DD142051A5 - PROCESS FOR PREPARING SPECIFIC DIASTEROMERS OF ERYTHRO-2- (2-ARALKYLAMINO-1-HYDROXY-AETHYL) -1,4-BENZODIOXANESE - Google Patents

Description

Field of application of the invention

The invention relates to a process for the preparation of specific optical isomers of 2-aminoethyl-1,4-benzodioxanes.

The compounds prepared according to the invention are used as medicaments for the treatment and cure of primary or secondary hypertension.

Characteristic of the known technical solutions

Complex isomeric mixtures of 2- (2-aralkylamino-1-hydroxyethyl) -1,4-benzodioxanes are disclosed in U.S. Patent 3,312,592, J. Med. Chem. 1J3, 169 (1970), or Chem. Abstr. 79, 126411j (1973) discloses β-adrenergic blocking, sympatho-lytic and adrenolytic agents for the treatment or prevention of diseases of the coronary arteries. These mixtures of at least eight erythro- and threodiastereomeric forms can not be easily separated.

Object of the invention

The aim of the invention is to provide a simple and economical process for the preparation of compounds which are suitable for the treatment and cure of primary or secondary hypertension.

Explanation of the essence of the invention

The invention is based on the Aufga.be to develop a method which gives the simplest possible mixtures of isomers.

Based on our new process for the production of. suitably substituted erythro-forms of α-oxiranyl-1, 4-benzodioxane intermediates, it is possible to obtain simple mixtures of said isomers, which are much easier to separate.

Surprisingly, it had been found that only the R, S., R-diastereoisomers of the general formula I have the said valuable pharmacological properties, while the S, R, S, S, R, R and R, S, S- Analogues rather contribute to their side effects, eg, "toxicity"

According to the invention, specific diastereomers of erytlir0-2- (aralkylamino-1-hydroxyethyl) -1,4-benzodioxane of the general formula I

CH-CH ₂ -M-CH- (CH ₂ ) _n - ¹ ^ (I), I *

OH ° m ^H 2m + l

manufactures, ... · ..

wherein each of the symbols X and Y is hydrogen, alkyl, lower alkoxy, halogen or trifluorine, I, each of the symbols ρ and q is the integer 1 or 2, and hedes the symbols m and η is the integer 1 to 4 , and their salts, in particular their pharmaceutically acceptable salts ·

The term "lower" in the above or below mentioned organic radicals or compounds defines those having at most 7 "preferably up to 4 carbon atoms. , - ·.

Accordingly, a lower alkyl group X and / or Y is preferably methyl, but also is, for example, ethyl, n- or isopropyl or -butyl. Mederalkoxy means, in particular methoxy, but also ethoxy, n- or iso-propoxy. or -butoxy- and halogen, in particular fluorine, chlorine or bromine.

21O 6BB - 3 -

The symbols m, ρ and q are preferably 1 and η is in particular 1 or 2.

Acid addition salts are preferably pharmaceutically acceptable acid addition salts of bases of general formula I, which are preferably those of strong inorganic or organic acids, e.g. Acid addition salts with the acids listed below.

The compounds of the invention show valuable pharmacological properties, primarily hypotensive, antihypertensive and bradycardic effects, which are due, inter alia, to their α- and 3-adrenergic blocking, vasodilatory and their inhibitory effects on the central sympathetic nervous system. These effects can be detected in animal experiments, preferably on mammals, such as rats, cats or dogs, as test subjects. The animals may be normotensive or hypertensive, e.g. be genetically hypertensive rats. The compounds mentioned may be administered enterally or parenterally, preferably orally or intravenously, e.g. by gelatin capsules or in the form of starch-containing suspensions or aqueous solutions. The dose used may range from about 0.01 to 50 mg / kg / day, preferably about 0.1 to 10 mg / kg / day, more preferably about 1 to 5 mg / kg / day. The. hypotensive effect is either directly with a catheter, e.g. is introduced into the femoral artery of the dog, or indirectly by sphygmomanometry on the rat tail, and a transfer instrument which indicates the eluent pressure before and after administration of the active ingredient in mm Hg. For example, e.g. the / 6-erythro-2R- [2- (4-phenyl-2R-butylamino) -13-hydroxyethyl] -1,4-benzodioxane, a typical representative of compounds of the present invention, preferably in the form of its hydrochloride,

