Process for resolving chiral acids with 1-aminoindan-2-ols

A process for the full or partial resolution of a mixture of enantiomers of a genus of chiral carboxylic acids is disclosed. The process uses a pure enantiomer of 1-aminoindan-2-ol as the resolving agent and achieves separation of the diastereomeric salts by fractional crystallization followed by liberation of the chiral acid from the salt by treatment with mineral acid. Diastereomeric salts and solyates of those salts are disclosed. The production of ketoprofen, flurbiprofen and other chiral medicaments and precursors thereto is disclosed.

FIELD OF THE INVENTION 
The invention relates to the use of single enantiomers of 
1-amino-2,3-dihydro-1H-inden-2-ol, hereinafter referred to as 
1-aminoindan-2-ol 
##STR1## 
for resolving chiral acids. 
BACKGROUND OF THE INVENTION 
Several chiral amines are known for the resolution of chiral acids on a 
manufacturing scale. Notable examples include brucine, strychnine, 
quinine, quinidine, cinchonidine, cinchonine, yohimbine, morphine, 
dehydroabietylamine, ephedrine, deoxyephedrine, amphetamine, 
threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol, 
.alpha.-methylbenzylamine, .alpha.-(1-naphthyl)ethylamine, and 
.alpha.-(2-naphthyl)ethylamine. Some of these chiral amines are expensive 
and are often difficult to recover. Furthermore, because many are natural 
products, usually only one enantiomer is readily available. 
The use of some of the foregoing amines for the resolution of chiral 
2-arylpropionic acids has been described. For example, U.S. Pat. No. 
5,015,764 discloses using (S)-.alpha.-methylbenzylamine to resolve racemic 
ibuprofen. U.S. Pat. No. 5,162,576 discloses using (-)-cinchonidine to 
effect resolution of ketoprofen. These methods, however, have a number of 
limitations including the following: they are not general; they require 
considerable volumes of solvent; some require relatively high temperature; 
they produce product of less than optimal chemical and enantiomeric purity 
and accordingly require further purification steps; they are 
space-consuming and time-consuming; and they are difficult to carry out at 
commercial scale. 
SUMMARY OF THE INVENTION 
The object of the present invention is to provide a general, efficient, and 
cost-effective method to resolve organic acids that contain one or more 
chiral centers. A second object of the present invention is to provide a 
more time- and cost-efficient means to produce .alpha.-arylpropanoic acid 
antiinflammatory medicaments ("profens"), particularly (S)- and 
(R)-ketoprofen. The aminoalcohols according to the invention are 
substantially pure enantiomers of 1-aminoindan-2-ol. 
Because 1-aminoindan-2-ol has two chiral centers, there exist two geometric 
isomers, each of which exists as a pair of enantiomers. Accordingly, there 
are four 1-aminoindan-2-ols pertinent to the present invention: 
##STR2## 
The aminoindanols of the present invention are simple and inexpensive to 
prepare, are readily resolved or obtained by asymmetric synthesis, are 
resistant to racemization under resolution conditions, and are readily 
recovered. The compounds of the present invention also have the advantage 
of being produced in the (+)- and (-) form with equal ease. This is in 
contrast to chiral resolving agents obtained from natural sources, which 
are generally available in only one form. 
The invention relates to the use of a single enantiomer of aminoindanol, 
substantially free of other enantiomers of aminoindanol, for the 
resolution of a chiral acid. The chiral acid may be present in the form of 
a racemate or a mixture in which one enantiomer is in excess. The 
resolution can be accomplished by fractional crystallization. 
One process for the resolution of a mixture of enantiomers of a chiral acid 
comprises the steps of; 
(a) preparing a mixture of the chiral acid, or a salt thereof, with an 
enantiomer of 1-aminoindan-2-ol; 
(b) separating the mixture into a first fraction enriched in one enantiomer 
of the acid as a diastereomeric salt and a second fraction enriched in the 
second enantiomer; and 
(c) recovering the chiral acid from at least one of the fractions. 
The chiral carboxylic acid is chosen from the genus of formula 
EQU R.sup.1 R.sup.2 R.sup.3 CCOOH 
wherein 
R.sup.1 is hydrogen or OH; 
R.sup.2 is methyl or cyclohexyl; and 
R.sup.3 is aryl, substituted aryl or heteroaryl; 
or R.sup.2 and R.sup.3 together form a tetrahydrofuran or tetrahydropyran 
ring. 
