Process for isolating organic compounds and lithium salt complexes useful in said process

An improved process for isolating organic compounds from crude product or reaction mixtures by dissolving said crude product or reaction mixture in a suitable solvent, contacting the resulting solution with a lithium salt to form a solid metal salt complex, separating, and thereafter recovering a pure product by decomposing the lithium salt complex.

BACKGROUND OF THE INVENTION 
The formation of alcoholates of anhydrous metal halides has been documented 
in the literature, and the separation of organic mixtures by formation of 
metal complexes has been reported. See Sharpless et al, J. Org. Chem., 
Vol. 40, No. 9, pp 1252-1257(1975). Sharpless et al teach the use of 
divalent metal salts, particularly the salts of calcium and manganese in 
the resolution of alcohol mixtures by preferential complexation by calcium 
chloride or manganese chloride with one alcohol of the mixture, using 
catalytic amounts of ethanol to enhance the complexing ability of metal 
halides. The Sharpless et al resolutions are restricted to simple 
alcohols. 
Weber et al. U.S. Pat. No. 4,057,541 disclose a process for isolating 
3-hydroxy steroids and 3-keto steroids from mixtures thereof by dissolving 
the mixtures in an organic solvent, mixing the dissolved mixture with 
calcium bromide to form insoluble adducts of the steroids, separating the 
insoluble adducts and splitting the adducts to regenerate the free 
steroid. Methyl isobutyl ketone and/or methyl n-amyl ketone is used as the 
solvent. 
Weber et al. specifically teach away from the use of metal salts other than 
calcium bromide (in its hydrate form) stating at Column 2, lines 32-34 
"The use of other metal salts which are otherwise suitable for adduct 
formation also leads to poorer results as compared to the method of the 
present invention." 
It has now been found that a number of organic compounds, particularly 
pharmaceutical compounds with complex structures i.e., prostaglandins, 
steroids, antibiotics, etc., which are generally difficult to isolate and 
purify, are readily and advantageously isolated and purified by the use of 
complexation of the crude product or reaction mixture with a lithium salt 
selected from the group consisting of lithium bromide, lithium iodide, 
lithium perchlorate, and lithium fluoroborate in the presence of a 
suitable solvent. 
SUMMARY 
The process of the present invention generally comprises forming a lithium 
salt complex with a crude reaction mixture in the presence of a suitable 
solvent, and recovering the pure product therefrom by decomposition. 
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
In the practice of the present invention, the crude reaction mixture, which 
may contain the crude product or a mixture of crude products, is contacted 
or dissolved in any suitable non-hydroxylic organic solvent, and from 
about 1.0 to about 10 moles of a lithium salt per mole of product is added 
thereto. It is preferred to add from about 2 to about 5 moles of lithium 
salt per mole of substrate to be complexed. More preferably, in specific 
embodiments of the present invention, prostaglandins may be complexed with 
about 2 to about 5 moles of lithium salt; steroids may be complexed with 
about 1.5 to 3 moles of lithium salt; and metronidazole may be complexed 
with about 1 to 2 moles of lithium salt per mole of substrate. 
A lithium salt is preferably selected from the group consisting of lithium 
bromide, lithium iodide, lithium perchlorate, and lithium fluoroborate. 
The solvent can be any non-hydroxylic organic solvent such as toluene, 
methylene chloride, hexane, etc., and the selection of solvent is 
primarily dependent upon the nature of the compound to be isolated. In the 
case of steroids, methylene chloride, toluene and ether are the preferred 
solvents. In the case of prostaglandins, the preferred solvents are 
toluene, hexane and methylene chloride. Ethers, hydrocarbons, halocarbons, 
etc., are also readily employed in the practice of this invention 
depending upon the substrate. 
The complexation reaction is run for an effective amount of time and at an 
effective temperature to complete the reaction. Commonly, temperatures of 
from about 0.degree. to about 100.degree. C., preferably from about 
20.degree. to 30.degree. C. for from about 15 minutes to about 48 hours, 
preferably for from about 2 to about 18 hours, are utilized. 
The addition of a small amount of water or a lower alcohol, i.e. a C.sub.1 
-C.sub.3 alcohol (methanol, ethanol, propanol, or 2-propanol) as a 
catalyst has been found to be advantageous. 
