DE2213044C3 - Racemic and optically active 1 - (23-dichlorophenoxy) -3-tert. - butylamino-2-propanol and its salts, processes for their production and pharmaceuticals based on these compounds - Google Patents

Description

3. Medicines, characterized by a content of one or more compounds according to claim 1 as an active ingredient or ingredients.

The invention relates to the subjects defined in the claims.

From the literature (J. Med. Chem. 12, 638 [1969]) are racemic 1- (2,5-dichlorophenoxy) -3-n-propylamino-2-propanol and racemic I- (2,5-dichlorophenoxy) -3-isopropylamino-2-propanol are known. Further describes the DT Auslcgeschrift 12 36 523 im Phenyl nucleus doubly chloro-substituted 1-phenoxy-3-tert.-butylamino-2-propanols.

It has now surprisingly been found that racemic and optically active 1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol and their salts have a pharmacological effectiveness that is superior to this.

The invention relates to racemic and optically active 1 (2,5-dichlorophenoxy) -3-tert-bulyl-amino-2-propanol and their salts. The amine base has the formula

0-CH ₂ CHCH ₂ -NH C (CH,).,
OH

Furthermore, according to the invention, medicaments are those which contain one or more of the above compounds as an active ingredient or contain active ingredients, provided.

The inventive spatial and optical Active compounds namely have a strong / i'-adrenergic blocking effect (hereinafter , i-blocker effect) and are therefore / ur prevention against or treatment of angina pectoris, coronary artery and knee vascular diseases, Taehy-

cardic or excessive heart function and for treatment of dysfunction caused by pheochromocytoma.

To demonstrate the superior pharmacological effects of the compounds of the invention comparative tests were carried out. The compounds recognized as having good effects were used as comparison compounds Handicraft product l - (\ - Naphthyloxy) -3-isoptopyIamino-2-propanol hydrochloride same direction of action (propranolol; L. S. Goodman and A. Cj i 1 m a η, The Pharmacological Basis of Therapeutics, The MacMillan Company, New York, Fourth Edition, 1970, page 565) as well as the constitutional

4S similar compounds i - (2,5-dichlorophynoxy) -3-isopropylamino-2-propanol, 1 - (2,6-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride, 1- (2,4-dichlorophenoxy) - 3 - tcrt. - butylamino - 2 - propanol hydrochloride and l- (2,3-dichlorophynoxy) -3-sec-butyl-

so contrasted amino-2-propanol. The LD ₅₀ values were determined according to JT Litchficld and F. WiI-co χ on (J. Pharm. Exp. Ther. 96, 99 [1948]), and the inhibition of the action of isopropyl noradrcnalin was determined according to RD R ο bs ο η and

See H. R. Kaplan (J. Pharm. Exp. Ther. 175, 157 [197O]) determined. Inhibition of bronchial ailment according to O. A r u η 1 a k s h a η a and H. O. Schild (Brit. J. Pharm. 14, 48 [1959]) and D. T. Burden and M. W. Parkes (Brit. J. Pharm. 41,

do 122 [197I]). The lifting of the by Cardiac arrhythmia caused by ouabain was described by C. R a ρ e r and J. Wale (Eur. J. Pharmacol. 4, 1 [1968]) and the inhibition of the lypolysis was determined according to J. J. L e c h and co-workers (Molecular

<vs Pharmacol. 2, 501 [1966]). The beneficial ones Properties of the compounds according to the invention are summarized in Tables I and 2 below.

Table 1

connection

Acute Inhibition of the effect inhibition The ouabain- The through adrenaline toxicity of isopropyl noradrenaline the bron- arrhythmia hcrpre- (p. V.) in dogs chuserwei- inhibiting > called LDso value change pA ₂ Minimum dose Lypolysis too in mg / kg Heart muscle pulse *) in cats in mg / kg 50% (Mouse) power * ·) (Cat) inhibiting Dose in moles

1- (α-Naphthyloxy) -3-isopropylamino-2-propanol hydrochloride (Propranolol) (±) -1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride (according to the invention)

(-) -1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride (according to the invention)

(+ H- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride (according to the invention)

35.0 34.7

32.0

34.0

4.1

2.4

5.9 7.17 2.5 7.7 ^'10

14.6 8.96 0.66 1.05 · 10 ~ ^lü

16.3 7.16 0.37 8.5 ■ 10 ""

3.0 8.1

8.62

0.35

2.5 x 10 "

·) Is the degree of inhibition caused by a dose of 0.25 mg / kg = ratio of the response sizes of the control animal and

of the test animal 30 minutes after administration of the dose.
** Is the negative logarithm of the double inhibitory dose (in mol / kg).

