Patent GB-653375-A (GB)
Title: Improvements in or relating to processes for refining penicillin g
IPC: C07D499/18
Filed: 1946-08-28
Abstract: Penicillin G is obtained as a pure crystalline salt from a solution of salts of penicillin (including G), in an aliphatic or cycloaliphatic alcohol having 2-8 carbon atoms in the molecule and optionally an ester or ether group as a substituent; the saturated solution is cooled or allowed to evaporate and the crystalline salt of penicillin G separates on standing; if the solution is super-saturated, the salt crystallizes on merely allowing to stand. Penicillin X may or may not be present, and in the former case, the solution is below the concentration of penicillin X salt necessary to saturate it.  Thus, penicillin X should be present only in a minor proportion or should be removed by a preliminary extraction with chloroform.  Specified salts that may be crystallized are those of potassium, sodium, rubidium, ammonium and substituted ammonium such as methylammonium, diethylammonium, trimethylammonium, benzyltrimethylammonium choline.  Specified solvents for the crystallization are ethanol, n- and iso-propanols, n-, sec.-and tert.-butyl alcohols, n-hexanol, n-octanol, capryl alcohol, 2-ethyl-hexanol, diethyl-carbinol, allyl alcohol, diacetone alcohol, cyclohexanol, ethylene glycol monobutyl ether and butyl actate. Alcohols of 4-6 carbon atoms are preferred.  The process and the preliminary purification steps are carried out in the same manner as for penicillin X in Specifications 653,377 and 653,379. Hydroxides, carbonates and bicarbonates are suitable for neutralization, phosphates leading to contamination of the product.  The products may be converted into salts of other cations by preparing an aqueous solution, proceeding as in step 3 (E), 3 (F) or 3 (G) (see Specification 653,377), and crystallizing as in step 4.  In the examples: (1) potassium penicillin G is crystallized from n-butanol after purification via steps 1 and 3(E); (2) potassium penicillin G from n-butanol via 2 and 3 (C); (3) ammonium penicillin G from n-butanol via 3 (A); (4) sodium penicillin G from n-butanol via 2 and 3 (B); (5) ammonium penicillin G from n-butanol via 2 and 3 (D); (6) ammonium penicillin G from n-butanol via 2 and 3 (B); (7) rubidium penicillin G from n-butanol via 2 and 3 (F); (8) sodium penicillin G from n-butanol via 2 and 3 (E); (9) ammonium penicillin G from sec.-butyl alcohol via 3 (C); (10) ammonium penicillin G from sec.-butyl alcohol via 3 (E); (11) ammonium penicillin G from isopropanol via 2 and 3 (B); and (12) ammonium penicillin G from n-hexanol via 3(A).  Specifications 628,251, 629,662, 642,369, 642,370, 642,371 and 642,372 also are referred to.  According to the Specification as open to inspection under Sect. 91, the process is applicable to starting materials containing comparatively large proportions of penicillin X.  The product does not then consist of pure penicillin G salt, but the latter has been freed at least in part from non-penicillin organic and inorganic impurities and from penicillins F and K.  It is also stated that any organic liquid may be used for the crystallization step that is capable of dissolving penicillin salts.  The list of suitable solvents includes alcohols, glycols, aldehydes, ketones, acetals, cyclic acetals, ketals, cyclic ketals, cyclic ethers, hydroxy ethers, hydroxy esters and keto esters.  Additional solvents specified are ethylene glycol, 2-methyl-2 : 4-pentanediol, propylene glycol, acetone, methyl ethyl ketone, cyclohexanone, benzaldehyde, dimethyl acetal, 1 : 3-dioxolane, 2 : 2-dibutoxy-propane, 2 : 2 : 4 : 5-tetramethyl - 1 : 3 - dioxolane, 1 : 4 - dioxane and methyl laevulinate.  Further examples show the crystallization of (1) potassium penicillin G from 2-methyl-2 : 4-pentanediol via step 3(C), and (2) ammonium penicillin G from dioxolane via step 3 (A).  This subject-matter does not appear in the Specification as accepted.