2-Aminopyrimidine synthesis

N-Aminooxazolidone, 228 6-Aminopenicillanic acid (6-APA), 409, 410 Aminophenazole, 248 p-Aminophenol, 111 Aminophylline, see theophylline Amlnopromazine, 390 Aminopropylon, 234 2-Aminopyrimidine synthesis, 127, 128... 

R = H) is made similarly from its ester (789 R = Et), itself prepared by several obvious steps (see (i) below) from the pyrimidine (788) which can be made by primary synthesis (66AP362). 4-Aminopyrimidine-5-carbonitrile (790 R = CN), which may be made by primary synthesis, undergoes hydrolysis in alkali to the amino acid (790 R = C02H) it may be made similarly from the amide (790 R = CONH2) (53JCS331). 

A major type of reaction in this class is the cyclization of 4-amino- or 4-halo-pyrimidines carrying 5-cyanoethyl or 5-ethoxycarbonylethyl groups, which cyclize to 7-amino or 7-oxo derivatives of 5,6-dihydropyrido[2,3- f]pyrimidine, e.g. (131)->(63). The intermediates may sometimes be prepared by reaction of 4(6)-aminopyrimidines with acrylonitrile, or even via a pyrimidine ring synthesis from an amidine and a cyanoacetic ester or malononitrile derivative, e.g. (132) -> (133) (7lJOC2 85, 72BCJ1127). 

Three general approaches to the synthesis of pjTido[2,3-d]pyrimi-dines from pyrimidines are available, all of which utilize an appropriately substituted 4-aminopyrimidine. The pyridine ring may be formed by the addition of three (route i), or two (route ii) carbon atoms, or by the intramolecular cyclization of a propionyl derivative (route in). 

A further eonvenient synthesis is that developed by Taylor and Gareia who showed that pyrido[2,3-d]pyximidines (86 and 87) were obtained by the aetion of malononitrile on 5-aeetyl-4-aminopyrimidin-6(li/)-one or 4-amino-5-benzoyl-l-methylpyrimidin-6(li/)-one. 

Tisler and his group published the first synthesis of the parent unsubstituted l,2,4-triazolo[l,5-c]pyrimidine 4 by transforming 4-aminopyrimidine 1... 

A related agent, g1 icetanile sodium (42), is made b / a variant of this process. Methyl phenyl acetate is reacted with chlorosulfonic acid to give 38, which itself readily reacts with aminopyrimidine derivative 39 to give sulfonamide Saponification to acid 4 is followed by conversion to the acid chloride and amide formation with 5-chloro-2-methoxyaniline to complete the synthesis of the hypoglycemic agent glicetanile (42). ... 

As for the solid support, several polymer-supported amines were tested (Fig. 2). For either the pyrazole and isoxazole synthesis, the best results were given by aniline-functionalized cellulose, which has also the advantage of a relatively low cost. For the 2-aminopyrimidine library, polystyrene-based piperazine and piperidine gave products with a much higher purity compared with other secondary non-cyclic or primary amines, hi both cases, the resins could be reused for up to four times before degradation in their behavior was observed. This reusability could be further enhanced (up to 10 cycles for cellulose-based aniline) when the microwave-assisted protocols were used. 

Fig. 2 Various polymer-supported bases used in the catch-and-release synthesis of pyra-zoles, isoxazoles and 2-aminopyrimidines...

Completion of the total synthesis afforded only six further steps, including the installation of the second 2-aminopyrimidine ring via a second domino sequence. This process presumably involves a conjugate addition of guanidine (2-293) to the enone system of2-292, followed by a cyclizing condensation and subsequent aromatization. Under the basic conditions, the ethyl ester moiety is also cleaved and 2-294 is isolated in form of the free acid, in 89 % yield. Finally, decarboxylation and deprotection of the amino functionality yielded the desired natural product 2-295. 

As the 2-aminopyrimidine moiety is found in various biologically important natural products, a variety of reactions involving these substituted heterocycles have been reported. For example, Grubb employed the cyclocondensation of a-bromoaldehyde 64 with diaminopyrimidone 65 in their total synthesis of queuine (66), also known as Q Base, found in tRNA <00T9221>. 

Similarly, aminopyrimidine 67 was treated with a-bromoketone 68 to produce 69, an intermediate used by Laneri and co-workers in subsequent studies of the Vilsmeier reaction in the synthesis of various imidazopyrimidines <00JHC1265>. 

Pyrimidinyl halides are not only precursors for Pd-catalyzed reactions, but also important pharmaceuticals in their own right. One of the most frequently employed approaches for halopyrimidine synthesis is direct halogenation. When pyrimidinium hydrochloride and 2-aminopyrimidine were treated with bromine, 5-bromopyrimidine and 2-amino-5-bromopyrimidine were obtained, respectively, via an addition-elimination process instead of an aromatic electrophilic substitution [4, 5], Analogously, 2-chloro-5-bromopyrimidine (1) was generated from direct halogenation of 2-hydroxypyrimidine [6], Treating 1 with HI then gave to 2-iodo-5-bromopyrimidine (2). In the preparation of 5-bromo-4,6-dimethoxypyrimidine (4), N-bromosuccinimide was found to be superior to bromine for the bromination of 4,6-dimethoxypyrimidine (3) [7]. 

The use of vinylphosphonium salts in heterocyclic synthesis continues to be exploited. The kinetically controlled reactions of the / -acylvinylphosphonium salts (143) with 2-aminopyridine lead to the salts (144) similar reactions occur with 2-aminopyrimidine and cytosine. Under conditions where thermodynamic control prevails, the salts (145) are formed predominantly, resulting from a Dimroth rearrangement of (144).136... 

In addition, we should note that data of H, NMR spectroscopy, mass-spectra, and elemental analysis given in [138] did not contradict the structure of compound 98, being regioisomer of 97. The similar situation had already been shown in the synthesis of 3-aminoimidazo[l,2-a]pyrimidines [139]. Mandair et al. carried out the model MCRs of 2-aminopyrimidine with several aldehydes and isonitrile components in the methanol under the ambient temperamre with the various catalysts. As a result, 3-aminoimidazo[l,2-a]pyrimidine and position isomeric 2-aminoimidazo[l,2-a]pyrimidines were isolated from the reaction mixture in different ratio (Scheme 45). The stmctures of the isomers obtained in this case were confirmed by the X-ray diffraction analysis, as well as the structures of the side-products isolated. 

Unsubstituted 5-aminopyrimidine derivatives can also be prepared by the use of benzophenone imine 132 as the amine source, as demonstrated by the synthesis of 2- /7-butyl-5-pyrimidinamine 135 from the bromide 133 via the imine 134 <20060PD70>. 

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