1-Aminoacridine

Submitted by Adrien Albert and Bruce Ritchie. Checked by R. L. Shriner and John C. Robinson, Jr. 

In a 500-cc. round-bottomed flask fitted with a water-cooled toiulenser, 50 g. (0.23 mole) of iV-phenylanthranilic acid (Org. Syn. 19, 6) [or 46 g. acridone (Org. Syn. 19, 7)] is mixed with WiO cc. (270 g., 1.76 moles) of phosphorus oxychloride (Note 1). The mixture is slowly heated (about fifteen minutes) to 85-90° on a water bath. A vigorous reaction sets in, and the flask is removed at once from the hot bath. If the reaction becomes too violent, I lie llask is immersed in a beaker of cold water for a moment. After live to ten minutes, when the boiling subsides somewhat, I lie llask is immersed in an oil bath. The temperature of the bath is then raised to 135-140°, where it is maintained for two hours. The excess phosphorus oxychloride is removed by distillation I mm an oil hath at 140 150° under a vacuum of about 50 mm. The residue, after cooling, is poured into a well-stirred mixture of 

200 cc. of concentrated ammonia solution, 500 g. of ice, and 200 cc. of chloroform. The flask is rinsed by shaking with a little chloroform-ammonia mixture (about 25-30 cc.). When no more undissolved solid remains (about half an hour is required), the chloroform layer is separated and the aqueous layer is extracted with an additional 40 cc. of chloroform. The united chloroform extracts are dried over 10 g. of calcium chloride and filtered, and the solvent is removed by distillation. The resultant greenish-gray powder is dried at 70° for twenty minutes (Notes 2 and 3). The yield of crude 9-chloroacridine is 50 g. (practically theoretical), m.p. 117-118° (Note 4). 

9-Chloroacridine is readily hydrolyzed in neutral and acid solutions hence it must not be exposed to the air after removal of the phosphorus oxychloride and before treatment with ammonia. I f the drying is carried out at a higher temperature, loss results through sublimation. Care should be taken to keep 9-chloro-acridine from entering the eyes, as it is distinctly irritating. 

It was found convenient to dry the chloroacridine by pouring the concentrated chloroform extract directly into the 1-1. beaker to be used for the next step, and heating the oil bath to 70° for the required twenty minutes. 

---

Aminoacridine hydrochloride monohydrate (Acramine yellow, Monacrin) [52417-22-8] M 248.7, m >355 , pKj 4.7, pKj 9.99. Recrystd from boiling H2O (charcoal Ig in 300 mL) to give pale yellow crystals with a neutral reaction. It is one of the most fluorescent substances known. At 1 1000 dilution in H2O it is pale yellow with only a faint fluorescence but at 1 100,000 dilution it is colourless with an intense blue fluorescence. [Albert and Ritchie Org Synth Coll Vol III 53 7955 Falk and Thomas Pharm J 153 158 1944.] See entry in Chapter 4 for the free base. 

Ultraviolet spectral data, including the similarity between 9-aminoacridine and 9-aminoanthracene, led Craig and ShorU to conclude that all the aminoacridines exist as such. The infrared solution spectra of the aminoacridines and aminoquinolines support the amino formulation similarly, infrared and ultraviolet spectral data have demonstrated that aminoisoquinolines also exist as such." The pX method was used to show that the value of piCj- for 9-aminophenanthridine (236, R =H) is 2.8, and ultraviolet spectral data are consistent with this conclusion when the fact that the dimethylamino derivative (236, R — Me) exhibits considerable steric hindrance to planarity is taken into consideration. ... 

Primary halides are more reactive than secondary compounds quaternary salt formation does not occur with tertiary halides, elimination always occurring to give the hydriodide and an olefln, Also, the larger the alkyl group the slower is the reaction this is shown by the very slow reaction of dodecyl bromide with quinoline, and even butyl iodide is much slower to react than methyl iodide. The longer chain primary halides commonly undergo elimination rather than cause quaternization for example, n-octyl and cetyl iodides give only the hydriodides when heated with 9-aminoacridine. ... 

Thus, at pH 7.3, 9-aminoacridine, which exists at this pH entirely as the cation, will inhibit the growth of Streptococcus pyogenes at a dilution of 1 160000 the... 

C13HuN2+ 4 C19H23IN8012P 21 H20 9-Aminoacridine-5-iodocytidylyl-(3 — 5 )-guanosine ACRACG40 43 302... 

Aminoacridines, substituted, 22, 7 2-Aminobenzothiazolc, 22, 18 o-Aminobenzyl alcohol, 21, 10 o-Aminobenzyl cyanide, 22, 23, 25 2-Amino- -cymenx, 22, 9 u-Aminodiethyiacetic acid, 22, 13 4-Amino-2,6-dimethylpyrimidine, 24,... 

Several complexes that involve intercalation of an acridine in a portion of a nucleic acid have been studied by X-ray crystallographic techniques. These include complexes of dinucleoside phosphates with ethidium bromide, 9-aminoacridine, acridine orange, proflavine and ellipticine (65-69). A representation of the geometry of an intercalated proflavine molecule is illustrated in Figure 6 (b) this is a view of the crystal structure of proflavine intercalated in a dinucleoside phosphate, cytidylyl- -S ) guano-sine (CpG) (70, TV). For comparison an example of the situation before such intercalation is also illustrated in Figure 6 (a) by three adjacent base pairs found in the crystal structure of a polynucleotide (72, 73). In this latter structure the vertical distance (parallel to the helix axis) between the bases is approximately... 

Aminoacridine, 22, 5 basic strength of, 22, 8 9-Aminoacridine hydrochloride, fluorescence of, 22, 7... 

Fermentation, 22, 53 Ferric nitrate, 23, 20 Fieser s solution, 21, 110 Filter fabric, Pyrex glass, 22, 33, 65 Vinyon, 22, 33, 67 Filter paper, hardened, 22, 45 Fischer indole synthesis, 22, 98 Flash distillation, 21, 85 Flask, modified Claisen, 22, 11 Fluorescence of 9-aminoacridine hydrochloride, 22, 7 Formaldehyde, 20, 60 Formalin, 22, 66 Formic acid, 20, 66, 102 23, 43 Formic acid, chloro-, benzyl ester, 23, 13... 

Aminoacridine carboxamide derivatives binding with DNA, 194, 195 Anomeric amides, 37, see also A-acyloxy-A-alkoxyamides... 

A-acetoxy-lV-/e//-butoxybenzamide, 55 /V-acyloxy- /V-alkoxyalky lam ides, 55 /V- acy I o x y- /V-a I k o x y u re as, 56 /V-chlorohydroxamic esters, 56 N, /V-dialkoxyamidcs, 56 Intercalative guest molecules, binding dynamics of DNA with, 186-201 acridine derivatives, 190-194 9-aminoacridine carboxamide derivatives, 194, 195... 

Alkylation of 9-aminoacridine, under conditions analogous to those used for acridone, provides a convenient route to the 9-alkylaminoacridines [70], which are... 

---