I © - 4 -

very effective in said hypertensive rats, at peroral doses of 5 mg / kg / day and below. The bradycardic effects of this compound can be registered after a lower intravenous dose of 0.03 mg / kg, using anesthetized, bilaterally vagotomized bastard dogs whose heart rate is increased by electrical stimulation. The compounds of the present invention may accordingly be used as antihypertensives and bradycardic agents, e.g. used in the treatment or management of primary or secondary hypertension, angina pectoris and chronic hypertension. They can also be used as intermediates for the preparation of other valuable compounds, in particular of pharmacologically active preparations.

Preferred compounds are those

of the formula I wherein each of the symbols X and Y is hydrogen, fluorine, chlorine, trifluoromethyl, or alkyl or alkoxy each having at most 4 carbon atoms, ρ is the number one, q is 1 or 2 and each of the symbols m and η is the number 1 or 2, and their pharmaceutically acceptable acid addition salts.

Particularly noteworthy are the compounds of general formula II

OH CH

wherein Y 'is hydrogen, alkyl or alkoxy, each having at most 4 carbon atoms, and η is the number 1 or 2, and their pharmaceutically acceptable acid addition salts.

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The compounds of the invention can be prepared by methods known per se, preferably by

1) Compounds of the general formulas III and IV

X - + - Il _ I _ CH ₀ "^ \

η ·. · R · S 2 R ·

^Ν · ° H Y ~ ^ ^{0 +} V- ^ Vn-N, O m ^H 2m + l

(III)

in which all symbols have the meanings given above, condenses.

The epoxide condensation of general formula III does not require condensing agents but rather elevated temperatures, e.g. up to 100 - 150 °.

The starting material of the formula III is preferably prepared according to our new process, which comprises the following steps:

^a) S \ ^{/ CE0 11} ^ - ⁰ V ² O S \ / ^{CH0 H} -jj- ^CH 2- ^Z o X -f- * +> XM .11

ρ% A ι 'ρ% / \ / ^ch ₂ - ^c - ^h

^N OM Z -CH ₉ -CH ^X · ^N 0

o ^

wherein M is an alkali metal atom, and Z is a Haa ο

logenatom stands;

^b) S \ / ^{0CH0 H} -

₊ V 2AC-OOH ^ X _p -4- N, η _ _C / I _H

^Ν · o ^{x λ} (VI),

210 688 - ⁶ -. . ''' wherein the radical Ac is lower alkanoyl, halo-lower alkanoyl, unsubstituted or substituted benzoyl or phthaloyl, the latter containing one or two substituents X, and

c) ring closure of said epoxides of formula VI in the presence of a strong base to obtain the epoxides of formula III.

GS £ ~)

The strong base is represented by the formula M ^U OH

wherein M ^{+ is} the cation derived from M. The symbol M is in particular the radical of a quaternary organic nitrogen-containing compound or an alkali metal atom, such as lithium, sodium or, preferably, potassium. The remainder of a quaternary organic nitrogen-containing compound is, for example, a tetra-lower alkylammonium, such as tetraethylammonium, tetrabutylammonium, trimethyl-butylammonium, but also a benzyl triniederalkylammonium-, zB-. Benzyl-trimethylammonium, or an analogous saturated heterocyclic group, for example a Ν, Ν-dimethyl-piperidinium or Ν, Ν-dimethyl-pyrrolidinium or an aryl tri ~ niederalkylammonium, for example a phenyl trimethylammonium.

