Acetamidine acetate

The above vinylogous ester (46.7 g, 0.24 mol) is combined with acetamidine acetate (28.6 g, 0.24 mol) and anhydrous sodium acetate (19.8g, 0.24 mol) in 1,4-dioxane (11), and heated at reflux (60 h). After cooling, the solid is removed by filtration, and the dioxane solution is concentrated in vacuo to an oily solid which is dissolved in water (200 ml), and adjusted to pH 10 with concentrated sodium bicarbonate solution. The solution is decolorized with activated charcoal and concentrated under reduced pressure to give a solid. This is slurried in chloroform, and the solid is removed by filtration. The organic solution is concentrated to produce a heavy oil. Trituration with ethyl acetate gives (10) (R =Me) (12.44 g, 42%) as a yellow solid, m.p. 127-128°C. Similarly prepared are 4-acetyl-2-hydroxymethyl- (12%) and 4-acetyl-2-(4 -pyridyl)imidazoles (39%). 

Acetamidine acetate 804 Ethyl orthoacetate (32.4 g) is heated under reflux for 45 min with ammonium acetate (15.4 g) whilst dry ammonia is led through the mixture. The product is distilled at a bath-temperature of 155-160° until the temperature of the condensing vapor falls to 75°. (This requires about 25 min with the above-mentioned quantities and gives 18.5 g of distillates.) The residue is then cooled to room temperature and filtered the solid acetamidine acetate is washed with a little ethanol and dried, then amounting to 16.5 g and melting at 189-191°. A further fraction can be isolated from the filtrate (total yield 19.75 g, 84%). 

Amino-2,6-dimethylpyrimidine has been prepared by heating the reaction product obtained from acetic anhydride and acetamidine 1 by treating 4-chloro-2,6-dimethylpyrimidine with ammonia 2 and by heating acetonitrile either with sodium ethox-ide in a sealed tube3 or with sodium.4 6... 

A researcher isolated a crystalline product from a mixture of acetamidine (13.g) and acetic acid (13.h). The ratio of 13.g and 13.h in the crystal was found to be 1 1, and the researcher proudly claimed to have formed a cocrystal of the two compounds. Draw the interaction between 13.g and 13.h that would be typically found in a cocrystal. Do you consider this to be a true cocrystal Why or why not ... 

The initial synthetic approach to conivaptan HCl (1) employed by the Yamanouchi discovery group26 commenced with commercially available benzazepinone 10. Acylation of 10 with p-nitrobenzoyl chloride provided benzamide 11. Subsequent hydrogenation of 11 over palladium on carbon yielded aniline 12, which was in turn condensed with biphenyl-2-carbonyl chloride to provide bis(amide) 13. Bis(amide) 13 was subsequently heated with copper(II) bromide in boiling chloroform/ethyl acetate to furnish a-bromoketone 14. It is interesting that condensation of a-bromoketone 14 with acetamidine hydrochloride in the presence of potassium carbonate in boiling acetonitrile afforded not only the desired imidazobenzazepine product (1 53% yield, 2 steps) but also the related oxazolobenzazepine 15 (7% yield, 2 steps), which presumably resulted from nucleophilic attack of the benzazepinone oxygen on the amidine moiety followed by loss of ammonia. Separation of oxazolobenzazepine byproduct 15 from imidazobenzazepine 1 by silica gel chromatography followed by treatment of the purified imidazobenzazepine free-base with hydrochloric acid then provided conivaptan HCl (1). 

A solution of 3,5-dimethyl-3H-imidazole-4-carboxylic acid (7.14 mmol) and 1,1 -carbonyl-diimidazole (10.7 mmol) in 35 ml DMF was stirred 3 hours at ambient temperature and then treated with A-hydroxy-acetamidine (9.18 mmol). The mixture was stirred an additional 16 hours at 80°C, then concentrated, and the residue dissolved in 30 ml acetic acid. This mixture was stirred 2 hours at 100°C and was then reconcentrated. The residue was then treated with 50 ml saturated NaHC03 solution and extracted seven times with 30 ml CH2C12. The extracts were washed with 70 ml brine, dried using MgS04, concentrated, and the product isolated in 61% yield as a white solid, mp = 95°C. 