More particularly, the invention relates to a method for resolving a chiral 
carboxylic acid comprising the steps of: 
(a) dissolving a mixture of enantiomers of a chiral carboxylic acid from 
the above genus in a suitable solvent; 
(b) adding a substantially pure enantiomer of a 1-aminoindan-2-ol to create 
a diastereomeric salt of at least one enantiomer of the acid; 
(c) allowing the diastereomeric salt to crystallize to form a solid phase, 
whereby the salt formed between 1-aminoindan-2-ol and a single enantiomer 
of the chiral acid predominates in the solid phase and the other 
enantiomer of the chiral acid, which may be as a salt or in part as the 
free acid depending on the amount of aminoindanol added, predominates in 
the solution phase; 
(d) separating the solid phase from the solution phase; and 
(e) recovering the chiral acid from at least one of the phases. 
The 1-amino-2-indanol may be (1S,2R)-1-aminoindan-2-ol (Ia), (1R, 
2S)-1-aminoindan-2-ol (Ib), (1R,2R)-1-aminoindan-2-ol (Ic), or 
(1S,2S)-1-aminoindan-2-ol (Id). 
In various preferred embodiments of the chiral acid, R.sup.1 is hydrogen 
and R.sup.2 is methyl. Among such compounds, ketoprofen, ibuprofen, 
flurbiprofen, and naproxen may be noted. Ketoprofen is particularly 
preferred. Other preferred acids include those wherein R.sup.1 is hydroxyl 
and R.sup.2 is cyclohexyl. Tetrahydrofuran-2-carboxylic acid is also 
preferred. The enantiomer of 1-aminoindan-2-ol may be used in an amount of 
from 0.1 to 1.1 equivalents based on said carboxylic acid. For 
crystallization, 0.4 to 0.6 equivalents are preferred. 
The foregoing process may further include the steps of recovering a 
non-racemic mixture of the enantiomers of the carboxylic acid, racemizing 
the mixture and recycling the racemized mixture. The non-racemic mixture 
will usually be enriched in the second enantiomer by virtue of the first 
enantiomer having been separated out as its diastereomeric salt. 
In a composition aspect the invention relates to salts of an optically 
active 1-aminoindan-2-ol and a chiral carboxylic acid of the above 
formula. Preferred salts include those in which R.sup.1 is hydrogen and 
R.sup.2 is methyl, particularly salts of ketoprofen, ibuprofen, 
flurbiprofen, and naproxen. Salts of the profens, like ketoprofen, may be 
solvates with acetonitrile. Other preferred salts include those in which 
R.sup.1 is hydroxyl and R.sup.2 is cyclohexyl and those in which the 
chiral acid is tetrahydrofuran-2-carboxylic acid.

DETAILED DESCRIPTION OF THE INVENTION 
The substantially enantiomerically pure aminoindanols needed for the 
process of the invention are, in the case of cis aminoindanols, 
synthesized by methods known in the art. See for example Thompson et al. 
J. Med. Chem. 35, 1685-1701 (1992) and Didier et al. Tetrahedron 47, 
4941-4958 (1991).! By substantially pure is meant that the ee is greater 
than 90%. In addition to the known methods, pure enantiomers of both cis 
and trans 1-aminoindan-2-ol may be prepared by the method disclosed in 
U.S. application Ser. No. 08/278,459, filed Jul. 21, 1994, the disclosure 
of which is incorporated herein by reference. The most pertinent part of 
that disclosure is reproduced here: 
A 5-L three neck Morton-type flask equipped with an overhead stirrer, an 
addition funnel and a thermometer was charged with 2.5 L of NaOCl (10% aq, 
2.0 eq, 4.0 mol). The solution was cooled to ca. 5.degree.-10.degree. C. A 
solution of (R,R)-Mn-Salen catalyst X 
##STR3## 
(19.1 g, 0.015 eq, 0.03 mol) in 150 mL of CH.sub.2 Cl.sub.2 was added, 
followed by a solution of indene (260 mL, 1.0 eq, 2.0 mol) in 100 mL of 
CH.sub.2 Cl.sub.2 at 5.degree.-10.degree. C. The mixture was stirred 
vigorously at 5.degree.-10.degree. C. for 4 hr. Heptane (1.4L) and Celite 
(40 g) were added and the mixture stirred for 40 min without cooling. The 
mixture was filtered and the flask and the solid cake were washed with 200 
mL of heptane. 
