Ureas, acylation hydrolysis

Schollenberger added 2% of a polycarbodiimide additive to the same poly(tetra-methylene adipate) urethane with the high level of acid (AN = 3.66). After 9 weeks of 70°C water immersion, the urethane was reported to retain 84% of its original strength. Carbodiimides react quickly with residual acid to form an acyl urea, removing the acid catalysis contributing to the hydrolysis. New carbodiimides have been developed to prevent hydrolysis of polyester thermoplastics. Carbodiimides are also reported to react with residual water, which may contribute to hydrolysis when the urethane is exposed to high temperatures in an extruder [90]. 

More than 25 different substituted urea herbicides are currently commercially available [30, 173]. The most important are phenylureas and Cycluron, which has the aromatic nucleus replaced by a saturated hydrocarbon moiety. Benzthiazuron and Methabenzthiazuron are more recent selective herbiddes of the class, with the aromatic moiety replaced by a heterocyclic ring system. With the exception of Fenuron, substituted ureas (i.e., Diuron, Fluometuron, Fig. 10, Table 3) exhibit low water solubilities, which decrease with increasing molecular volume of the compound. The majority of the phenylureas have relatively low vapor pressures and are, therefore, not very volatile. These compounds show electron-donor properties and thus they are able to form charge transfer complexes by interaction with suitable electron acceptor molecules. Hydrolysis, acylation, and alkylation reactions are also possible with these compounds. 

The instability of primary nitramines in acidic solution means that the nitration of the parent amine with nitric acid or its mixtures is not a feasible route to these compounds. The hydrolysis of secondary nitramides is probably the single most important route to primary nitramines. Accordingly, primary nitramines are often prepared by an indirect four step route (1) acylation of a primary amine to an amide, (2) A-nitration to a secondary nitramide, (3) hydrolysis or ammonolysis with aqueous base and (4) subsequent acidification to release the free nitramine (Equation 5.17). Substrates used in these reactions include sulfonamides, carbamates (urethanes), ureas and carboxylic acid amides like acetamides and formamides etc. The nitration of amides and related compounds has been discussed in Section 5.5. 

The serine proteases act by forming and hydrolyzing an ester on a serine residue. This was initially established using the nerve gas diisopropyl fluorophosphate, which inactivates serine proteases as well as acetylcholinesterase. It is a very potent inhibitor (it essentially binds in a 1 1 stoichiometry and thus can be used to titrate the active sites) and is extremely toxic in even low amounts. Careful acid or enzymatic hydrolysis (see Section 9.3.6.) of the inactivated enzyme yielded O-phosphoserine, and the serine was identified as residue 195 in the sequence. Chy-motrypsin acts on the compound cinnamoylimidazole, producing an acyl intermediate called cinnamoyl-enzyme which hydrolyzes slowly. This fact was exploited in an active-site titration (see Section 9.2.5.). Cinnamoyl-CT features a spectrum similar to that of the model compound O-cinnamoylserine, on denaturation of the enzyme in urea the spectrum was identical to that of O-acetylserine. Serine proteases act on both esters and amides. 

A preparatively useful approach to the enantiomerically pure antihypertensive agent (R)-SQ 32,926 was disclosed by Atwal et al. (Scheme 4.13) [169]. In the first step, the 1,4-dihydropyrimidine intermediate 38 is acylated at N3 with 4-nitrophenyl chloroformate followed by hydrolysis with HC1 in THF to give DHPM 39. Treatment with (R)-a-methylbenzylamine provided a mixture of diastereomeric ureas from which the (R,R) isomer 40 was separated by crystallization. Cleavage with TFA provided (R)-SQ 32,926 in high enantiomeric purity. Similar strategies have been used to obtain a number of pharmacologically important DHPM derivatives in enantiomerically pure form [169, 186, 187]. 

A15.1.1.9 Imides. Compounds that have two acyl groups bonded to a single nitrogen are known as imides (R—CO—NH—CO—R ). The most common imides are cyclic ones (maleimide). Maleimide will convert to maleic acid under water and acid/base. Another example of imide hydrolysis is pheno-barbital in which phenobarbital (a cyclic imide) is hydrolyzed to form urea and a-ethylbenzeneacetic acid. 

Life as we know it would be impossible without the astonishing characteristics of enzymic catalysis. This catalysis is not only highly efficient, so that reactions may proceed at low temperature and at neutral pH with the speed required by living cells, but it exhibits also a remarkable specificity. Let us cite two typical examples First, the enzyme urease catalyzes the hydrolysis of urea but of no other compound (1). Second, the catalytic action is frequently restricted to one of the antipodes of optically active substrates. Thus, chymotrypsin will catalyze the hydrolysis of acylated L-tyrosinamides, but will not catalyze the reaction of the corresponding derivatives of D-tyrosine (2). 

Both steps of the process are catalyzed by the basic form of the imidazole group of a histidine residue forming part of the active site. If the native conformation of the enzyme is disrupted by denaturation reagents such as urea, the unique seryl hydroxyl loses its characteristic reactivity in both the acylation and the deacylation process (15). This is easily understood if we realize that the reactive serine and the catalytically active histidine are extremely far from one another along the polypeptide chain, being separated by 137 amino acid residues (16) they are brought into the necessary juxtaposition only by the specific folding in the native enzyme structure. The mechanism by which the enzyme acetylcholine esterase catalyzes the hydrolysis of its substrate acetylcholine appears to be very similar (17). As we shall see, a number... 

