Methyl carbamate synthesis

The Chemical Development Drug Evaluation branch of Johnson Johnson Pharmaceutical Research Development LLC in Raritan, NJ, USA, performed the exothermic reaction of methyl chloroformate with amines to give methyl carbamates [42]. Due to large heat release hot spots occur. For the reaction of N-methoxycar-bonyl-L-tert-leucine with methyl chloroformate to give the amino add derivative, this is even observed at laboratory scale. 

In case of complete malfunction of cooling and stirring systems, the temperature may exceed the solvent reflux temperature [42]. Accordingly, a slow dosing of the methyl chloroformate is necessary to have control over the heat release. After having determined the reaction parameters at 1 g scale, the reaction was carried out in a microreactor with 91% yield at 7 min residence time. More than 1kg of N-methoxycarbonyl-r-tert-leucine was prepared within 12 h. 

Scale-up by using a microreactor was done also for the amidation of p-tolyl chlorodithionoformate with dimethylamine to give p-tolyl dimethyldithio-carbamate without further safety precautions at 96% yield, which is comparable 

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In general, benzimidazole-2-methyl carbamate derivatives (28) can be synthesized by the reaction of an appropriate diamine (26) with 1,3-dicarbo-methoxy-5-methylisothiourea (27) [43], This is the most general and economic synthesis for benzimidazole carbamates. However, the same reaction was less than satisfactory when the aza analogues of o-phenylenediamines (29) were used. In order to synthesize the aza analogues of mebendazole (2) or flubendazole (3), the reactions of methoxycarbonyl isothiocyanate (30) with a wide variety of diamines such as 3,4-diaminopyridines, 4,5-diaminopyrimi-dines, o-phenylenediamines have been investigated in the presence of dicyclo-hexylcarbodiimide [44, 45] and were found to be quite successful in the synthesis of carbamates (31). 

Replacing the benzyl carbamate in 65 with a chiral carbamate derived from (R)-pantolactone generates diaster-eomeric molybdenum 1,2-dihydropyridine complexes 76 and 77, which are easily separable by crystallization <20000L3909>. Once separated, these chiral complexes 76 and 77 are easily converted to the more reactive methyl carbamate molybdenum 1,2-dihydropyridine complexes 78 and 79, respectively, and allow the synthesis of enantio-pure 2,6-disubstituted tetrahydropyridines (Scheme 21). 

T(2-Alkylcycloalk-l-enyl)methyl carbamates of type 56 are useful 1,2-dianion synthons that can be combined with two aldehydes in adjacent positions to provide a versatile synthesis of [fjannulated tetrahydrofurans (Scheme 81). At first, a carbanion of carbamate 56, which exhibits considerable configurational stability, is generated by (—)-sparteine-mediated deprotonation this is then converted to an optically active homoaldol product 57 with up to %% ee. An (it)-oxonium ion, which is subsequently formed under the influence of BF3, undergoes an intramolecular Mukaiyama-type addition of the enolic moiety onto the carbonyl group of a second aldehyde in the least-hindered conformation. Finally, the carhamoyl group is extmded, and after aqueous workup, diastereomerically pure tetrahydrofurans can be isolated <2005ASC1621>. 

Dioxo-1,2,4-Oxadiazolidines have been found as a moiety of the natural excitatory amino acid Quisqualic acid and their synthesis by numerous methods has been extensively studied by Zinner and co-workers (Ref. 256). Reaction of methyl-N-chlorocarbonyl-N-methyl carbamate, (VIII), (preparation given in section 3-3-4, this volume) with hydroxylamine affords 3,5-dioxo-4-methyl-1,2,4-oxadia-zolidine (Acronym MODD) in good yield as shown in scheme 204 (Ref. 257). 

The BF3-promoted reaction of aldehydes or acetals, methyl carbamate, and homochiral crotylsilanes is valuable for highly diastereo- and enantioselective synthesis of homoallylamines (Scheme 10.147) [419]. Interestingly, reaction using aromatic aldehydes or their acetals at low temperature forms stereo-controlled functionahzed pyrrolidines predominantly by a formal [3-1-2] cycloaddition (Section 10.3.3.1). 

Various catalysts have been studied for these reaction processes. The major disadvantages of these reaction processes are (i) the need for an energy intensive separation step for catalyst recovery and (ii) limiting solubility of CO and O2 in the liquid reactant medium. One of the objectives of our study is to develop a heterogeneous gas-solid catalytic reaction process for the synthesis of methyl-N-phenylcarbamate involving step 3 and dimethyl carbonate involving step 4 over Cu-based catalyst. This gas-solid process would eliminate the solubility limitation and catalyst separation step, thus enhancing the overall economics of the carbamate synthesis (6-8). 

A similarly tethered phosphonate was used to prepare the exocyclic olefin in Danishefsky s synthesis of calicheamicinone 347 [147]. Chemoselective acylation of the advanced intermediate 348 provided the olefination precursor 349, and subsequent cyclization gave 5-lactone 350, enforcing the desired stereochemistry of the double bond. The additional conjugative stabilization of the exocyclic olefin with the ester also facilitated subsequent transformations of the azide to the methyl carbamate functionality, and further manipulations ultimately led to the first synthesis of calicheamicinone 347 (Scheme 10-117). 

