CA1257279A - R- and s-4-(2,3-epoxypropoxy)-carbazoles - Google Patents

Abstract

Abstract R- and S-4-(2,3-Epoxypropoxy)-carbazoles of formula (X):

Description

~LZ57279 The present invention is concerned with intermediates for the preparation of optically-active R- and S-carbazole derivatives; more especially the invention is concerned with R- and S-4-(2,3-epoxy-propoxy)-carbazoles and their preparation.
This application is a division of Canadian Application No. 454,948, filed May 23, 1984.
R- and S-Carbazole derivatives with high optical purity are disclosed herein of -the formula (I):
. o-CH2 - ,CH--CH2 Rlo N ~ (I) ~ in which R1o is an unsubstituted or substituted amino radical, and their pharmacologically compatible, pharmaceutically acceptable salts.
In formula (I), R1o is preferably an amino radical which is substituted by a lower alkyl radical of 1 to 5, preferably 1 to 4 carbon atoms, for example, methyl, ethyl, isopropyl or tert.-butyl radical; or is a radical:

~A, ~2S'7279 -~ CH - CH - X ~ Ar )

2 3 4 ~

in which R2 is a hydrogen atom, a lower alkyl radical or a benzyl, phenylethyl or phenylpropyl radical, R3 is a hydrogen atom or a lower alkyl radical, R4 i3 a hydrogen atom or a lower alkyl radical, ~ a valency bond, a -CH2- group or an oxygen or sulphur atom, Ar is a phenyl naphthyl, indanyl, tetrahydronaphthyl or pyridyl radical and R5 and R6, which can be the same or different, are hydrogen or halogen atoms, lower alkyl radicals, aminocarbonyl groups, hydroxyl groups, lower alkoxy radicals, benzyloxy radicals, lower alkylthio radicals, lower alkylsulphinyl radicals or lower alkylsulphonyl radicals or together represent a methylenedioxy radical.
The lower alkyl radicals R2, R3, R4, R5 and R6 and the lower alkoxy, lower alkylthio, lower alkylsulphinyl and lower alkylsulphonyl radicals R5 and R6 suitably have 1 to 6, and preferably 1 to 4, carbon atoms.
Compounds with the above-mentioned sub-stituents Rlo are described in Federal Republic of Germany Patent Specification ~o. 22 40 599 and in ~25'7279 European Patent Specification No. 4,920.
According to the processes set out in the aforementioned Patent Specifications, in all cases racemates of the described compounds are obtained. A
separation of the racemate into the optically-active antipodes takes place according to per se known methods via a diasteromeric splitting with the use of known, optically-active acids or bases. This process is very laborious and, as a rule, does not give pure optically-active substances, contaminations due to the other antipodes being practically unavoidable.
The present invention seeks to provide a synthesis route for the preparation of the antipodes in pure form, via novel intermediates.
Thus in one aspect of the invention there is provided R-(-)-4-(2,3-epoxypropoxy)-carbazole and S-(+)-4-(2,3-epoxypropoxy)-carbazole as novel inter-mediates useful in the manufacture of optically pure R- and S-carbazoles of the aforementioned formula (I).
In another aspect of the invention there is provided a process for preparing R-~-)-4-(2,3-epoxy-propoxy)-carbazole which comprises reacting an S-epoxide derivative of formula (II), as defined hereinafter, with 4-hydr~xycarbazole- and a process ~25~7~7!~

for preparing S-(+)-4-(2,3-epoxypropoxy)-carbazole which comprises reacting R-(-)-epichlorohydrin with 4-hydroxycarbazole.
- The R-carbazole derivatives of formula (I) may be obtained by reacting an S-epoxide of the formula:

o ~ O-Rl H ~ (II) in which Rl is the residue of a substituted sulphonic acid derivative with 4-hydroxycarbazole to produce the novel R-4-(2,3-epoxypropoxy)-carbazole of the invention which is reacted with ammonia or substitu-ted ammonia of formula RloH, in which Rlo has the same meaning as above, whereafter the compound obtained is, if desired, converted into a pharmaco-logically compatible, pharmaceutically acceptable salt.
Substituted sulphonic acids in the defini-tion of Rl are, for example, methanesulphonic acid, p-toluenesulphonic acid and benzenesulphonic acid.
In particular the reaction is carried out in the presence of an organic solvent in an alkaline medium.