In order to cleave the lithium salt complex and obtain the pure product, 
the complex is separated and placed in a large excess (about 10 to about 
100 moles) of water or a lower alcohol i.e., C.sub.1 -C.sub.3 alcohol, and 
allowed to decompose for an effective amount of time and at an effective 
temperature to complete the reaction. The time and temperature commonly 
utilized for cleaving the lithium salt complex are from 5 minutes to 24 
hours at temperatures of from about 0.degree. C. to about 100.degree. C., 
preferably about 10.degree. to about 35.degree. C. for from 5 minutes to 
about 24 hours. Any common organic solvent can be added if desired, but 
the presence of solvent is not necessary. 
The time and temperature for the cleavage step depend upon the nature of 
the compounds being isolated. In the case of prostaglandins, temperatures 
of from 0.degree. to 10.degree. C. are preferred and the reaction time 
ranges from about 5 minutes to about 2 hours. Steroids generally require 
from 20 minutes to 3 hours, while metronidazole requires a 24 hour 
cleavage period. In some instances, it is advantageous to boil the 
reaction mixture to speed up the cleavage. 
It has been found that certain lithium salts exhibit selectivity toward 
various functional groups and the choice of the particular lithium salt 
depends upon the nature of the substrate. For example, lithium bromide 
advantageously complexes alcohols, phenols, amides, imides, carboxylic 
acids primary or secondary amines having a K.sub.b (dissociation constant 
in water at 25.degree. C.) of at least 10.sup.-10 and sulfoxides. Lithium 
perchlorate advantageously complexes all of the above plus ketones and 
aldehydes. Thus, the choice of the particular lithium salt is dependent on 
the particular substrate. 
The method of the present invention has wide applicability to a number of 
organic compounds which are advantageously isolated and/or purified by the 
use of a lithium salt. For example, analgesic agents such as acetominophen 
and mefenamic acid; anti-inflammatory agents such as indomethicin and 
phenlbutazone; beta-blockers such as isoproteranol and propanolol; 
antibiotics such as penicillin G, ampicillin, amoxicillin, cephalosporins, 
chloramphenicol, erythromycin, tetracycline and sulfachlorpyridizines; 
anti-protozoal agents such as metronidazole; antimetazoal agents such as 
hycanthone and mebendazole; vitamins such as vitamins A, D, E, biotin and 
folic acid; prostaglandins; H.sub.2 receptor antagonists such as 
cimetidine; progestins such as norgestrel and norethindrone; tranquilizers 
such as diazepam and chlordiazepoxide; diuretics such as furosemide; 
antihypertensive agents such as spironolactone, clonidine and propranolol 
hydrochloride; corticosteriods such as cortisol and dexamethasone; and 
antiarrhythmic agents such as disopyramide phosphate. 
The present invention also provides intermediates or metal salt complexes 
of organic compounds, having the formula 
EQU R.(Li X).sub.m (H.sub.2 O).sub.n 
wherein R is an organic compound to be isolated; X is an anion selected 
from the group consisting of bromide, iodide, perchlorate, and 
flouroborate; m is a number from 1 to 10 and n is a number from 0 to 10. 
The present invention has been found to be particularly advantageous in 
isolating prostaglandins and steroids. By using the present lithium salt 
complex process in the isolation of prostaglandins, over 70% of the 
undesired reaction products, which are normally separated by 
chromatography, are eliminated and the amount of chromatography is reduced 
by about 60%. 
The isolation of steroids is also greatly facilitated by the present 
process, and in the case of methyl testosterone, the present process 
provides an excellent way of isolating the steroid from the reaction 
mixture. In all cases, yields are increased.

The invention will appear more fully from he examples which follow. These 
examples are given by way of illustration only and are not to be construed 
as limiting the invention either in spirit or scope as many modifications 
both in materials and in methods will be apparent from the disclosure to 
those skilled in the art. 