Table 2

connection

(±) -1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride (according to the invention)

(-) -1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride (according to the invention)

(+) -1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride (according to the invention)

l - ((X-Naphthyloxy) -3-isopropylamino-2-propanol hydrochloride (Propranolol, comparison substance) 1- (2,5-dichlorophenoxy) -3-isopropylamino-2-propanol (Comparison substance)

! - ^, o-DichlorophenoxyJ-S-tert-butylamino ^ -propanol hydrochloride (Comparison substance) l - ^^ Dichlorphenoxyi-S-tert.-butylamino ^ -propanol hydrochloride (Comparison substance) l- (2,3-dichlorophenoxy) -3-sec-butylamino-2-propanol (comparison substance)

acute toxicity
(iv)
LD ₅₀ -WcH The Ouabainar
inhibiting rhythm
Minimum dose (iv) quotient
LD ^ value in mg / kg
(in mice) in mg / kg
(in cats) inhibiting
Minimum dose (the therapeu
table index
proportional) 34.7 0.66 52.6 32.0 0.37 86.5 34.0 0.35 97.1 35.0 2.5 14.0 37.8 5.13 7.4 16 14.8 1.1 43 12.3 3.5 22nd 10.2 2.2

According to the available pharmacological investigations are therefore (t) - or (-) - I- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanoI specific // blockers. From Table 1 it can be seen that with respect to its effect on the inhibition of the adrenaline-induced lipolysis is 7.3 and 9 times as strong as that of the compound l - (> - Naphthyloxy) -3-isopropykimino-2-propanol hydrochloride which is currently generally used in this field. As for the inhibition of the arrhythmia caused by ouabain, this is Racemate (±) -1- (2,5-dichlorophenoxy) -3-tert-bulylamino-2-propanol hydrochloride 3.8 times and the enantiomer (-) -l- (2,5-Diehlophenoxy) -3-tert-butylamino-2-propanol hydrochloride 6.8 times as effective

ds like l - (\ - Naphthyloxy) -3-isopropylamino-2-propanol hydrochloride. [Since the acute toxicity and the bronchodilator-inhibiting effect of the invention Connections with those of the

1 - (α-naphthyloxy) -3-isopropylamino-2-propanol hydrochloride practically coincide, these compounds are therapeutic in a broader sense Area applicable. Its main application is in heart diseases associated with respiratory disorders or advantageous in the treatment of thrombosis.

Table 2 shows the inhibition of the arrhythmia caused by ouabain In addition, the above results show that the therapeutic index of the racemate according to the invention (±) -1 - (2,5 - dichlorophenoxy) -3 part. - butylamino-2-propanol hydrochloride 3.8 times and the therapeutic index of the enantiomer according to the invention (-) - 1 - (2,5-dichlorophenoxy) - 3 - tert. -butylamino-2-propanol hydrochloride 6.2 times as high as the therapeutic index of the comparative compound 1 - (n, - naphthyloxy) - 3 - isopropylamino - 2 - propanol hydrochloride is.