12~2~9 For convenience it is observed here that 4-carbazole has the formula:
OH

The corresponding S-carbazole derivatives of formula ~I) are obtained in similar manner. For this purpose, R-(-)-epichlorohydrin is first reacted with 4-hydroxycarbazole to produce the novel S-4-(2,3-epoxypropoxy)-carbazole of the invention which is reacted with ammonia or a substituted amine of the formula RloH, in which Rlo hàs the same meaning as above, whereafter the compound obtained is, if - desired, converted into a pharmacologically compa-tible, pharmaceutically acceptable salt.
In particular the 4-hydroxycarbazole and R-(-)-epichlorohydrin are reacted in the presence of an organic solvent in an alkaline medium.
Thus an R- or S-carbazole deriva-tive of formula (I) may be obtained by reacting a novel R- or S-4-(2,3-epoxypropoxy)-carbazole of the invention with a compound of formula RloH in which Rlo is amino or a substituted amino radical, whereafter the ~Z5~2~

compound is, if desired, converted into a pharmaco-logically compatible, pharmaceutically acceptable salt.
Pharmaceutical compositions are also disclosed comprising a non-racemic combination of R-carbazole and S-carbazole of formula tI), as defined above, or pharmaceutically acceptable, pharmacologically compatible salts thereof, in association with a pharmaceutically acceptable carrier therefor.
In this specification a "non-racemic combination" is one in which the R- and S-enantiomers are derived independently rather than as a racemic mixture. In particular the enantiomers are not present in a racemic 50:50 mixture.

~L2:5~7~

.
The preparation of the key compounds of general fonmula (II), preferably of the mesyl derivative, and of the R-~-)-epichlorhydrin are described in the literature (see Bald~in, J. org. Chem., 43, 4876/1978).
According to this reference, D-mannitol is converted wQth acetone in the presence of zinc chloride into 1,2,5,6-di-0-isopropylidene-D-mannitol, splitting of which with sodium metaperiodate ~nd subsequent immediate reduction of the intermediate aldehyde function formed gives S-(+)-isopropylidene-glycerol.
Tosylation of this substance gives the R-3-tosyloxy-propanediolacetonide which, without isolation, is immediately converted into R-(-)-3-tosyloxy-1,2-propanediol. From this, by reaction with sodium methylate, there is obtained R-glycidol which, because of the danger of racemisation, is immediately reacted with methanesulphonyl chloride to give S-(+)-

3-mesyloxy-1,2-epoxypropane.
For the preparation of the R-(-)-epichlorhydrin, S-(+)-3-mesyloxy-1,2-epoxypropane is opened with hydrochloric acid to give R-l-chloro-2-hydroxy-3-mesyloxypropane which, without purification, is reacted in ethylene glycol with sodium methylene-glycolate to give ~ )-epicnlorhydrin.
The two mentioned key substances are each - reacted with 4-hydroxycarbazole, with reversal of the configuration, to give the previously ùnknown R-(-)-. , . .... .. . . . ... . _ . . _ _ . ., . . _ . . ..... . . . . . .. ...... .... , . .. .. . .. ...
. . ... . _ .. . _ .... . . . ..... .... ...

