1-Indanyloxy- or tetrahydronaphthyloxy-3-amino-2-butanol derivatives, especially erythro-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol, processes for their manufacture and pharmaceutical compositions containing them. The compounds possess peripherally-selective .beta.-adrenergic blocking activity.

This invention relates to new alkanolamine derivatives which possess 
peripherally-selective .beta.-adrenergic blocking activity. 
It is known that many 1-aryloxy-3-amino-2-propanol derivatives possess 
.beta.-adrenergic blocking properties, and it is also known that 
differential blockade of the .beta.-adrenergic receptors in the heart and 
in the peripheral vasculature is possible. Compounds are known for which a 
dose of administration may be selected which will cause blockade of the 
cardiac (or .beta..sub.1) receptors but which will not cause blockade of 
the peripheral (or .beta..sub.2) receptors. These are known as 
cardioselective .beta.-adrenergic blocking agents and examples of such 
compounds are practolol and atenolol. Compounds are also known which are 
more effective in blocking the .beta.-adrenergic receptor of the 
peripheral vasculature than those of the heart. Such compounds are known, 
by analogy with cardioselective agents, as vascular-selective 
.beta.-adrenergic blocking agents. No compound is known, however, which 
produces clinically effective peripheral blockade but does not at the same 
time produce cardiac blockade. For example, propanolol is slightly more 
effective in blocking peripheral receptors than in blocking cardiac 
receptors, but is so active that it produces cardiac blockade at the 
lowest doses used. 
It is further known that insertion of a methyl group into the propanol 
side-chain, to produce 1-aryloxy-3-amino-2-butanol derivatives, in some 
cases enhances the vascular selectivity of the compounds, but in general 
reduces the overall .beta.-adrenergic blocking activity. This has been 
demonstrated particularly in the case of .alpha.-methylpropranolol where 
there is a clear reduction in potency and an arguable increase in 
vascular-selectivity (Todd, Pharmacologist, 1976, 18, 138). 
We have now found, and herein lies our invention, that .alpha.-methyl 
analogues of certain 1-indanyloxy- or 
1-tetrahydronaphthyloxy-3-amino-2-propanol derivatives possess a high 
level of peripheral .beta.-adrenergic blocking activity but at doses which 
produce such activity have no cardiac .beta.-adrenergic blocking activity. 
According to the invention there is provided an alkanolamine derivative of 
the formula: 
##STR1## 
wherein R.sup.1 is alkyl of up to 6 carbon atoms which is branched at the 
.alpha.-carbon atom, wherein R.sup.2 is alkyl of up to 3 carbon atoms, 
wherein R.sup.3 is hydrogen, halogen or alkyl of up to 3 carbon atoms and 
wherein n is 1 to 2, or an acid-addition salt thereof. 
R.sup.1 may be, for example, isopropyl or t-butyl, and is preferably 
isopropyl. 
R.sup.2 may be, for example, methyl or ethyl, and is preferably methyl. 
R.sup.3 may be for example, hydrogen, chlorine, bromine, methyl or ethyl, 
and is preferably methyl. 
n is preferably 1. 
It will be observed that the alkanolamine derivative of the invention 
possesses two asymmetric carbon atoms, namely those of the --CHOH-- group 
and the --CHR.sup.2 -- group, and that it can therefore exist in two 
racemic diastereoisomeric forms, the threo and erythro forms, and four 
optically-active forms. these being the (+) and (-) isomers of each of the 
racemic forms. It is to be understood that this invention encompasses any 
one of these isomeric forms which possess peripherally-selective 
.beta.-adrenergic blocking activity as defined below, it being a matter of 
common general knowledge how any particular isomer may be isolated and how 
any peripherally-selective .beta.-adrenergic blocking activity it may 
possess may be measured. 
It is to be understood that in general an optical isomer which has the 
(S)-absolute configuration of the --CHOH-- group is more active as a 
.beta.-adrenergic blocking agent than the corresponding isomer which has 
the (R)-absolute configuration. We have also found that in general the 
erythro-isomer is more peripherally-selective than the corresponding 
threo-isomer, but that both threo- and erythro-isomers of the compounds of 
the present invention possess the required selectivity. 