The combined filtrates containing partially resolved indene oxide were 
concentrated to ca. 400 mL and the concentrate treated with 1.4 L of 
aqueous ammonia (28% aq.) in 600 mL of MeOH in the presence of 20 g of 
Celite at 25.degree.-30.degree. C. for 15 hr. The MeOH and excess of 
ammonia were removed by distillation over a period of 4-5 hr until the pot 
temperature reached 90.degree. C. Water (550 mL) was added and the hot 
mixture filtered. The flask and solid filter cake were washed with ca. 400 
mL of hot water. The combined filtrates were placed under vacuum for 40 
min to remove remaining ammonia and transferred to a 5-L Morton-type 
flask. 
The above solution, containing partially resolved 
trans-(1S,2S)-1-aminoindan-2-ol, was cooled to ca. 15.degree.-25.degree. 
C. and NaOH (50% aq., 192 g) and acetone (800 mL) were added. Benzoyl 
chloride (1.2 eq, 2.4 mol, 280 mL) was added at 15.degree.-25.degree. C. 
over 1 hr and the resulting slurry stirred at 20.degree.-25.degree. C. for 
2 hr. The mixture was filtered and the solid washed with 400 mL of 
acetone-water (1:1, v/v) and recovered as crude trans-benzamide of 
enantiomerically enriched trans-(1S,2S)-1-aminoindan-2-ol. 
The crude benzamide (ca. 464 g) was dissolved in 1125 mL of DMF at 
90.degree. C. and MeOH (750 mL) was added at 80.degree.-86.degree. C. over 
1 hour to the DMF solution. The solution was slowly cooled to 
0.degree.-5.degree. C. over 1.5 h and held at 0.degree.-5.degree. C. for 2 
h. The solid was recovered by filtration, washed with 500 mL cold 
(0.degree.-5.degree. C.) MeOH and dried under vacuum at 40.degree. C. to 
give enantiomerically pure trans-benzamide of 
trans-(1S,2S)-1-aminoindan-2-ol as pale yellow crystals (240 g, 47% yield 
from indene, 99% ee, m.p. 232.degree. C). 
A mixture of the trans-benzamide (25 mmol, 6.33 g) from above and 58.3 mL 
of 6N aqueous HCl was refluxed for 14 hr, cooled to room temperature, 
washed with 20 mL of C.sub.2 Cl.sub.2 and neutralized with 50% aq. NaOH 
(24 mL) to about pH 13. The mixture was extracted with total of 65 mL of 
C.sub.2 Cl.sub.2, decolorized with 0.5 g of active carbon, filtered and 
concentrated to ca. 20 mL. Heptane (10 mL) was added to the hot CH.sub.2 
Cl.sub.2 solution and the solution was cooled to 0.degree.-5.degree. C. 
for 3 h. The white crystals were recovered by filtration and dried as 
cis-(1S,2R)-1-aminoindan-2-ol (2.45 g, 66% yield, 99.5% ee). 
Alternatively, a mixture of the trans-benzamide from above (90g, 355 mmol) 
and 227 g of 80% wt H.sub.2 SO.sub.4 was heated at 80.degree.-85.degree. 
C. for 1 h. The mixture was treated with 377 mL of water and heated to 
100.degree.-115.degree. C. for 3.5 h. The mixture was cooled to 
30.degree.-35.degree. C. and washed with 355 mL of CH.sub.2 Cl.sub.2. The 
aqueous solution was then neutralized with 370 g of 50% NaOH at 
&lt;50.degree. C., and 175 mL water was added to dissolve the inorganic salts 
(Na.sub.2 SO.sub.4). The aqueous mixture was extracted with 535 mL of 
CH.sub.2 Cl.sub.2 at 30.degree.-35.degree. C., and the CH.sub.2 Cl.sub.2 
extracts decolorized with 4.5 g activated carbon and dried with 7.5 g 
MgSO.sub.4 (anhydrous). The mixture was filtered through Celite and the 
filter cake washed with 100 mL of CH.sub.2 Cl.sub.2. The combined 
filtrates were concentrated to ca. 450 mL and 215 mL heptane was added at 
40.degree. C. over 30 min. The solution was cooled to 0.degree.-5.degree. 
C. and the resulting solid recovered by filtration affording 
cis-(1S,2R)-1-aminoindan-2-ol (45.2 g, 84%&gt;99.5% ee). 
