Preparation of Acetamide

Most of the known processes for producing acetamide prescni serious operating difficulties if a pure product is desired, and especially where the product must be anhydrous. Thus the usual method oi distilling ammonium acetate requires a slow and long distillation, li has also been proposed to bring about reaction between ethyl acetate and ammonia but this process also produces an acetamide which is not pure and which notably contains water due to the great hygroscopicity of the acetamide. 

In order to obtain a pure product in a good yield, the reaction should be carried out below 80 C., because at higher temperature the formation of ammonium acetate becomes a disturbing factor. The reaction proceeds with sufficient speed and completeness at ordinary temperatures and neither heating nor cooling are therefore necessary which reduces the cost of apparatus. 

Ethyl acetate may be used in a similar manner but the reaction is not as rapid or as complete as with methyl acetate and the methyl acetate therefore constitutes a preferred embodiment of the invention, particularly as the solvent power of methyl acetate for water is greater than that os ethyl acetate and it is therefore a more efficient washing medium thai ethyl acetate so that improved results are also obtained in the scconc step of the process. It will be apparent that the present inventior eliminates costly equipment for a troublesome fractional distillation oi for distillation of the acetamide itself and the reaction is not carried oir at high temperatures or under high pressures which further eliminate-the necessity for expensive apparatus. The expense and loss incident iv recrystallization which may be necessary in processes used hitherto, i-also avoided without any loss in purity of the acetamide. 

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An excess of acetic acid is usually added before heating in order to repress the hydrolysis (and also the thermal dissociation) of the ammonium acetate, thus preventing the escape of ammonia. The excess of acetic acid, together with the water, is removed by slow fractional distillation. The method is rarely used except for the preparation of acetamide. 

A good method for the preparation of acetamide is to pass ammonia gas into an ethereal solution of acetic anhydride, evaporate the ether and extract the residual mixture of ammonium acetate and acetamide with benzene in an extraction apparatus (Fig. 25). The salt remains undissolved. Amides can also be prepared by the action of ammonia on acid chlorides and esters. 

A) Preparation of Acetamide (Sm.). Place in an eight-inch distilling tube 10 ml of glacial acetic acid, and add slowly 4 g of ammonium carbonate, a little at a time. When the evolution of carbon dioxide has subsided, attach to the mouth of the tube a micro condenser arranged for reflux. The end of the condenser should be just... 

In other respects, benzoyl chloride is a wholly normal add-chloride, and what was said under acetyl chloride is applicable to this chloride only it is possible to prepare aromatic amides by a different method from that used for the preparation of acetamide-... 

Preparation of Acetamide from Ethyl Acetate (SECTION 221).—Mix in a 250-cc. distilling flask 50 grams of ethyl acetate and 100 cc. of a concentrated aqueous solution of ammonia... 

Fig. 12. Preparation of acetamidate-bridged oligonucleosides. Polymerization is effected by triphenylphosphine, 2,2 -dipyridyldisulfide in pyridine, 14 h, 54%.

The classical dehydration of ammonium acetate to acetamide is accelerated by acetic acid, consequently the usual procedure for the preparation of acetamide involves careful distillation of an ammonium acetate-acetic acid mixture. The distillate is a solution of acetic acid and water. Finally excess acetic acid is distilled out followed by acetamide (yield 87-90% of theory, mp SrC). The product may be recrystallized from a benzene-ethyl acetate mixture [1]. 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Sulfation by sulfamic acid has been used ia the preparation of detergents from dodecyl, oleyl, and other higher alcohols. It is also used ia sulfating phenols and phenol—ethylene oxide condensation products. Secondary alcohols react ia the presence of an amide catalyst, eg, acetamide or urea (24). Pyridine has also been used. Tertiary alcohols do not react. Reactions with phenols yield phenyl ammonium sulfates. These reactions iaclude those of naphthols, cresol, anisole, anethole, pyrocatechol, and hydroquinone. Ammonium aryl sulfates are formed as iatermediates and sulfonates are formed by subsequent rearrangement (25,26). 

Amino-5-nitrosopyrimidines also condense with benzoylacetonitrile, phenacyl-pyridinium bromide and acetonylpyridinium chloride in the presence of sodium cyanide to produce. 7-amino-6-pteridinyl ketones (63JOC1197). Pteridine syntheses from pyridinium salts are not limited to the preparation of pteridyl ketones since pyridinium acetamide... 

