330 



i:)ESCRIPTI()\S OF ANTIBIOTICS 



to eighteen carbons, such as contained in the 

 various "Arquads" (see chlortetracycline). The 

 complex is cleaved by dissolving in methanol at 

 acidic pH, and filtering (58). III. Adsorbed from 

 broth-filtrate on activated carbon at a pH near 

 neutrality. Eluted with butanol-saturated water 

 at pH 1.5. Eluate adjusted to pH 6 to 9, and (a) 

 freeze dried; or (b) extracted into butanol at pH 9, 

 extract concentrated, and extracted with aqueous 

 acid. Aqueous extract adjusted to pH 6 to 9 with a 

 base or Amberlite IR4 (15). IV. Can be precip- 

 itated as the salt of an organic sulfonic acid from 

 broth-filtrates; as the picrate from acidic aciueous 

 solution; as the orange II salt or other arylazosul- 

 fonic acid salt and recovered by treatment with 

 Bad-. (15). 



Purification: I. .Sohition in dilute aqueous 

 HCl (pH 2.5) filtered, and treated with NaCl and 

 shaking. Solid which separates dissolved in 

 methanol and water added. Cooled to give crystals. 

 II. Countercurrent distribution (butanol-water 

 adjusted to pH 3.0 with liCl; 1:1) (15). III. 

 Acid solutions (from IIA) puriHed by addition of 

 j)otassium ferrocyanide to precipitate contami- 

 nating inorganic and organic substances (57). 



Chemical and physical properties: Amphoteric 

 substance (1). Andhydrous Base: Pale yellow sub- 

 stance; m. p. 184. 5-185.5°C (decomposition) (1,18). 

 Dihydrate: Thick hexagonal plates or thick 

 needles; m.p. 181-182°C. Soluble in methanol, 

 ethanol, acetone, propylene glycol, and dioxane 

 (1, 14). Solubility in organic solvents decreases on 

 addition of water; little increase in solubility on 

 heating (2). Sparingly soluble in water (0.25 mg 

 per ml at 25°C), butanol, 90 per cent aqueous ace- 

 tone, and 95 per cent methanol (14). Insoluble in 

 ether and petroleum ether (1). Ultraviolet absorp- 

 tion spectrum maxima in: methanol: 270 (Ei^m 361) 

 and 370 m^ (i^lL 343) ; methanolic 0.01 N HCl: 270 

 {E\7,n 353) and 359 m^ (E^lL 267); methanolic 0.01 

 N NaOH: 245 (EI'L 415), 264 (E\1'„, 405), and 375 

 niM (filcm 352); dilute HsPOiipH 1.7): 268 (iJ'iL 

 379) and 353 m^ (^IL 277); 0.1 M phosphate buffer 

 ipH 4.6): 249 (fi'lL 240), 276 (J5Jlem 322), and 353 

 niju (£Ji!m 301). Fluoresces bright yellow in idtra- 

 violet light (2, 15, 18). Infrared spectrum given in 

 references 2, 15, and 18. [a]f^ = —196.6° (c = 1 per 

 cent in 0.1 iV HCl); -2.1° (c = 1 per cent in 0.1 N 

 NaOH); +26.5° (c = 1 per cent in methanol) 

 decreasing to -1-11.3° after 16 hours; 0° (c = 1 per 

 cent in methanol containing 1 per cent boric acid) ; 

 — 234.2° (c = 0.5 per cent in methanol containing 

 1 per cent saturated CaClj-methanol solution) (2, 

 18). Positive FeCls , Pauly, Friedel-Crafts, Feh- 

 ling, Molisch, modified Fearon-Mitchell, and 



amino antipyridine (phenols) tests (2, 24). Gives a 

 deep red color with H2SO4 and NaNOo and a simi- 

 lar color with diazotized /3-naphthylamine (24). 

 Negative tests with carbonyl reagents and nega- 

 tive furfural (24). Most stable at pH 2.5; less stable 

 at neutrality and alkaline pH (2). pKa' = 3.49, 

 7.55, and 9.24 (18). Crystallographic data given in 

 reference 15. X-ray measurements of various salts 

 given in reference 37. C22H-24N.;0.., . Molecular 

 weight, 440 ± 30 (18). C = 53.05%; H = 5.91%; 

 N = 5.64% (1). Structural formula (40) given in 

 Chapter 6. 4-1 )imethylamino-l ,4,4a,5,5a,6,ll , 

 r2a -octahydro -3,5,(),10, 12, r2a -hexahydroxy-6 - 

 met hy 1-1 ,ll-dioxo-2-naphthacene carboxamide. 

 Alkaline degradation products include ammonia 

 and dimethylamine. Carried out in the presence of 

 zinc, alkaline hydrolysis yields, among other 

 products: tribasic terracinoic acid (4-carboxj^-5- 

 hydro.xy-3-methyl indanone-2-acetic acid), Ci.r 

 H12O6 , white crystals, m.p. 232-234°C (decomposi- 

 tion); a phenolic lactone, 7-hydroxy-3-methyl- 

 I)thalide, m.p. 110-112°C; acetic acid; and car- 

 bon dioxide (17, 19). Mild acid hydrolysis yields a 

 yellow crystalline, optically active rearrangement 

 product, a-apoterramycin , which is a stronger acid 

 than oxytetracycline (C22H22N2OS) ; HCl: m.p. 

 198-202°C (decompo.sition); and its stereoiso- 

 mer, fi-apoterramycin (17, 39). Treatment with 

 strong acid immediately gives an insoluble red 

 product (24). Strong acid hydrolysis yields di- 

 methylamine, CO 2 , and "terrinolide," C20- 

 Hi.sNOs ; m.p. 210-213°C (38). Other information 

 on degradation products given in references 24 and 

 54. Hydrochloride: Bitter-tasting, bright yellow 

 needles (from methanol) or platelets (from water) 

 (2, 18); m.p. 190-194°C (93). Soluble in acetone, 

 methanol, ethanol, and other polar organic 

 solvents (2). Soluble in water, but excess acid must 

 be added to pH 1.5 or the free base separates on 

 standing (18). Least soluble in water at pH 5.0 

 (93). Insoluble in ether and petroleum ether (14). 

 Disodium and dipotassium salts: Lemon-yellow 

 crystals. Aqueous solutions are brown, becoming 

 darker on standing. Soluble in water and insoluble 

 in ethanol (4, 18, 24). Calcium and magnesium salts: 

 Slightly soluble in water (18). Oxytetracycline 

 also forms mixed salts (e.g.. barium-calcium), 

 complexes with such salts as CaCl2 , a triacetyl 

 derivative, and a crystalline pentabromo deriva- 

 tive (18, 24). 



Biological activity: In rilro: Active on gram- 

 positive and gram-negative bacteria, including 

 Clostridia, mycobacteria, and Actinomyces, and 

 certain jirotozoa, rickettsiae, and psittacosis. 

 Not active on l^rotcus or Pseudomonas. Not active 