The corresponding cis (1R,2S)-1-aminoindan-2-ol may be obtained by the same 
procedure beginning with (S,S) salen. 
The process stream from the aminolysis analogous to the procedure described 
above employing (S,S)-Salen was treated with 102 mL of HCl (36 wt. %) to 
pH&lt;1.0 and extracted with 500 mL of methylene chloride. The aqueous phase 
was basified with 50% sodium hydroxide to pH=13 and extracted with 600 mL 
of methylene chloride at 30.degree. to 35.degree. C. The methylene 
chloride extracts were decolorized with 6.0 g of Darco G-60.RTM. and dried 
with 7.5 g of magnesium sulfate (anhydrous) at 30.degree. to 35.degree. C. 
The mixture was vacuum filtered and washed with 150 mL of methylene 
chloride. The filtrate was heated to reflux and 750 mL of heptane was 
added dropwise at 40.degree. to 45.degree. C. The slurry was cooled to 
0.degree. to 5.degree. C. and held for three hours. The off-white product 
was collected by vacuum filtration and washed with 50 mL of heptane 
followed by drying in vacuo at 40.degree. C., for 5 hours to afford 97.9 g 
(65.6% of theory, 94.7%ee) of (R,R)-trans-1-aminoindan-2-ol. Pure 
(S,S)-trans may be obtained in analogous fashion. 
Use of Aminoindanols to Effect Resolution 
The aminoindanols of the present invention can be used to separate the 
enantiomers of chiral acids including various drug products or 
intermediates leading to drug products, and they are relatively general in 
their applicability. 
For example, using (1S,2R)-1-aminoindan-2-ol it is possible to separate the 
enantiomers of a range of commercially important chiral acids including 
ketoprofen, flurbiprofen, tetrahydrofuran carboxylic acid, 
cyclohexylphenyl glycolic acid and ibuprofen. 
In a first series of experiments, diasteromeric salts of R- and 
S-ketoprofen with aminoindanol were shown to exhibit an unexpectedly large 
difference in solubility under a range of solvent conditions. 
(S)-Ketoprofen-(1S,2R)-aminoindanol and 
(R)-Ketoprofen-(1S,2R)-aminoindanol diasteromers (&gt;99% diasteromeric 
excess) were utilized in the solubility studies. 
TABLE 1 
______________________________________ 
Solubilities of (R)- and (S)-ketoprofen 
diastereomer salts with (1S,2R)-1-aminoindan-2-ol in 
a range of solvents. Selectivity corresponds to the 
ratio of solubilities of the more soluble to the less 
soluble diastereomer. 
Diastereomer Solubility (wt %) 
Solvent (R)-ketoprofen 
(S)-ketoprofen 
Selectivity 
______________________________________ 
Tetrahydrofuran 
4.0 13.3 3.3 
Methyl isobutyl ketone 
3.5 17.0 4.8 
Isobutyl acetate 
0.3 13.0 43.3 
Isopropyl acetate 
0.2 13.0 65.0 
Ethyl acetate 
0.3 12.4 39.0 
Water &lt;0.02 1.5 &gt;75 
Acetonitrile.sup.1 
0.43 0.1 4.3 
______________________________________ 
The results are from (1R,2S)1-aminoindan-2-ol. 
The results show that using (1S,2R)-aminoindanol allows unexpectedly 
selective crystallization of (R-)-ketoprofen in the presence of 
(S)-ketoprofen. Alternatively, using (1R,2S)-aminoindanol allows for the 
selective crystallization of (S)-ketoprofen in the presence of 
(R)-ketoprofen. 
In the second set of experiments, diasteromeric salts of R- and 
S-ketoprofen with aminoindanol were shown to exhibit unexpectedly larger 
differences in solubilities than diastereomeric salts of R- and 
S-ketoprofen with other chiral amines. 
TABLE 2 
______________________________________ 
Solubilities of (R)- and (S)-ketoprofen 
diastereomer salts with various chiral amines in 
ethyl acetate. Selectivity corresponds to the ratio 
of the more soluble to the less soluble diastereomer. 
