Racemic (.+-.)-1-azobicyclo[2.2.1]heptan-3-one may be efficiently resolved into its (1S,4R)- and (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one isomers by formation of di-p-toluoyl hemitartrate salts by combination with di-p-toluoyl-L-tartaric acid and di-p-toluoyl-D-tartaric acid, respectively. Selective crystallization using one of the di-p-toluoyltartaric acids in less than stoichiometric amount in a suitable solvent mixture allows isolation of the desired isomer as its respective di-p-toluoyl hemitartrate in high isomeric purity. The isolated hemitartrates are storage stable and may be used as such in the preparation of pharmaceuticals and other biologically active compounds, or may be used to provide the free base of the respective 1-azabicyclo[2.2.1]heptan-3-one isomer.

TECHNICAL FIELD 
This invention relates to a method of obtaining 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, the di-p-toluoyl-L-tartaric acid 
hemisalt of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, 
(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one and the di-p-toluoyl-D-tartaric 
acid hemisalt of (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one from 
(.+-.)-1-azabicyclo[2.2.1]heptan-3-one. 
BACKGROUND OF THE INVENTION 
(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one as well as enantiomerically pure 
forms of 1-azabicyclo[2.2.1]heptan-3-one and mixtures thereof have been 
shown to be useful in the preparation of compounds which are useful as 
pharmaceutical agents. See, e.g., U.S. Pat. No. 5,514,812, incorporated 
herein by reference. Certain compounds formed from enantiomerically pure 
forms of 1-azabicyclo[2.2.1]heptan-3-one are muscarinic agonists, 
rendering them useful as pharmaceutical agents in the area of cognition 
disorders, as disclosed, for example, in U.S. Pat. No. 5,346,911; European 
Published Applications EP 414,394 A2; EP 427,390 A2; EP 402,056 A2; EP 
307,142 A1; and various publications, e.g. H. Tecle et al., BIOORGANIC AND 
MEDICINAL CHEMISTRY LETTERS, 5, 631-636, (1995) ; H. Tecle, et al., 
BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, 5, 637-642, (1995), all 
incorporated herein by reference. 
In order to be commercially viable, an efficient and cost-effective, large 
scale process for preparing substantially enantiomerically pure forms of 
1-azabicyclo[2.2.1]heptan-3-one isomers is needed. Jakob Boelsterli et 
al., HELV. CHIM. ACTA, 75, 507-12 (1992) prepared 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one by oxidation of 
(1S,3S,4R)-1-azabicyclo[2.2.1]heptan-3-ol. See also, U.S. Pat. No. 
5,346,911. This route involves the formation of racemic 
1-azabicyclo[2.2.1]heptan-3-exo-ol in four or more steps. The racemic 
alcohol is then resolved using D-tartaric acid (unnatural tartaric acid) 
by formation of a 1 to 1 salt. (1S,3S,4R)-1-azabicyclo[2.2.1]heptan-3-ol 
is then freed from the D-tartaric acid and recrystallized several times. 
The (1S,3S,4R)-1-azabicyclo[2.2.1]heptan-3-ol is then oxidized (Swern 
oxidation) at low temperatures (-60.degree. C.) to give 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. The crude 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one is then isolated as the 
hydrochloride salt and recrystallized. A similar reaction sequence is 
carried out using L-tartaric acid in order to obtain 
(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one. 
