Barbiturates, alkylation

Barbiturates Alkylation with trimethylanilinium hydroxide (TMAH)... 

Urea derivadves are of general interest in medicinal chemistry. They may be obtained cither from urea itself (barbiturates, sec p. 306) or from amines and isocyanates. The latter are usually prepared from amines and phosgene under evolution of hydrogen chloride. Alkyl isocyanates are highly reactive in nucleophilic addidon reactions. Even amides, e.g. sulfonamides, are nucleophilic enough to produce urea derivatives. 

These compounds are prepared m a manner analogous to that of barbituric acid itself Diethyl malonate is alkylated twice then treated with urea... 

Section 21 8 Alkylation of diethyl malonate followed by reaction with urea gives derivatives of barbituric acid called barbiturates, which are useful sleep promoting drugs... 

Barbituric acid — see also Pyrimidine-2,4,6-trione, perhydro-acidic pK, 3, 60 bromination, 3, 70 fluorination, 3, 70 structure, 3, 68 tautomerism, 2, 27 in thermography, 1, 392 Barbituric acid, iV-alkyl-chlorination, 3, 70 Barbituric acid, 5-aminomethylene-synthesis, 3, 524 Barbituric acid, 5-arylidene-pyridopyrimidines from, 3, 227 Barbituric acid, 1,3-dicyclohexyl-synthesis, 3, 113 Barbituric acid, 2-thio-sensitizing dye... 

Early investigators adduced various kinds of chemical evidence in support of a monohydroxy-dioxo structure for barbituric acid (112) (a) reaction with diazomethane afforded a mono-O-methyl deriva- iye,i59,i6o barbituric acid and its 5-alkyl derivatives are much stronger acids than the 5,5-dialkyl derivatives, and (c) the 5-bromo and 5,5-dibromo derivatives have different chemical properties. - The early physical evidence also appeared to substantiate the monoenol structure, this formulation having been suggested for barbituric acid in 1926 on the basis of its ultraviolet spectrum and again in 1934, In the 1940 s, ultraviolet spectroscopic studies led to the suggestion of other monohydroxy and dihydroxy structures for barbituric acid, whereas its monoanion was assigned structure 113 (a clear distinction between ionization and tautomerism was not made in these papers). 

An early application of this reaction to the preparation of barbiturates starts by the condensation of the ketone, I21, with ethyl cyanoacetate by Knoevenagel condensation. Alkylation of the product (122) with ethyl bromide by means of sodium ethoxide affords 123. Condensation of this intermediate with guanidine in the presence of sodium ethoxide gives the diimino analog of a barbiturate (124). Hydrolysis affords vinbarbital (111). > ... 

Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double Internal alkylation of ethyl... 

It is probably best to avoid p-methoxyamphetamine (PMA) and 2,5-dimethoxy-4-methylamphetamine (STP), the former because it seems to have a high toxicity and the latter because it lasts too long (e.g., 24 hours for a minimum dose). Other 4-alkyl amphetamines also seem to be toxic. A number of apparent fatalities due to MDA have been noted, but the reports usually involve very large amounts, often in combination with other drugs (e.g., 7 g MDA plus barbiturates) and screening for other, more toxic drugs (in particular, PMA) has not been done. 

In order to determine the applicability of retention indices, based on the alkyl arylketone scale, as the basis of a reproducible method of reporting retentions, the separation of 10 barbiturates and a set of column test compounds were examined on an octadecylsilyl bonded silica (ODS-Hypersil) column with methanol-buffer of pH 8.5 as eluent [100]. The effects on the capacity factors and retention indices, on changing the eluent composition, pH, ionic strengthened temperature, showed that the retention indices of the barbiturates were much less susceptible to minor changes in the eluent than the capacity factors. 

Barbiturates [94, 95] and diazapinones [96-99] are alkylated (e.g. Scheme 5.23) and arylated (see Chapter 2.2) on the amidic nitrogen atom under liquiddiquid phase-transfer catalytic conditions and the procedure has been used as pretreatment of the non-volatile heterocycles for GLC analysis. 

