Benzamidine hydrochloride

Methoxyphenyl)-2-phenyl-lH-imidazole. A 2-L, three-necked, round-bottomed flask equipped with an addition funnel, reflux condenser, and mechanical stirrer is charged with 500 mL of tetrahydrofuran (THF) and 125 mL of water. Benzamidine hydrochloride monohydrate (50 g, 0.29 mol) (Note 1) is added, followed by the slow, portionwise addition of potassium bicarbonate (54.4 g, 0.57 mol) (Note 2). The reaction mixture is vigorously heated to reflux. A solution of 4-methoxyphenacyl bromide (65.3 g, 0.29 mol) in 325 mL of THF is then added dropwise via the addition funnel over a period of 30 min while the reaction is maintained at reflux. After completion of the addition, the mixture is heated at reflux for 18-20 hr (Note 3), then cooled in an ice bath (Note 4), and THF is removed under reduced pressure using a rotary evaporator. An additional 100 mL of water is added, and the resulting suspension is stirred at 50-60°C for 30 min. The mixture is cooled in an ice bath and the solids are collected by filtration. The filter cake is rinsed with two 100-mL portions of water and air-dried in the filter funnel for 2 hr. The crude product is transferred to a 500-mL flask and 150 mL of diisopropyl ether and 150 mL of hexanes are added. The mixture is stirred for 2 hr at room temperature, and the solids are again collected by filtration. The filter cake is dried in a vacuum oven for 48 hr (68°C/ca. 100 mm) to give 68.6 g (96%) of the desired imidazole as an off-white solid (Notes 5, 6). 

Benzoguanamine has been prepared by the reaction of dicyandiamide with benzonitrile in a sealed tube at 220-230°,2 with an excess of benzonitrile in the presence of piperidine and potassium carbonate,3 with benzonitrile in a solvent in the presence of a basic catalyst,4 and with benzamidine hydrochloride at elevated temperatures.5 It has also been prepared from the reaction of biguanide acetate with benzamidine hydrochloride,5 or of bigua-nide sulfate with benzoyl chloride in an alkaline medium,7 and by the distillation of guanidine benzoate.5... 

The successfully generated chalcones could be cleaved by treatment with trifluoro-acetic acid or used for the subsequent synthesis of pyrimidines [45], Condensation of the polymer-bound chalcones with benzamidine hydrochloride under microwave irradiation for 30 min furnished the corresponding pyrimidines in good yields after TFA-induced cleavage. This new robust support/linker system for SPOT synthesis has been demonstrated to be compatible with a range of organic reactions and highly applicable for microwave conditions. 

Besides quaternary pyrimidinium salts, pyrimidines with a strong electron-withdrawing substituent on one of the carbons of the pyrimidine ring show enhanced reactivity of the heterocyclic ring toward nucleophiles. In light of the results mentioned previously with pyrimidinium salts, it is not too surprising that reflux of an ethanolic solution of 5-nitropyrimidine with benzamidine hydrochloride or pivalamidine hydrochloride in the presence of triethylamine afforded 5-nitro-2-phenylpyrimidine (108, 84%... 

Another supporting piece of evidence was obtained in a study of the reaction of 5-nitropyrimidine with benzamidine hydrochloride in the absence of triethyl amine (which usually was added to liberate the free benzamidine). In amidinium salts the C-N bonds are about equal in length [1.314 A... 

Pentaphenyl-imidazolium-ehlorid343 6,29 g (125 mmol) N,N -Diphenyl-N-(1,2-diphenyl-2-oxo-ethyl)-benzamidin-Hydrochlorid werden in 30 ml Thionylchlorid 20 min zum RuckfluB erhilzt. Nach dem Abkiihien wira mit Eiswasser nydrolysiert und derNiedcrscniag abfiltriert Ausbeute 6,01 g (99%) Schmp. 450° (Zers. Diethylether/Ethanol = 5 1). 

A solution of 6.3 g (0.0525 mol) of benzamidine 1, prepared from 8.3 g (0.0525 mol) of benzamidine hydrochloride and an equimolar amount of sodium in methanol with subsequent removal of NaCl and evaporation of the solvent, and 7.3 g (0.05 mol) of benzalacetone 2 in 100 ml of dry benzene was heated under reflux (Scheme A. 19) with a Dean-Stark trap until the calculated volume of water had separated (after about 4 h). After allowing it stand overnight at 5°C, 8.6 g (78%) of 2-methyl-2,4-diphenyl-1,4-dihydropyrimidine 3 was filtered off melting point 145-146°C. An additional portion of dihydropyrimidine could be isolated from the filtrate. 

A 3-L, three-necked, round-bottomed flask equipped with a high-speed mechanical stirrer and a 250-mL pressure-equalized dropping funnel is charged with 22.5 g (0.143 mol) of benzamidine hydrochloride (Note 1), 37.5 g (0.62 mol) of sodium chloride, 300... 

Commercial benzamidine hydrochloride may be used without further purification. 

A modification of this method, which produces 2-aminoimidazoles in up to 90% yield, utilizes benzoins and diguanylhydrazine. The 2,2 -azoimidazoles (123) can be catalytically hydrogenated to the 2-amino compounds (Scheme 66) (66RCR122). When the disubstituted guanidine (124) is treated with phenacyl bromide the first product formed is the expected 2-( l-pyrazolyl)imidazole (125), but subsequent hydrolysis of this occurs to give a 57% yield of l-isopropyl-4-phenylimidazolin-2-one (Scheme 66) (70AHC(12)103). Benzamidine hydrochloride reacts with monosubstituted glyoxals to form 2-imidazolin-4-ones. 