A suitable acid-addition salt of an alkanolamine derivative of the 
invention is, for example, a salt derived from an inorganic acid, for 
example a hydrochloride, hydrobromide, phosphate or sulphate, or a salt 
derived from an organic acid, for example an oxalate, lactate, tartrate, 
acetate, salicylate, citrate, benzoate, .beta.-naphthoate, adipate or 
1,1-methylene-bis(2-hydroxy-3-naphthoate), or a salt derived from an 
acidic synthetic resin, for example a sulphonated polystyrene resin. 
Specific alkanolamine derivatives of the invention are hereinafter 
described in the Examples. Of these, particularly preferred compounds are 
erythro-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol; 
threo-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol and 
erythro-(indan-4-yloxy)-3-isopropylaminobutan-2-ol and the acid-addition 
salts thereof. 
The alkanolamine derivative of the invention may be manufactured by any 
process known to be useful for the manufacture of chemically-analogous 
compounds. 
A preferred process for the manufacture of an alkanolamine derivative of 
the invention comprises the reaction of a compound of the formula: 
##STR2## 
wherein R.sup.3 and n have the meanings stated above and wherein X stands 
for the group: 
##STR3## 
wherein R.sup.2 has the meaning stated above and wherein Z stands for a 
displaceable radical, with an amine of the formual R.sup.1 NH.sub.2. 
wherein R.sup.1 has the meaning stated above. 
Z may be, for example, a halogen atom, for example a chlorine or bromine 
atom, or it may be a sulphonyloxy radical, for example the 
methane-sulphonyloxy or p-toluenesulphonyloxy radical. The reaction may be 
carried out in a diluent or solvent, for example water, an alcohol, for 
example methanol or ethanol, or an excess of an amine of the formula 
R.sup.1 NH.sub.2, wherein R.sup.1 has the meaning stated above, and it may 
be carried out at a temperature up to the boiling point of the diluent or 
solvent. 
The starting material may be obtained by the reaction of a compound of the 
formula: 
##STR4## 
wherein R.sup.3 and n have the meanings stated above, with an epoxide of 
the formula: 
##STR5## 
wherein R.sup.2 and Z have the meanings stated above. It may alternatively 
be obtained by the reaction of a compound of the formula: 
##STR6## 
wherein R.sup.2, R.sup.3 and n have the meanings stated above, with a 
peroxide, for example hydrogen peroxide. 
A compound which has the threo-configuration of the --CHOH-- and 
--CHR.sup.2 -- groups may be converted into the corresponding compound 
which has the erythro-configuration of said groups by successive 
protection of the secondary amino function --NHR.sup.1 -- by acetylation 
with acetyl chloride, replacement of the hydroxy function by chlorine by 
reaction with thionyl chloride (this replacement causing no inversion of 
the stereo-chemistry at the carbon atom of the original --CHOH-- group), 
and then replacement of the chlorine by hydroxy by reaction with an alkali 
metal hydroxide (this replacement causing inversion of the stero-chemistry 
at the said carbom atom), the alkali metal hydroxide simultaneously 
removing the amino-acetyl protecting group by hydrolysis. 
Optically-active enantiomorphs of the alkanolamine derivative of the 
invention may be obtained by the resolution by conventional means of the 
corresponding racemic alkanolamine derivative of the invention. 
The said resolution may be carried out by reacting the racemic alkanolamine 
derivative with an optically-active acid, followed by fractional 
crystallisation of the diasteroisomeric mixture of salts thus obtained 
from a diluent or solvent, for example ethanol, whereafter the 
optically-active alkanolamine derivative is liberated from the salt by 
treatment with a base. A suitable optically-active acid is, for example 
(+)- or (-)-0,0-di-p-toluoyltartaric acid or 
(-)-2,3:4,5-di-O-isopropylidene-2-keto-L-gulonic acid. 
The resolution process may be facilitated by treating the partially 
resolved alkanolamine derivative in free base form obtained after a single 
fractional crystallisation of the diastereoisomeric mixture of salts with 
a solubilishing agent, for example a primary amine, for example 
allylamine, in a relatively non-polar diluent or solvent, for example 
petroleum ether. 
The alkanolamine derivative of the invention in free base form may be 
converted into an acid-addition salt thereof by reaction with an acid by 
conventional means. 