In the above reactions, M represents lithium or

Potassium, preferably sodium, and the strong base is primarily such a metal hydroxide, e.g. Potassium hydroxide or a strong quaternary organic nitrogen-containing base, e.g. a tri-lower alkyl benzyl ammonium hydroxide. Above all, the symbol Z_ means chlorine, but also bromine or iodine. The percarboxylic acid AcOOH is e.g. peracetic, trifluoroperacetic, perbenzoic, m-chloroperbenzoic or monoperphthalic acid. Peroxidation is said to be carried out in low boiling haloalkanes, e.g. Methylene chloride for said aromatic peracids or in lower alkyl alkanoates for the aliphatic peracids, are performed.

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The stated starting materials of the general formula III can also be prepared in situ, according to our new process. This consists in condensing in the presence of a strong base, compounds of the formulas given below:

.'V

OH H-C-CH ^ -Z

2 "1

ο: · γόη ^ - <->'in

wherein Z. ^ represents a reactive esterified hydroxy group, and the other symbols have the meanings given above. It is preferred to work in the presence of diluents, e.g. Lower alkyl formamides or sulfoxides and at temperatures. Between about 50 and about 70 °.

A reactive esterified hydroxy group Z is preferably a halogen atom, in particular chlorine, but also bromine or iodine; or an aliphatic or aromatic sufonyloxy group, e.g. Methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy or 'Brombenzolsulf onyloxygruppe.

The thus obtained d, £ -erythro compounds of formula III containing the R, S and S, R enantiomers may be reacted with optically active acids, e.g. Mandelic acid, tartaric acid, camphorsulfonic acid or 1- (1-naphthyl) ethyl isocyanate, to be separated. Such a separation may preferably be carried out as illustrated in the examples, according to process variant 3) described further below, or according to J. Org. Chem. 4J3, 3803 (1978). A starting material of formula III may also be prepared by chiral synthesis, as illustrated below. One uses in this synthesis the cheap, natural d-wine

9 U _ 8 -

acid for the construction of the four carbon atoms containing aliphatic portion of the starting material.

Another method for the preparation of compounds of the invention is that

2) Compounds of the general formula VIII

^{X # / Xq / oh C}

wherein all symbols have the meanings given above, chirally reduced with complex chiral alkali metal organoboranes or alanines.

The reduction is carried out in the usual way, e.g. with lithium β-isopinocampheyl-9-borabicyclo [3,3,1] nonyl hydride or with substitution products of lithium aluminum hydride with chiral bases, e.g. Ephedrine or amphetamines, performed.

The Schiff'sehen bases of formula VIII can be prepared starting from amines of general formula IX

χ _J_ s τ ^s

P · ν · 5 * CH-CH-NH (IX)

^Ν · Ό ι OH

and corresponding ketones are produced. The amines mentioned can be obtained by reacting an epoxide of the general formula III with ammonia. The ketones are known, or they can be prepared from known alcohols of the general formula X ^

HO-CH (CH _) - ~ ί t ^Y q

I ^{Δη x} ·

^C m ^H 2rn + l

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according to known methods, e.g. by oxidation with chromic acid or its anhydride.

Finally, the compounds of the invention can be prepared by

3) a d, ^ -erythro-2-oxiranyl-l, 4-benzodioxane compound of the general formula XI

I Il

VV * V

HH with a ^ -R-amino compound of general formula XII

R S \

^C m ^H 2rn + l

in which all symbols have the meanings given above, the resulting diastereomeric compounds are converted into their acid addition salts and the erythro mixture of salts of the diastereomeric compounds corresponding to the formula I, which mixture is R, S, R and S, R, R diastereomers, separated by selective crystallization.

The acid addition salts are e.g. those of pharmaceutically acceptable acids mentioned below. For example, Preferably, the hydrochloride of the desired R, S, R, stereoisomers from the solution, while the undesired S, R, R, stereoisomers remains in the solution. If necessary, the recrystallization is repeated until the optical rotation of the desired left-handed compound remains constant.