EXAMPLE 1 
Preparation and isolation of (.+-.)-methyl 
11.alpha.,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate 
To a mixture of 40 ml tetrahydrofuran (THF) and 40 ml water is added 68.8 g 
of crude (.+-.)-methyl 
16-methyl-9-oxo-11.alpha.-[(triethylsilyl)oxy]-16-[(trimethylsilyl)oxy]-pr 
ost-13E-en-1-oate (containing 26.3 g maximum of pure compound) and 120 ml 
of acetic acid. The mixture is stirred under nitrogen for 1-2 hours. The 
resulting mixture is diluted with 300 ml of water and 300 ml of ether. The 
ether layer is separated and washed with 150 ml of water, 500 ml of 
saturated aqueous sodium bicarbonate and twice with saturated aqueous 
sodium chloride. All of the ether extracts are combined and dried over 
sodium carbonate, filtered and evaporated to dryness `in vacuo` to give 
67.5 g of an oil containing (.+-.)-methyl 
11.alpha.,16-dihydroxy-16-methyl-9-oxoprost-13E-3en-1-oate. 
The crude oil obtained above is dissolved in 250 ml toluene and added over 
a 30 second period to a vigorously stirred suspension of 135 g lithium 
bromide in 500 ml of toluene. After 30 minutes, the solid complex is 
removed by filtration, washed with 500 ml of toluene, and pulled dry on 
the filter under nitrogen. 
Analysis: C, 6.46 H, 1.91 Br, 73.11, H.sub.2 O, 7.89. 
DSC: Endotherms at 43 (sharp), 77 (broad, shallow), 162 (sharp) and 
251.degree. C. (sharp). 
DSC refers to a method of analysis described in Differential Scanning 
Colorimetry by J. L. McNaughton and C. T. Mortimer; Perkin & Elmer, 1975. 
The apparatus used for evaluation is a DuPont model 900. 
The complex is dissolved in 400 ml of ethyl acetate with external cooling. 
One liter of water is added and the mixture stirred briefly. The ethyl 
acetate layer is separated and washed with 100 ml of water and 100 ml 
saturated aqueous sodium chloride. After filtration through Celite, 
manufactured by Johns Mansville Co., the solvent is evaporated `in vacuo.` 
The residual oil weighed 16.4 g (88% of Theory) and contained only 
(.+-.)-methyl 11.alpha.,16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate 
and small amounts of other prostaglandins. 
EXAMPLE 2 
Preparation and isolation of (.+-.)-methyl 
11.alpha.,16-dihydroxy-16-methyl-9-oxoprost-4Z,13E-dien-1-oate 
To a mixture of 250 ml water and 750 ml acetic acid is added 124.92 grams 
of crude (.+-.)-methyl 
16-methyl-9-oxo-11.alpha.-[(triethylsilyl)oxy]-16-[(trimethylsilyl)oxy]-pr 
ost-4Z,13E-dien-1-oate (containing 24 g maximum of pure compound) and 
stirred under argon for 2 hrs. The resulting mixture is diluted with 1.0 
liter of water and 1.0 liter of ether. The ether layer is separated and 
washed with 600 ml of water (twice), 800 ml of 5% aqueous sodium 
bicarbonate, 300 ml of 5% aqueous sodium bicarbonate (twice), and 100 ml 
of saturated aqueous sodium chloride. The aqueous extracts are combined 
and extracted with 200 ml of ether (twice). The ether extracts are 
combined and washed with 250 ml of 5% aqueous sodium bicarbonate (5 times) 
and 100 ml of saturated aqueous sodium chloride. The resultant ether 
solution is dried over sodium sulfate, filtered through Celite, and 
evaporated to dryness `in vacuo` to give 119 g of an oil containing 
(.+-.)-methyl 
11.alpha.,16-dihydroxy-16-methyl-9-oxoprost-4Z,13E-dien-1-oate. 
The crude oil obtained above is dissolved in 458 ml of ether and 229 ml of 
hexane and added rapidly (about 1 min) to a stirred suspension containing 
228.88 g of lithium bromide in 915 ml of ether and 457 ml of hexane. The 
solid complex is removed by filtration and washed with 1750 ml of 2:1 
ether:hexane. The complex is added to a stirred mixture containing 1.0 
liter of ethyl acetate and 1.0 liter of water. After 30 minutes, the ethyl 
acetate layer is separated, dried over sodium sulfate, filtered through 
Celite, and evaporated in `in vacuo`. The residual oil weighed 21.35 g 
(89% of Theory) and contained (.+-.)-methyl 
11.alpha.,16-dihydroxy-16-methyl-9-oxoprost-4Z,13E-dien-1-oate and only 
small amounts of impurities. 