Further, regarding the inhibition of the arrhythmia caused by ouabain, the following is shown in Table 2 out: The inventive racemate (±) -l - (2,5-dichlorophenoxy) - 3 - tert. - butylamino - 2 - propanol hydrochloride is 7.8 times as effective as the comparison substance 1 - (2,5-dichlorophenoxy) -3-isopropylaniino-2-propanol, 22.4 times as effective as the comparison substance 1 - (2,6-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride, 18.6 times as effective as the comparison substance 1 - (2,4-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride and 15.5 times as effective as the comparative substance 1- (2,3-dichlorophenoxy) -3-sec-butylamino-2-propanol. The therapeutic index of the racemate according to the invention (±) - 1 - (2,5 - dichlorophenoxy) - 3 - tert. - butylamino-2-propanol hydrochloride is 7.1 times as high as the therapeutic index of the reference substance 1- (2,5-dichlorophenoxy) -3-isopropylamino-2-propanol, 47.8 times as high as the therapeutic index of the reference substance 1 - (2,6-dichlorophenoxy) -3-lert.-butylamino-2-propanol hydrochloride, 15.0 times as high as the therapeutic index of the reference substance 1- (2,4-dichlorophynoxy) - 3 - tert. - butylamino - 2 - propanol hydrochloride and 25, O times as high as the therapeutic one Index of the comparison substance 1- (2,3-dichlorophynoxy) -3-sec-butylamino-2-propanol. The enantiomer according to the invention (-) -l- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride is 13.9 times as effective as the comparison substance l- (2,5-dichlorophenoxy) -3-isopropylamino-2-propanol, 40.0 times as effective as the comparison substance l- (2,6-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride, also 33.2 times as effective as the comparison substance 1- (2,4-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride and 27.6 times as effective as the comparison substance 1 - (2,3-dichlorophenoxy) -Z-sec-butylamino-2-propanol. The therapeutic index of the enantiomer of the invention (-) - l- (2,5-dichlorophenoxy) - 3 - tert. - Butylamino - 2 - propanol hydrochloride is 11.7 times as high as the therapeutic index the comparison substance l- (2,5-dichlorophenoxy) -3-isopropylamino-2-propanol, 78.6 times as high as the therapeutic index of the reference substance 1 - (2,6-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride, 24.7 times as high as the therapeutic index of the reference substance 1- (2,4-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride and 39.3 times the therapeutic index of the reference substance I - (2,3-dichlorophenoxy) -3-sec-butyl-

amino-2-propanol. The enantiomer (+) -1- (2,5-dichlorophenoxy) K3-tert-butylamino-2-propanol hydrochloride according to the invention is 14.7 times as effective as the comparison substance 1 - (2,5-dichlorophenoxy) -3-isopropylamino-2 -propanol, 42.3 times as effective as the comparison substance 1 - (2,6-dichlorophenoxy) -3-terl.-butylamino-2-propanol hydrochloride, furthermore 35.1 times as effective as the comparison substance 1- (2.4 -Dichlorophenoxy) - 3 - tert. - butylamino - propanol hydrochloride and 29.1 times as effective as the comparison substance l- (2,3-dichlorophenoxy) -3-sec-butylamino-2-propanol. The therapeutic index of the enantiomer according to the invention (+) - 1 - (2,5-dichlorophenoxy) -3-tert.-butylamino-2-propanol hydrochloride is 13.1 times as high as the therapeutic index of the comparison substance 1 - (2.5 - Dichlorophenoxy) -3-isopropylamino-2-propanol, 88.3 times as high as the therapeutic index of the reference substance 1 - (2,6-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride, 27.7 times as high as that therapeutic index of the comparison substance 1 - ( 2,4-dichlorophenoxy) -3-tcrt.-butylamino-2-propanol hydrochloride and 44.1 times as high as the therapeutic index of the comparison substance I - (2,3-dichlorophenoxy) -3-sec .-Butylamino-2-propanol.

From all of this it is clear that the invention Compared to the comparison connections, connections have an outstanding mushroom effect regarding the inhibition of the arrhythmia caused by ouabain.

It is also very surprising that of the compounds according to the invention both (±) -l- (2,5-dichlorophenoxy) - 3 - tert. - butylamino - 2 - propanol hydrochloride and (-f) -l - (2,5-dichlorophynoxy) -3-tert-butylamino - 2 - propanol hydrochloride and (-) - 1 - (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride have a superior effect on the inhibition of the arrhythmia caused by ouabain, because of the isomeric forms of the Comparison substance 1 - (, * - Naphthyloxy) -3-isopropylamino-2-propanol hydrochloride (Propranolol) only have the racemic compound and the (-t -) - isomcr an effect on the inhibition of the arrhythmia caused by oubain (cf. R. Hο wc and R. G. Sh anks: Nature 210 [1966], 1338), which is also incomparably less than that of the compounds of the invention is as demonstrated above.