The recrystallization is preferably carried out in anhydrous or aqueous lower alkanols, e.g. Ethanol, iso- or n-propanol. "

The diastereomeric products obtained in the first step of process 3), which are formed by reacting the starting material XI with a compound XII, are prepared in a manner similar to that described in process 1). However, instead of the optically pure R, S, compound of the formula III, their corresponding (erythro) -R, S and S, R- * mixtures are used, which are obtained in accordance with process steps a) to c), as described above can be.

In a modification of process 3), the first step, which gives as intermediates the diastereomeric compounds, can be carried out in a manner analogous to process 2). However, instead of the optically pure R, S compound of the formula VIII, their corresponding (erythro) R, S and S, R mixtures are used. These can be prepared according to process steps a) to c), then by reaction with ammonia and subsequently with a corresponding ketone to obtain the Schiff base used as the starting material of the formula VIII. .

The compounds of the invention can be obtained in the form of free bases or as salts. A free base obtained may be converted into the corresponding acid addition salt, preferably with acids which yield therapeutically acceptable acid addition salts or with anion exchangers. Salts obtained can be converted to the corresponding free bases, e.g. by treatment with a stronger base, such as with a metal hydroxide or ammonium hydroxide, basic salt or a cation exchanger, e.g. with egg-

21 O 688

alkali metal hydroxide or carbonate. Acids - which yield therapeutically acceptable acid addition salts are e.g. inorganic acids such as hydrogen halides, e.g. Hydrochloric or hydrobromic acid, or sulfuric, phosphoric, nitric or perchloric acid; or organic acids, such as aliphatic or aromatic carboxylic or sulphonic acids, e.g. Formic, acetic, propionic, succinic, glycolic, lactic, acetic, tartaric, citric, maleic, hydroxymalein, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicyl, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethylsulfonic, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sufolanilic or cyclohexylsulfamic acid; or the ascorbic acid. These or other salts, e.g. the picrates, can also be used in the purification of free bases. The bases are converted into their salts, the salts are separated off and the bases are released from the salts.

As a result of the close relationship between the new compounds in free form and in the form of their salts, the corresponding salts or free compounds are to be understood as meaningful and appropriate in the preceding and following among free compounds and salts.

The abovementioned reactions are carried out by methods known per se, in the presence or absence of diluents, preferably in those which are inert towards and dissolve the reagents, catalysts, condensation agents or other agents mentioned above and / or in an inert atmosphere Cooling, at room temperature or at elevated temperatures, preferably at the boiling point of the solvent used, carried out at normal or elevated pressure.

21 O 698 - ¹² -

The invention also relates to modifications of the present process, according to which an intermediate obtained at any stage of the process is used as starting material and the remaining process steps are carried out, or the process is stopped at any stage, or after which a starting material is formed under the reaction conditions, or in which Starting material in the form of a salt or optically pure antipodes, is used.

In the process of the present invention, it is advantageous to use those starting materials which lead to the compounds described above as being particularly valuable, in particular those of the formula II.

The pharmacologically useful compounds of the present invention may be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with excipients suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules containing the active ingredient together with diluents, e.g. Lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. Magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, enzymes of the binders and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Injectable preparations are

preferably isotonic aqueous solutions or suspensions, and suppositories are prepared primarily from fat emulsions or suspensions. The preparations mentioned can be sterilized and / or contain auxiliaries, for example preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances are prepared in a conventional manner, for. B) by means of conventional mixing, granulating or coating methods, and containing from about 0.1% to about 90%, more preferably from about 1 % to about 75 % of the active ingredient

Export example

The invention will be explained in more detail below with reference to some examples. Temperatures are given in degrees Centigrade and the parts information refers to parts by weight. Unless defined otherwise, evaporation of solvents is carried out under reduced pressure, preferably between about 15 and 100 mmHg.

