2-Chloro-4-aminopyrimidine

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). ... 

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]. 

Benzenesulfonylureas were prepared from 2-aminopyrimidines substituted in the 4- and 6-positions. Growth retardant activity was found in the 4-methyl-6-chloro compound (Figure 9). This activity was lost when both substituents were chlorine. However, a substantial improvement in growth retardant activity was observed with the 4,6-dimethyl analog. 

Cyclic amidines (213) react with chlorocarbonylsulfenyl chloride to give bicyclic 1,2,4-thia-diazoles. The product isolated from this reaction depends on the mode of addition. When (213) is added to chlorocarbonylsulfenyl chloride, 3-oxo derivatives (214) are isolated via the postulated intermediate (215). Addition of chlorocarbonylsulfenyl chloride to (213) leads to 5-oxo derivatives (216), via the proposed bis(intermediate) (217) (Scheme 47) <84CHEC-I(6)463). Cyclic amidines (213) have also been treated with 1-chloro-l-phenyliminomethanesulfenyl chloride (210) to afford 2>H-1,2,4-thiadiazoles (218). The other possible product from this reaction, the 2/7-isomer (219) has been shown to be unstable, rearranging to a benzothiazole. Heterocycles (213) which have been used in this transformation include 2-aminopyridine, 3-aminopyridazine, 2-aminobenzothiazole, 2-aminopyrimidine and 2-aminothiazole (Equation (33)) <86S1027>. 

Nucleophilic reagents can also react with 2- and 4-aminopyridines at the carbon atom which carries the amino group in a replacement reaction (e.g. 738 — 739) similar to, but far less facile than, that undergone by chloro and alkoxy compounds, etc. In this way aminopyrimidines can be converted into pyrimidinones by direct acidic or alkaline hydrolysis under rather vigorous conditions. 

Polystyrene-bound isothiuronium chloride, which is readily prepared from chloro-methyl polystyrene and thiourea, has been used as a starting material for the preparation of various substituted pyrimidines (Entries 9-11, Table 15.28). After oxidation to the corresponding sulfones, nucleophilic cleavage with amines proceeds smoothly to yield substituted 2-aminopyrimidine derivatives (see Section 3.8). 

Conversion of diazonium halides into chloropyrimidines has employed excess chloride ion or copper(I) chloride. These reactions have been mainly used to make 2- and 4-chloropyrimidines although the 5-chloro derivatives are also available in this way. One drawback is the substantial amount of oxo product formed, especially when 2-aminopyrimidines are... 

The stabilities of pyridine-2- and -4-diazonium ions resemble those of aliphatic rather than benzenoid diazonium cations. Benzenediazonium ions are stabilized by mesomerism which involves electron donation from the ring, but such electron donation is unfavorable in 2- and 4-substituted pyridines. On formation, pyridine diazonium cations normally immediately react with the aqueous solvent to form pyridones. However, by carrying out the diazotization in concentrated HC1 or HBr, useful yields of chloro- and bromopyridines 752 can be obtained. Iodinated pyridines can be obtained in good yield using the Sandmeyer reaction. Aminopyridazines and -pyrazines, 2- and 4-aminopyrimidines, and amino-1,2,4-triazines behave similarly. Nucleophilic fluorination via the BalzSchiemann reaction of diazonium fluoroborates yields fluoropyridines, including 2-fluoropyridines. Fluoroborates can also be converted into fluoro compounds by ultraviolet irradiation. 

The treatment of 4,6-dichloro-5-aminopyrimidine 1198 with indoline 1197 gave 4-chloro-6-(2,3-dihydro-l//-indol-l-yl)-5-pyrimidinamine 1199 in 79% yield (Scheme 230) <2005JC0813>. Subsequent oxidation of the indoline moiety to the corresponding indole was achieved with DDQ in refluxing benzene to yield the indole-substituted pyrimidine 1200, the key compound in the cyclization reactions with various aldehydes and ketones leading to a novel heterocyclic scaffold consisting of indole-fused pteridines. 