Ketoprofen Diastereomer 
Solubility (wt %) 
(R)- (S)- 
Chiral Amine enantiomer enantiomer 
Selectivity 
______________________________________ 
(1S,2R)-1-aminoindan-2-ol 
0.3 12.4 39.0 
Cinchonine 0.8 0.2 4.0 
(R)-Phenylpropylamine 
1.9 7.4 3.9 
Cinchonidine 1.1 0.3 3.7 
(R)-Methylbenzylamine 
1.3 1.3 1.0 
______________________________________ 
In a third set of experiments, diastereomeric salts of R- and S-acids with 
aminoindanol were shown to exhibit an unexpectedly large difference in 
solubility for a range of chiral acids. 
TABLE 3 
______________________________________ 
Solubilities of diastereomer salts composed 
of chiral acids with (1S,2R)-1-aminoindan-2-ol. 
Selectivity corresponds to the ratio of the more 
soluble to the less soluble diastereomer. 
Diastereomer Solubility (wt %) 
Solvent Chiral Acid 
(R)-enantiomer 
(S)-enantiomer 
Selectivity 
______________________________________ 
methyl ketoprofen 
3.5 17.0 4.8 
isobutyl 
ketone 
methanol 
tartaric acid 
1.1 8.9 8.0 
______________________________________ 
EXAMPLES 
The invention is illustrated by the following examples. 
(R)-Naproxen 
A sample of 2.9 g (12.6 mmole) of (R,S)-naproxen was combined with 56.5 g 
of an acetonitrile/water mixture (3.8% water), heated to 40.degree. C. and 
stirred until the mixture dissolved. The solution was treated with 0.78 g 
(5.2 mmole) of (1R,2S)-cis-1-aminoindan-2-ol, mixed for 10 minutes. Solids 
began to precipitate within seconds of adding the 
(1R,2S)-cis-1-aminoindan-2-ol. The solution was stirred for 15 minutes. 
The solids that formed were collected by filtration, and washed with 
acetonitrile. The acid was released by combining the wet solids with 50 mL 
of deionized water, 2 mL of 5N H.sub.2 SO.sub.4, and 50 mL of tert-butyl 
methyl ether. After mixing, the aqueous phase was separated and the 
organic phase washed twice with 50 mL of deionized water. The organic 
phase was evaporated under vacuum. The weight of the solid residue was 1.3 
g, and the specific optical rotation was .alpha..sub.D !.sup.20.degree. 
C. =-31(C=1, MeOH). 
(S)-Ketoprofen 
A sample of 88.2 g (347 mmole) of (R,S)-ketoprofen was combined with 560 g 
of methyl isobutyl ketone, heated to 40.degree. C. and stirred until the 
mixture dissolved. The solution was treated with 38.8 g (260 mmole) of 
(1R,2S)-cis-1-aminoindan-2-ol, mixed for 30 minutes, seeded with 1.4 g of 
(S)-ketoprofen (1R,2S)-cis-1-aminoindan-2-ol diastereomer salt and held at 
40.degree. C. for 1 hour. The mixture was cooled to 15.degree. C. over the 
course of 4 hours and held at 15.degree. C. for 47 hours. The solids that 
formed were collected by filtration, washed twice with 80 g of MIBK and 
dried under vacuum to yield 37.2 g of (S)-ketoprofen 
(1R,2S)-cis-1-aminoindan-2-ol diastereomer. A portion of the salt (about 
50 mg) was treated with 10 drops of 5N H.sub.2 SO.sub.4 to release the 
acid. The enantiomeric excess of the released acid was measured by chiral 
HPLC and found to be 95.8% (s)-Ketoprofen. 
(S)-Ketoprofen 
A sample of 100.7 g (396 mmole) of (R,S)-ketoprofen was combined with 565 g 
of an acetonitrile/water mixture (3.8% water), heated to 40.degree. C. and 
stirred until the mixture dissolved. The solution was treated with 32.5 g 
(218 mmole) of (1R, 2S)-cis-1-aminoindan-2-ol, mixed for 10 minutes, and 
seeded with 1 mL of a slurry containing 7.5 mg of 
(S)-ketoprofen(1R,2S)-cis-1-aminoindan-2-ol diastereomer salt per mL of 
acetonitrile. The solution was held at 40.degree. C. for 30 minutes and 
then cooled to 5.degree. C. over the course of 4 hours and held at 
5.degree. C. for an additional 30 minutes. The solids that formed were 
collected by filtration, washed twice with 80 g of acetonitrile and dried 
under vacuum to yield 66.4 g of (S)-ketoprofen 
(1R,2S)-cis-1-aminoindan-2-ol diastereomer. A portion of the salt (about 
50 mg) was treated with 10 drops of 5N H.sub.2 SO.sub.4 to release the 
acid. The enantiomeric excess of the released acid was measured by chiral 
HPLC and found to be 97.2% (S)-Ketoprofen. 
