QUINACRINE HYDROCHLORIDE..
..
Improvements in Manufacturing Processes' 1
A number of improvementshave been made in the process for manufacturing quinaorine hydrochloride. The quantity of phenol used in the initial reaction has been substantially reduced. The phenol has been removed from the reaction mixture by aqueous sodium hydroxide. The concentration of hydrochloric acid from which quinacrine hydrochloride ie precipitated has been reduced to 1%. Water-insoluble impurities have been removed from the ~ryetallizedproduct by washing with warm acetone.
R, G . JONES,G . L. SHAW, WITH
JOHN H. WALDO
Eli Lilly
and
Company, Indianapolis,
Id.
T
solution by agitation with aqueous acetic acid. Upon treatment of the acetic acid solution with sodium hydroxide, the quinacrine is released as the free-base which is taken up in ether. Finally, the ether solution is dried and treated with hydrogen chloride to precipitate quinacrine hydrochloride. Obviously this process would have to be modified for operation on any commercial scale. I n practice, quite a different procedure hae been employed. The hot phenol reaction mixture is transferred into a large volume of acetone, and the resulting solution is treated with an excess of 36% hydrochloric acid to precipitate quinacrine dihydrochloride. The product is collected and washed twice by suspension in acetone to remove all of the phenol. The crude dihydrochloride is recrystallized by solution in warm water followed by treatment of the 6ltered solution with concentrated hydrochloric acid until the solution contains 5% of free acid. This brings about almost complete precipitation. The crystals are collected and washed twice by slurrying with acetone. Finally the product is dried at 50" to 60" C. There are a number of serious drawbacks to the process as just outlined. The first precipitation from acetone by the addition of concentrated hydrochloric acid must be conducted carefully, and the mixture must be cooled slowly in order to obtain crystals which can be easily filtered. Even with the most careful control, extremely fine crystals are sometimes obtained which are difficult to handle. The process is wasteful of acetone. Experience has indicated that, for every pound of quinacrine produced, about 2.5 pounds of acetone are lost, even though a fairly e5cient acetone recovery system is employed. The several washings of the product with acetone and subsequent filtrations require an excessive amount of handling of the product and the use of much equipment. Both the acetone- hydrochloric acid solution and the 5y0 aqueous hydrochloric acid solution, from which the crystallizations are made, are highly corrosive to equipment.
HE wartime need for vast quantities of antimalarial drugs made the largescale manufacture of quinacrine hydrochloride ( I ) a problem of prime importance. This paper deals only with the last stage of the complete manufacturhg process-that is, the condensation of 2-rnethoxy-6,Q-dichloroacridinewith 1diethylamino-4-minopentane and the purification of the resulting quinacrine after conversion to the dihydrochloride (dihydrate) :
CzHo
CH+H-CHn-CHp-CHz-
d,
HA I
The condensation of the two intermediates is best effected by heating them together in the presence of phenol, and previous investigators (1)recommended that a large quantity of phenol be used :
c1
CH,-CH-CH2-CHpCHn-N(CrHr)n I
phenol A
,
cH80-cl$& .ac1
REMOVAL OF PHENOL
The resulting reaction mixture is a viscous liquid a t 100' C. and a hard resinous mass a t room temperature. From this mixture the quinacrine must be separated and converted to the dihydrochloride dihydrate (formula 1) in a high state of purity. The process as disclosed in the patent literature (5') is, briefly, as follows: A mixture of 1 mole of 2-methoxy-6,9-dichloroacridine, 1 mole of l-diethylmino-Paminopentane, and 5 or 6 moles of phenol is heated at 130" C. for 1 hour. The melt is shaken with 2 N sodium hydroxide solution, and the quinacrine frce-base is extracted with ether. The quinacrine is removed from the ether I Publication of this papsr wad withheld, at the time of ita original submission, by the government oenaor for reasons of national security.
I n improving the process, our approach was to remove the phenol from the reaction mixture by treatment with sodium hydroxide solution. This would eliminate the use of the large volumes of acetone. It would also greatly reduce the amount of equipment needed, because the reaction, the removal of phenol, and the conversion of the quinacrine to the dihydrochloride could all be carried out in the same vessel. When the reaction mixture is treated with sodium hydroxide solution, the phenol is taken into the aqueous phase as sodium phenate, and the quinacrine free-base remains as a gummy, water-insoluble mass. As mentioned, this can be taken up in ether and separated from the water solution, but the use of ether would introduce objectionable problems of handling and solvent recovery.