A solution of benzamidine hydrochloride dihydrate (48 g, 0.25 mol) in water (100 ml) is added to a solution of a-bromopropiophenone (53 g, 0.25 mol) in chloroform (250 ml) to form a two-phase mixture. While stirring vigorously at room temperature, a solution of KOH (28 g, 0.5 mol) in water (100 ml) is added dropwise, then heated to boiling and refluxed (3-4h). The chloroform phase is then separated from the hot aqueous phase and cooled. Tlie ciwstalline material which separates is washed with benzene, then with diethyl ether to give the above product (which may separate as an oil, but which solidifies gradually on addition of benzene). Ilie yield is in the range 26-32 g (45-55%), m.p. 214-215°C. Similarly prepared are 4-methyl-2,5-bis-(m-nitrophenyI)-(39%), 4-methyl-2,5-bis-(m-bromophenyl)- (40%), and 4-methyl-2,5-bis-(p-nitrophenyl)imidazolcs (64%). 

Amino-1 H-indazol [Schmp. 152" (Petrolethcr)] kann aur ahnliche Weise durch Thermolyse aus 2-Azido-benzamidin-Hydrochlorid erhalten werden212. 

The appropriate 5-acyl-4-chloropyrimidine 38 (6 mmol) was slowly heated to 130°C. To the resulting melt was added freshly prepared amidine salt [(R3 = Me, Ph) Na (0.92 g, 40 mmol) was dissolved in EtOH (150 mL), acetamidine or benzamidine hydrochloride (1 equiv) were added, the mixture was stirred for 1 h at rt, NaCl was filtered off, and the solvent removed under reduced pressure] or phenyl guanidine (40 mmol) was added portionwise. The temperature immediately rose and, after the addition was complete, the mixture was maintained at this temperature for 30 min. After cooling to rt, the product obtained was recrystallized from EtOH. 

Several reports describe the reaction of pyrazol-3-ones with amidines and iminium salts where the group displaced is an amine. Nucleophilic substitution of ammonia by 2,5-dimethylpyrazol-3-one 591 attack on benzamidine hydrochloride 592 requires 220 °C to give via addition intermediate 593 4-[imino(phenyl)methyl]pyrazol-3-one... 

Detector F ex 370 em 480 following post-column reaction. The column effluent mixed with 400 mM NaOH and reagent pumped at 0.5 mL/min and the mixture flowed through a 30 m X 0.5 mm ID PTFE coil at 95° and another coil immersed in water to the detector. (Reagent was 0.5% benzamidine hydrochloride in isopropanol water 50 50.)... 

To a 75 mL solution of NaOEt in absolute ethanol prepared by addition of 4.5 g sodium in absolute ethanol were added 9.0 g benzamidine hydrochloride and 10 g carefully purified methyl a,a-diethylmalonate. The mixture was heated for 5 h at 70°C. The alcohol was partially removed by a current of dry air, and the residue was acidified with a slight excess of cone. HCl. After removal of the precipitated NaCl, the solution was further concentrated on the steam bath. The addition of water caused 5,5-diethyl-2-phenyl-4,6-diketo-tetrahydro-pyrimidine to separate in white needles, in an amount of 3.0 g. The product was further purified by recrystallization from dilute acetic acid. 

Benzamidine hydrochloride hydrate [206752-36-5] M 156.6 (anhydrous), m 86-88°, pK 11.6 (see free base above). Recrystallise it from dilute HCl (crystals contain XH2O) or EtOH/few drops HCl dry it in a vacuum. It is a proteolytic inhibitor [Jeffcoate White J Clin Endocrinol Metab 38 155 1974, Beilstein 9 IV 898.]... 

Beifuss and his group developed a copper-catalyzed domino reaction to prepare 2-arylquinazolines from 2-bromobenzyl tosylates and benzamidine hydrochloride salts in the presence of copper(I) iodide (10mol%), potassium phosphate (3 equivalents), and pivalic acid (40mol%) in 1,2-dichlorobenzene... 

Warm aq. 50%-NaOH added to a vigorously stirred mixture of benzamidine hydrochloride, benzyltriethylammonium diloride as phase transfer catalyst, and chloroform, then refluxed 15 min. beuzonitrile. Y 92%. F. e. s. J. Graefe, Z. Chem. 15, 301 (1975). 

Benzonitrile heated 18 hrs. with NH4GI and 2 moles of NH3 in methanol at 125° in stainless steel rocking autoclave benzamidine hydrochloride. Y 81%.— This simple and economical process is well suited for the common relatively unreactive nitriles. F. e. without solvent, also with NH4Br, s. F. G. Schaefer and A.P. Krapcho, J. Org. Ghem. 27, 1255 (1962). 

Substituted 2-R -chromones are effective in the reaction with amidines to create R -containing pyrimidine derivatives. Reflux of chromones 13 with benzamidine hydrochloride or guanidinium nitrate in the presence of KOH yielded the pyrimidines 173 in moderate to high yields [87] (Scheme 55). 

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