EXAMPLE 3 
Preparation and isolation of 17.alpha.-methyltestosterone 
To 106 ml THF is added 16.0 g of androst-4-ene-3,17-dione-3-ethyl enol 
ether and the mixture is treated with 55.0 ml of a (1.4M) 
methyllithium/ether solution at 5.degree. C. The product is extracted with 
methylene chloride after treatment with water and phosphoric acid. The 
extracts are dried over sodium sulfate and evaporated to dryness `in 
vacuo` to yield 15.6 g yellow solids. 
The crude reaction products are dissolved in 140 ml toluene, 65 ml 
methylene chloride and 25 ml ether. While stirring vigorously, 2.0 ml 
water, followed by 8.9 g of lithium bromide are added and the mixture 
stirred for two hours at 24.degree. C. 
The resultant slurry is filtered and washed with 2.times.50 ml cold wash 
solution (4:1, hexane:methylene chloride). Solids are dried in a vacuum 
oven at 24.degree. C. to yield 19.98 g of the 
17.alpha.-methyltestosterone/lithium bromide complex. 
Analysis: C,31.56; H,5.72; Br,34.55; H.sub.2 O, 19.30. 
m.p. 150.degree.-154.5.degree. C. 
The complex is decomposed by treating 5.0 g with 120 ml water and 5 ml 
acetone and stirring the mixture for 20 minutes. The freed product is 
filtered and washed with 2.times.20 ml water, then dried to yield 1.85 g 
of 17.alpha.-methyltestosterone (which when projected for the whole sample 
gives an overall 55.8% recovery). 
EXAMPLE 4 
`In situ` isolation of 17.alpha.-methylestosterone 
In a dry flask under an inert atmosphere, 16.0 g of 
androst-4-ene-3,17-dione-3-ethyl enol ether in 140 dry toluene is treated 
with 48.0 ml of a (1.4M) methyl lithium/ether (containing LiBr) solution 
at 0.degree. C. After stirring for 1 hr., the reaction is treated with 
water and phosphoric acid and the resulting slurry diluted with 65 ml 
methylene chloride. After stirring vigorously for 60 minutes, the tan 
solids are filtered and washed with 2.times.125 ml cold wash solution (4:1 
hexane:methylene chloride). The solids are dried `in vacuo` to yield 29.73 
g of 17.alpha.-methyltestosterone/lithium bromide complex. 
The complex is decomposed by treating 5.0 g with 120 ml water and 5 ml 
acetone and stirring the mixture for 20 minutes. The freed product is 
filtered and washed with 2.times.20 ml water, then dried to yield 2.30 g 
of 17.alpha.-methyltestosterone (which when projected for the whole sample 
gives an overall 88.8% yield). 
EXAMPLE 5 
Isolation of 17.alpha.-Methyltestosterone 
A mixture containing 13.1 g of methyltestosterone and 2.2 g of 
androstenedione is dissolved in 140 ml toluene, 65 ml of methylene 
chloride, 25 ml of ether and 3.0 ml of water. 6.2 grams of lithium bromide 
is added and the mixture is stirred vigorously for 16 hrs. The resultant 
mixture is filtered and the solids washed with a cold 4:1 solution of 
hexane and methylene chloride. The product is dried `in vacuo` to give 
21.05 g of the 17.alpha.-methyl testosterone/LiBr complex. 
Analysis: C,45.59; H,7.02; Br,24.94; H.sub.2 O, 15.28, 
m.p. 156.degree.-159.degree. C. 
The complex is hydrolyzed by treating 5.0 g with 120 ml water and 5 ml 
acetone and stirring for 20 minutes. The resultant precipitate is 
filtered, washed with water and dried to yield 2.76 g of pure 
17.alpha.-methyltestosterone (which when projected for the whole sample 
gives an 88.7% yield). 
EXAMPLE 6 
Preparation and isolation of 
6.beta.,17-dihyroxy-3-oxo-17-preg-4-ene-7.alpha.,21-dicarboxylic 
acid-7-isopropyl ester-.gamma.-lactone 
To 80 ml isopropyl alcohol is added 15.5 g of 
17-hydroxy-3-oxo-17.alpha.-preg-4-ene-7.alpha.,21-dicarboxylic 
acid-7-isopropylester-lactone and the mixture is treated with 0.68 g tosic 
acid and 15.9 ml of triethyl orthoformate at 24.degree. C. The reaction is 
complete after 30 minutes. Pyridine is added, the reaction stirring for 15 
minutes, and the solvents are evaporated `in vacuo` at 40.degree. C. 