1044
November, 1945
INDUSTRIAL AND ENGINEERING CHEMISTRY
1046
It was found that the gummy, quinacrine free-base becomes a mobile liquid at 80" to 90"C. Further, when the reaction mixture containing phenol was treated with hot aqueous sodium hydroxide solution and then cooled to about 40" C., the quinacrine base could be sharply separated from the water solution, provided the density differential between the two was great enough, If the specific gravity of the water solution w a s 1.13 or greater, the quinacrine base separated to the top, whereas if the specific gravity of the water solution was 1.06 or lower, t8hebase separated to the bottom. When the specific gravity of the aqueous solution was between these two values, separation was not satisfactory. I n practice it was advantageous to use sufficient water so that the resulting water mlution had a specific gravity of about 1.04. If 6 moles of phenol had been used with each mole of the reactants aa specified, the large volume of water required would have presented a handling problem. Thus, for each 100 pounds of resultant quinacrine about 260 gallons of water solution were necessary to remove the phenol. This difficulty was overcome when it waa found that a large excess of phenol was not necessary in the reaction. I n fact, the yield of quinacrine was slightly improved if only 1.26 to 1.6 moles of phenol were used with each mole of intermediates. T o obtain optimum yields and a final product having the desired color, it was necessary to control the reaction temperature closely. The reaction proceeded spontaneously with heat evolution at 110"t o 115" C.,and it was necessary to resort to efficient cooling to hold the temperature below 115" C. The adverse effect of higher reaction temperatures on yield is indicated by the following figures: Reaction Temp., O C.
Reaction Time, Hr. 1
% Yield .of Quinacrine Dih drcchloride DihyJate
1
1
't 1
Reaction temperatures above 115" C. also led to a product containing colored impurities which were difficult to remove in order to meet the desired color standard. The removal of phenol from the reaction mixture by stirring for an hour with hot 1.2 N sodium hydroxide solution introduced the question as to whether the quinacrine decompoaed appreciably under these conditions. Laboratory tests indicated that not more than 0.6 to 1% decomposition occurred when it. waa heated for 1 hour at 100' C. with 1.2 N sodium hydroxide. After the treatment with sodium hydroxide solution, the quinacrine base was washed twice by agitation with hot distilled water. HYDROCHLORIC ACID CONCENTRATION
The conversion of the base to the dihydrochloride and its final purification involved dissolving it in hydrochloric acid, treating the resulting aqueous solution with carbon, filtering, crystallizing, and washing the crystalline dihydrochloride with acetone. The quinacrine base was taken into solution by heating and agitating it with four or five volumes of water containing approximately the theoretical quantity of hydrochloric acid necessary to form the dihydrochloride. The pH of the solution was adjusted to 3.6-4.5, in which range the solubility of quinacrine hydrochloride is at a maximum. A quantity of acrtivated carbon equal to 2.6% of the total weight of the solution waa added, and the resulting mixture agitated and heated to 80" C. for an hour. Adsorption isotherm studies indicated a grade of activated carbon known as Darco 0 60 gave best results. Other studies indicated that the decomposition of quinacrine hydrochloride in water solution (pH 4.5) at 80" to 100' C. was less than 0.6% per hour.
After heating for 1 hour with carbon, the solution was cooled t o below 40"C. and allowed to stand for 2 hours or longer. This period of standing wm found to be necessary in order to allow the precipitation of difficultly soluble impurities which otherwise appeared in the finished product. The mixture was then rapidly
INDUSTRIAL A N D ENGINEERING CHEMISTRY
To46
heated with agitation t o 58-60' C. and filtered through a preheated press. It was necessary to maintain the temperature carefully within these limits. Above 60" C. objectionable quantities of impurities were carried through into the finished product. Below 58 " considerable quantities of quinacrine hydrochloride were left on the carbon.