(R)-Ketoprofen 
A sample of 126 g (500 mmol) of (R,S)-ketoprofen was combined with 800 g of 
methyl isobutyl ketone, heated to 40.degree. C. and stirred until the 
mixture dissolved. The solution was treated with 74 g (500 mmol) of 
cis-(1S,2R)-1-aminoindan-2-ol, mixed for 30 minutes, seeded with 20 g of 
(R)-ketoprofen cis-(1S,2R)-1-aminoindan-2-ol diastereomer salt and held at 
40.degree. C. for 30 minutes. The mixture was cooled to 25.degree. C. over 
the course of 4 hours and further cooled to 15.degree. C. over the course 
of 1 hour and then held at 15.degree. C. for 18 hours. The solids that 
formed were collected by filtration and dried under vacuum to yield 86 g 
of (R)-ketoprofen cis-(1S,2R)-1-aminoindan-2-ol diastereomer with an 
(R)-ketoprofen diastereomeric excess of 97%. The acid was released from 
the diastereomer salt by combining the solid with equal amounts (315 g) of 
ethyl acetate and aqueous (12 wt %) sulfuric acid. After mixing, the 
aqueous phase was separated (saved for recovery of aminoindanol) and the 
organic phase washed twice with equal volumes of water. The organic phase 
was evaporated under vacuum. The weight of the solid residue was 54 g (66% 
yield based on available enantiomer and corrected for added seed 
diastereomer salt crystals) corresponding to (R)-ketoprofen of 97% 
enantiomeric excess. 
The two diastereomers, (S)-ketoprofen(1R,2S)-cis-1-aminoindan-2-ol and 
(R)-ketoprofen (1R,2S)-cis-1-aminoindan-2-ol, were prepared under 
identical conditions (using acetonitrile as a solvent). Loss on drying 
analysis showed a 2.5% weight loss for the 
(S)-ketoprofen(1R,2S)-cis-1-aminoindan-2-ol diastereomer and no weight 
loss for the (R)-ketoprofen(1R,2S)-cis-1-aminoindan-2-ol diastereomer. 
Infrared analysis of the two diastereomeric salts showed a distinct 
absorption band typical of acetonitrile in the 
(S)-ketoprofen(1R,2S)-cis-1-aminoindan-2-ol diastereomer only. NMR 
analysis of the two diastereomeric salts showed an absorption peak at 2 
ppm (typical of acetonitrile) for the (S)-ketoprofen 
(1R,2S)-cis-1-aminoindan-2-ol diastereomer. The same peak was not observed 
for the (R)-ketoprofen(1R,2S)-cis-1-aminoindan-2-ol diastereomer. The two 
diastereomers were subjected to differential scanning calorimetry. The 
(S)-ketoprofen (1R,2S)-cis-1-aminoindan-2-ol diastereomer showed two 
unique endotherm peaks, the first one occurring at 93.degree.-100.degree. 
C. and the second one at 108.degree.-115.degree. C. The (R)-ketoprofen 
(1R,2S)-cis-1-aminoindan-2-ol diastereomer showed a single endotherm peak 
at 127.degree.-132.degree. C. The same two diastereomers, when prepared 
using toluene as a solvent, showed almost identical endotherm peaks at 
127.degree.-135.degree. C. All of these findings strongly suggest that, 
when using acetonitrile as solvent, the 
(S)-ketoprofen(1R,2S)-cis-1-aminoindan-2-ol diastereomer precipitates as 
an acetonitrile solvate containing approximately 1/3-2/3 moles of 
acetonitrile per mole of diastereomer salt. 
The addition of a small amount of water to the acetonitrile was found to 
have a significant impact on the rate of crystallization. When performing 
the precipitation at room temperature (20.degree.-22.degree. C.) and in 
the absence of water, precipitation of the diastereomer begins prior to 
all the (1R,2S)-cis-1-aminoindan-2-ol being dissolved. As the amount of 
water in acetonitrile was increased to 3.8% it was found that all the 
(1R,2S)-cis-1-aminoindan-2-ol could be dissolved resulting in a clear 
solution. Other experiments done at 40.degree. C. with various 
concentrations of water showed a definite trend; as the amount of water is 
increased, the start of the crystallization takes longer and the rate of 
crystallization is slower. 