The residue is dissolved in 100 ml dry THF and the turbid solution is 
cooled to 0.degree..+-.10.degree. C. To this solution is added a mixture 
containing 17.5 ml of 40% peracetic acid, 0.80 g of sodium acetate and 
11.6 ml of water over 30 minutes. The reaction is stirred for an 
additional 30 minutes at 0.degree..+-.10.degree. C., then let stand 
overnight. 
The reaction is diluted with 200 ml of water and extracted with 
2.times.108.9 ml of a solution containing 99 ml ethyl acetate and 9.9 ml 
hexanes. The organics are washed with 3.times.140 ml of water, 115 ml of 
5% sodium bicarbonate, 56 ml of 5% sodium sulfite and water, then dried 
over sodium sulfate. The solvents are evaporated in `in vacuo` to give a 
yellow oil. 
The resultant oil is dissolved in 145 ml toluene and 26 ml ether and 
treated with 2.0 ml water and 7.1 g lithium bromide. The mixture is 
stirred vigorously for 2 hours. The solids are filtered and washed with 
2.times.50 ml of cold wash solution (4:1, hexane:methylene chloride). The 
filter cake is dried in `in vacuo` overnight to yield 17.6 g of off-white 
solid complex. 
Analysis: C,35.94; H,4.67; Br,34.82; H.sub.2 O, 14.32; 
m.p. 175.degree.-178.degree. C. 
The complex is hydrolyzed by treating 5.0 g with 120 ml water and 5 ml 
acetone and stirring the mixture for 20 minutes. The freed product is 
filtered and washed with 2.times.20 ml of water, then dried overnight to 
yield 2.37 g of 
6.beta.,17-dihydroxy-3-oxo-17.alpha.-preg-4-ene-7.alpha.,21-dicarboxylic 
acid 7-isopropyl ester-.gamma.-lactone. 
EXAMPLE 7 
Preparation of metronidazole/lithium bromide complex 
To a solution containing 2.18 g of metronidazole in 150 ml chloroform is 
added 11.0 g lithium bromide and the resulting mixture is stirred for 18 
hours under argon. The white solids are removed by filtration and washed 
with 100 ml cold chloroform, then dried in `in vacuo` for 20 hours to 
yield 12.09 g of white, solid, metronidazole/lithium bromide complex. 
Analysis: C, 7.45; H, 1.61; N, 4.18; Br, 72.04; H.sub.2 O, 4.33; m.p.: 
softens at 147.degree. C. 
EXAMPLE 8 
Isolation of 11.alpha.-hydroxyandrostene-3,17-dione 
To a solution of 28.1 ml methylene chloride, 7.8 ml hexane and 0.2 ml water 
is added 1.52 g of a fermentation mixture with a sterol content of 30-60% 
(consisting of androstenedione and 11.alpha.-hydroxy androstenedione). To 
the resulting solution 1.34 g of lithium bromide is added and the mixture 
stirred overnight at ambient temperatures. The resultant mixture is 
filtered, the solids washed with a 3.5:1, hexane methylene chloride 
solution and dried `in vacuo.` 
The yield of 11.alpha.-hydroxyandostenedione/LiBr complex is 1.95 g. 
Analysis: C, 15.65; H, 4.42; Br, 61.40; H.sub.2 O, 15.42. DSC: Endotherms 
at 45.degree. (sharp), 219.degree. (sharp) and 278.degree. C. (sharp). 
The complex is hydrolyzed by treating with 60 ml water and 2.5 ml acetone 
with stirring for 20 minutes. The freed product is filtered and washed 
with 2.times.10 ml of water, then dried in `in vacuo` to give 0.91 g of 
11.alpha.-hydroxy androstene-3,17-dione. 