A newer method for the preparation of nitronic esters, namely utilizing the (9-trimethyl-silyl ester, has been reported and these are prepared by the reaction of alkylnitro compounds and (V,(V-bis(trimethylsilyl)acetamide. These nitronic esters also undergo cycloaddition with alkenes to produce isoxazolidines (equation 54) (74MIP41601, 74DOK109, 78ACS(B)ll8). 

Finally, attachment of a rather complex side chain to the para position of the benzene ring on the sulfonamide leads to the very potent, long-acting oral antidiabetic agent, glyburide (215). Preparation of this compound starts with the chlorosul-fonation of the acetamide of 3-phenethylamine (209). The resulting sulfonyl chloride (210) is then converted to the sulfonamide (211) and deacylated (212). Reaction with the salicylic acid derivative, 213, in the presence of carbodiimide affords the amide, 214. Condensation of that with cyclohexylisocyanate affords glyburide (215). ... 

Preparation of 1 -(/3-D-arabinofuranosyl)-2-thiocytosine A solution of 2.0 g of 1 -(2, 3, 5 -0-triacetyl-/3-D-arabinofuranosyl)-2,4-dithiouracil in 100 ml of methanol is saturated with anhydrous ammonia at 0°C. The mixture, in a glass liner, is heated in a pressure bomb at 100°C for three hours. The reaction mixture is concentrated to a gum in vacuo, and most of the byproduct acetamide is removed by sublimation at 60°C/0.1 mm. The residue is chromatographed on 100 g of silica gel. Elution of the column with methylene chloride-methanol mixtures with methanol concentrationsof 2-25% gives fractions containing acetamide and a series of brown gums. The desired product is eluted with 30% methanol-methylene chloride to give a total yield of 0.386 g (30%), MP 175°-180°C (dec.). Recrystallization from methanol-iso-propanol furnishes an analytical sample, MP 180°-182°C (dec.). 

Preparation of 7-(D-0t-phenyigiycyiamido)-3-chioro-3-cephem-4-carboxyiic acid To a suspension of 280 mg (1.2 mmol) of 7-amino-3-chloro-3-cephem-4-carboxylic acid in 14 ml of acetonitrile was added with stirring at room temperature 0.5 ml of N, 0-bis-(trimethylsilyl)acetamide to form the soluble disilylmethyl derivative thereof. The solution was cooled to 0°C and was slowly added to a solution of the mixed anhydride formed by reacting 408 mg (1.5 mmol) of methyl-3-a-carboxybenzylaminocrotonate sodium salt with 161 mg (1.7 mmol) of methyl chloroformate in the presence to 2 drops of N, N-dimethylbenzyl amine in 7 ml of acetonitrile. 

The enolized form of 2-acetyl-2-cyclohexen-l-one has been synthesized in low yield by dehydrochlorination of 2-acetyl-2-chlorocyclohexanone in collidine at 180° and by elimination of acetamide from 3-acetamido-2-acetylcyclohexanone at 120-140°. The preparation of other a,/3-unsaturated /3-dicarbonyl compounds has been attempted with varying degrees of success. The... 

Several comparative procedures are included. The formation of 1-BENZYLINDOLE and GERANYL CHLORIDE by two different procedures are representative. An interesting comparison of three of the recent adaptations of the Claisen rearrangement on the same substrate is presented in the preparations of N.N-DIMETHYL-5/ -CHOLEST-3-ENE-5-ACETAMIDE, ETHYL-5/S-CHOLEST-3-ENE-5-ACETATE, and 5/9-CHOLEST-3-ENE-5-ACETALDEHYDE. For the utility of the procedure itself as well as for comparison with previously presented syntheses, the preparation and use of triflates in the synthesis of CYCLOBUTANONE is included. 

An alternative explanation for the formation of monoacetamides has also been suggested by Hockett and Chandler, who point out that the monoamide could have been formed from the diamide by the loss of acetamide. However, this explanation seems unlikely in view of the fact that Niemann and Hays have reported the preparation of AT-acetyl-D-glucofuranosylamine by the action of ammonia on pentaacetyl-/3-D-glucose, a reaction which involves the conversion of a pyranose to a furanose ring. 

Smietana, M., and Mioskowski, C., Preparation of silyl enol ethers using (bistrimethylsilyl)acetamide in ionic liquids, Org. Lett, 7,1037-1039,2001. 

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