~ZS7~9

4-(2,3-epoxypropoxy)-carbazole and S-(+)-4-(2,3-epoxypropoxy)-carbazole, which are also the subject of the present invention. The processes give both new antipodes with an optical purity of almost 10~/o~
The optically-active antipodes of 4-(2,3-epoxypropoxy)-carbazole are reacted, with maintenance of the configuration, with appropriate amines to give the optically-active compounds of general formula (I).
For this purpose, as a rule, the carbazole derivative is heated under reflux for a comparatively long time with amine in an organic solvent, for example methanol, ethanol or isopropanol.
The optically-active carbazole derivatives of general formula (I) are new compounds. The pharma-cological effectiveness of the particular antipodesis, in comparison with the racemate, greatly different.
Whereas, for example, in the case of carvedilol, only S~ Q-carbazole-4-yloxy)-3~[2-(2-methoxyphenoxy)]-ethylaminopropan-2-ol (laevorotary isomer, Example 8) displays ~-blocking properties, the vasodilatory action is present in both isomers of this compound (see the following experimental report). On the basis of this fact, the differing pharmacological properties are utilised in the development of pharmaceutical compositions~
By means of the freely selectable mixing ratios of the R and S-enantiomers, the particularly most favourable relationship of the two activity qualities can be objectively adjusted.
Example.
If, in the case of a racemate, the ~-blockade, carried by the S-enantiomer, in comparison with the blood pressure lowering, carried by the R- and S-enantiomers, is too strong, then a more balanced activity relationship can be achieved by alteration of the proportion of the S-component.
Consequently, there can be used mixtures of R:S of from 1:99 to 99:1 except, in the meaning of the present invention, the ratio of 50:50 (racemate).
Experimental protocol The ~-blocXing action was determined on awake rabbits on the basi~ of the inhibition of isoprenaline J tachycardia (a~cording to the method of Bartsch et al.
(Experiments in animals on the pharmacological effects of metipranolol in comparison with propranolol and pindolol - Drug. Res., 27, (II~, 12, 2319-2322/1977).
A~ a measure for the ~-blocking activity strength, there was calculated the 50YO inhibiting dosage.
Vasodilation (measured as direct blood pre~sure lowering after a single administration).
In awake, spontaneously hypertonic rats (SHR), catheters were implanted in the arteria femorali~
and the vena jugularis. Via the veins, there were - ~ 2 S ~ j l7 --10 _ injected appropriate dosages of the enantiomers (R-carvedilol and S-carvedilol in dosageq of 0.03;
0.1: 0.3: 1.0 and 3 mg/kg. i.v.) and the arterial blood pressure lowering was determined via the arterial pressure catheter (as an expres~ion of the vasodilation). As a measure of the anti-hypertensive effect, there were calculated the dosages for lowering of the blood pressure by 30 mm.Hg.
Results The results of the investigations, not only with regard to the ~-blockade but also to the blood pressure and blood vessel action, are summarised in the following Table:-~ ~57~7~

o I 1~

a v ~ ,~ _ ,, V _ O O l 0 ~ _ V D O O tl O N

O ~ QU~ 0~3 ~I w r~
~p i ~a E~ O
u ~ ~l ~
l o ~o ~ ~ ~

.4 ~ O O l R
0 _ . t~ o o o o ~I~n 3 ~ _ ~ s ~o U ~ ~ . ~ . o .,, .,, ~ ~ ~ o~ .,, ~ 0 h a~ ~ g D U A u A h ~L~S~

According to the above results, with cor-relation coefficients (r) of from 0.96 to 0.99, there is given a very good ~osage action relation-ship. With regard to the ~-blockade, between the two en~ntiomers there is such a great difference that practically only s-carvedilol can be regarded as being a ~-blocker. Only at a 160 fold higher dosage is a ~-blockade detectable for R-carvedilol, which is possibly to be attributable to traces of S-carvedilol.
With regard to the blood pressure lower-ing action, a comparatively small difference lS
ascertainable between S- and R-carvedilol. The difference factor is 11 and the absolutely necessary dosage in order to achieve a blood pressure lower-ing of 30 mm.Hg is, in the case of S-carvedilol with 270 mcg./kg,. i.v., in comparison to the ~-blockade, about 10 times higher.
A further particularity of the different pharmacological properties of the enantiomers of a compound of formula (I) is that only the R-enantiomers display an outstanding antiglaucoma action and, therefore, can be used as optically pure substances for the treatment of glaucoma.