EXAMPLE 9 
Isolation of .beta.-naphthol 
To a solution containing 140 ml of toluene, 25 ml of ether and 7.35 g of 
.beta.-naphthol is added 1.0 ml of water, followed by 8.86 g of lithium 
bromide. The mixture is stirred for 18 hrs. The solids are removed by 
filtration, washed with 50 ml of cold 4:1, hexane:methylene chloride and 
dried `in vacuo` to give 15.58 g of .beta.-naphthol/lithium bromide 
complex. 
Analysis: C, 30.14; H, 5.61; Br, 50.42; H.sub.2 O, 8.31. DSC: Endotherms at 
48 (sharp), 153 (broad, shallow), 162 (broad), 283.degree. C. (sharp). 
A mixture of 200 ml water and 14.6 g of the complex is stirred for 2 hrs, 
filtered, washed with 100 ml of water and air dried to give 4.8 g of 
.beta.-naphthol (72% overall recovery when projected for entire sample). 
EXAMPLE 10 
Isolation of 1-aminoindan 
To a solution containing 140 ml toluene, 25 ml ether and 6.8 g of 
1-aminoindan is added 8.86 g of lithium bromide. The mixture is stirred 
for 18 hrs. The solids are removed by filtration, washed 2 times with 50 
ml of cold 4:1, hexane:methylene chloride, and dried `in vacuo` to give 
14.09 g of 1-aminoindan/lithium bromide complex. 
Analysis: C, 30,73; H, 4.77; N, 4.10; Br, 45.98; H.sub.2 O, 7.24. 
DSC: Endotherms at 46 (sharp), 79 (sharp), 92 (sharp), 210.degree. C. 
(sharp). 
A mixture of 200 ml water and 13.5 g of the complex is stirred with 100 ml 
of ether for 2 hrs. The ether layer is separated, dried (Na.sub.2 
SO.sub.4) and evaporated `in vacuo` to give 4.7 g of 1-aminoindan (72% 
overall recovery when projected for the entire sample). 
EXAMPLE 11 
Isolation of N-(1-adamantyl)-acetamide 
To a solution containing 140 ml toluene 65 ml methylene chloride, 25 ml 
ether and 9.84 g of N-(1-adamantyl)-acetamide is added 2.0 ml of water and 
18.5 g of lithium perchlorate. The mixture is stirred for 18 hrs. The 
solids are removed by filtration, washed with 50 ml of cold 4:1, 
hexane:methylene chloride, and dried `in vacuo` to yield 30.53 g of 
N-(1-adamantyl)-acetamide/lithium perchlorate complex. 
Analysis: C, 22.62; H, 4.93; N, 2.34, Cl, 17.66; IR(KBr): 1660 cm.sup.-1. 
DSC: Endotherm at 93.degree. C. (sharp), Exotherm at 345.degree. C. 
(sharp). 
A portion of the complex weighing 24.12 g is hydrolyzed as in Example 9 to 
give 6.69 g N-(1-adamantyl)- -acetamide (86% overall recovery when 
projected for the entire sample). 
EXAMPLE 12 
Isolation of diphenyl sulfoxide 
To a solution containing 140 ml toluene, 65 ml methylene chloride, 25 ml 
ether and 14.3 g of diphenyl sulfoxide is added 2.0 ml of water and 18.5 g 
of lithium perchlorate. The mixture is stirred for 18 hrs. The solids are 
removed by filtration, washed with 50 ml of cold 4:1, hexane:methylene 
chloride, and dried `in vacuo` to give 30.49 g of diphenyl 
sulfoxide/lithium perchlorate complex. 
IR(KBr): 1640 cm.sup.-1. 
DSC: Endotherm at 95.degree. C. (sharp). 
Exotherms at 335 (broad) and 349.degree. C. (sharp). 
A portion of the complex weighing 29.36 g is hydrolyzed as in Example 9 to 
give 7.46 g of diphenyl sulfoxide (54% overall recovery when projected for 
the entire sample). 
EXAMPLE 13 
Isolation of 3,4dibenzyloxy benzaldehyde 
To a solution containing 140 ml toluene, 65 ml methylene chloride, 25 ml 
ether and 16.2 g of 3,4-dibenzyloxybenzaldehyde is added 2.0 ml of water 
and 18.5 g of lithium perchlorate. The mixture is stirred for 18 hrs. The 
solids are removed by filtration, washed with 50 ml of cold 4:1, 
hexane:methylene chloride and dried `in vacuo` to yield 26.85 g of 
3,4-dibenzyloxybenzaldehyde/lithium perchlorate complex. 
