Anhydrides, preparation with phosgene

Anhydrides, preparation with phosgene and tnethylamine, 47, 91 Anisole, chlorination with sulfuiyl chloride, 47, 23... 

Anhydrides, preparation with phosgene and triethylamine, 47, 91 Aniline, reaction with e-nitrobenzalde-hyde, 48,113... 

Fig. 45. IR spectra of pure (a) and impure (b) symmetric amino add anhydrides prepared with phosgene...

The coupling method with symmetric anhydrides prepared with phosgene and used in situ with permanent monitoring of the anhydride by flowthrough IR measurement was practized in the synthesis of several linear decapeptide precursors of antamanide. These were obtained in yields between 84% and 96% and in the synthesis of fully protected somatostatin [71], which was built up on polymer with 83% yield as determined by analytically quantified Edman degradation on pol)oner. 

Fig. 46. IR spectra of Ddz-tryptophane anhydride (a, impure) and of Ddz-N -formyltryptophane anhydride (b, pure) prepared with phosgene...

Rea.ctlons, As with other tertiary alcohols, esterification with carboxyUc acids is difficult and esters are prepared with anhydrides (181), acid chlorides (182), or ketene (183). Carbamic esters may be prepared by treatment with an isocyanate (184) or with phosgene followed by ammonia or an amine (185). 

The mechanism of the condensation in Part D probably involves thioformylation of the metallated isocyanoacetate followed by intramolecular 1,1-addition of the tautomeric enethiol to the isonitrile. This thi2izole synthesis is analogous to the formation of oxazoles from acylation of metallated isonitriles with acid chlorides or anhydrides. " Interestingly, ethyl formate does not react with isocyanoacetate under the conditions of this procedure. Ethyl and methyl isocyanoacetate have been prepared in a similar manner by dehydration of the corresponding N-formylglycine esters with phosgene and trichloromethyl chloroformate, respectively. The phosphoryl chloride method described here was provided to the submitters by Professor U. Schollkopf and is based on the procedure of Bohme and Fuchs. The preparation of O-ethyl thioformate in Part C was developed from a report by Ohno, Koi/.uma, and Tsuchihaski. " ... 

This procedure is a modification of preparations of 3-phen)d, sydnone described earlier. The dehydration of N-nitroso-N phenylglycine has also been effected by the use of thionyl chloride and pyridine in dioxane, thionyl chloride in ethertrifluoroacetic anhydride in etherand diisopropylcarbodiimide in water or by reaction of the alkali metal salts of N-nitroso-N-phenylglycine with phosgene or benzenesulfonyl chloride in water or with acetyl chloride in benzene. ... 

The Merck process group subsequently published a more detailed route amenable towards multikilogram scales (Blacklock et al., 1988). This synthesis begins with treatment of alanine with phosgene to produce A-carboxyanhydride (NCA) 16 (Scheme 10.3). Under basic aqueous conditions this anhydride is coupled with proline to produce, upon acidic work-up, the dipeptide alanyl-proline (14). Enalapril is then prepared in one synthetic step by a diastereoselective reductive amination between ethyl-2— oxo-4-phenylbutyrate (13) and 14. This reaction was the subject of extensive optimization, and it was found that the highest diastereoselectivity was obtained by hydrogenation over Raney nickel in the presence of acetic acid (25%), KF (4.0 equiv.), and 3 A molecular sieves (17 1 dr). Enalapril is then isolated in diastereomerically pure form as its maleate salt (Huffman and Reider, 1999 Huffman et al., 2000). 

The use of activated anthranihc acid derivatives facUitates the preparation of the amides in those cases where the amines are either umeactive or difficult to obtain. Thus, reaction of (87-1) with phosgene gives the reactive the isatoic anhydride (89-1). Condensation of that with ortho-toluidine leads to the acylation product (89-2) formed with a simultaneous loss of carbon dioxide. This is then converted to the quinazolone (89-3) by heating with acetic anhydride. Reaction with sodium borohydride in the presence of aluminum chloride selectively reduces the double bond to yield the diuretic agent metolazone (89-4) [99]. 

Rude and coworkers prepared the per-O-acetylated 3-O-glycosyl-serines from several mono- and di-saccharides, which were converted into the N-carboxy anhydrides (Leuchs anhydrides) of serine by treatment with phosgene in an inert solvent,68-70 as shown in Scheme 8. 