Although the route disclosed by the prior art provides (1S,4R)- and 
(1R,4S)-azabicyclo[2.2.1]heptan-3-ones as the respective hydrochloride 
salts in high enantiomeric purity, the process is difficult to conduct on 
large-scale for the following reasons: 1) the process is long, involving 
at least five steps in addition to the resolution and free alcohol 
formation steps, 2) the process utilizes a low temperature oxidation step 
(-60.degree. C.) which requires specialized equipment on a manufacturing 
scale, and 3) the process relies upon a potentially hazardous oxidation 
step. In the latter respect, see, e.g., L. Bretherick, "Bretherick's 
Handbook of Reactive Chemical Hazards", Fourth Edition, Butterworths, 
Boston, Mass., pp. 299-300 (1990). The known potential alternative to the 
hazardous oxidation step, utilized in the formation of racemic 
1-azabicyclo[2.2.1]heptan-3-one as reported by Spry et al., J. ORG. CHEM, 
34, 3674 (1969), does not work as well, and utilizes chromic acid, a toxic 
and environmentally problematic substance and a known carcinogen. See, 
e.g., Budavari, S., Ed., THE MERCK INDEX, Twelfth Edition, p. 375, Merck, 
Whitehouse Station, N.J. (1996). It would be desirable to provide an 
efficient and economical process for obtaining substantially 
enantiomerically pure (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one and 
(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one. It would be further desirable to 
provide these substantially enantiomerically pure isomers in a stable, 
easily stored form. 
SUMMARY OF THE INVENTION 
The present invention provides an efficient means for obtaining 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, the stable easily stored 
di-p-toluoyl-L-tartaric acid hemisalt of 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, 
(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, and the stable easily stored 
di-p-toluoyl-D-tartaric acid hemisalt of 
(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one. It is readily conducted on a 
scale suitable for commercial use and involves at least 2 fewer steps than 
the published procedure. It further avoids the use of low temperature 
reactions, the use of a potentially hazardous oxidation step, and the use 
of toxic chromic acid. Unexpectedly, the resolution procedure of the 
present invention provides a salt in which both of the carboxylic acid 
groups of the respective resolving agents, di-p-toluoyl-L-tartaric acid or 
di-p-toluoyl-D-tartaric acid, are efficiently utilized in the formation of 
a 2 to 1 salt (hemisalt). Therefore, the process may be carried out using 
less resolving agent than expected, resulting in a more economical 
process. In addition, the resolution procedure was unexpectedly found to 
give a stable, easily stored salt which can be converted to compounds of 
pharmaceutical interest without the need for prior isolation of the 
1-azabicyclo[2.2.1]heptan-3-one free base. The process comprises combining 
(.+-.)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-L-tartaric acid in 
an appropriate solvent or solvent mixture, allowing a precipitate to form, 
and collecting the solid precipitated 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one hemisalt; or combining 
(.+-.)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-D-tartaric acid in 
an appropriate solvent or solvent mixture, allowing a precipitate to form, 
and recovering the precipitated (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one 
hemisalt. The respective hemisalts (hemitartrates) may be stored as the 
hemisalt, or may be reacted with base to liberate the respective 
1-azabicyclo[2.2.1]heptan-3-one free base. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The present invention provides the compounds: 
##STR1## 
and a process for their preparation. 
(.+-.)-1-azabicyclo[2.2.1]heptan-3-one may be prepared by known methods. 
See, e.g., Saunders et al., J. CHEM. SOC., CHEM. COMMUN., 24, 1618-9 
(1988) ; Street et al., J. MED. CHEM. 33 2690-7 (1990); European Published 
Patent Application EP 307,140 A1; European Published Patent Application EP 
414,394 A2; U.S. Pat. Nos. 5,217,975 and 5,405,853; and European Published 
Patent Application EP 239,309 A2. (1S,4R)-1-Azabicyclo[2.2.1]heptan-3-one 
may be obtained from (.+-.)-1-azabicyclo[2.2.1]heptan-3-one by combining 
racemic (.+-.)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-L-tartaric 
acid in a protic or aprotic solvent or a mixture of protic or aprotic 
solvents; allowing a precipitate to form; and collecting the solid 
precipitate. The (1R,4S) isomer, (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one 
may be obtained from (.+-.)-1-azabicyclo[2.2.1]heptan-3-one by combining 
(.+-.)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-D-tartaric acid in 
a similar solvent or solvent mixture; allowing a precipitate to form; and 
collecting the solid precipitate. The reaction sequence for preparation of 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acid 
hemisalt and the corresponding free base, 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, is illustrated in accordance with 
Scheme I below: 
##STR2## 
Scheme I 
Scheme I illustrates a method for obtaining the di-p-toluoyl-L-tartaric 
acid hemisalt of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one from 
(.+-.)-1-azabicyclo[2.2.1]heptan-3-one and for obtaining 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one from 
(.+-.)-1-azabicyclo[2.2.1]heptan-3-one, the method comprising combining 
(.+-.)-1-azabicyclo[2.2.1]heptan-3-one and di-p-toluoyl-L-tartaric acid in 
a protic or aprotic solvent or a mixture of protic or aprotic solvents; 
allowing a precipitate to form; and collecting the solid precipitate 
corresponding to the di-p-toluoyl-L-tartaric acid hemisalt, and obtaining 
the free base by treatment with base. Scheme II reflects the identical 
reaction sequence employing di-p-toluoyl-D-tartaric acid, whereby the 
di-p-toluoyl-D-tartaric acid hemisalt of 
(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one precipitates, from which the free 
base (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one can be liberated. 