Analysis: C, 21,96; H, 3.14; 
DSC: Endotherms at 88 (sharp, weak), 94.degree. C. (sharp). Exotherm at 
332.degree. C. (broad). 
A portion of the complex weighing 25 g is hydrolyzed as in Example 9 to 
give 4.98 g of 3,4-dibenzyloxybenzaldehyde (33% overall recovery when 
projected for the entire sample). 
EXAMPLE 14 
Preparation of 1,3-cyclohexanedione/lithium bromide complex 
To a solution containing 140 ml of toluene, 65 ml methyl chloride, 25 ml 
ether and 5.72 g of 1,3-cyclohexane-dione is added 2.0 ml of water and 
8.86 g of lithium bromide. The mixture is stirred for 18 hrs. The solids 
are removed by filtration, washed with 100 ml of cold 4:1, 
hexane:methylene chloride and dried `in vacuo` to give 16.58 g of 
1,3-cyclohexanedione/lithium bromide complex. 
Analysis: C, 21,55; H, 3.77. 
DSC: Endotherms at 102 (sharp), 118 (sharp), 
140 (sharp), 176 (sharp), 211 (broad), 265.degree. C. (broad). 
Exotherm at 225.degree. C. (broad). 
EXAMPLE 15 
Preparation of succinimide/lithium perchlorate complex 
To a solution containing 420 ml toluene, 195 ml methylene chloride, 75 ml 
ether and 5.15 g of succinimide is added 2.0 ml of water and 18.5 g of 
lithium perchlorate. The mixture is stirred for 18 hrs. The solids are 
removed by filtration, washed 2 times with 50 ml of cold 4:1, 
hexane:methylene chloride, and dried `in vacuo` to give 24.18 g of 
succinimide/lithium perchlorate complex. 
DSC: Endotherm at 93.degree. (sharp), 
Exotherm at 307.degree. (broad), 
IR (KBR): 1695 cm.sup.-1 
EXAMPLE 16 
Preparation of benzoic acid/lithium bromide complex 
To a solution containing 2.49 g of benzoic acid, 85 ml hexane and 15 ml 
methylene choride is added 3.54 lithium bromide and the resulting mixture 
is stirred for two hours under argon. The solids are removed by filtration 
and washed wtih 2.times.20 ml cold wash solution (85:15, hexane:methylene 
chloride), then dried `in vacuo` for three hours to yield 5.7 g of benzoic 
acid/lithium bromide complex. 
C, 22.43; H, 2.72; Br, 53.00; H.sub.2 O,-3.56 
DSC: Endotherms at 90, 106, 162, 228, 245 & 263.degree. C. 
EXAMPLE 17 
Preparation of testosterone/lithium fluoroborate complex 
To a solution containing 14.7 g of testosterone in 140 ml of toluene, 65 ml 
of methylene chloride, 25 ml of ether and 2.0 ml of water is added 9.6 g 
of lithium fluoroborate and the resulting mixture is stirred for 2 hours. 
The solids are removed by filtration and washed with 2.times.50 ml cold 
wash solution (4:1, hexane:methylene chloride). The solids are dried `in 
vacuo` for 16 hours to yield 12.99 g of testosterone/lithium fluoroborate 
complex. 
Analysis: C, 13.42; H, 3.12; F, 49.39; H.sub.2 O, 12.49; DSC: Endotherms at 
117 (sharp), 225 (broad), 333.degree. C. (sharp) 
EXAMPLE 18 
Preparation of testosterone/lithium iodide complex 
To a solution containing 14.7 g of testosterone in 140 ml of toluene, 65 ml 
methylene chloride, 25 ml of ether and 2.0 ml of water is added 13.65 g of 
lithium iodide and the resulting mixture is stirred for 2 hours. To aid in 
filtration of the mixture 160 ml toluene and 50 ml ether is added. The 
solids are removed by filtration and washed with 2.times.50 ml of cold 
wash solution (4:1, hexane:methylene chloride) followed by 100 ml of 
hexane. The solids are dried `in vacuo` for 16 hours, then under high 
vacuum for 24 hours to yield 31.73 g of testosterone lithium iodide 
complex. 