The compounds of the present invention have been found to be useful in cardiac arrhythmia patients and one complete resistance to other / i-blockers, such as propranolol and 1-isopropylamino-3- (4-indolyloxy) -2-propanol hydrochloride as surprisingly outstandingly effective. The compounds according to the invention were found not only in sinus tachycardia, supraventricular or overlying the ventricle paroxysmal tachycardia in the case of atrial flutter and taehycardic forms of absolute arrhythmia (for these diseases the therapy was 100% effective) as outstandingly effective, but also resulted in ventricular extrasystoles (premature Hitting) in 50% of cases to full effect or at least 50% reduction the number of extrasystoles.

In contrast, it is known that the known / (- blocking agents are generally not used for treatment of ventricular arrhythmias are suitable.

In case of essential circulatory hypcrkincsc show-

In the compounds of the invention when administered in a peroral single dose of 2.5 mg a surprisingly strong negative chronotropic resp. the effect of reducing the pulse rate, while at the same time increasing the duration of the Krcishiufdaucr; simultaneously their negative inotropc or heart muscle weakening effect is also not significant.

Decreased in patients with anginal symptoms the compounds according to the invention not only alleviated the number of anginal attacks, but also alleviated them also the anomalies which are symptomatic of the disease and can be detected by the egg electrocardiograph.

It should be emphasized that the surprisingly strong therapeutic effect of the during the clinical trials Compounds according to the invention neither by for /. 'Blockers often have characteristic specific side effects (cardiodepressive effects and effects impairing respiratory function) nor from unspecific side effects (such as effects on the blood-forming organs, the liver function, the kidneys and metabolism) still from for some / f-blockers characteristic side effects (such as eye damage, fibrous peritonitis or fibrous Peritonitis and butterfly-like or lupus erythematosus-like changes) was accompanied.

The racemic form of 1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol can be used in therapy as a tablet or injection solution. The tablets expediently each contain H) mg of the active ingredient, while the injection solutions preferably each have 1 mg of the active ingredient in 2 cm 'solution contain. The enantiomers of! - (2,5-dichlorophynoxy) -3-tert-butylamino-2-propanol can be used in a similar way, but with the difference that In this case, the active ingredient content in both forms of use is only half that of the Raccmat target. 3 to 6 tablets per day and 1 to 6 tablets per day for injection solutions 2 ampoules are administered.

That used as starting material in embodiments a) and f) of the process according to the invention 1- (2,5-Dichlorophenoxy) -2.3-epoxypropane is expediently made by reacting 2,5-Dichlorphcnol with epichlorohydrin in an aqueous alkaline medium.

The 1- (2,5-dichlorophynoxy) -3-chloro-2-propanol used as starting material in embodiments b) and f) is conveniently obtained by reacting 2,5-dichlorophynol with epichlorohydrin in one anhydrous medium or prepared without a solvent in the presence of an organic base.

The reactions of embodiments a), b), c) and d) of the process according to the invention are expediently carried out in an ethanol medium. In embodiment c) of the invention Procedure is called l-halo-3-terL-butylamino-2-propanol preferably 1-chloro- or 1-bromo ^ -tert-butylamino ^ -propanol used.

For the preparation of the enantiomers of M2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol and their salts is either the racemate obtained according to one of embodiments a), b), c) or d) cleaved, or the cleavage into the optical isomers is carried out on an intermediate product.

The fractional crystallization of the diastereomeric salt pair of (1 ) -I- (2,5-dichlorophenoxy) -3-tert-butylamino-2- formed in embodiment c) of the process according to the invention with (-) - or (+) -dibcnzoyltartaric acid propanol must be carried out at a temperature above 40 C, since this salt pair is surprisingly only stable above 40 C. This is because the salt of the racemic compound is formed at a lower temperature and cannot be separated into a diastreoisomeric salt pair by crystallization. Examples of lower

ίο alcohols, in which the fractional crystallization Can be done are methanol and ethanol. The desired enantiomer is preferred obtained as hydrochloride and purified by recrystallization from water.