These compounds have been prepared in two ways from 3-amino-l,2,4-triazines. In the first case, the aminotriazine is converted into the amidine (359) with iV,iV-dimethylfor-mamide or -acetamide acetal. Reaction of the amidine with hydroxylamine produces the amidoxime (360) and cyclization with phosphorus oxychloride forms the desired bicyclic product (361) (77JOC1018). Also, the desired ring system can be synthesized by treating 3-amino-l,2,4-triazines with acetonitrile in the presence of aluminum chloride to afford the acetamidines (362) which, in one case (R = = Me), can be transformed into... 

When 3,4-disubstituted 4-aminoisoxazolin-5(4Af)-ones (9) are hydrogenated, and then subsequently recyclized, high yields of imidazoles (10) are obtained (Scheme 6.1.4). The starting materials can be readily made from isoxazolin-5(4Af)-ones by sequential bromination, reaction with sodium azide and conversion of azide into amino by reaction with hydrobromic acid in acetic acid. The amines are then converted into formamidine or acetamidine derivatives with DMF or dimethylacetamide under reflux in phosphoryl chloride-chloroform. Yields at this stage are 50-93%. Catalytic... 

The acetates of acetamidine and benzamidine were condensed with 4-aminotriazole-S-carboxamide (73a) and its 7- and 8-methyl derivatives to give 2-metoyl- and 2-phenyl-8-azapurin-6-ones, respectively, in 80-90% yield, after refluxing for 4 - 8 h in butanol, hexanol, or octanol (toe choice of solvent determined toe optimal yield in each case). The reaction with tri-chlOFoacetamidine terminated at, e.g., (a-amino-i ) )9-trichloroethyliden-amino) 1,2,3-triazole (84) (from 73a). These intermediates were cyclized to 2-trichlorometoyl-8-azapurin-6-ones, in excellent yields, by stirring with 0.5 N potassium hydroxide (24°C, 5 h). This reaction gave only poor yields with 73b,c. 

The oxidation of acetamidine by sodium hypochlorite, in the presence of a large excess of acetate ions, afforded a mixture of 3-chloro-3-methyl- and 3-acetoxy-3-methyl-3H-diazirine. Unfortunately, this reaction lacks generality (for an exhaustive discussion on the mechanism of this reaction and on the halide exchange in diazirines, see ref 3). When the mixture of both diazirines was photolyzed in the presence of 2-methylpropene, two cyclopropanes 3 and 4 were formed which were separated by preparative gas chromatography. ... 

Acylation of nitrogen compounds by orthoesters. The formation of amidines from orthoesters (preferably orthoformates) and ammonia or an aromatic amine has been known for about 100 years (for a review see Post803). As an example for the acylation of ammonia a modern procedure is reproduced, in which acetamidine is obtained as acetate 804... 

Formamidine acetate was prepared in similar high yield by a similar procedure but with glacial acetic acid as solvent.804 A A-Disubstituted formamidine and acetamidine derivatives have been obtained analogously from orthoesters and alkylamines in the presence of glacial acetic acid805 or boron trifluoride etherate 806 In the reaction of orthoesters with secondary amines in the presence of toluenesulfonic acid the formation of ketene aminals (alkyl l -amino-vinyl ethers) was also observed.807... 

This reaction was extended to the 2-methyl and 3-benzyl analogs of the starting material, making use of formamidine, acetamidine, and trichloro-acetamidine. Butanol proved to be the best solvent, and condensation times from 1 to 4 hr gave good to excellent yields. Neither the free bases nor the hydrochlorides of the amidines gave much product. It was thought that the free amidines were rather unstable under the conditions of the reaction and that the acetates furnished a steady supply of them.60... 

Bromoacetoacetaldehyde was methylated with dimethyl sulphate to give the enol ether (272). Treatment with an acetamidine salt in the presence of triethylamine or sodium acetate gave 2-methyl-4-acetylimidazole (273) which was brominated at the acetyl methyl group and exposed to amidinothiourea to form zaltidine (274) [322-324]. The intermediate imidazole (273) can also be generated by photolysis of l-acetyl-2-methylimidazole (271) [323,325], or from 3-chloro-4,4-dimethoxy-3-buten-2-one (275) ( Scheme 5.61) [326]. 

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