The above erythro-epoxides of formula III can be recorded as follows:

while the undesirable threo epoxides have the following Forme1

2 1 O 688

example 1

A mixture of 11 g of d, £ -erythro-2-oxiranyl-l, 4-. Benzodioxane and 9.2 g of ~ 3R-amino-1-phenylbutane are heated in a nitrogen atmosphere for 4 hours with stirring to 100 °. The still warm reaction mixture is dissolved in 100 ml of 2-propanol, the solution acidified with 17 ml of 4-normal ethanolic hydrogen chloride and mit.einigen crystals of the resulting salt inoculated. The mixture is allowed to stand at room temperature for 5 hours and at -10 ° overnight. The resulting precipitate is filtered off and washed with 25 ml of cold 2-propanol. Reflux 8.1 g of the resulting precipitate in 100 ml of 2-propanol and approximately 10 ml of water until dissolved. The solution is again slowly cooled to -10 °, the precipitate obtained filtered off and washed with water and diethyl ether. The ε-erythro-2R- [2- (4-phenyl-2R-butylamino) -ISS-hydroxyethyl] -1,4-benzodioxane hydrochloride, which melts at 200-202 °, gives [cc] = -13.5 ° (in dimethyl sulfoxide).

The starting material is prepared as follows: 2,000 ml of water are refluxed and, with vigorous stirring, admixed first with 3 ml of 40% aqueous tetrabutylamine magnesium hydroxide, 250 ml of salicylaldehyde and 280 ml of trans-1,4-dichloro-2-butene then dropwise with a solution of 83 g of sodium hydroxide in 400 ml of water until the pH of the mixture remains between 7 and 8 for 25 minutes. Then, the mixture is refluxed for about 6 minutes until the pH reaches 7, cooled to 20 °, and the aqueous layer extracted with diethyl ether. The extract is combined with the organic layer, washed with 5% aqueous sodium hydroxide solution, dried and evaporated. The residue will be

210

- 15 -

distilled and collected at 141-147 ° / 0.7 mmHg boiling fraction. 2- (4-chloro-trans-2-butenyloxy) -benzaldehyde is obtained. ,

To a solution of 155.7 g of the latter compound in 3800 ml of methylene chloride is added 357 g of 85% strength 3-chloroperbenzoic acid and the mixture is stirred for 1 hour and refluxed for 4 days. The reaction mixture is cooled and filtered. The filtrate is washed with methylene chloride and saturated aqueous sodium bicarbonate solution, dried and evaporated at 40 °. The 2- (4-chloro-trans-2,3-epoxybutyloxy) -phenol format is obtained, which has NMR "peaks" at 3.2, 2.5, 4.1, 7.0 and 8.2 ppm having.

A solution of 229.4 g of the latter compound in 900 ml of methanol is added dropwise with stirring under a nitrogen atmosphere between 8 and 15 ° with 1100 ml of a 10% aqueous potassium hydroxide solution. Stirring is continued at said temperature and at room temperature overnight, the mixture is decanted from the residue and extracted with diethyl ether. The extract is combined with the residue, washed with water, dried and evaporated. The residue is recrystallized from diethyl ether. This gives the d, 2-erythro-2-oxiranyl-l, 4-benzodioxane, which melts at 51-52 °.

A solution of 300 g of mercandic acid ([cc] _D = -147.3 ° in water) in 3500 ml of anhydrous ethanol is first stirred with 118.4 g of glacial acetic acid and then with 630.6 g 93.4% d, -3 -3-amino-1-phenylbutane, the container is washed with 400 ml of anhydrous ethanol. The mixture is stirred at room temperature for 6 hours and at 5 ° for 20 hours and then filtered. The residue is washed with 200 ml of petroleum ether and dissolved in 1100 ml of hot ethanol. You leave the solution

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Cool and 19 hours at room temperature, filtered and the residue washed with 100 ml of water, free ethanol. This gives the d-3-amino-l-phenyl-butanss-mandelate, which melts at 140-142 °.

Dissolve 228 g of the latter compound in a minimum amount of water, basify the solution with a 15% aqueous sodium hydroxide solution and extract with methylene chloride. The extract is washed with water, dried and evaporated. You get

* 2 p

the Q.- 3R-amino-1-phenyl-butane. [cc] * - -7,0 ° (in ethanol)

25 Its hydrochloride shows a [«] _η value of + 7.23 °

(in water), i. the salt formation reverses the direction of rotation.

