Process for the resolution of 1-aminoindanes

An improved process for the resolution of 1-aminoindanes into the R-isomer on a large scale is described. The resolving agent used in the process is R-N-acetyl-3,4-dimethoxyphenylalanine. The process is of intermediates in the production of certain adenosines and their pharmaceutically acceptable acid addition salts. The adenosines have desirable central nervous system and cardiovascular activities such as antipsychotic, sedative, antihypertensive, and antianginal.

BACKGROUND OF THE INVENTION 
The process of the present invention is an efficient method of resolving 
1-aminoindanes into the R-isomer. The process is a simple method which 
gives high yields of the desired isomer. 
In contrast the method in the literature gives a low yield. That resolution 
uses N-acetylleucine as the resolving agent and uses an aqueous solution. 
In 100 consecutive crystallizations of the salt obtained by combining 
equimolar quantities of DL-1-aminoindane and L-(-)-N-acetylleucine it was 
possible to obtain the R(-)-1-aminoindane L-(-)-N-acetylleucine from which 
R(-)-1-aminoindane and the R(+) hydrochloride were obtained. Low yield 
prompted attempts to recover and fractionally crystallize the salts 
present in the mother liquors of the resolution. Bull Chim e Farm 115: 
489-500 (1976). 
In the present invention the resolving agent used is 
R-N-acetyl-3,4-dimethoxyphenylalanine which is disclosed in U.S. Pat. No. 
3,734,952 but not used as a resolving agent. 
The process of the present invention may be used for producing 
intermediates in the synthesis of indanyladenosines which compounds are 
described in U.S. Pat. No. 4,501,735 herein incorporated by reference. 
The present process gives greatly improved yield, 83% yield of 
R(-)-1-aminoindane compared to very low yields in the process described 
above. 
DETAILED DESCRIPTION 
The present invention is a greatly improved process for the resolution of 
1-aminoindanes into the R-isomer. These are intermediates in the synthesis 
of indanyladenosines of the formula 
##STR1## 
where R.sub.1 is of the formula 
##STR2## 
wherein X is hydrogen, lower alkyl or lower alkyl terminally substituted 
by hydroxy, lower alkoxy or carboxyl, or where R is hydrogen, lower alkyl, 
lower alkanoyl or benzoyl, phenyl or phenyl substituted by halogen, 
hydroxy, lower alkoxy or trifluoromethyl; Y is hydrogen, lower alkyl or 
lower alkyl substituted by hydroxy, lower alkoxy, OR where R is hydrogen, 
lower alkyl, lower alkanoyl or benzoyl; Z and Z' are independently 
hydrogen, halogen, nitro, trifluoromethyl, lower alkyl, hydroxy, or lower 
alkoxy; R.sub.3 is hydrogen or lower alkyl; R' is hydrogen, acetyl or 
benzoyl, R.sub.2 is hydrogen or halogen, and the diastereomers or mixtures 
thereof, or a pharmaceutically acceptable acid addition salt thereof. 
In the compounds of Formula I and II, the term lower alkyl is meant to 
include a straight or branched alkyl group having from one to six carbon 
atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl, 
sec-butyl, isobutyl, tertiarybutyl, amyl, isoamyl, neopentyl, hexyl, and 
the like. 
Lower alkoxy is O-alkyl of from one to six carbon atoms as defined above 
for lower alkyl. 
Halogen includes fluorine, chlorine, or bromine. 
Compounds of Formula I are useful both in the free base form and in the 
form of acid addition salts. 
Pharmaceutically acceptable salts are those derived from mineral acids such 
as hydrochloric acid and sulfuric acid, and organic acids such as 
methanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid and the 
like. 
The compound of Formula I may contain more assymmetric carbon atoms at the 
N.sup.6 side chain. 
Steps 3 and 4 of synthetic Scheme I are illustrative of the present 
invention. 
The essential feature of present invention is the discovery that the 
resolving agent R-N-acetyl-3,4-dimethoxyphenylalanine obtained as a by 
product of the L-DOPA synthesis in U.S. Pat. No. 3,734,952, improves the 
resolution which results in greater overall yields of the desired 
enantiomeric form of the final product. 