~2s~æi~

In this specification, it will be understood that the qualification that the salts are "pharmaceutically acceptable" means that the salts have the necessary physical characteristics, for example, stability, to render them suitable for formulation into pharmaceutical compositions. The qualification that the salts be "pharmacologically compatible" is to be understood as extending to salts with non-toxic inorganic or organic acids which have no adverse effects to the extent that such salts would be unsuitable for administration to living bodies.
Salts of compounds of formula (I) which are not pharmaceutically acceptable and pharmacologically compatible are also useful, inasmuch as they can be readily converted to different salts having the required physical and chemical characteristics to make them suitable for administration in pharmaceu-tical compositions to living bodies.
For the conversion of the compoun~s of formula (I) into their pharmacologically compatible, pha.rmaceutically acceptable salts, these are re-acted, preferably in an organic solvent, with the equivalen-t amount of an inorganic or organic acid, for e~ample hydrochloEic acid, - ~2~;72~9 _ 14 -hydrobromic acid, phosphoric acid, sulphuric acid, acetic acid, citric acid, maleic acid or benzoic acid.
For the preparation of pharmaceutical compos-itions, the compounds of general formula (I) aremixed in known manner with appropriate pharmaceutical carrier materials, aroma, flavouring and colouring materials and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvant materials, suspended or dissolved in water or an oil, for example olive oil.
For the treatment of glaucoma, compounds of general formula (I) or their pharmacologic~lly accept-able salts are used in the form of eye drops. It is preferred to use salts with physiologically accept-able inorganic or organic acids, for example hydro-chloric acid, hydrobromic acld, phosphoric acid, sulphuric acid, acetic acid, salicylic acid, citric - acid, benzoic acid, naphthoic acid, o-acetoxybenzoic acid, adipic acid or maleic acid.
It is preferred to use isotonic solutions with a pH of about 7Ø As medium, it is preferred to use water which can cont~in conventional additives, such as preserving agents, solubilising agents or buffers. Th~ pre~erving agent is preferably benzyl alcohol, benzalkonium chloride, phenol or chlor-hexidine acetate. The ~olubili~ing agènt is - ~25727!~
_ 15 -especially a polyethylene glycol, polyvinylpyrrolidone or glycerol. As buffers, it is preferable to use acetic acid/sodium acetate, citric acid/sodium citrate or sodium EDTA.
The compounds of general formula (I) according to the present invention and their salts can be administered enterally or parenterally in liquid or solid form. As injection medium, water is preferably used which contains the additives usual in the case l~ of injection solutions, such as stabilising agents, solubilising agents or buffersO Such additives are, for example, tartrate and citrate buffers, ethanol, complex formers (such as ethylenediamine-tetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carrier materials are, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers (such as poly-ethylene glycols). Compositions suitable for oral administration can, if desired, contain flavouring and sweetening materials.
The following Examples are given ~or the pur-pose of illustrating the present invention:

~ZS~3 Example 1.
S-~+)-3-Mesyloxy-1,2-epoxYPropane 10.5 g. R-Glycidol are dissolved in a mixture of 23.3 ml. trie~hylamine and 210 ml. anhydrous toluene. To this is added dropwise at 0 to 5 C., with stirring, a solution of 11.5 ml. methanesulphonyl chloride in 50 ml. anhydrous toluene, whereafter the reaction mixture is left to stand overnight in a refrigerator. It is then flltered off with suction and the filtrate is evaporated in vacuo. The residue is dissolved in methylene chloride, the solution is washed with lN hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulphate and evaporated. The residue is distilled. Yield: 9 g. S-(+)-3-mesyloxy-1,2-epoxypropane; b.p.: 100 C./0.8 mm.Hg, [a]D :
+24.2 tc = 2.9; methanol~.
The R-glycidol used is prepared as follows:
a) 1,2,5,6-Di-0-isopropylidene-D-mannitol To 2350 ml. acetone dried over neutral aluminium oxide are added 200 ml. molecular sieve 3A.
456 g. Zinc chloride are slowly introduced, while stirring, the solution thereby warming up slightly, whereafter the reaction mixture is left to ~tand overnight at ambient temperature. Subsequently, 285 g. D~ mannitol are introduced, while stirrin~, and stirring is continued for 3 hours at ambient ~ZS7279 temperature, the mannitol thereby going into solution.
The reaction mixture is filtered with suction, the filter residue is washed with a little dry acetone and the solution is immediately added, with stirring, to a mixture of 570 g. potassium carbonate, 600 ml.
water and 1700 ml. diethyl ether. Precipitated zinc carbonate is filtered off and the filtrate is evapor-ated. The residue is taken up in methylene chloride and the water still present is separated off. Subse-quently, the methylene chloride solution is dried over anhydrous sodium sulphate, treated with fuller's earth (floridin) and substantially evaporated.
3 Litres cyclohexane are then added thereto and left to crystallise. For further purification, the residue is again recrystallised from cyclohexane.
Yield: 200 g. 1,2,5,6-di-0-isopropylidene-D-mannitol, m.p. 120 - 121C.
b) S- (f ? -Isopropylidene-qlycerol To a solution of 199 g. sodium metaperiodate in 1680 ml. water is added portionwise, with stirring and ice cooling, in the course of 45 minutes, 244 g.
1,2,5,6-di-0-isopropylidene-D-mannitol. After the addition is complete, stirring is continued for 15 minutes and then 5 litres ethanol are added thereto.
The reaction mixture is filtered off with suction, the filter residue is then washed with ethanol and the filtrate is mixed, with slight cooling, in th~