In embodiment f) of the process according to the invention, the conversion of 1- (2,5-Dichlüiphcnoxy) -2,3-epoxypropane is carried out or 1- (2,5-dichlorophenoxy) -3-chloro-2-propanol in 1- (2,5-dichlorophenoxy) -3-amino-2-propanol expediently carried out with the aid of aqueous or ethanolic ammonia. The fractional crystallization of the diastercoma formed with (-) - or (+ (-Dibcnzoyltartramid) Salt pairing is preferably carried out in an ethanolic medium. The alkylation of the resulting optically active 1- (2,5-dichlorophenoxy) -3-amino-2-propanol with a tert-butyl halide is expediently carried out by heating to boiling in an ethanol medium.

Depending on the pH of the medium, the optically active 1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol is used or its corresponding salt, which can also be used in another in therapy water-soluble salt can be transferred, obtained. Acids suitable for salt formation are, for example Salt, hydrogen bromide, sulfur, phosphorus, Älhansulfon-, Tartaric, almond, salicylic and ascorbic acids.

The use of the hydrochloride is most beneficial for therapeutic purposes.

The invention is explained in more detail with reference to the following examples.

example 1

A solution of 32.6 g (0.2 mol) of 2,5-dichlorophenol, 8.08 g (0.202 mol) of sodium hydroxide and 16 cm '(0.202 mol) of epichlorohydrin in 400 cm ^{3 of} water was kept at 40 ° C. for 5 hours and then extracted 3 times with 100 cm ^{3 of} chloroform each time. The combined chloroform phases were washed twice with 80 cm 'of water each time and dried over sodium sulfate. The solvent was then removed in vacuo. The 33.1 g of l- (2,5-dichlorophenoxy) -2,3-epoxypropane thus obtained were dissolved in 200 cm ^{3 of} anhydrous alcohol, ^{heated with 30 cm 3 of} tert-butylamine for 8 hours on a water bath and the solution in vacuo evaporated to dryness. The crystalline residue, the weight of which was 43.6 g, was dissolved in 120 cm ^{3 of} boiling anhydrous alcohol, and 50 cm ^{3 of} ethanolic hydrochloric acid were added. The precipitated 1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride was filtered off. After drying it weighed 35.5 g; Melting point 210 to 212 "C. The base was released in such a way that the hydrochloride

f, _{5 dissolved} in 700 cm ^{3 of} water and 160 cm ^{3 of} a 10% sodium bicarbonate solution was added to the solution. The product woe 31.3 c: melting point 82 to 83 C.

Example 2

A solution of 3.26 g (0.02 mol) of 2,5-dichlorophenol in 5.7 g (0.06 mol) of epichlorohydin was admixed with 0.04 cm of pyridine and then heated on the water bath for 10 hours. After the excess epichlorohydrin had been driven off in vacuo, the resulting 4.82 g of crude! - (2,5-dichlorophenoxy) -3-chloro-2-propanol were dissolved in 10 cm ^{3 of} anhydrous ethanol and 3 cm ^{3 of} tert-butylamine were added . Otherwise, the procedure described in Example I was followed.

Example 3

A solution of 18.5 g (0.1 mol) of the sodium salt of 2,5-dichlorophenol and 17 g (0.1 mol) of 1-chloro-3-tert.-butylamino-2-propanoi in 100 cm ¹ anhydrous ethanol was heated on the water bath for 10 hours. The sodium chloride which separated out during the reaction was filtered off and 30 cm ^{1 of} ethanolic hydrochloric acid were added to the solution. Otherwise, the same procedure as in Example I was followed.

Example 4

32.6 g (0.2 mol) of 2,5-dichlorophenol were mixed with a solution of 8 g (0.2 mol) of sodium hydroxide in 1000 cm ^{3 of} ethanol, then 31.2 g (0.24 mol) of l, 2-epoxy-3-tert-butylaminopropane was added, the solution was kept on the boiling water bath for 4 hours, acidified with ethanolic hydrochloric acid and then evaporated to dryness in vacuo. The residue was recrystallized several times from water to separate off the sodium chloride; Otherwise, the procedure described in Example 1 was followed.

