriate acetylenic dipolarophile. Formation of the substituted furan was found to be temperature-dependent higher temperatures (ca. 120°C) were needed for complete conversion to the furan. It was reasoned that the extrusion of methyl isocyanate was not as facile as the loss of carbon dioxide from sydnones and miinchnones [50]. 

Since it had already been shown by Polonovski and Nitzberg (11) that eseroline could be converted into physostigmine by the action of methyl-isocyanate, Julian and Pikl s synthesis of /-eseroline constituted the first complete synthesis of physostigmine. 

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