Deazaflavines and pyrido[2,3-d 6,5-d ]dipyrimidines, which possess an ability to oxidize an alcohol, are obtained from 6-chloro-5-formyl-3-methyluracil and anilines or 6-aminopyrimidines [76CC203 78CPB3208 81JA5943 84TL(25) 1741 86JHC241]. This method is applied to the total synthesis of coenzyme factor 420 [90JCS(P1)253] (Scheme 100). 

Many amides have been prepared from pyrazinecarboxylic acid chlorides some are listed below with the relevant amines and references 2-chlorocarbonyl [MeNHj/ EtOAc (138) Me NH/EtOAc (138) BujNH etc/EtOAc (138) aniline/EtOAc (138, 1335) other aromatic and heterocyclic amines/EtOAc (138) sulfanilamide/ pyridine (1336) p-(2 -aminoethyl)benzenesulfonamide (1385) p-anisidine/benzene (1334) 4-hydroxypiperidine/benzene chloroform (1386) morpholine/DMF/20° (1387) 2-aminopyrimidine/benzene (1388) glycine/NaOH/ether (1201, cf. 1333, 1360)] 2-chlorocarbonyl-5-methyl [MeNHj/benzene (1337) MejNH/benzene (1337) 4-phenylpiperazine or diethanolamine/benzene-chloroform (1386) 2-chlorocarbonyl-3-phenyl (6-aminopenicillanic acid) (1024) 2-chloro-3-chloro-carbonyl (morpholine/benzene) (838) 2-chloro-5-chlorocarbonyl (NH4OH) (839) 2-chloro-6-chlorocarbonyl (Et2NH/benzene) (870, 1389) 2-chlorocarbonyl-5-hydroxy (aniline/benzene) (1055) 2-chlorocarbonyl-3-methoxy (morpholine/ benzene) (867) 2-chlorocarbonyl-5-methoxy (morpholine/benzene-chloroform) (1386) and 2-(l -chlorocarbonylethyI) (morpholine/benzene) (364). 

Pyrimidines (see Sections I, II, and V,D). In the previous review, a number of incorrect deductions were made from preparative work about the effect of an amino substituent on reactivity. The positional order 5 > 2 > 4 was arrived at for the activating effect of this group. Consideration of kinetic results for 2-, 3-, and 4-aminopyridines shows that the order of the activating effect of an amino group is para > meta > ortho and the reactivity order for aminopyrimidines is therefore predicted to be 4 (with reaction occurring at N-1) > 5 > 2. Furthermore, kinetic data (Table II) show an amino substituent to be more activating than a methyl or chloro group in the same position, in contrast to predictions made from preparative work. 

In a,)8-unsaturated nitriles, reaction can occur at a vinylogous methylene group, as in example 202, to give a 2-chloro-3-cyanopyridine (Eq. 162).Yields are poor, but are much better with the vinylogous cyanoacetates such as compound 203. Aminopyrimidines 204 can be obtained from arylcyanocarbonyl compounds, using formamide and phosphoryl chloride (Eq. 163). Yields, when quoted, are very poor. 

In special cases diazotized amines can be converted into chloro compounds by HC1 alone for instance, diazotizing 2-aminopyrimidine in concentrated HC1 at —15° to —10° and stirring the acid solution for 1 hour at —10° to — 5° gives about 27% of 2-chloropyrimidine (for details see Organic Syntheses1194). 

Amino-substituted heterocycles (e.g., 2-aminopyrimidine), sodium A-chloro-f-butyl-sulfonamide, and primary amides have been developed as a nitrogen source for these... 

Other synthons for 1,3-dicarbonyl compounds which have been successfully applied include / -chloro-a,/ -unsaturated ketones and aldehydes,/J-amino-a,/J-unsaturated ketones, vinylamidinium salts,and propiolic acid, reaction of which with urea gives uracil directly in about 50% yield. " 1,3-Ketoesters with formamidine produce 4-pyrimidones. 2-Aminomalondialdehyde leads to 5-aminopyrimidines. In analogy, pyrimidines fused to other rings, for example as in quinazolines, can be made from ort/io-aminonitriles and in general, from (3-... 

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