~25~7 course of 5 minutes, with 71 g. sodium borohydride.
After further stirring for 2 hours at ambient temper~
ature, the pH value is adjusted with semiconcentrated acetic acid to 7.5. The mixture is left to stand for 15 minutes and then filtered off with suction. The filter residue is discarded and the filtrate is evaporated to such an extent that no more alcohol passes over. The remaining aqueous solution is extracted several times with methylene chloride. The combined methylene chloride phases are dried over anhydrous sodium sulphate and evaporated. The residue is distilled over a 40 cm. Vigreux column. Yield:
198.5 g. S-(~)-isopropylidene-glycerol, b.p. 45C./
0.7 mm.Hg, [a]D : +11.6 (c = 10: methanol), [~]D :
~15.1 (c = 100).
c) R-(-~-3-TosyloxYpropane-l L 2-diol To an ice-cold solution of 36 g. S-(+)-isopropylidene-glycerol in 150 ml. anhydrous pyridine is added portionwise, with stirxing, 52 g. ~-toluene-sulphonyl chloride~ After completion of the addition,the mixture is left to stand overnight in a refriger-ator. The solution is then diluted with 150 ml.
diethyl ether and washed with 1~ hydrochloric acid until the a~ueous phase ha~ an acidic pH value, a total of about 600 ml. lN hydrochloric acid being needed. Subsequently, the solutiGn is washed twice with saturated aqueous sodium hydrogen'carbonate ~25~9 solution, dried over anhydrous sodium sulphate, treated with floridin and evaporated. There are obtained ~9.1 g. of an oily residue of R-3-tosyloxy-propanediol acetonide which, without further puriic-ation, is further reacted. The acetonide is warmedto 80 C. in a mixture of 50 ml. acetone and 147 ml. lN
hydrochloric acid or 40 minutes, a clear solution being obtained. The solution is evaporated in vacuo and the residue is dissolved in methylene chloride.
The methylene chloride solution is dried over anhydrous sodium sulphate and evaporated. The residue is re-crystallised from diisopropyl ether. Yield: 45 g.
- R-(-)-3-tosyloxypropane-1,2-diol, m.p.... 62 C., [~]D : ~9 9 ~c = 7.9, methanol), [a]D : -6.8 (c = 7.5, pyridine).
d) ~=5~
45 g. R-(-)-3-Tosyloxypropane-1,2-diol are dissolved in a mixture of 40 ml. anhydrous methanol and 75 ml. anhydrous diethyl ether. To this is added dropwise, with stirring, at 0 to 5C., within the course of 20 minutes, a solution of 4 g. sodium in 90 ml. methanol. The reaction mixture is ~urther stirred for 2 hours and filtered off with suction.
The ilter residue is washed with diethyl ether and the filtrate is evaporated in vacuo at a bath temper-ature of 20C. The residue is again taXen up in diethyl ether and the solution treated with 10ridin, 1'25~7~

