Acetamidine Hydrochloride

Several 4-amino-2-methylthieno[2,3-synthesized directly by heating o-aminocarbonitriles 48 in a methanolic solution of acetamidine hydrochloride containing sodium ethoxide (83CPB1177). By an indirect route, 4-amino-2-substituted methyl-5,6-dihydrothieno[2,3-c/]-... 

The initial synthetic approach to conivaptan HCl (1) employed by the Yamanouchi discovery group26 commenced with commercially available benzazepinone 10. Acylation of 10 with p-nitrobenzoyl chloride provided benzamide 11. Subsequent hydrogenation of 11 over palladium on carbon yielded aniline 12, which was in turn condensed with biphenyl-2-carbonyl chloride to provide bis(amide) 13. Bis(amide) 13 was subsequently heated with copper(II) bromide in boiling chloroform/ethyl acetate to furnish a-bromoketone 14. It is interesting that condensation of a-bromoketone 14 with acetamidine hydrochloride in the presence of potassium carbonate in boiling acetonitrile afforded not only the desired imidazobenzazepine product (1 53% yield, 2 steps) but also the related oxazolobenzazepine 15 (7% yield, 2 steps), which presumably resulted from nucleophilic attack of the benzazepinone oxygen on the amidine moiety followed by loss of ammonia. Separation of oxazolobenzazepine byproduct 15 from imidazobenzazepine 1 by silica gel chromatography followed by treatment of the purified imidazobenzazepine free-base with hydrochloric acid then provided conivaptan HCl (1). 

Diamino-l,3-thiazol-Hydrochlorid(R = R2 = H R3 = CH2—C Hs)439 Eine Losungvon 1,1 g (0,005 mol) N-Benzyl-2-chlor-acetamidin-Hydrochlorid und 0,056 g (0,005 mol) Thioharnstoff-Hydrochlorid in 30 ml 2-Propanol wird 30 min unter RiickfluB erhitzt. Der sich bildende Niederschlag wird heiB abfiltriert, mit 4 ml 2-Propanol gewaschen und i. Vak. bei 25° 18 h getrocknet Ausbeute 0,67 g (89%) Schmp. > 360°. 

Cycloaddition reaction of triethyl 1,3-5-triazinetricarboxylate (585) with 1,1-diamino-ethene, which is generated in situ from acetamidine hydrochloride, provides an adduct (586) which subsequently eliminates ammonia (587) and undergoes a retro Diels-Alder reaction with loss of ethyl cyanoformate, thereby forming the pyrimidine (588). The reaction sequence is highly dependent... 

Diaminoethene, produced in situ by reversible tautomerism of acetamidine hydrochloride. 

The preparation of acetamidine hydrochloride from acetonitrile is described in detail in Organic Syntheses 23... 

A flow process was reported for the synthesis of P-keto esters via the BF3 OEt2-catalyzed formal C-H insertion of ethyl diazoacetate into aldehydes.The P-keto esters were then condensed with a range of amidines to give a variety of 2,6-substituted pyrimidin-4-ols. The crude reaction mixture containing the P-keto esters was treacted with acetamidine hydrochloride, DBU, and EtOH to provide the corresponding pyrimidin-4-ol in excellent yields. 

Reaction of acylimidates with amidines affords a practical route to hitherto inaccessible 1,3,5-triazines with 3 different substituents. — E A soln. of cinnamoyl chloride in methylene chloride added dropwise below 0° during 0.5 hr. to a stirred soln. of isopropyl propionimidate and triethylamine in the same solvent, and stirring continued 20 hrs. at room temp. isopropyl N-cinnamoylpropionimidate (Y 83.1%) added to a stirred soln. of acetamidine hydrochloride in ferf-butanol previously treated at 35° with a mineral oil suspension of the equimolar amount of NaH, and stored 4 days at room temp. 

A more direct (but related) route to l,l-diamino-2,2-dinitroethene was also reported in the same paper [2]. This involved nitration of the methanol adduct of 2-methylimidazoHdine-4,5-dione (15, synthesized from acetami-dine hydrochloride and diethyl oxalate, followed by recrystallization from methanol). This gave 2-dinitromethyleneimidazolidine-4,5-dione (13, 67% yield), which, on hydrolysis with aqueous ammonia, gave l,l-diamino-2,2-dinitroethene (87% 37% overall from acetamidine hydrochloride. Scheme 3). 

A mixture of 4,5-diaminoditbiouracil, 2 equivalents of acetamidine hydrochloride, and 2 equivalents of Na-acetate heated to 180-190° whereupon NH3-evolution begins, the product isolated when the reaction has ceased 2,6-dithio-8-methylxanthine. Y 86%. F. e., also without Na-acetate, and limitations s. F. Bergmann and M. Tamari, Soc. 1961, 4468. 

Dry HGl passed with cooling into a soln. of the equimolar amount of thio-benzamide in acetonitrile, and stored 24 hrs. at room temp. -> thiobenzoyl-acetamidine hydrochloride. Y 68%, F. e. s. J. Goerderler and H. Porrmann, B. 94, 2856 (1961). 

N-deri vatives of Trichloro Acetamidine Hydrochlorides (Two Bands Due to NH Group)... 

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