The absolute configuration of the above 2R- [2- (4-phenyl-2R-butylamino) -ISS-hydroxyethyl] -1,4-benzodioxane hydrochloride can be determined as follows: its mother liquors containing its expected S, R, R diastereomers Form [the configuration of its 4-phenyl-2R-butylamino ₇ part is already in Rec. Trav. Chim. 82, 189 (1963)] are evaporated. Dissolve 1 g of the residue in 20 ml of ethanol and 10 ml of water. The solution is treated with a solution of 0.85 g of sodium meta-periodate in 10 ml of water and the mixture allowed to stand for 24 hours at room temperature. It is filtered, the filtrate is evaporated and the residue taken up in 20 ml of ethanol. The solution is treated with 0.2 g of sodium borohydride and the mixture is stirred for one hour at room temperature. It is evaporated, the residue taken up in 100 ml of diethyl ether and 20 ml of ethyl acetate and the solution washed with normal hydrochloric acid. The organic layer is dried, evaporated and the residue is gas-chromatographed at 160 °. This gives the 2R-hydroxymethyl-l, 4-benzodioxan, which has a [α] ~ - value of + 33.4 ° (in ethanol).

2 1 O 688 -17 -

Its absolute configuration is described in J. Med. Chem. 20, 880 (1977). Considering the sequence rules [Experientia JL2, 81 (1956)], the abovementioned mother liquor contains the d-erythro-2S- [2- (4-phenyl-2R-butylamino) -LR-hydroxyethyl] -1, benzodioxane hydrochloride whose diastereomeric form corresponding to formula I must be the R, S, R stereoisomers.

Example 2

A mixture of 3.75 gd, £ -erythro-2-oxirane-1, 4-benzodioxane and 3.5 g of 2R-amino-1-p-methoxyphenyl-propane [J. Med. Chem. 16, 480 (1973)] is heated with stirring for 4 hours at 100 °. The reaction mixture is poured into 25 ml of isopropanol, the solution acidified with 4-normal hydrogen chloride in ethanol, the precipitate separated and recrystallized from isopropanol. The ε -erythrol-2R- [2- (3-p-methoxy-phenyl-2R-propylamino) -ISS-hydroxyethyl] -l, 4-benzodioxane hydrochloride, which melts at 161-163 °, [cc] ^ ⁵ = -39.2 ° (in dimethyl sulphoxide).

Example 3

According to the method described in the preceding examples, starting from equivalent amounts of corresponding starting materials, the following compounds of the formula I are prepared (X = H, m = q = 1):

Example 4

No. η Υ salt

1 '1 H hydrochloride

2 1 o-OCH methanesulfonate

3 2 P-OCH ₃ hydrochloride

4 2 p-F hydrochloride

A mixture of 3 g of d, £ -erythro-2-oxirane-1, 4-benzodioxane and 2.8 g of R-3- (m-methoxyphenyl) -2-propylamine is stirred at 100 ° for 3 hours. After cooling, it is dissolved in 10 ml of isopropanol and the solution is acidified with 4-normal hydrogen chloride in ethanol. After addition of diethyl ether, the 1: 1 mixture of RSR and SRR-2- [2- (3-m-methoxyphenyl-2-propylamino) -l-hydroxy-ethyl] -1,4-benzodioxane crystallizes. hydrochloride, which melts at 110-115 ° and, as previously shown, is separable.

The starting material is prepared as follows: a mixture of 33.5 g of m-methoxy-phenylacetone, 25 g of d-cc-methylbenzylamine and 120 ml of benzene is refluxed for 24 hours, the resulting water (3.5 ml) being separated azeotropically. The reaction mixture is evaporated, the residue dissolved in 20 ml of ethanol and the solution hydrogenated over 20 g of Raney nickel at 50 ° and 3.1 atmospheres until the intake of one molar equivalent of hydrogen. The mixture is filtered, the filtrate is evaporated, the residue taken up in 100 ml of isopropanol and the solution acidified with ethanolic hydrogen chloride. The resulting precipitate is recrystallized from ethanol-isopropanol three times until a constant rotation and a constant melting point are reached.