filtered off over Celite~and evaporated. 10.5 gO
R-glycidol are obtained as an oily residue. This is immediately further reacted in order to avoid a racemisation.
Example 2.
R-(-)-Epichlorhydrin To 32.7 g. (+)-3-mesyloxy-1,2-epoxypropane are added dropwise, with good cooling, 130 ml. concentrated hydrochloric acid. After completion of the addition, stirring is continued for 30 minutes at ambient temp-erature and the solution is then evaporated at a bath temperature o~ 30 C. After removal of remaining amounts of water, the solution is evaporated several times after the additiGn of ethanol. The last residues o~ solvent are removed by application of a high vacuum. There are thus obtained 40.4 g. R-l-chloro-2-hydroxy-3-mesyloxypropane. This is dissolved in 105 ml. dry ethylene glycol. After the addition of a solution of 5.2 g. sodium in 130 ml. dry ethylene glycol, the mixture is further stirred for 15 minutes at ambient temperature~ The resultant R-(-)-epichlor-hydrin is immediately distilled from the r~action solution by the application of a high vacuunt (O.1 -0.2 mm.Hg) at ambient temperature. For the condens-ation of the R~ epichlorhydrin, the cooler issupplied with a cooling brine with a temperature of -~0 to -50 C~ The collecting flask is also cooled to ~ tr2de mark this temperature. There are thus obtained 15.7 g.
R-(-)-epichlorhydrin, yield: 78%, []D0: -33.8 (c = 1, methanol).
Example 3.

5 s_ ( + ? -4-(2,3-EpoxyPropoxv)-carbazole 27.5 g. 4-H~droxycarbazole are dissolved in a mixture of 150 ml. lN aqueous sodium hydroxide sol-ution and 70 ml. dimethyl sulphoxide. To this is added at ambient temperature 13.9 g. R-(-)-epichlor-hydrin, followed by stirring for 18 hours at ambienttemperature. 280 ml. Water are then added thereto, followed by stirring for 15 minutes and filtering off with suction. The filter residue is washed with O.lN aqueous sodium hydroxide solution and water and subsequently dissolved in methylene chloride. The methylene chloride solution is dried over anhydrou~
sodium sulphate, treated with active charcoal and floridin and evaporated. The residue is purified by recrystallising twice from ethyl acetate. Yield:
- 20 15.2 g. S-(~)-4-(2,3-epoxypropoxy)-carbazole, m.p.:
163 - 164 C~ []D : ~64.4 (c = 1, pyridine).
From the mother liquors, there are isolated a further 6.7 g. of product, m.p.: 163 - 164C.
~a]D : +64.5 (c = 1, pyridine).
Example 4 21.9 g. 4-Hydroxycarbazole are dissolved in a ;7Z79 mixture of 120 ml. lN aqueous sodium hydroxide sol-ution and 40 ml. dimethyl sulphoxide. To this is added dropwise, at ambient temperature, a solution of 18.2 g. S-(+)-3-me~yloxy-1,2-epoxypropane in 20 ml. dimethyl sulphoxide. The mixture is stirred for 7 hours at ambient temperature, ~25 ml. water are added thereto, further stirred for 15 minutes and filtered off with suction. The filter residue is washed with O.lN aqueous sodium hydroxide solution and water and subsequently dissolved in methylene chloride. The methylene chloride phase is dried over anhydrous sodium sulphate, treated with active charcoal and floridin and evaporated. The residue is purified by recrystallising twice from ethyl acetate. Yield: 18.5 g. R-(-)-4-(2,3-epoxypropoxy)-carbazole, m.p.: 162 - 163 C., [~]D : -63.4 (c = 1, pyridine).
Example 5.
S-(-)-(l-Carbazol-4-Yloxy)-3-isopropylaminopropan-2-ol hydroacetate 500 mg. S-(+)-4-(2,3-Epoxypropoxy)-carbazole are dissolved in 4 ml. methanol and, after the addition of 2.8 ml. isopropylamine, the solution is heated to 65C. for 2 hours. It is then evaporated to dryness, taking care that no more isopropylamine is pre~ent. The residue is dissolved in 10 ml. hot ethyl acetate and the solution is mixed with 0.24 mlO

3L~St7279 glacial acetic acid. Upon cooling, S-(-)-carbazole hydroacetate crystallises out. The precipitate is filtered off, washed with ethyl acetate and dried.
Yield: 410 mg.; m.p.: 158 - 160C ; [a]20: -20.1 (c - 1, glacial acetic acid); optical purity accord--ng to gas chromatography findings: 99.5%.
Example 6.
R- t ~ ~ - 51-Carbazol-4-yloxy)-3-isopr~eyLami~npropan 2-ol hYdroacetate 18 g. R-(-)-4-(2,3-Epoxypropoxy)-carbazole are dissolved in 140 ml. methanol and, after the addition of 100 ml. isopropylamine, the solution is heated to 65C. for 2 hours. The solution is then evaporated to dryness, further dried for 1 hour in high vacuum for the removal of residual isopropylamine and the residue is dissolved in 300 ml. hot ethyl acetate.
The ethyl acetate solution is treated with floridin and, after suction filtration, mixed while still hot with 8.6 ml. glacial acetic acid. After cooling, the precipitated crystals are filtered off with suction.
- For further purification, the crystals are re-crystallised from ethyl acetate, with the addition of a little methanol. Yield: 23 g. R-~+)-(l-carbazol-4-yloxy)-3-isopropylaminopropan-~-ol hydroacetate m.p.: 158 - 160 C.; [a]D: ~20.2 (c = l; glacial acetic acid); optical puriiy: 98.6%, chemical purity: 99.97%