Analysis: C, 40.07; H, 6.17; I,38.04; H.sub.2 O, 9.76; 
DSC: Endotherms at 228.degree. and 234.degree. C. 
Exotherm at 355.degree. C. 
EXAMPLE 19 
Preparation of androstenedione/lithium perchlorate complex 
To a solution containing 1.46 g of androstenedione, 14.0 ml toluene, 6.5 ml 
methylene chloride, 2.5 ml ether and 0.2 ml water is added 1.85 g lithium 
perchlorate and the resulting mixture is stirred vigorously for 75 minutes 
under argon. The solids are removed by filtration and washed with 
2.times.5 ml of hexane and dried `in vacuo` to yield 3.42 g, 
androstenedione/lithium perchlorate complex. 
C, 31.85; H, 4.20 Cl, 19.37; H.sub.2 O 5.63; 
EXAMPLE 20 
Substitution of an equivalent quantity of 
11.beta.,15-dihydroxy-15,20-dimethyl-9-oxoprost-13E-en-1-oic acid in the 
procedure of Example 1 affords the corresponding lithium bromide complex 
that is hydrolyzed to yield a pure product. 
EXAMPLE 21 
Substitution of an equivalent quantity of methyl 
3-hydroxy-5-oxo-1-cyclopentene-1-heptanoate in the procedure of Example 1 
affords the corresponding lithium bromide complex that is hydrolyzed to 
yield a pure product. 
EXAMPLE 22 
Substitution of an equivalent quantity of (.+-.) 
1,11,16-trihydroxy-16-methyl-prost-13E-en-9-one in the procedure of 
Example 1 affords the corresponding lithium bromide complex that is 
hydrolyzed to yield a pure product. 
EXAMPLE 23 
Substitution of an equivalent quantity of (.+-.) 
11,16-dihydroxy-1-(hydroxymethy)-16-methylprost-13E-ene-1,9-dione in the 
procedure of Example 1 affords the corresponding lithium bromide complex 
that is hydrolyzed to yield a pure product. 
EXAMPLE 24 
Substitution of an equivalent amount of 
11.alpha.,15S-dihydroxy-15-methyl-9-oxo-prost-13E-en-1-oic acid in the 
procedure of Example 1 affords the corresponding lithium bromide complex 
that is hydrolyzed to yield a pure product. 
EXAMPLE 25 
Substitution of an equivalent amount of 
11,.alpha.,15S-dihydroxy-15-methyl-9-oxoprosta-5Z,13E-dien-1-oic acid in 
the procedure of Example 1 affords the corresponding lithium bromide 
complex that is hydrolyzed to yield a pure product. 
EXAMPLE 26 
Substitution of an equivalent amount of 
11.alpha.,15S-dihydroxy-16,16-dimethyl-9-oxoprosta-5Z,13E-dien-1-oic acid 
in the procecure of Example 1 affords the corresponding lithium bromide 
complex that is hydrolyzed to yield a pure product. 
EXAMPLE 27 
Substitution of an equivalent amount of 
11,15-dihydroxy-11,16,16-trimethyl-9-oxoprosta-5,13-dien-1-oic acid in the 
procedure of Example 1 affords the corresponding lithium bromide complex 
that is hydrolyzed to yield a pure product. 
EXAMPLE 28 
Substitution of an equivalent amount of methyl 
7-[3,5-dihydroxy-2-(3-hydroxy-4-phenoxy-1-butenyl)cyclopentyl]-5-heptenoat 
e in the procedure of Example 1 affords the corresponding lithium bromide 
complex that is hydrolyzed to yield a pure product. 
EXAMPLE 29 
Substitution of an equivalent amount of 
3-[[3.alpha.-hydroxy-2-(3-hydroxy-1-octenyl)-5-oxocyclopentyl]methyl]pheno 
xyacetic acid in the procedure of Example 1 affords the corresponding 
lithium bromide complex that is hydrolyzed to yield a pure product. 
EXAMPLE 30 
Substitution of an equivalent amount of 
7-[2-[4-(-3-chlorophenoxy)-3-hydroxy-1-butenyl]-3,5-dihydroxycyclopentyl]- 
4,5-heptadienoic acid in the procedure of Example 1 affords the 
corresponding lithium bromide complex that is hydrolyzed to yield a pure 
product.