As stated above, an alkanolamine derivative of the invention possess 
peripherally-selective .beta.-adrenergic blocking activity. This may be 
demonstrated by its ability to antagonise the effect of a catecholamine 
such as isoprenaline in lowering the blood pressure of a perfused 
denervated hind limb of a dog at a dose which does not antagonise the 
effect of the same catecholamine in increasing the heart rate of the dog. 
Because of this selective activity a dose may be selected for the 
administration of such an alkanolamine derivative to a warm-blooded mammal 
such that .beta.-adrenergic blockade of the peripheral blood vessels may 
be produced without unwanted effects on the heart. At a dose of an 
alkanolamine derivative of the invention which produces effective 
peripheral .beta.-adrenergic blockade in the dog, no symptom of toxicity 
is apparent. 
The alkanolamine derivative of the invention may be administered to 
warm-blooded animals, including man, in the form of a pharmaceutical 
composition comprising as active ingredient at least one alkanolamine 
derivative of the invention, or an acid-addition salt thereof, in 
association with a pharmaceutically-acceptable diluent or carrier 
therefor. 
A suitable composition is, for example, a tablet, capsule, aqueous or oily 
solution or suspension, emulsion, injectable aqueous or oily solution or 
suspension, dispersible powder, spray or aerosol formulation. 
The pharmaceutical composition may contain, in addition to the alkanolamine 
derivative of the invention, one or more drugs selected from sedatives, 
for example phenobarbitone, meprobamate, chloropromazine and the 
benzodiazepine sedative drugs, for example chlordiazepoxide and diazepam; 
analgesic agents, for example acetylsalicylic acid, codeine and 
paracetamol; hypotensive agents, for example reserpine, bethanidine and 
guanethidine; and agents used in the treatment of Parkinson's disease and 
other tremors, for example benzhexol. 
When used for the treatment of tremor, migraine, anxiety, schizophrenia, 
glaucoma or hypertension in man, it is expected that the alkanolamine 
derivative would be given to man at a total oral dose of between 2 mg. and 
100 mg. daily, at doses spaced at 6-8 hourly intervals, or at an 
intravenous dose of between 0.2 mg. and 5 mg. 
Preferred oral dosage forms are tablets or capsules containing between 2 
and 100 mg., and preferably 1 mg. or 10 mg. of active ingredient. 
Preferred intravenous dosage forms are sterile aqueous solutions of the 
alkanolamine derivative or of a non-toxic acid-addition salt thereof, 
containing between 0.05% and 1% w/v of active ingredient, and more 
particularly containing 0.1% w/v of active ingredient.

The invention is illustrated but not limited by the following Examples: 
EXAMPLE 1 
A mixture of trans-2,3-epoxy-1-(7-methylindan-4-yloxy)-butane (19.9 g.), 
isopropylamine (100 ml.) and water (100 ml.) is heated under reflux for 16 
hours and then evaporated to dryness under reduced pressure. The residue 
is dissolved in a mixture of concentrated aqueous hydrochloric acid (50 
ml.) and water (50 ml.), the solution becoming hot during the dissolution. 
The solution is cooled and filtered and the solid product is crystallised 
from a 4:1 v/v mixture of ethanol and methanol. There is thus obtained 
erythro-1(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol hydrochloride 
m.p. 222.degree.-224.degree. C. 
The trans-2,3-epoxy-1-(7-methylindan-4-yloxy)butane used as starting 
material may be obtained by either of the following processes: 
A. A solution of 7-methylindan-4-ol (118 g.) in dry N,N-dimethylformamide 
(296 ml.) is added during 30 minutes to a stirred suspension of sodium 
hydride (20.8 g.) in dry N,N-dimethylformamide at such a rate that the 
temperature of the mixture does not exceed 30.degree. C. The mixture is 
stirred at laboratory temperature for a further 30 minutes and 
trans-crotyl chloride (106 ml.) is then added during 30 minutes. The 
mixture is stirred at laboratory temperature for 16 hours and water (1200 
ml.) is then added at such a rate that the temperature of the mixture does 
not exceed 30.degree. C. The aqueous layer is decanted off and the residue 
is stirred with cyclohexane (340 ml.). The mixture is filtered and the 
filtrate is washed once with aqueous 2 N-sodium hydroxide solution (240 
ml.) and six times with saturated aqueous sodium chloride solution (120 
ml. each time), dried over magnesium sulphate and evaporated to dryness 
under reduced pressure. The residue is crystallised from ethanol (at 
-7.degree. C.) and there is thus obtained 1-(7-methylindan-4-yloxy) 
but-trans-2-ene, m.p. 29.degree.-29.5.degree. C. 