##STR3## 
Scheme II 
(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one can be resolved in accordance with 
the present invention, i.e. the enantiomers separated, by selective 
crystallization with di-p-toluoyl-L-tartaric acid or 
di-p-toluoyl-D-tartaric acid. (.+-.)-1-Azabicyclo[2.2.1]heptan-3-one and 
either (but not both) di-p-toluoyl-L-tartaric acid or 
di-p-toluoyl-D-tartaric acid can be combined in solvents such as alcohols, 
ethers, esters, nitrites, mixtures of water and one or more alcohols, or 
mixtures of the aforementioned solvents. Examples of suitable alcohols 
include methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 
tert-butanol, and the like. Examples of suitable ethers include diethyl 
ether, tert-butylmethyl ether, tetrahydrofuran and the like. Examples of 
suitable esters include methyl acetate, ethyl acetate, isopropyl acetate, 
n-butyl acetate and the like. Examples of suitable nitrites include 
acetonitrile and the like. This list of solvents is illustrative and not 
limiting. 
The suitability of a given solvent mixture may be readily assessed by 
adding (.+-.)-1-azabicyclo[2.2.1]heptan-3-one and the particular 
di-p-toluoyltartaric acid to the solvent mixture in the presence of seed 
crystals of the respective hemitartrate salt. The precipitate can be 
collected and its quantity gravimetrically determined. Its purity can be 
assessed by HPLC using a chiral adsorbent. Such determinations are easily 
performed by one skilled in the art. A solvent or solvent mixture which 
provides the desired purity, generally greater than 90% pure with respect 
to the 1-azabicyclo[2.2.1]heptan-3-one isomers, and in sufficient quantity 
(i.e. solubility is not too great), is a "selective 
crystallization-effective" solvent or solvent mixture as that term is used 
herein. 
In general, the (1S,4R) isomer of 1-azabicyclo[2.2.1]heptan-3-one 
precipitates from the solution as approximately a 2 to 1 salt with 
di-p-toluoyl-L-tartaric acid. A shortage of di-p-toluoyl-L-tartaric acid 
is preferably used in order that a product of high isomeric purity is 
obtained. Additional di-p-toluoyl-L-tartaric acid can be used in the 
crystallization if a lower isomeric purity can be tolerated in the 
product. For example, the stoichiometry relative to di-p-toluoyltartaric 
acid is calculated based on the formation of the hemitartrate of the 
desired isomer. Thus, 1 mol of racemic 
(.+-.)-1-azabicyclo[2.2.1]heptan-3-one will contain 0.5 mol of the (1S,4R) 
isomer, or 0.5 mol-equivalent. Since the hemitartrate is formed in the 
reaction, 1 mol of di-p-toluoyl-L-tartaric acid represents 2 
mol-equivalents. Thus, for 1 mol (.+-.)-1-azabicyclo[2.2.1]heptan-3-one, 
the stoichiometric amount of di-p-toluoyl-L-tartaric acid required to form 
the respective hemitartrate is 0.25 mol. However, it is generally 
desirable to enhance the isomeric purity of the product. Enhanced isomeric 
purity may be achieved by utilizing from 50% to about 95% of the 
stoichiometric amount of the respective di-p-toluoyltartaric acid, more 
preferably from about 70% to 90% of this amount. Thus, to resolve 1 mol of 
the racemic mixture of (.+-.)-1-azabicyclo[2.2.1]heptan-3-one and isolate 
a substantially pure (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one 
di-p-toluoyl-hemi-(L)-tartrate, approximately 0.20 mol of 
di-p-toluoyl-L-tartaric acid may be used. Similarly, when isolating the 
(1R,4S) isomer, di-p-toluoyl-D-tartaric acid is employed, the (1R,4S) 
isomer precipitating as a 2:1 salt (hemisalt; hemitartrate) with the 
resolving agent. 