2 1 O 688

The N-d-a-methylbenzyl-in-methoxyphenyl-2-prcpylamin hydrochloride, [α] ^ = + 19.16 ° (2% in methanol), which melts at 230 ° with decomposition.

A solution of 16 g of the latter compound in 120 ml of ethanol and 30 ml of water is hydrogenated over 5 g of a 10% palladium on carbon catalyst until one molar equivalent of hydrogen is consumed. The mixture is filtered, evaporated, the residue taken up in water and the solution basified with sodium hydroxide. It is extracted with methylene chloride, the extract is dried and evaporated. The R-3- (m-methoxy-phenyl) -2-propylamine is obtained as an OeI.

Example 5

A mixture of 2.45 g of d, 2-erythro-2-oxiranyl-1,4-benzodioxane and 2.3 g of R-3- (p-fluorophenyl) -2-propylamine is stirred for 3 hours at 100 °. After cooling, the reaction mixture is dissolved in 20 ml of hot isopropanol and the solution is acidified with 4-normal hydrogen chloride in ethanol. The mixture is cooled slowly, filtered and the residue recrystallized from aqueous isopropanol. The ε-erythro-2R- [2- (3-p-fluorophenyl-2R-propylamino) -IS-hydroxyethyl] -1,4-benzodioxan hydrochloride is obtained,

25 which melts at 238-240 ° with decomposition. [a] _D =

-11.97 ° (2% in dimethyl sulfoxide).

The starting material is prepared as follows: A solution of 10 g of racemic R-S-3- (p-fluorophenyl) -2-. propylamine in 50 ml of hot isopropanol is added 12 g of -2 -2-benzodioxanylacetic acid. The precipitate obtained after cooling is filtered off and recrystallized from isopropanol. The product is in a minimum

21O 686

Dissolved the amount of water, the solution basified with sodium hydroxide and extracted with methylene chloride. The extract is dried and evaporated. The R-3- (p-fluorophenyl) -2-propylamine is obtained. Its hydrochloride melts at 142 °. [a] ^ ⁵ = + 6.25 ° (2% in water).

Example 6

»Production of 10'000 tablets containing 10 mg each of the active substance:

ingredients:

^ [2- (4-Phenyl-2R-butylann.no) -IS-hydroxyäthy1] -1,4-benzodioxan

hydrochloride 100 g

Lactose 1706 g

Cornstarch 90 g

Polyethylene glycol 6000 90 g

Talcum powder 90 g

Magnesium stearate - 24 g

Purified water q.s.

Procedure: All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is mixed with lactose, talc, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 45 ml of water and the suspension added to the boiling solution of polyethylene glycol in 180 ml of water. The resulting paste is added to the powders and optionally granulated with the addition of another amount of water. The granules are dried overnight at 35 °, through

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a sieve of 1.2 mm mesh size and compressed into tablets of 7.1 mm diameter, which have a breaking groove pressed.

Example 7

Preparation of 1O ¹ OOO capsules with a content of 25 mg of the active substance:

ingredients:

2R- [2- (3-p-Methoxyphenyl-2R-propylamino) -ISS-hydroxyethyl] -1,4-benzodioxane hydrochloride 250 g

Milk sugar 2350 g

Talcum powder 150 g

Procedure: All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is first homogenized with talc and subsequently with the lactose in a suitable mixer. Capsules No. 2 are filled with 300 mg each of the Geraisches with a filling machine.

Example 8

A mixture of 1.1 g of erythro-2R- (1S-oxiranyl) -1,4-benzodioxan and 0.92 g of 3R-amino-1-phenylbutane is heated to 100 ° with stirring in a nitrogen atmosphere for 4 hours. The reaction mixture is then dissolved in a minimal amount of 2-propanol, the solution acidified with 4N hydrochloric acid in anhydrous ethanol and allowed to stand at -10 ° overnight. The obtained

The precipitate is filtered off, washed with cold 2-propanol and diethyl ether. The erythro-2R- [2- (4-phenyl-2R-butylamino) -ISS-hydroxyethyl] -1,4-benzodioxane hydrochloride, which melts at 200-202 °, gives [a] ^ ⁵ = -13, 5 °. The product is identical to that of Example 1.