##STR3## 
In Step 1 a 1-indanone is treated with a hydroxylamine and a base to 
produce a 1-indanone oxime. In Step 2 the oxime is hydrogenated to produce 
a corresponding primary amine, both R and S forms. In Step 3 the primary 
amine is then added to D-N-acetyl-3,4-dimethoxyphenylalanine in alcohol to 
produce the (R,R) and (R,S) salts of the primary amine. The (R,S) salt 
crystallizes first and the (R,R) salt is soluble. These are separated by 
filtration. The mother liquor, on concentrating and cooling precipitates 
the desired R,R isomer in high yield and optical purity. In Step 4 a 
solution of R,R isomer is treated with a base to produce the R form of the 
primary amine. In Step 5 the R primary amine is reacted with a tertiary 
amine and 6-chloropurineriboside to produce the adenosine compounds of 
Formula I of the present invention, for example, N.sup.6 
-[1-(R)-indanyl]adenosine. 
##STR4## 
A preferred embodiment of the present invention is the use of methanol in 
Step 3 in producing the salts of the primary amine by which the R,S and 
R,R diastereomers are cleanly separated in high yield. 
Another preferred embodiment is the use of the base potassium hydroxide for 
treating the filtrate. 
Still another preferred embodiment is the process wherein the R form of 
Compound II in which X, Y, Z, and Z' are hydrogen is produced. 
A particular preferred embodiment is the process whereby the compound of 
Formula I is N.sup.6 -[1-(R)-indanyl]adenosine or a pharmaceutically 
acceptable salt thereof which is obtained by the process wherein the 
resolving agent is R-N-acetyl-3,4-dimethoxyphenylalanine. 
The compounds of Formula 1 have been found to possess differing affinities 
at adenosine receptors. These compounds are active in animal tests which 
are predictive of neuroleptic activity for the treatment of major 
psychoses such as schizophrenia. These compounds also have sedative and 
hypnotic properties and, as such, are useful for the treatment of sleep 
disorders. 
Additionally, these compounds are useful as antihypertensive agents for the 
treatment of high blood pressure. They also increase coronary blood flow 
and as such are useful in the treatment of angina and myocardial ischemia.

The following examples are illustrative of the invention but are not meant 
to limit the invention in any way. 
EXAMPLE 1 
Preparation of 1-Indanone Oxime 
In a 12 l four-necked flask fitted with a mechanical stirrer, a reflux 
condenser and a thermometer was placed 3.6 l of deionized water. 
Hydroxylamine hydrochloride was added. A clear, colorless solution formed 
(pH 2.5) to which was added 475 ml of 50% sodium hydroxide which had been 
diluted to 2.4 l with deionized water (pH 6.2). 1-Indanone was dissolved 
in 2.4 l of 3A anhydrous ethanol and added to the flask. The slightly 
turbid solution was heated at reflux for 15 minutes. A white solid started 
to precipitate at 39.degree. C. The mixture was cooled to room temperature 
and then in an ice-water bath. The product was filtered off and washed 
with three 2 l portions of chilled water. The product was dried in a 
vacuum oven at 46.degree. C. A white fluffy solid was obtained. 
Weight=522.4 g 
Yield 98.6% 
mp 142.degree.-144.degree. C. 
HPLC (18170X142A): 99.5% 
IR (KBr) N 1841.950, satisfactory 
NMR (d.sub.6 DMSO) X 284.A883, satisfactory 
Microanalysis: Calcd. for C.sub.9 H.sub.9 NO: C, 73.45; H, 6.16; N, 9.52. 
Found: C, 73.33; H, 6.21; N, 9.50 
EXAMPLE 2 
Preparation of 1-Aminoindane 
The oxime (160 g, 1.087 mole) was dissolved in cold 1.6 l of methanol 
containing 16% of anhydrous ammonia. Raney nickel catalyst (12 g) was 
added and the mixture hydrogenated at a constant pressure of 50 psi. A 
nearly theoretical amount of hydrogen had been absorbed after 24.5 hours. 
The temperature range during hydrogenation was 15.degree.-40.degree. C. 
The filtered methanol solution was concentrated on the rotary evaporator 
(maximum bath temperature, 40.degree. C.). The residue was distilled 
through a short four inch column packed with Goodloe teflon packing. The 
main fraction of 125 g was collected at 57.degree. C. (0.35 mm). 
Yield 86.4% 
GC (18096X135) 99.3% 
HPLC (18170X146C) 99.6% 
EXAMPLE 3 
Resolution of (R,S) 1-Aminoindane into the (R,R) and (R,S) Salts of 
R-N-acetyl-3,4-dimethoxyphenylalanine 
To a 5 l, three-necked flask fitted with a mechanical stirrer, a nitrogen 
blanket adapter, a reflux condenser and a thermometer was added 
D-N-acetyl-3,4-dimethoxyphenylalanine and 2.5 l of methanol. The solution 
was heated to 60.degree. C. and a solution of (R,S)-1-aminoindane in 250 
ml of methanol was added slowly to keep refluxing under control. A white 
solid precipitated which was the (R,S) salt. The (R,R) salt remained in 
solution. After stirring and cooling to room temperature, the mixture was 
stored in the cold room overnight. The solid was filtered off, washed with 
small portions of cold methanol and dried in a vacuum oven at 10 mm 
pressure for 24 hours. There was obtained 200 g (97.5%) of the R,S salt. 
mp 212.5.degree.-214.5.degree. C. 
