Anhydrides reaction with, phosgene

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

Acetazolamide Acetazolamide is 5-acetamido-l,3,4-thiadiazole-2-sulfonamide (9.7.5). The synthesis of acetazolamide is based on the production of 2-amino-5-mercapto-l,3, 4-thiadiazole (9.7.2), which is synthesized by the reaction of ammonium thiocyanate and hydrazine, forming hydrazino-N,N -( ji-(thiourea) (9.7.1), which cycles into thiazole (9.7.2) upon reaction with phosgene. Acylation of (9.7.2) with acetic anhydride gives 2-acetylamino-5-mercapto-l,3,4-thiadiazol (9.7.3). The obtained product is chlorinated to give 2-acetylamino-5-mercapto-l,3,4-thiadiazol-5-sulfonylchloride (9.7.4), which is transformed into acetazolamide upon reaction with ammonia (9.7.5) [24,25]. 

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]. 

A carboxyl group can be introduced in almost any compound by various methods. In cases where a free thiol is present, the carboxyl group can be introduced easily by reaction with bromo- or iodoacetic acid. This reaction is very mild and is usually performed at pH around 8-9. When the hapten contains a hydroxyl group, carboxylic acid may be introduced by one of the following methods (a) carboxymethylation of the hydroxyl group with bromo- or iodoacetic acid (b) esterification with dicarboxylic acid anhydrides, such as succinic anhydride, to yield hemi-succinates, which are unstable above pH 9 (c) reaction with phosgene, which results in the formation of chlorocarbonates. ... 

Another interesting example of DMF catalysis involves the reaction of isatoic anhydride (XCVI) with phosgene to afford 2-isocyanatobenzoyl chloride (XCVII), which most likely occurs via o-isocyanatobenzoic acid (XCVIII) as the intermediate... 

N-carboxy anhydrides of amino acids (326), obtained fromN-benzyloxy-amino acids as crystalline derivatives by reaction with phosgene. Acylation of glycine methyl ester by (326) gave the corresponding peptides... 

Nucleophilic centers of trifunctional carboxylic components naturally have to be masked before the formation of synunetric anhydrides. Ddz-tryptophane, for example, shows several side reactions with phosgene, whereas the same compound with formyl masked indole nitrogen results in an excellently pure symmetric anhydride [71] (Fig. 46). 

A more highly oxidized derivative of quinazoline forms the heterocyclic moiety of a compound with CNS activity. Condensation of the aminopropylpiperazine 141 with isatoic anhydride gives the anthranilamide 142. Reaction of that amide with phosgene gives directly the heterocyclic ring. (The reaction may proceed by initial formation of the carbamoyl chloride ... 

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). 

Reaction of isatoic anhydride with a-aminoalkynes gave 209, which cyclized to a mixture of the oxazolo[3,2-b]quinazolines (210) and 2-aminophenyloxazoles (211) upon treatment with phosgene (89JHC1495). 

Notes. (I) Keten is a poisonous gas having a toxicity comparable with phosgene leaks from the apparatus, which must be contained in a fume cupboard, are recognised by a pungent odour resembling acetic anhydride. For this reason it is customary to attach a second receiver flask containing a compound which readily reacts with keten, e.g. aniline, to the other arm of the three-way stopcock. In this way when the reaction in the main flask is complete the keten gas may be diverted to the second receiver flask while the apparatus is switched off and allowed to cool. Escape to the atmosphere of keten is thereby avoided. 

Bisbenzothiazolylalkanes could be obtained by cyclization of o-aminothiophenol with aromatic and certain aliphatic diacids. Acetic anhydride is used to obtain the most important 2-methylbenzothiazole. The reaction of an o-aminothiophenol with phosgene, and with thiophosgene or carbon disulfide, gives a 2-hydroxy- and a 2-mercapto-benzothiazole, respectively, o-Aminothiophenol adds to alkynecarbonitriles (514) forming vinylamines... 

Phenoxazine is easily acylated with acetic anhydride or on heating with acyl chlorides in benzene.12-71,75 A very convenient method is the reaction of phenoxazine with phosgene to give phenoxazine-10-carbonyl chloride (37).73- 76 This acyl chloride is very stable it is not decomposed by short boiling in water or methanol, and gives phenoxazine only with hot sodium hydroxide. On prolonged boiling... 

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