Racemization of (R)-Ketoprofen 
To 468 g of a toluene/(R)-ketoprofen (63% EE) solution containing 94 g of 
ketoprofen, 671 g of deionized water was added followed by 153 g of 50% 
NaOH. The phases were mixed and then separated. The aqueous phase was 
heated to 115.degree. C. (under pressure) and maintained at this 
temperature for 3 hours. The solution was then cooled to room temperature 
and 842 g of toluene were added, followed by 103 g of concentrated 
sulfuric acid. The phases were mixed and the aqueous phase decanted. After 
decolorization with activated carbon, the organic phase was concentrated 
to 25% ketoprofen concentration. The concentrate was cooled to 0.degree. 
C. and kept at this temperature for 5 hours. The solids were filtered, 
washed with toluene, and dried under vacuum. The weight of the racemized 
ketoprofen was 62 g and the enantiomeric excess was 1.4% (R)-ketoprofen. 
Resolution of Ketoprofen with cis-(1R,2S)-1-aminoindan-2-ol and 
triethylamine and racemization of unwanted (R)-Ketoprofen 
A sample of 100.7 g (396 mmole) of (R,S)-ketoprofen was combined with 565 g 
of an acetonitrile/water mixture (3.8% water), heated to 40.degree. C. and 
stirred until the mixture dissolved. While mixing, 18 g (178 mmoles) of 
triethylamine were added. The solution was then treated with 32.4 g (217 
mmole) of (1R,2S)-cis-1-aminoindan-2-ol, mixed for 10 minutes, and seeded 
with 1 mL of a slurry containing 7.5 mg of (S)-ketoprofen 
(1R,2S)-cis-1-aminoindan-2-ol diastereomer salt per mL of acetonitrile. 
The solution was held at 40.degree. C. for 30 minutes and then cooled to 
5.degree. C. over the course of 4 hours and held at 5.degree. C. for an 
additional 30 minutes. The solids that formed were collected by 
filtration, washed twice with 80 g of acetonitrile and dried under vacuum 
to yield 63.9 g of (S)-ketoprofen (1R,2S)-cis-1-aminoindan-2-ol 
diastereomer. A portion of the salt (about 50 mg) was treated with 10 
drops of 5N H.sub.2 SO.sub.4 to release the acid. The enantiomeric excess 
of the released acid was measured by chiral HPLC and found to be 96.2% 
(S)-ketoprofen. 
The enantiomeric excess of the ketoprofen in the collected filtrate was 
measured by chiral HPLC and found to be 62.6% (R)-ketoprofen. The filtrate 
was evaporated under vacuum to a weight of 86.3 g. Subsequently, 100 g of 
acetonitrile and 87.7 g (867 mmoles) of triethylamine were added to the 
concentrate. The (R)-ketoprofen was racemized by heating the solution to 
120.degree. C. (under pressure) for two hours. The enantiomeric excess of 
the ketoprofen in the racemized solution was measured by chiral HPLC and 
found to be 10.3% (R)-ketoprofen. 
(S)-Flurbiprofen 
A sample of 6.2 g (25 mmol) of R,S flurbiprofen was combined with 40 g of 
methanol and stirred until dissolved. The solution was treated with 3.14 g 
(21 mmol) of cis (1R,2S)-1-aminoindan-2-ol, seeded with a small amount of 
(1R,2S)-1-aminoindan-2-ol (S)-flurbiprofen diastereomer, and allowed to 
crystallize over a period of 17 hours at ambient temperature. The mixture 
was then cooled and held at 4.degree. C. for 5 hours. The solids were 
isolated by filtration, washed with 35 mL methanol, and dried to afford 
3.8 g (38M % yield) of white crystals. The acid was released by dissolving 
the solid in 200 mL of an ethyl acetate-water (50/50; v/v) mixture and 
treating the solution with 3 g of 5N aqueous sulfuric acid. After mixing, 
the aqueous phase was decanted and the organic phase washed twice with 100 
mL of water. The organic phase was then evaporated under vacuum. The 
weight of the solid residue was 2.1 g. The rotation .alpha.!.sub.D of 
this solid was -18.8 (c=1, ethanol) corresponding to (S)-flurbiprofen of 
44.6% enantiomeric excess. 