~s7279 - 24 ~ --Example 7.
R-(+)~ Carbazol-4-yloxY]-3- r 2-(2-methoxY~henoxy)1-ethYlami~propan-2-ol 5 g. R-(-)-4-(2,3-Epoxypropoxy)-carbazole are, S together with 6.9 g. o-methoxyphenoxyethylamine, heated under reflux in 35 ml. isopropanol for 2 hours~
The solvent is evaporated off and the residue is stirred for 2 hours with a mixture of 115 ml. toluene, 35 ml. cyclohexane and 40 ml. ethyl acetate. The reaction mixture is filtered off with suction and the residue is recrystallised from 150 ml. ethyl acetate.
Yieid: 3.7 g. R-(+)-(l-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)]-ethylaminopropan-2-ol, m.p.: 121 -123C., [a]20: +18.4 (c = 1, glacial acetic acid).
Example 8.
S-(-)-(l-Carbazol-4-vloxY~-3- r 2-(2-methoxyphenoxy~1-ethylaminoPropan-2-ol 10 g. S-(+)-4-(2,3-Epoxypropoxy)-car~azole are, together with 13.97 g. o-methoxyphenoxyethylamine, heated under reflux in 70 ml. isopropanol for 2 hours.
The solvent is evaporated off and the re~idue is stirred for 2 hours with a mixture of 115 ml. toluene, 35 ml. cyclohexane and 40 ml. ethyl acetate. ~fter filtering off with suction, the residue is recrystall-ised from 150 ml. ethyl acetate. Yield: 7.2 g. S~
(1-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)]-ethyl-aminopropan-2-ol, m.p. 121 - 123C., [a~20: -18.4 (c - 1, glacial acetic acid).

~25~7279 The patent specifications referred to `
herein are more particularly identified below:
Federal Republic of Germany Patent Speci-fication ~o. 22 40 599, published OctQber 16, 1975, Herbert Leinert et al, assigned to Boehringer Mannheim GmbH.
European Patent Specification 0, 004! 920 published August S, 1981, Fritz Wiedemann et al, assigned to Boehringer Mannheim GmbH.

Claims (9)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. An R- or S-4-(2,3-epoxypropoxy)-carbazole of formula (X):

(X)

2. R-(-)-4-(2,3-Epoxypropoxy)-carbazole.

3. S-(+)-4-(2,3-Epoxypropoxy)-carbazole.

4. A process for producing an R- or S-compound of formula (X), as defined in claim 1, comprising:
a) reacting an S-epoxide derivative of formula (II):

(II) in which R1 is the residue of a substituted sulphinic acid derivative, with 4-hydroxycarbazole to produce the R-compound, or b) reacting R-(-)-epichlorohydrin with 4-hydroxycarbazole to produce the S-compound.

5. A process for preparing R-(-)-4-(2,3-epoxy-propoxy)-carbazole comprising reacting an S-epoxide derivative of formula (II):

(XI) in which R1 is the residue of a substituted sulphinic acid derivative, with 4-hydroxycarbazole.

6. A process according to claim 5, wherein said reacting is in the presence of an organic solvent in an alkaline medium.

7. A process according to claim 5, wherein R1 is derived from methanesulphonic acid, p-toluene-sulphonic acid or benzenesulphonic acid.

8. A process for preparing S(+)-4-(2,3-epoxy-propoxy)-carbazole comprising reacting R-(-)-epi-chlorohydrin with 4-hydroxycarbazole.

9. A process according to claim 8, wherein said reacting is in the presence of an organic solvent in an alkaline medium.