Val. 37, No. 11
solubility, and the minimum solubility is reached in approximately 8% acid solution. The use of 8% hydrochloric acid waa objectionable, however, because of its corrosive action on the process equipment, and also because it created numerous di5culties in drying the final product. Figure 2 presents the effect of temperature on the solubility of quinacrine hydrochloride in 1% acid. This curve shows that effective precipitation is obtained at 0" to 5' C. I n this temperature range the solubility in 1% hydrochloric acid is less than 0.006 pound per gallon. CRYSTALLIZATION
%ACE7ONC
e ut,
--
aqueoua hydroohlor$ add at !2Ta C. aqueous hydroohlorro acid a t 0' C. 2.54% aqueoau h y h h l o r i o acrid a t Oo C.
5
The solubility of quinacrine hydrochloride is greatly decreased
in the presence of hydrochloric acid. Usually, enough concentrated hydrochloric acid has been added t o the filtered quinacrine hydrochloride solution at 50-55" C. so that the solution contained about 5% free acid. Upon cooling this solution, practically all of the quinacrine hydrochloride is precipitated. The solubility characteristics of quinacrine hydrochloride in aqueous hydrochloric acid were carefully studied. In Figure 1 the solubility at 27" C. is plotted as a function of acid concentration. A distilled water solution saturated at 27' C. contains 4.92 grams of quinacrine dihydrochloride per 100 cc. The presence of a vsry small quantity of free hydrochloric acid greatly lowers the
The characteristics of the crystals obtained in the precipitation from acid solution were highly important from the standpoint of both filtration and of the disintegration rate of tablets made from the quinacrine dihydrochloride dihydrate. Agitation during precipitation brought about the formation of extremely small crystals which were difficult to handle. It was found highly important to avoid any agitation until the temperature throughout the entire mixture was below 20" C. Following filtration at 5" C., the wet cake of quinacrine hydrochloride crystals was slurried with acetone to facilitate removal of the remaining hydrochloric acid solution and colored impurities. The solubility of quinacrine hydrochloride in mixtures of acetone and aqueous hydrochloric acid solutions of various concentrations waa investigated. Figure 3 discloses that, in mixtures containing 40 to 45% acetone, the solubility reaches a sharp maximum. To avoid appreciable loss of quinacrine hydrochloride in the acetone slurry stage, it was therefore advantageous to use sufficient a c e tone so that the resulting solution contained more than 80% acetone. A second acetone slurry a t 30" to 35" C. removed any residual water-insoluble impurities. The product was dried to the dihydrate (formula 1) in a hot air dryer for 13 hours at 50" C. The process outlined here has a number of advantages over the former one. The yields have been 85% of theoretical, or higher, of a product of consistently high purity. Maximum yields by the old procesa were about 77%. A 33% increase in the volume of production has been achieved with only 60% of the original equipment, which was relatively easily adapted to the present process. The consumption of acetone has been reduced by approximately 40%, phenol by 65%, and hydrochloric acid by 55%. The reduction in the quantity of phenol, removed in the present procesa as sodium phenate, simplifies the problem of recovery or disposal of phenol residues. Corrosion of equipment by hydrochloric acid has been reduced to a minimum. Simplification of the process and equipment has reduced labor requirements aa well as maintenance. LITERATURE CITED
(1) Drosdov and Cherntzov, J . Om. Chem. (U.S.S.R), 5, 1576, 1736 (1935); Magidaon and Grigorovski'l, Khim. Farm. Prom., 1933,
187; Jensch and Eisleb, U.S. Patent 1,782,727(1930): Schulemann, Mietzach, and Wingler, U. S. Patent 1,889,704(1932). (2) Mietesch and Mauss, U. 8. Patent 2,113,357(1938).
Empirical Correction for Compressibility Factor and Activity Coefficient CurvesCorrection Two errors in the July, 1945, issue have been called to our attention by Robert M, Trapp. Both occur on page 670 and correctiona are indicated as follows: First column, second line from This bottom, the last figure should be -1.46 instead of -1.61. does not change the correction factors, however, since the nearest whole numbers for T'and PI are 28 and 14, respectively, aa shown in the article. I n the second column, the third line should read
It should be pointed out that these correction factors should not be considered accurate to better than 1%. If these curves approximate actual conditions t o within 1 or 2%, their use will be justified. RALPEA. MORQEN AND J. H.CHILDS
f/p = 1.16 instead of 1.15.
UNrVEasrTY o, Q A I N ~ B V I L L E , FLA.