A mixture of the above compound (110 g.) acetonitrile (115 ml.), hydrogen 
peroxide(125 ml. of a 50% w/w aqueous solution), anhydrous potassium 
hydrogen carbonate (44 g.) and methanol (1300 ml.) is stirred at 
laboratory temperature for 5 days and is then poured into water (5.3 
liters). The mixture is filtered and the solid product is washed with 
water (700 ml.), dried at laboratory temperature and crystallised from 
petroleum ether, b.p. 60.degree.-80.degree. C. (570 ml.). There is thus 
obtained trans-2,3-epoxy-1-(7-methylindan-4-yloxy)butane, m.p. 
68.degree.-69.degree. C. 
A solution of bromine (63.3 g.) in methylene chloride (50 ml.) is added 
dropwise to a cooled, stirred solution of cis-crotyl alcohol (28.5 g.) in 
methylene chloride (50 ml.) and the mixture is stirred for 30 minutes at 
laboratory temperature and is then washed successively with dilute aqueous 
sodium thiosulphate solution and then with water, dried over magnesium 
sulphate and evaporated to dryness under reduced pressure. The residue is 
distilled under reduced pressure and there is thus obtained 
threo-2,3-dibromobutan-1-ol, b.p. 108.degree.-110.degree. C./13 mm.Hg. 
A solution of the above compound (140 g.) in diethyl ether (700 ml.) and a 
solution of potassium hydroxide (45 g.) in water (400 ml.) are vigorously 
stirred together for 6 hours and the two layers are then separated. The 
ethereal layer is washed repeatedly with saturated aqueous sodium chloride 
solution until the washings are no longer alkaline and is then dried over 
magnesium sulphate and evaporated to dryness. The residue is distilled 
under reduced pressure and there is thus obtained 
erythro-3-bromo-1,2-epoxybutane, b.p. 39.degree.-42.degree. C./20 mm.Hg. 
A stirred mixture of the above compound (33 g.), 7-methylindan-4-ol (25.2 
g.), sodium hydroxide (7.5 g.), water (250 ml.) and 1,2-dimethoxyethane 
(25 ml.) is heated at 60.degree. C. for 15 hours, cooled and extracted 4 
times with chloroform (75 ml. each time). The combined extracts are washed 
with water until the washings are no longer alkaline, dried over magnesium 
sulphate and evaporated to dryness under reduced pressure. The residue is 
stirred with petroleum ether (b.p. 40.degree.-60.degree. C.) until it 
solidifies, and the solid is crystallised from a 2:1 v/v mixture of 
cyclohexane and petroleum ether (b.p. 60.degree.-80.degree. C.). There is 
thus obtained trans-2,3-epoxy-1-(7-methylindan-4-yloxy)butane, m.p. 
68.degree.-69.degree. C. 
EXAMPLE 2 
The process described in Example 1 is repeated except that 
cis-2,3-epoxy-1-(7-methylindan-4-yloxy)butane [prepared by a similar 
process to that described in the last paragraph of Example 1 from the 
known (J. Organic Chemistry, 1956, 21, 429) threo-3-bromo-1,2-epoxybutane] 
is used in place of the trans-isomer. There is thus obtained 
threo-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol hydrochloride, 
m.p. 164.degree.-166.degree. C. 
EXAMPLE 3 
The process described in Example 1 (first paragraph; starting material 
prepared by Method B) or 2 is repeated except that the appropriate 
7-substituted-or unsubstituted-indan-4-ol, the appropriate 
3-bromo-1,2-epoxybutane and the appropriate amine are used as starting 
materials. There are thus obtained the compounds described in the 
following table: 
______________________________________ 
##STR7## 
R.sup.1 R.sup.3 isomer m.p.(.degree.C.) 