Example 5

A solution of 9.70 g of (-) -dibenzoylwcinsäuremonohydrat and 7.45 g of 1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol in 50 cm ^{1 of} anhydrous alcohol at 45 to 50 "C left to stand overnight. The precipitated dl salt weighed 6.67 g. Melting point (165) - 166 167 C (with decomposition): [λ],: = -57.1 "(1% i,; c alcoholic solution) . After recrystallization from 50 cm 'alcohol, 3.41 g of optically pure salt were obtained. Melting Point (168)

169 170 C (with decomposition); [λ] ,: = -54.1 (1% alcoholic solution). The product was dissolved in 15 cm ^{3 of} alcohol and 3 cm ^{3 of} HCl in alcohol were added. The precipitated crystals were filtered off and then recrystallized twice ^{from 10 cm 3 of water.} 1.20 g of (+) -1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride were obtained. Melting point 211 to 212 "C; [λ] /: = +3.90" (1% aqueous solution).

9.45 g of H salt, which after recrystallization from ether weighed 7.02 g, were obtained from the mother liquor of the dl salt. Melting point (150) - 152 153 "C (with decomposition); [«]? = -64.3 "(1% ethanolic solution). The product was dissolved in 20 cm ^{3 of} alcohol and left to stand at room temperature overnight. The precipitated racemic salt was filtered off, the mother liquor was evaporated to dryness in vacuo and the residue on the filter was washed with ether. Yield 5.25g; Melting point (155) - 156-157 ° C (with decomposition); M? = -66.1 ° (1% ethanol solution). The product was dissolved in ethanol and ^{mixed with 5 cm 3 of} hydrochloric acid ethanol. The precipitated crystals were filtered off and recrystallized twice ^{from 20 cm 3 of water.} There was thus obtained 2.10 g of (-) - 1- (2,5-dichlorophenoxy) -3-tert-butylamino-2-propanol hydrochloride. Melting point 211 to 212 C; [\ | = -3.93 (1% aqueous solution).

Example 6

tune solution of 16.3 g (0.1 mol) 2,5-dichlorophenol,

ο 4.04 g of sodium hydroxide and 8 cm 'epiehlorhydrin in 200 cm' of water was kept at 40 ° C. for 5 hours and then extracted ^{3 times with 50 cm 3 of} chloroform each time. The combined chloroform phases were ^{washed twice with 40 cm 3 of} water each time, dried over sodium

i_s sulfate dried and the solvent driven off in vacuo. The 17.3 g of l- (2,5-dichlorophenoxy) -2,3-epoxypropane thus obtained were dissolved in 200 cm ^{3 of} ethanol, 200 cm ^{3 of} a 25% aqueous ammonia solution were added and the mixture was left to stand for 4 to 5 days at room temperature. The deposited precipitate was filtered off and the mother liquor was evaporated to dryness in vacuo. The residue was dissolved in 200 cm ^{3 of} 2 N hydrochloric acid while being heated to boiling, the solution obtained was clarified with charcoal and then cooled. This gave 12.22 g of 1 - (2,5 - dichlorophynoxy) - 3 - amino - 2 - propanol hydrochloride with a melting point of 222 to 223 ° C. The product was dissolved in 500 cm ^{3 of} hot water and 70 cm ^{3 of} 10% strength Sodium bicarbonate solution precipitates the base. The product weighed 9.32 g; melting point 129 to 130 "C (with decomposition).

A solution of 2.36 g of 1- (2,5-dichlorophenoxy) -3-amino-2-propanol and 3.57 g of (-) - dibenzoyltartramide the formula

COOH

C ₆ H ₅ COO CH
Ce ₁ H ₅ COO-CH

CONH,

4i in 30 cm ^{3 of} anhydrous alcohol was left to stand overnight at room temperature. 2.60 g of I] salt were thus obtained; Melting point 169 to 170 "C (with decomposition); [*] ',', ' = - 89.1" (1% solution in dimethylformamide). This product was dissolved in 25 cm ^{3 of} hot ethanol, and 4 cm ^{3 of} alcoholic hydrochloric acid were added. After cooling, 1.10 g of (-) - 1 - (2,5 - dichlorophenoxy) - 3 - amino - 2 - propanol hydrochloride with a melting point of 226 to 228 ° C. were obtained. The product was ^{recrystallized twice from 10 cm 3 of} water. Yield 0.92 g; melting point 227 to 228 "C;[>] £ '= -6.77 "(1% aqueous solution). The compound was dissolved in 50 cm ^{3 of} water and 5 cm ^{3 of} a 10% sodium bicarbonate solution were added, whereupon 0.80 g of base separated out. Melted point 130bisl32 "C (under heat dissipation); [, \] ?: ^; = -2.02 "(1% solution in dimethylformamide).

