Amino alcohols reaction with, phosgene

Conversion of the amino alcohol 53 to Efavirenz (1) was readily accomplished by reaction with phosgene or phosgene equivalents. The most convenient and economically sound method is to react 53 with phosgene in the absence of base in THF-heptane at 0-25 °C. After aqueous work-up, Efavirenz was crystallized from THF-heptane in excellent yield (93-95%) and purity (>99.5%, >99.5% ee). 

SYNTHESIS The first step involves the s)mthesis of the amino acid 7-benzyl-L-glutamate by a standard Fischer esterification reaction of L-glutamic acid with benzyl alcohol in the presence of strong acid. The amino acid is subsequently converted to the N-carboxyanhydride (NCA) monomer by reaction with phosgene gas, or by reaction with the less hazardous compound triphosgene.The NCA is polymerized by initiation with a variety compounds such as primary and secondary amines, and alkoxides. Typical comonomers include other amino acid NCAs. 

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

Oxidative carbonylation is not necessarily associated with C - C bond formation. Indeed, heteroatom carbonylation may occur exclusively, as in the oxidative carbonylation of alcohols or phenols to carbonates, of alcohols and amines to carbamates, of amino alcohols to cyclic carbamates, and of amines to ureas. All these reactions are of particular significance, in view of the possibility to prepare these very important classes of carbonyl compounds through a phosgene-free approach. These carbonylations are usually carried out in the presence of an appropriate oxidant under catalytic conditions (Eqs. 31-33), and in some cases can be promoted not only by transition metals but also by... 

Reaction of phosgene with the following two amino alcohols at < -30 C in CHjClj gives the corresponding iV-carbamoyl chlorides cyclization was induced by treatment with NEtj to give bicyclic urethanes [870] ... 

Figure 22.4 for the successful separation of the propranolol enantiomers on a chiral stationary phase the molecule should have a rigid structure. This was obtained by a precolumn derivatization with phosgene. This reagent gives an oxazolidone ring from the alcohol and secondary amino groups. The reaction is fast at 0°C. 

The reaction of phosgene with benzyl alcohol yields benzyl chloroformate (carbobenzoxy chloride), CICO2CH2C6H5, useful in protecting (Ege, 1999) amino groups of amino acids. (Deprotection is accomplished with H2/Pd/C.)... 

The starting compound was also condensed with an aldehyde in 82-84% yield with more than 98% ee. A corresponding amide from an fi unsaturated acid underwent the Diels-Alder reaction in 86-90% yield with more than 99% ee. The original amino alcohol was probably treated with phosgene to close the oxazolidone ring.63 The less toxic dimethyl carbonate might be a suitable replacement for the phosgene. The use of another chiral auxiliary for alkylation is shown in 10.30.64... 

Before concluding the discussion of protection of the amino group we have to mention the methods used for the preparation of N-blocked amino acid derivatives. The classical procedure, still applied for the introduction of the benzyloxycarbonyl group, is acylation with the appropriate alkyl chlorocar-bonate These, in turn, are obtained through the reaction of phosgene with the alcohol ... 

The reactions of amino acids or amino alcohols with phosgene are interesting since they provide in one step molecules with two different functional groups, namely isocyanato acid chlorides or isocyanato chloroformates. 

A phosgene-free process for preparing urethane and carbonate monomers and polymers has been reported [257]. The process involves reaction of CO2 with amines (e.g. 4,4 -methylenebis(cydohexylamine)), alcohols, or amino alcohols in the presence of an amidine- or guanidine-type base (e.g. N-cydohexyl-N, N, N",N"-tetra-ethylguanidine), followed by treatment of the resulting ammonium carbamate or carbonate salt with a primary or secondary hydrocarbyl halide of a specified structure in a polar, aprotic solvent (e.g. N-methylpyrroUdinone). When hydrocarbyl dihalides or -polyhalides are used in the second step, polyurethanes and polycarbonates are formed. 

Carbobenzoxy function (CBz) is also an acyl protecting group for the amino function which is removed by hydrogenolysis or under acidic conditions. The chloride is prepared by reaction of benzyl alcohol with phosgene ... 

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