Removal of the respective di-p-toluoyltartaric acid from the hemitartrate 
salt to give the respective isomer-enriched 
1-azabicyclo[2.2.1]heptan-3-one free base can be accomplished by methods 
well known to those skilled in the art, or by partitioning the salt 
between an acidic aqueous phase, such as aqueous hydrochloric acid, and an 
organic phase, such as tert-butylmethyl ether. The acidic aqueous phase 
may then be concentrated, and rendered basic by the addition of a base 
such as potassium carbonate, sodium hydroxide or the like. Extraction of 
the aqueous phase with an appropriate solvent such as ethyl acetate, 
methylene chloride, chloroform, or the like followed by removal of the 
solvent from the organic extracts by distillation gives the enriched 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. 
Following separation of the desired isomer as its respective di-p-toluoyl 
hemitartrate salt by precipitation from solution, a second, somewhat less 
pure crop of crystals may be collected by addition of further amounts of 
the particular di-p-toluoyltartaric acid to the mother liquor and cooling 
to a temperature sufficient to precipitate further amounts of the 
hemisalt. In general, this temperature is lower than that of the first 
precipitation (crystallization). Both precipitations are advantageously 
promoted through addition of seed crystals of the desired isomerically 
pure product. 
If it is desired to isolate the non-precipitated isomer, a quantity of the 
requisite di-p-toluoyltartaric acid may be added to the solution and 
precipitate collected as before. For example, if di-p-toluoyl-L-tartaric 
acid is added to (.+-.)-1-azabicyclo[2.2.1]heptan-3-one to precipitate the 
di-p-toluoyl-L-hemitartrate of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, 
this precipitation may be followed by addition of a further amount of 
di-p-toluoyl-L-tartaric acid to recover a second crop of somewhat less 
pure (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. The (1R,4S) isomer enriched 
1-azabicyclo[2.2.1]heptan-3-one may then be isolated from the mother 
liquor by methods well known to those skilled in the art. 
It is entirely feasible, and desired, to combine mixtures having enriched 
concentrations of the desired isomer for further purification. For 
example, mixtures containing the hemitartrate of 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one in isomeric purities of less than 
90% may be combined and recrystallized, or may be converted to the 
respective free base, and reprecipitated with di-p-toluoyl-L-tartaric 
acid, to obtain the hemitartrate in high purity, typically greater than 
95%. The mother liquor will still contain further (1S,4R)-isomer and can 
be combined with other similar mother liquor fractions for later 
purification. In this manner, expensive starting materials are conserved 
in an economical fashion. The di-p-toluoyl-L-tartaric acid and 
di-p-toluoyl-D-tartaric acid resolving agents can themselves be separated, 
i.e. after liberation of the 1-azabicyclo[2.2.1]heptan-3-one free base, 
and purified by conventional techniques. 
It was highly surprising that the use of the (L) and (D) 
di-p-toluoyltartric acids facilitated such an efficient resolution of the 
(1S,4R) and (1R,4S) isomers of (.+-.)-1-azabicyclo[2.2.1]heptan-3-one. It 
was even more surprising that the respective hemitartrates were formed, 
allowing the resolution of 2 mols of 1-azabicyclo[2.2.1]heptan-3-one for 
only 1 mol of resolving agent. Not only is the process efficient, but most 
importantly, it is capable of practice in commercial scale quantities, all 
without use of low temperature, potentially dangerous oxidation, or use of 
environmentally questionable and carcinogenic oxidizing agents such as 
chromium trioxide. 