The mother liquor of the 11-salt was evaporated to dryness in vacuo and the residue was ^{recrystallized from 20 cm 3 of} ethanol, a further 0.23 g of 11-salt precipitating out. After filtering off the latter, evaporating the mother liquor and recrystallizing the residue from ether, 2.30 g of dl salt were obtained; Melting point 156 to 157 "C (under

Decomposition); [V]; ' = -81.5 "(1% solution in dimethylformamide). The product was dissolved in 10 cnr 'ethanol and the solution was ^{treated with 3 cm 1 of} alcoholic hydrochloric acid. Thus 0.80 g of (+) -l- (2.5 -Dichlorophenoxy) -3-amino-2-propanol hydrochloride with a melting point of 226 to 228 ° C. After repeated recrystallization from 8 enr 'water, the product weighed 0.64 g. Melting point 227 to 228 ° C; [\] .. = I 6, 42 (1% aqueous solution). The latter product was dissolved in 32 cm ^{1 of} water, and 3.5 enr ^{1 of} a 10% sodium carbonate solution was poured into the rabbit. This gave 0.52 g of base. Melting point 130 to M2 C ( with decomposition); [x] «: = +2.01
(I ".ιige solution in dimethylformamide).

f-. a solution of 2.36 g (0.010 mol) (-) -l- (2,5-dichlorophynoxy) -3-amino-2-propanol and 3 cm ¹ (0.026 mol) tert-butyl bromide in KK) Ethanol was heated on the water bath for 20 hours. The deposited precipitate was filtered off, the mother liquor was evaporated to dryness in vacuo and the residue was recrystallized twice from water. The hydrobromide obtained was dissolved in 50 cnr 'water and the base with 10% sodium bicarbonate

I like the solution. The base was then dissolved in ethanol and by adding hydrochloric acid alcohol to (-) - I - (2,5 - dichlorophynoxy) - 3 - tcrt. - butylamino-2-piopanol hydrochloride implemented. Melting point 211-212'C; | \] ·, Ί '= -3.90 "(1% aqueous solution).

Claims (2)

Patent claims: 1. Racemic and optically active 1- (2,5-dichlorophenoxy) - 3 - tert. - butylamino - 2 - propanol and their salts. 2. Process for the preparation of the compounds according to claim 1, characterized in that one in each case in a manner known per se IO a) l- (2,5-dichlorophenoxy) -2,3-epoxypropane with tert-butylamine or b) 1 - (2,5-dichlorophenoxy) -3-chloro-2-propanoI with tert-butylamine or c) the sodium salt of 2,5-dichlorophenol with ^ an I-halogen ^ -tert.-butylamino ^ -propanol or d) 2,5-dichlorophenol is reacted with 1,2-epoxy-3-tert-butylaminopropane and / or e) that with (-) - or (+ (-Dibenzoylwcinsäure formed diastereomeric Safzpaar des f -t) -1 - (2,5 - dichlorophenoxy) -3 - tert-butylamino-2-propanol subjected to fractional crystallization in a lower alcohol above 40 ° C. or 0 1 - (2,5 - dichlorophenoxy) - 2,3 - epoxypropane or 1 - (2,5-dichlorophenoxy) -3-chloro-2-propanol converted with ammonia into 1- (2,5-dichlorophenoxy) -3-amino-2-propanol, its formed with (-) - or (+ J-dibenzoyltartramide) The (-) - and (+) -l- (2,5-dichlorophynoxy) -3-amino-2-propanols thus obtained are subjected to a fractional crystallization of the diastereomeric salt pair alkylated with a tert-bulyl halide on the nitrogen atom and optionally the base obtained in a Acid addition salt transferred or the base liberated from its salt.