To conclude this section, it is important to note that alkenes are not the only hydrocarbon dienophiles that are useful partners in the Diels-Alder reaction. Alkynes and even benzyne are quite useful. As a structure proof of an intermediate in Pandey s synthesis of epiboxidine, the methyl carbamate of pyrrole (34) reacted with dimethyl-2-butynoate (35),in the presence of aluminum chloride (see sec. 11.6.A for a discussion of Lewis acid catalysis) to give a 90% yield of azanorbomadiene (36). A benzyne derivative of pyridine was... 

Ajmaline (14) was chosen as a starting material because its total synthesis and absolute configuration were already established (14-16), and furthermore, the equilibrium isomer 17 from ajmaline chemically corresponds to the hypothetical intermediate 13. Ajmaline (14) was first converted into the hydrazone derivative by treatment with A,)V-dimethylhydrazine and a catalytic amount of sulfuric acid. After protection of the resulting secondary amine with methyl carbamate, the hydrazone was hydrolyzed with cop-per(II) chloride in aq. tetrahydrofuran (pH 7) to afford the aldehyde 19 in 75% yield. The hydroxy group in compound 19 was protected with the methoxyethoxymethyl (MEM) ether, and then bromine was selectively... 

Azide 65, an intermediate of the synthesis of lycoposerramine-V, was converted into primary amine by the Staudinger reaction and the resulting amine was directly treated with methyl chloroformate to give methyl carbamate derivative 69 (Scheme 13). Reduction of the carbamate with LiAlH4 gave A-methyl derivative 70 and then the resulting secondary amine was acylated with chloroacetylchloride... 

These crude phenol fractions were combined and distilled at 1.5 mm/Hg. Following a sizeable forerun, a fraction boiling at 158-160 deg C was the anhydrous product, 3,4-diethoxyphenol. It was a clear, amber oil, and weighed 70.0 g. The slightest exposure to H20, even moist air, give a solid hydrate, with mp of 63-64 deg C. This phenol can be used for the synthesis of MEE (this recipe) or for the preparation of EEE (see the separate recipe). A solution of 2.0 g of this phenol in 5 mL CH2CI2 was diluted with 15 mL hexane. This was treated with 2 g methyl isocyanate followed by a few drops of triethylamine. After about 5 min, white crystals formed of 3,4-diethoxyphenyl-N-methyl carbamate, with a mp of 90-91 deg C. 

Carbamate synthesis Methyl carbamates 91% Control over exothermic conditions 2004/[54]... 

In 2011, Qiu and coworkers reported a racemic synthesis of minfiensine (109). Their synthesis began with tetrahydrocarbazole 156, which had been obtained via a Fischer indole synthesis (Scheme 14). Palladium catalyzed aUylation at the indole 3-position furnished indolenine 157, which upon protection of the nitrogen as a methyl carbamate, followed by a two-step oxidation of the terminal alkene, provided aldehyde 158. Reductive... 

Uses Intermediate in mfg. of dimethylol methyl carbamate-based resins for textile industry applies. pharmaceutical intermediate (Europe) Manuf./Distrib. Acros Org. http //www.acros.be, Aldrich http //www.sigma-aldrich.com, Alfa Aesar http //www.alfa.com. Am. Radiolabeled Chems. http //www.arc-inc.com, D8iO http //WWW. dochem. com ICN Biomed. Research Prods. http //www.icnbiomed.com, Kingchem http //www. kingchem. com, Lancaster Synthesis Pfaltz Bauer http //WWW.pfaltzandbauer. com-, Spectrum Quality Prods. 

The modification of the HR that employs alkoxide, often methoxide, is usually an efficient route to carbamates. For example, methyl carbamates 67-72 are synthesized from the corresponding primary amides using bromine and sodium methoxide. Carbamate 68 is used in a synthesis of phenanthroviridin aglycon, and cyanoester 70 is a key feature in the commercial synthesis of the DuPont herbicide azafenidin. Carbamate ester... 

The newest variation of the HR is an electrochemical method e.g., 46- 48, which does not appear to have been explored beyond its discoverers/ " The method is particularly useful for the synthesis of alkyl carbamates from primary alcohols containing sensitive functional groups since this electrochemical HR operates under neutral conditions. Some of the alkyl carbamates prepared using this HR are shown (202-205). The yields of the same methyl carbamates are uniformly higher with this electrochemical HR than with the classical bromine and sodium methoxide HR. Furthermore, little or no urea products are formed in the electrochemical HR. ... 

Tosylimino)phenyl-X -iodane, another iodine(III)-based reagent, also facilitates the conversion of a large variety of amides such as 16 into the corresponding isocyanates 17, which are suitable precursors for the synthesis of methyl carbamates 18 as shown in Scheme 6 [6]. The reaction proceeds in very good yields with a variety of electron-rich and electron-poor aryl-substituted amides as well as bulky alkyl-substituted amides. Although no conversion was observed when a 2,4,6-trimethylphenyl substituent was present, the authors successfully synthesized isopropyl Af-(4-methylphenyl)carbamate and ferf-butyl iV-(4-methylphenyl)carbamate by treatment of the corresponding isocyanates with suitable alcohols. 

Zhao W, Wang F, Peng W, ZhaoN, Li J, Xiao F, Wei W, Sun Y (2008) Synthesis of dimethyl carbonate from methyl carbamate and methanol with zinc compounds as catalysts. Ind Eng Chem Res 47 5913-5917... 

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