The inventive process allows the isolation of the desired isomers as 
storage stable salts. Thus, also provided by the present invention are the 
novel compounds: 
##STR4## 
It is contemplated that the compounds of the present method can be found or 
isolated in the form of hydrates or solvates as well as the hemitartrates 
per se, all of which are considered to fall within the scope of the 
present invention. 
The examples below are intended to illustrate specific embodiments of the 
invention and are not intended to limit the scope of the specification, 
including the claims, in any manner.

EXAMPLES 
Example 1 
Formation of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, 
di-p-toluoyl-L-tartaric acid hemisalt 
Di-p-toluoyl-L-tartaric acid (20.0 kg, 51.8 mol) was dissolved in 
acetonitrile (55 kg) and heated to 40-43.degree. C. with agitation. Seed 
crystals of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, 
di-p-toluoyl-L-tartaric acid hemisalt (0.1 kg) were added. 
(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one (28.8 kg dissolved in 26.1 kg ethyl 
acetate, 259 mol) was dissolved in acetonitrile (115 kg) and heated to 
40-43.degree. C. The (.+-.)-1-azabicyclo[2.2.1]heptan-3-one solution was 
added to the di-p-toluoyl-L-tartaric acid solution over a period of 2 
hours. The mixture was cooled to 20-25.degree. C. over a period of 1 hour. 
The solid product was collected by filtration and washed with cold 
acetonitrile (40 kg). The product was dried under reduced pressure (2 
mmHg) at 40-45.degree. C. for 21-22 hours to give 27.0 kg of product. 
Chiral HPLC: (Chiralpak AD (Chiral Technologies, Inc., Exton, Pa.) 
Hexane/IPA/DEA, 70:30:0.1, (solution concentration: .about.40 mg sample 
dissolved in .about.5 mL isopropyl alcohol containing 5 drops of 
diethylamine)) enantiomeric purity 97.2% 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. .sup.1 H-NMR (DMSO, 200 MHZ): 
.delta. 9.6 (s (broad), 1H), 7.87 (d, 2H, J=8.1 Hz), 7.35 (d, 2H, J=8.1 
Hz), 5.69 (s, 1H), 3.28-2.99 (m, 4H), 2.92-2.81 (m, 3H), 2.38 (s, 3H), 
2.19-2.02 (m, 1H), 1.71-1.58 (m, 1H). .sup.13 C-NMR (DMSO, 50 MHZ): 
.delta. 213.2, 168.5, 164.8, 143.8, 129.3, 129.2, 126.7, 72.4, 62.1, 58.0, 
50.9, 47.4, 24.2, 21.1. IR (KBr): 700.0, 757.9, 1112.7, 1128.2, 1172.5, 
1268.9, 1342.2, 1612.2, 1718.3, 1772.3, 2989.1, 3008.4 cm.sup.-1. 
Additional material may be obtained from the filtrate using the following 
procedure: 
Di-p-toluoyl-L-tartaric acid (7.5 kg, 19 mol) was dissolved in acetonitrile 
(7.5 kg) at 20-25.degree. C. The di-p-toluoyl-L-tartaric acid solution was 
added to the acetonitrile filtrate. Seed crystals of 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acid 
hemisalt (0.05 kg) were added. The mixture was cooled to 0-5.degree. C. 
and stirred for 1-2 hours. The solid was collected by filtration and 
washed with cold acetonitrile (20 kg). The solid was dried under reduced 
pressure (4 mmHg) at 40-45.degree. C. for 19 hours to give 6.1 kg of crude 
product. Chiral HPLC: 91.1% (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. The 
crude product (6.1 kg, 20 mol) was dissolved in methanol (6.1 kg) and 
added to a mixture of isopropyl alcohol (45 L) and 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acid 
hemisalt seed crystals (0.04 kg) at 20-25.degree. C. The mixture was 
stirred at 20-25.degree. C. for 1 hour. The solid was collected by 
filtration and washed with isopropyl alcohol (15 L). The product was dried 
under reduced pressure (3 mmHg) at 40-45.degree. C. for 20-21 hours to 
give 4.6 kg of product. Chiral HPLC: 98.4% 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. 