[.alpha.].sub.D.sup.23 =-53.1.degree. (1.03% in CH.sub.3 OH) 
Microanalysis: Calcd. for C.sub.22 H.sub.28 N.sub.2 O.sub.5 : C, 65.98; H, 
7.05; N, 6.99. Found: C, 65.96; H, 7.01; N, 7.11 
The filtrate from above was charcoaled, filtered, and reduced in volume to 
1.8 l on a rotary evaporator. A small amount of precipitate was filtered 
off, weight=1.54 g, mp 189.degree.-190.degree. C. 
The filtrate was stored in the refrigerator overnight. The white solid was 
filtered and washed with three 50 ml portions of cold methanol. The 
product was dried in a vacuum oven at 68.degree. C. to give 140 g of the 
R,R isomer. 
Yield 68.2% 
mp 194.5.degree.-195.8.degree. C. 
[.alpha.].sub.D.sup.23 =-52.8.degree. (1.09% in methanol) 
The filtrate from above was concentrated to approximately 900 ml and 
further stored in the refrigerator overnight to afford a second crop of 
the R,R isomer. 
Weight=29.9 g 
Yield 14.6% 
mp 191.degree.-193.degree. C. 
[.alpha.].sub.D.sup.23 =-49.2.degree. 
Microanalysis: Satisfactory 
Total yield of first and second crops=82.8%. Both first and second crops 
were combined for subsequent reactions. 
EXAMPLE 4 
Preparation of R-(-)-aminoindane 
The R-1-aminoindane free base was isolated by dissolving 187 g of the R,R 
salt in 1.4 l of deionized water, and adding sufficient 50% KOH solution 
to reach a pH of 12.9. The mixture was extracted with three 1.4 l portions 
of diethyl ether. The combined extracts were dried over anhydrous 
MgSO.sub.4 and the solvent removed as much as possible on a rotary 
evaporator (bath temperature 36.degree. C.). The vacuum on the flask was 
released with nitrogen to avoid the carbonate formation. A 0.5 ml portion 
of R-1-aminoindane obtained in this manner was converted to the 
hydrochloride salt for identification purpose. 
mp 237.degree.-238.degree. C. 
[.alpha.].sub.D.sup.23 =+3.5.degree. C. (1% solution in methanol) 
Microanalysis: Calcd. for C.sub.9 H.sub.11 N.HCl: C, 63.72; H, 7.13; N, 
8.26. Found, C, 63.83; H, 7.21; N, 8.25 
The residual liquid was diluted with 200 ml of anhydrous 3A ethanol and 
kept under a nitrogen atmosphere. 
EXAMPLE 5 
Preparation of N.sup.6 -[1-(R)-indanyl]adenosine 
A 5 l, four-necked flask was fitted with a sealed mechanical stirrer, a 
thermometer, a reflux condenser, and a N.sub.2 blanket adapter. To this 
flask was added 156 ml of 3A anhydrous ethanol, 126.8 g of 
6-chloropurineriboside, 65.4 ml of dry triethylamine and the alcoholic 
solution of R-1-aminoindane obtained above. the slightly green suspension 
was heated at reflux for 24 hours, cooled to room temperature, and then 
stored in the refrigerator overnight. 
The product was collected by filtration, washed with three 100 ml portions 
of cold 3A alcohol, and dried in a vacuum oven at a maximum temperature of 
88.degree. C. There was obtained 121.8 g of a white crystalline solid. 
Yield 74.9% 
mp 186.7.degree.-188.5.degree. C. (clear melt) 
A mixture melting point with an authentic sample was underpressed. 
HPLC (18643X2C) 99.7% 
IR (KBr) N 1842 482, satisfactory 
NMR (d.sub.6 DMSO 11840772 and D.sub.2 O exchange), satisfactory 
Rotation A-26628 [.alpha.].sub.D.sup.23 =+4.3.degree. (1.07% in DMF) 
Water (K-F) None 
Microanalysis: Calcd. for C.sub.19 H.sub.21 N.sub.5 O.sub.4 : C, 59.52; H, 
5.52; N, 18.27. Found, C, 59.21; H, 5.56; N, 18.62