Mixed bis-lactim ethers of type (20) are best prepared by the following route, outlined for the bis-lactimether (20a) of Cyclo(L-Val-Ala). L-Val, the chiral auxiliary, is converted with phosgene into its N-carboxyanhydride (L-Val-NCA, Leuchs anhydride) (17)l5). This gives with D,L-Ala-OCH3 the dipeptide (18) which on heating in toluene cyclizes to the diketopiperazine (19). This is converted into the bis-lactim ether (20a) [(3RS, 6S)-2,5-dimethoxy-6-isopropyl-3-methyl-3,6-dihydropyra-zine] with methyl Meerwein s salt. 

Wilchek, M., Ariely, S., and Patchornik, A., The reaction of asparagine, glutamine, and derivatives with phosgene, J. Org. Chem. 33, 1258-1259, 1968 Hamilton, R.D. and Lyman, D.J., Preparation of A-carboxy-a-amino acid anhydrides by the reaction of copper(II)-amino acid complexes with phosgene, J. Org. Chem. 34, 243-244,1969 Pohl, L.R., Bhooshan, B.,... 

Anhydrides. The preparation of nicotinic anhydride by reaction of nicotinic ucid with phosgene has been published.1... 

These amino acid anhydrides are usuaiiy made with phosgene. The use of dimethyi carbonate shouid be tested in the preparation of the monomers. Poiyaspartic acid can be made by heating aspartic acid without soivent to form a polysuccinimide which is then hydrolyzed (12.34).186 It can also be made directly from maleic anhydride and ammonia. It promises to be useful as a scale inhibitor in water, an antiredeposition agent in detergents, and such. Gamma-irradiation converts it to a biodegradable superabsorbent material that takes up 3400 g water per gram of dry polymer.187 (Most superabsorbent polymers are based on acrylamide, a neurotoxin.)... 

A resin with mixed carbonic-carboxylic anhydride function has been prepared and used as acylating reagent [144], Thus, the supported chloroformate 140 was obtained by reaction of hydroxymethylated polystyrene with phosgene in benzene (Scheme 7.43). Further treatment with benzoic acid in the presence of triethyl-amine in benzene gave rise to the supported mixed anhydride 141. This polymer has been used in the benzoylation of several amines, although variable amounts of benzoic acid from attack to the internal carbonyl were obtained when using aromatic amines. 

Significant shortcomings of such a technique for the preparation of 4,4 -keto-bis(naphthalic anhydride) are low yields of bis-acenaphthyls (4,4 -diacenaphthylmethane-15% 4,4 -diacenaphthyl ketone-5 %) and work with phosgene and carbon disulfide. 

Formation oflS[ Carboxy OC Amino Acid Anhydride (NCA) (85). NCAs are important as starting materials for amino acid polymers. They are prepared by the reaction of amino acids with phosgene in an aprotic solvent. 

Analogous to amino acids, a-hydroxy acids form cyclic anhydrides when treated with phosgene. However, a much more efficient reagent for this transformation with lactic acid is trichloromethyl chloroformate. By this method, L-lactic acid O-carboxyanhydride (3) is prepared as a crystalline solid in 46% yield [2]. Although 3 has found application in polymer chemistry, its use in asymmetric synthesis has been limited. Reaction of 3 with 4-bromo-benzaldehyde methylthio(thiocarbonyl)hydrazone in the presence of TFA gives a mixture of 4 (25%) and 5 (56%), which is separable by column chromatography [3]. 

Indole-1-carboxylic acid can be converted by treatment with a carbodiimide to the anhydride (413), which can undergo reaction with amines or the sodium salts of phenols, thiophenols, pyrroles, and indoles. For example, it reacts with the sodium salt of pyrrole-2-carbaldehyde to give the product (414) (Scheme 143) <87JOC3934>. V-Chloroformylcarbazole (415), prepared by the reaction of carbazole with phosgene, has been used effectively for the fluorogenic labeling of amino acids (Equation (118)) <90TL1455>. 

The loss of half of the carboxylic acid is no cause for concern in acetylation with acetic anhydride, but appeared to be prohibitive when blocked amino acids, obtained sometimes with considerable effort, had to be sacrificed. This situation changed with time. Protected amino acids are now prepared with increasing facility and decreasing cost and their anhydrides are frequently applied. An interesting but not widely practiced approach to symmetrical anhydrides is the use of phosgene ... 

Preparation of polyamino acids through N-carboxyanhydrides (NCA-s or Leuchs anhydrides) is a classical approach. These compounds, oxazolidine-2,5-diones are readily obtained from amino acids on treatment with phosgene in aprotic solvents, followed by heating ... 

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