Example 2 
Formation of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, 
di-p-toluoyl-L-tartaric acid hemisalt 
(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one (15 g, 135 mmol) was dissolved in 
acetonitrile (60 g). The solution was heated to 40-43.degree. C. Seed 
crystals of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, 
di-p-toluoyl-L-tartaric acid hemisalt were added. Di-p-toluoyl-L-tartaric 
acid (10.4 g, 34 mmol) dissolved in acetonitrile (29 g) was added dropwise 
over a period of 2.25 hours. The mixture was cooled to 25.degree. C. The 
mixture was filtered and the solid was washed with acetonitrile (30 g, 
23.degree. C.). The solid was dried under reduced pressure (60.degree. C.) 
to give 13.48 grams of product as a white solid. Chiral HPLC: 98.3% 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. 
Example 3 
Formation of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acid 
hemisalt (14.3 g, 0.047 mol) was placed in tert-butylmethylether (200 g) 
and extracted with 1 molar aqueous hydrochloric acid solution (130 mL). 
The aqueous extract was concentrated under reduced pressure at 70.degree. 
C. Ethyl acetate (30 g) and saturated aqueous potassium carbonate (7 g) 
were added. The layers were separated and the aqueous layer was extracted 
with ethyl acetate (20 g). The two ethyl acetate solution were combined 
and the solvent was removed under reduced pressure at 22.degree. C. to 
give 3.4 g of (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one. HPLC: (Zorbax 
300-SCX (MAC-MOD Analytical, Inc., Chadds Ford, Pa.) 0.03 molar KH.sub.2 
PO.sub.4 (adjusted to pH 2.5 with H.sub.3 PO.sub.4)/methanol, 1:1) purity 
96%. 
Example 4 
Formation of (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, 
di-p-toluoyl-D-tartaric acid hemisalt 
(.+-.)-1-Azabicyclo[2.2.1]heptan-3-one (15 g, 135 mmol) is dissolved in 
acetonitrile (approximately 60 g). The solution is heated to 40-43.degree. 
C. Seed crystals of (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one, 
di-p-toluoyl-D-tartaric acid hemisalt are added. Di-p-toluoyl-D-tartaric 
acid (10.4 g, 34 mmol) dissolved in acetonitrile (approximately 29 g) is 
added dropwise. The mixture is cooled to 25.degree. C. The mixture is 
filtered and the solid is washed with acetonitrile. The solid is dried 
under reduced pressure to give the product as a white solid. 
Example 5 
Formation of (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acid 
hemisalt (14.3 g, 0.047 mol) is placed in tert-butylmethylether 
(approximately 200 g) and extracted with 1 molar aqueous hydrochloric acid 
solution (approximately 130 mL). The aqueous extract is concentrated under 
reduced pressure. Ethyl acetate (approximately 30 g) and saturated aqueous 
potassium carbonate (approximately 7 g) are added. The layers are 
separated and the aqueous layer is extracted with ethyl acetate 
(approximately 20 g). The two ethyl acetate solution are combined and the 
solvent is removed under reduced pressure to give 
(1R,4S)-1-azabicyclo[2.2.1]heptan-3-one. 
Example 6 
Formation of (4R)-1-azabicyclo[2.2.1]heptan-3-one, 
O-[3-(3-methoxyphenyl)-2-propynyl)oxime 
The utility of the resolved hemitartrate salts is illustrated herein. 