______________________________________ 
isopropyl H erythro free base 
103-106 
isopropyl H threo hydrochloride 
179-181 
t-butyl H threo hydrogen oxalate 
162-163 
isopropyl ethyl threo hydrochloride 
175-177 
isopropyl chloro threo hydrochloride 
174.5-175.5 
______________________________________ 
The 7-ethylindan-4-ol used as starting material may be obtained as follows: 
3-Chloropropionyl chloride (133 g.) is added in portions of 5-10 ml. to 
molten 4-ethylphenol (63.8 g.) which is heated at 95.degree.-100.degree. 
C. When addition is complete the mixture is heated at 
95.degree.-100.degree. C. for 90 minutes and is then kept at laboratory 
temperature for 18 hours. The mixture is shaken with ice-water (200 ml.) 
and diethyl ether (100 ml.) and the organic layer is separated. The 
aqueous layer is extracted with diethyl ether (50 ml.) and the combined 
organic solutions are washed twelve times with aqueous 2 N-sodium 
hydroxide solution (50 ml. each time) and then dried over magnesium 
sulphate and evaporated to dryness. The residue is distilled and there is 
thus obtained 4-ethylphenyl-3-chloropropionate, b.p. 
121.degree.-122.degree. C./1.5 mm.Hg. 
A mixture of the above compound (87.9 g.) and aluminium chloride (110 g.) 
is heated at 165.degree.-170.degree. C. for 5 hours, cooled and ice-water 
(200 ml.) is cautiously added. The mixture is steam-distilled and 
distillate is extracted three times with diethyl ether (50 ml. each time). 
The combined extracts are dried over magnesium sulphate and evaporated to 
dryness and the residue is crystallised from cyclohexane. There is thus 
obtained 4-ethyl-7-hydroxyindan-1-one, m.p. 89.degree.-94.degree. C. 
A stirred mixture of the above compound (9.3 g.), amalgamated zinc (35 g.), 
water (35 ml.) and concentrated aqueous hydrochloric acid (35 ml.) is 
heated under reflux for 16 hours and the liquid phase is then decanted off 
the metallic residue and extracted with toluene (25 ml.). The toluene is 
evaporated off, the residue is dissolved in diethyl ether and the solution 
is dried over magnesium sulphate and evaporated to dryness. The residue is 
crystallised from petroleum ether (b.p. 60.degree.-80.degree. C.) and 
there is thus obtained 7-ethylindan-4-ol, m.p. 49.degree.-51.degree. C. 
EXAMPLE 4 
The process described in Example 2 is repeated exept that 
threo-2,3-epoxy-1-(5,6,7,8-tetrahydronaphth-1-yloxy)butane is used as 
starting material. There is thus obtained 
threo-1-(5,6,7,8-tetrahydronaphth-1-yloxy)-3-isopropylaminobutan-2-ol 
hydrochloride, m.p. 218-.degree.224.degree. C. 
EXAMPLE 5 
A mixture of trans-2,3-epoxy-1-(7-methylindan-4-yloxy)pentane (1.3 g.), 
isopropylamine 10 ml. and water (10 ml.) is heated under reflux for 16 
hours, cooled and evaporated to dryness under reduced pressure. The 
residue is shaken with aqueous 2 N-hydrochloric acid (25 ml.) and ethyl 
acetate (25 ml.) and the organic layer is separated, dried over magnesium 
sulphate and evaporated to dryness. The residue is applied in ethyl 
acetate solution to thick-layer silica gel chromatography plates (20 
cm..times.20 cm..times.2 mm. thick, Merck F.sub.254) and the plates are 
developed with a 100:20:3 v/v mixture of ethyl acetate, ethanol and 
triethylamine. The relevant band is separated and extracted with methanol, 
the solution is filtered and the filtrate is evaporated to dryness. The 
residue is dissolved in chloroform, the solution is filtered and the 
filtrate is evaporated to dryness. The residue is crystallised from 
petroleum ether (b.p. 60.degree.-80.degree. C.) and there is thus obtained 
erythro-1-(7-methylindan-4-yloxy)-3-isopropylaminopentan-2-ol, 
m.p.72.degree.-73.degree. C. 
The trans-2,3-epoxy-1-(7-methylindan-4-yloxy)pentane used as starting 
material may be obtained as follows: 
A mixture of 7-methylindan-4-ol (1.48 g.), tetrahydrofuran (25 ml.) and 
sodium hydride (0.4 g. of a 60% dispersion in mineral oil) is stirred at 
laboratory temperature for 90 minutes, and a solution of 
erythro-3-bromo-1,2-epoxy-pentane (2.2 g.; prepared from 
cis-pent-2-ene-1-ol by a similar method to that described in part B of 
Example 1) in tetrahydrofuran (10 ml.) is then added during 10 minutes. 