In 1909, 4-amino-6-methyl-l,3,5-triazin-2-ol was obtained by cyclization of (acetylcarbamimi-doyl)urca under basic conditions.443 Subsequently, several new processes based on acylated dicyanodiamides were developed.444-447,449 Thus, when acyldicyanodiamides 1 are heated to reflux in 2-ethoxyethanol, 4-amino-1,3,5-triazin-2-ols 2 are obtained in crude yields of 60 to 100%.444,445 Catalytic amounts of amine salts significantly accelerate this reaction. After selective acid hydrolysis of acyldicyanodiamides, (acylcarbamimidoyl)ureas 3 are obtained which can also be cyclized to the 1,3,5-triazines 2. These reactions are carried out in excess sodium hydroxide solution and provide the triazines in 90 to 99% yield.443,444,446 447 Cyclization of 1-acylbiurets 4, prepared by acid hydrolysis of (acylcarbamimidoyl)ureas 3, is effected by treatment with potassium hydroxide solution.444,448 While the benzoyl derivative 3 (R = Ph) yields the corresponding l,3,5-triazine-2,4-diol 5 (R = Ph) in quantitative yield, the acetyl derivative 3 (R = Me) cyclizes only partially to the corresponding triazinediol 5 (R = Me).448... 

Coordinated cyanamide does not add OH" to form the N-bound urea complex since it de-protonates 5.2) to ve the unreactive [Co(NCNH)(NH3)5p ion, but in acid it readily loses NH to form N-coordinated cyanate (equation 27). The analogous dimethylcyanamide complex cannot deprotonate and adds OH" to form urea (Scheme 21), but this does not proceed further to coordinated carbamic add and NHMCj in a process analogous to that suggested for the function of Ni in the metalloenzyme jack bean urease (which catalyzes the convemioo of urea to these products), nor does it lose NHMc2 to form the cyanato complex as suggested by Balahura and Jordan for the similar urea derivatives (equation 28). Alternatively, in acid solution the protonated urea rapidly isomerizes to the O-coordinated complex (r,/2 a 40 s, 25 °C Scheme 21). This isomer undergoes OH -catalyzed hydrolysis at the metal rather than at acyl carbon, so the function of the metalloenzyme has not been duplicated in this system. A similar property is found for 0-bound urea (equation 29). ... 

Hydrolysis of compounds 80 in the presence of base afforded the acyl ureas 95 (Equation 18) <1995JPR385>. 

Turnkey Process for Celiprolol Celiprolol has a unique Af,Af-diethylurea in its structural framework we wished to integrate HKR into a process. The existing route starts with 4-ethoxyaniline which was treated with diethylcarbamoyl chloride in the presence of potassium bicarbonate to give A -p-ethoxyphenylacetamide (Scheme 30.7). Friedel-Crafts acylation with acetyl chloride and anhydrous aluminum chloride followed by acid hydrolysis furnished the acetophenone derivative. Reaction of the urea derivative with epichlorohydrin followed by treatment with hydrobromic acid yielded a bromohydrin. Celiprolol was obtained as a free base by reaction of this bromohydrin with feri-butylamine in the presence of triethylamine, and was later converted to its hydrochloride salt. 

Alkyl-, vinyl-, and aryl-substituted acyl azides undergo thermal 1,2-carbon-to-nitrogen migration with extrusion of dinitrogen — the Curtius rearrangement — producing isocyantes. Reaction of the isocyanate products with nucleophiles, often in situ, provides carbamates, ureas, and other A-acyl derivatives. Alternatively, hydrolysis of the isocyanates leads to primary amines. 

Mioskowsld built up a chiral acylating reagent 41 [N-acetyl-l,2-bis (ttifluoromethanesulfonamide)j from trans-l,2-diaminocyclohexane [51]. This active amide that proved to be insensitive to hydrolysis could resolve various primary amines in either polar or apolar solvents, at or below room temperature. As a typical example, 1-phenylethylamine reacted in N,N -dimethylpropylene urea (DMPU) at —20 °C, to give, at fuU consumption of the reagent, after 24h reaction, 33% of recovered amine with 90% ee. 

The acid moiety was converted to an amine and the alkene moiety in 5.223 was converted to a nitrile and, thereby, to an acid.55 This sequence for accomplishing this reacted 5.223 with urea to give 5.224. Reduction followed by acylation and ozono-lysis (with a reductive workup) gave 5.225. 5 Conversion to the chloride and displacement with cyanide gave 5.226 and acid hydrolysis led to 5-meihyl-7-amino-heptanoic acid, 5.227. In this lengthy sequence, the acid moiety in 5.223 functioned as the amine precursor and the alkenyl group functioned as the eventual acid moiety. 

When one-half of the usual quantities of bromine and alkali are employed, alkyl acyl ureas are obtained. The isocyanates, in the absence of excess alkali, react with the sodium s ts of the haloamides to give salts of the alkyl acyl ureas from which the ureas themselves result on hydrolysis. ... 

Isocyanates derived from the higher aliphatic amides react more rapidly with the haloamide salts than with water and alkali, so that, when these amides are subjected to the Hofmann reaction in aqueous mediiun, only small amounts of the expected amines are formed. Although amines arise from the hydrolysis of the alkyl acyl ureas, they are largely oxidized to nitriles by the excess of hypobromite present. 

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