(1S,4R)-1-azabicyclo[2.2.1]heptan-3-one, di-p-toluoyl-L-tartaric acid 
hemisalt, (4.57 g) and O-(m-methoxyphenylpropargyl)hydroxylamine oxylate 
(3.26 g) were dissolved in di-methylsulfoxide (DMSO) (20 mL). 
Triethylamine (7.0 g) was added at 20.degree. C. After 1 day at room 
temperature additional O-(m-methoxyphenylpropargyl)hydroxylamine oxylate 
(0.56 g) and triethylamine (1.2 g) were added. After an additional 6 days 
at room temperature additional O-(m-methoxyphenylpropargyl)hydroxylamine 
oxylate (0.76 g) and triethylamine (2 g) were added. After 1 day at room 
temperature the mixture was heated to 60-70.degree. C. for 1 hours. The 
mixture was reduced in volume by distillation under reduced pressure until 
a homogeneous solution with a weight of approximately 35 g was obtained. 
The mixture was combined with water (10 mL), saturated aqueous sodium 
bicarbonate solution (30 mL) and tert-butylmethylether (30 mL). The 
mixture was filtered and the phases were separated. The aqueous phase was 
extracted with tert-butylmethylether (3.times.50 mL). The 
tert-butylmethylether extracts were combined and the solvent was removed 
under reduced pressure to give (4R)-1-azabicyclo[2.2.1]heptan-3-one, 
O-[3-(3-methoxyphenyl)-2-propynyl)oxime (4.33 g) as a mixture of E and Z 
isomers. The oil was dissolved in tert-butylmethylether (25 mL) and 
extracted with aqueous citric acid (1.times.20 mL, and 1.times.10 mL of 
0.33 M). The aqueous extracts were combined and the pH was adjusted to 8.5 
with sodium bicarbonate. The aqueous mixture was extracted with 
tert-butylmethylether (2.times.25 mL). The tert-butylmethylether extracts 
were combined and extracted with water (10 mL). The organic phase was 
concentrated under reduced pressure at 40-48.degree. C. to give 3.52 g of 
(4R)-1-azabicyclo[2.2.1]heptan-3-one, 
O-[3-(3-methoxyphenyl)-2-propynyl)oxime. HPLC: (Zorbax SB-CN (MAC-MOD 
Analytical, Inc., Chadds Ford, Pa.) 0.05 molar triethylamine (adjusted to 
pH 3 with H.sub.3 PO.sub.4)/acetonitrile/methanol, 8:1:1) purity 98% by 
area as a 39:61 mixture of E and Z isomers, di-p-toluoyl-L-tartaric acid 
content &lt;0.05%. 
Example 6 illustrates the utility of the respective hemitartrate salts 
without the necessity of first isolating the free base. The product of 
Example 6 particularly the Z-isomer, is known to exhibit anti-muscarinic 
activity. 
By the claim term "substantially one but not both" relative to the compound 
pairings (1S,4R)-1-azabicyclo[2.2.1]heptan-3-one/di-p-toluoyl-L-tartaric 
acid; and (1R,4S)-1-azabicyclo[2.2.1]heptan-3-one/di-p-toluoyl-D-tartaric 
acid is meant a separable mixture containing predominately one compound 
pairing but not the other. The term does not simply mean that the 
separable mixture is free of the other compound pairing, but that the 
other compound pairing, if present, is present in such quantity that its 
concentration will not interfere with obtaining a precipitate which is 
enriched in the desired di-p-toluoyltartrate hemisalt. The amount of the 
"non-desired" isomer/di-p-toluoyltartaric acid pairing which is tolerable 
may also be described as a "non-enrichment interfering amount." The term 
"substantially enantiomerically pure" and similar terms used herein are as 
understood by one skilled in the art. Substantial enantiomeric purity is 
preferably greater than 90% pure relative to the isomers in question, more 
preferably greater than 95% pure, and most preferably greater than 98% 
pure on this basis. 
Having now fully described the invention, it will be apparent to one of 
ordinary skill in the art that many changes and modifications can be made 
thereto without departing from the spirit or scope of the invention as set 
forth herein.