The mixture is heated under reflux for 16 hours, N,N-dimethylformamide (10 
ml.) is added and the mixture is heated under reflux for a further 84 
hours and is then poured into an equal volume of water. The mixture is 
extracted twice with diethyl ether (25 ml. each time) and the combined 
extracts are washed with aqueous2 N-sodium hydroxide solution (25 ml.) and 
twice with saturated aqueous sodium chloride solution (10 ml. each time), 
dried over magnesium sulphate and evaporated to dryness. The residue 
consists of trans-2,3-epoxy-1-(7-methylindan-4-yloxy)pentane which is used 
without further purification. 
EXAMPLE 6 
Acetyl chloride (1.03 ml.) is added to a stirred mixture of 
threo-1-(7-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol (4.0 g.), 
methylene chloride (50 ml.) and triethylamine (1.5 ml.) and the mixture is 
stirred at laboratory temperature for 2 hours and is then washed 
successively with water (25 ml.), twice with aqueous 2 N-hydrochloric acid 
(25 ml. each time), and three times with water (25 ml. each time), is 
dried over magnesium sulphate and is evaporated to dryness under reduced 
pressure. Thionyl chloride (6 ml.) is added to the residue and after the 
exothermic reaction is over the mixture is kept at laboratory temperature 
for 30 minutes. The excess of thionyl chloride is distilled off under 
reduced pressure and the residue is stirred for 48 hours with a mixture of 
aqueous 7 N-sodium hydroxide solution, water (15 ml.) and 
N,N-dimethylformamide (15 ml.). More water (30 ml.) is added and the 
mixture is extracted three times with ethyl acetate (25 ml. each time). 
The combined extracts are dried over magnesium sulphate and evaporated to 
dryness, and the residue is crystallised from isopropanol. There is thus 
obtained erythro-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol, 
m.p. 90.5.degree.-93.5.degree. C. 
EXAMPLE 7 
A solution of (-)-di-p-toluoyl-(L)-tartaric acid (7.13 g.) in ethanol (15 
ml.) is added to a solution of 
(.+-.)-threo-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol (5.12 
g.) in ethanol (15 ml.) and the mixture is boiled for 3 minutes and then 
allowed to cool. The mixture is filtered and the solid residue is 
crystallised twice from ethanol. The di-p-toluoyltartrate salt thus 
obtained (m.p. 114.5.degree.-116.degree. C.) is shaken with aqueous 2 
N-sodium hydroxide solution (50 ml.) and ethyl acetate (50 ml.) and the 
organic layer is separated, washed with water, dried over magnesium 
sulphate and evaporated to dryness. The residue is dissolved in diethyl 
ether, an excess of saturated ethereal hydrogen chloride is added and the 
mixture is filtered. The residue is crystallised from isopropanol and 
there is thus obtained 
(+)-threo-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol 
hydrochloride, m.p. 173.5.degree.-175.degree. C.; [.alpha.].sub.23.sup.D 
=+41.3.degree. (methanol). 
The combined ethanolic filtrates from the isolation and crystallisation of 
the di-p-toluoyltartrate salt described above are evaporated to dryness 
and the residue is shaken with aqueous 10 N-sodium hydroxide solution (25 
ml.) and ethyl acetate (25 ml.). The organic layer is separated, washed 
with water, dried over magnesium sulphate and evaporated to dryness. The 
residue is dissolved in ethanol (10 ml.) and a solution of 
(+)-di-p-toluoy-(D)-tartaric acid (2.1 g.) in ethanol (10 ml.) is added. 
The mixture is boiled for 3 minutes and then allowed to cool. The 
precipitated salt is crystallised and the free base is isolated and 
converted to a hydrochloride salt by a similar procedure to that described 
in the preceding paragraph. There is thus obtained 
(-)-threo-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol 
hydrochloride, m.p. 173.5.degree.-175.degree. C.; [.alpha.].sub.23.sup.D 
=-41.1.degree. (methanol).