The haloalkane (60 mmol for monoalkylation) is added with stirring to the heterocycle (50 mmol) and TBA-Br or TEBA-C1 (5 mmol) in PhH or CH2C12 (50 ml) and aqueous NaOH (50%, 20 ml). The mixture is stirred at 60 °C for ca. 4-5 h and then cooled to room temperature. The organic phase is separated, washed with H20 (2 x 25 ml), dried (MgS04), and evaporated to yield the /V-alkylated product. ( The preformed sodium salts of the barbiturates have been used in the absence of a solvent or aqueous NaOH.)... 

This subsection examines the hydrolytic stability of cyclic structures containing a ureido link. Schematically, ring closure can be achieved by N-alkylation or by /V-acylation of the second N-atom of the ureido moiety. The former results in the formation of, e.g., hydantoins and dihydropyrimidines. The latter ring closure leads to, e.g., barbituric acids. Taken together, cyclic ureides can also be regarded as ring structures that contain an imido function with an adjacent N-atom. We begin our discussion with the five-membered hydantoins, to continue with six-membered structures, namely dihydropyrimidines, barbituric acids, and xanthines. 

In a number of barbiturates, the 5-alkyl side chain is known to undergo metabolic hydroxylation at C(2 ) and/or C(3 ). Examples include allobarbi-... 

A variety of other carbon nucleophiles have been alkylated with alcohols including malonate esters, nitroaUcanes, ketonitriles [119, 120], barbituric acid [121], cyanoesters [122], arylacetonitriles [123], 4-hydroxycoumarins [124], oxi-ndoles [125], methylpyrimidines [126], indoles [127], and esters [128]. Selected examples are given in Scheme 35. Thus, benzyl alcohol 15 could be alkylated with nitroethane 147, 1,3-dimethylbarbituric acid 148, phenylacetonitrile 149, methyl-pyrimidine 150, and even f-butyl acetate 151 to give the corresponding alkylated products 152-156. 

By using the same catalytic system, alkylations of 1,3-dimethylbarbituric acid with alcohols were also accomplished (Scheme 5.31) [68]. The Cp lr-catalyzed alkylation using 2-iodobenzyl alcohol, followed by palladium-catalyzed carbon-carbon bond formation with allene, gave spirocyclic barbituric acid derivatives in a one-pot process. 

The [Cp IrCl2]2 and [IrCl(cod)]2 catalysts have also been used in the alkylation of barbituric acid [43] and nitroalkanes [44] with primary alcohols. 

Alkyl and 1-aralkyl-5,6-dihydrouracils (LXXIX), prepared by condensation of A -(2-carbamoylalkyl)aralkylamines with urea or by treating a suitable primary amine with an ester of acrylic acid followed by cyanic acid, are CNS depressants and anticonvulsants [639, 640], as well as anti-inflammatory agents [641]. Such compounds are to be compared with the corresponding barbituric acid derivatives in which not more than one hydrogen in the 5-position is substituted, and also with barbiturates in which the 5,5-substituents are similar to the R and groups of the 5,6-positions here. 

Pentobarbital Pentobarbital, 5-ethyl-5-(2-amil)barbituric acid (4.1.13), is synthesized by methods analogous to that of amobarbital, the only difference being that the alkylation of... 

The alkylated barbituric acid 286 readily undergoes dehydration in cone. H2SO4 to produce the 6-methyl compound 287 (Equation 103) <1995H(41)937>. 

This technique can be also applied when the water-miscible acetonitrile is added to the serum sample for extracting the analytes. Following the addition of acetonitrile, the solution is saturated with potassium chloride so that the water and acetonitrile phases separate and derivatization is performed in the acetonitrile layer. Such alkylating procedures have been applied for prechromatographic derivatization of various drug residues with carboxylic groups, including penicillins (252) and barbiturates (253). 

Curry, K. Novel amino carboxy alkyl derivatives of barbituric acid, WO 0179185. 

Barbiturates (96) and nitrazepan (97) have been methylated by the extractive alkylation procedure, using ICH3.155,156... 

Friedel-Crafts reactions are almost unknown in pyridine and azine chemistry. Direct electrophilic alkylation in the pyrimidine 5-position can be carried out on pyrimidines with at least two strongly donating groups, and more readily with three such groups. Thus, a-haloketones and a-bromocarboxylic esters can be used for direct alkylation of 6-aminouracils (118), for example in the formation of (119). The 5-position can also act as the nucleophile for Michael additions (e.g. 118 — 120, where a subsequent elimination occurs) (92AHC(55)129). For similar reactions in barbituric acids see (85AHC(38)229). 

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