(S)-Tetrahydrofuran carboxylic acid 
A mixture of 1.16 g of racemic tetrahydro-2-furoic acid (97 wt % chemical 
purity, 10 mmol) in 9 g of 4-methyl-2-pentanone was heated at 
40.degree.-50.degree. C. for 10 minutes. The solution was treated with 
0.66 g of (1S,2R)-cis-1-aminoindan-2-ol (4.4 mmol, &gt;99.5% ee, 99 wt % 
chemical purity) and maintained at 40.degree.-45.degree. C. for 15 
minutes. The mixture was slowly cooled to 5.degree.-10.degree. C. and the 
resulting white solid recovered by filtration, affording 0.75 g of 
(1S,2R)-1-aminoindan-2-ol tetrahydro-2-furoic acid diastereomer 64M % 
yield, mp=150.degree.-152.degree. C., .alpha.!.sub.D =-31.degree. 
(C=0.606, methanol)!. The acid was released by treating the solid with a 
mixture of dichloromethane and 5N aqueous sulfuric acid. After mixing, the 
aqueous phase was removed and the organic phase washed with water. The 
organic phase was evaporated to yield solid (S)-(-)-tetrahydrofuran 
carboxylic acid. 
(R)-Cyclohexylphenyl Glycolic Acid 
A mixture consisting of 1.17 g (5 mmol) of racemic cyclohexylphenyl 
glycolic acid (98 wt % chemical purity), 0.75 g (5 mmol) of 
cis-(1S,2R)-1-aminoindan-2-ol in 23 mL of an ethyl acetate-ethanol mixture 
(20/3; v/v) was heated at reflux until all solids dissolved. The resulting 
solution was then allowed to cool to ambient temperature and held until 
solids formed. The solids were collected by filtration affording 0.23 g of 
cis-(1S,2R)-1-aminoindan-2-ol (R)-cyclohexylphenyl glycolic acid (12M %). 
HPLC analysis showed the presence of 98.6% diastereomeric excess of 
(R)-cyclohexylphenyl glycolic acid. The acid was released by treating the 
mixture with equal volumes (50 mL) of ethyl acetate and aqueous 
hydrochloric acid (5 wt %). After mixing, the aqueous phase was removed 
and the organic phase was washed with an equal volume of water. The 
organic phase was evaporated under vacuum to yield solid 
(R)-cyclohexylphenyl glycolic acid of 98.6% enantiomeric excess. 
Recovery of Aminoindanol 
This example illustrates that aminoindanol can be recovered for reuse, an 
important feature for commercial applications. Aqueous phase containing 
cis-(1S,2R)-1-aminoindan-2-ol sulfate was evaporated until the 
concentration of aminoindanol was 20 g per 100 g of water. The acidic 
aqueous aminoindanol concentrate was treated with aqueous sodium hydroxide 
(50 wt %) with cooling and vigorous stirring until the pH was raised above 
10. The resulting slurry of aminoindanol was mixed at 20.degree. C. for 1 
hour. The solids were isolated by filtration and washed with cold 
(9.degree. C.) water to yield cis-(1S,2R)-1-aminoindan-2-ol with 84% 
recovery. 
As will be apparent from the examples above, the particular acid used to 
liberate the chiral acid from the diastereomeric salt is not critical. 
Indeed the chiral acid could be recovered as its salt using a strong base. 
Normally, a mineral acid would be used; any acid that is a stronger acid 
than the chiral acid and that exhibits high water solubility would be 
suitable; other acids could be used, but would not be preferred. 
The aminoindanol may be added to the solution of chiral acid enantiomers 
either undiluted or as a solution in a suitable solvent. The indanol may 
be used in any proportion desired, but the use of much more than one 
equivalent is wasteful and we have observed no advantage to such 
proportions. The optimal ratio for separating a racemic mixture of chiral 
acid by crystallization appears to be 0.4 to 0.6 equivalents (i.e. about 
the amount needed to form the less soluble diasteromeric salt). In some 
cases it may be advantageous to use less than one equivalent of 
aminoindanol and replace the remainder with another base; this often 
provides advantages in cost, solubility or ease of recycling the residual 
enantiomer through a racemization process such as the one described above 
for R-ketoprofen. It may also be advantageous, for the same reasons, in 
some cases to begin with a salt derived from the carboxylic acid and an 
achiral base (e.g. a sodium, potassium or ammonium salt) rather than with 
the free acid.