The starting material is prepared as follows: A solution of 8 g of thiophenol in 150 ml of tetrahydrofuran is added under cooling in an ice bath with 4 g of 50% sodium hydride in mineral oil with stirring in a nitrogen atmosphere. After hydrogen evolution ceases, 12.8 g of d, 2-erythro-2-oxiranylbenzodioxane are added and the mixture is allowed to warm to room temperature. The reaction mixture is then refluxed for 2 hours, cooled, acidified with 10% hydrochloric acid and evaporated. The residue is taken up in diethyl ether, the solution washed with water and evaporated. The d, ε-erythro-2- (2-phenylthio-1-hydroxyethyl) -1,4-benzodioxan is obtained. This is taken up in 50 ml of toluene containing 1% Ν, Ν-dimethylethanolamine, the solution with 14 g of (R) -N- [1- (1-naphthyl) ethyl] isocyanate and refluxed for 6 hours , The reaction mixture is evaporated and the residue chromatographed on neutral alumina eluting with hexane-methylene chloride (5: 1) on a 280 mm column. The first fractions are collected and evaporated. The N- [IR- (1-naphthyl) -ethyl] -IS- (1,4-benzodioxan-2R-yl) -2-phenylthioethylcarbamate is obtained.

A solution of 18.8 g of the latter compound in 200 ml of methylene chloride and 10.2 g of triethylamine is added dropwise with a solution of 3.4 ml of trichlorosilane in 50 ml of methylene chloride and the reaction mixture is refluxed overnight. After cooling, it is washed with saturated aqueous ammonium chloride solution.

210

'see and evaporated. The erythro-2R- (2-phenylthio-1S-hydroxyethyl) -1,4-benzodioxan is obtained.

The latter compound is dissolved in 60 ml of methylene chloride and the solution is added with stirring 4 g of trimethyloxonium fluoroborate. Stirring is continued until all the salt is dissolved (3 hours). The mixture is then added with stirring 47 ml of a 10% aqueous sodium hydroxide solution, after 3 hours the organic layer separated, dried and evaporated. This gives 3.4 g of the desired erythro-2R- (IS-oxiranyl) -1,4-benzodioxane, which has a sufficient purity.

The starting material can also be prepared according to the following chiral synthesis. The four carbon atoms of the cheap, natural d- (R, R) tartaric acid are used for the formation of the four-carbon aliphatic part of the starting material:

A solution of 6.5 g of o-benzyloxyphenol and 1.8 g of sodium methoxide in 100 ml of isopropanol is mixed with 15 g of 2,2-dimethyl-1,3- (4S, 5S) -dioxolane-4,5-dimethanol bistosylate [prepared according to D. Seebach, HeIv. j> 0, 301 (1977)]. The reaction mixture is refluxed for 48 hours and evaporated. The residue is taken up in methylene chloride, the solution washed with water and evaporated. The 5- (o-benzyloxyphenoxymethyl) -2,2-dimethyl-1,3-4S, 5S-dioxolane-4-methanol tosylate is obtained.

A mixture of 25 g of the latter compound, 60 ml of 2N hydrochloric acid and 120 ml of methanol is refluxed for 6 hours and partly concentrated. 'Steamed. The concentrate is diluted with water and washed with water

210 6

Extracted methylene chloride. The extract is washed with aqueous sodium bicarbonate solution, dried and evaporated. The residue is recrystallized from isopropanol. The pure 1-Or (o-benzyloxyphenyl) -L-threitol, which melts at 105 °.

A solution of 10 g of the latter compound in 100 ml of methylene chloride is first treated with 0.2 g of methanesulfonate and then slowly with 5.1 g of isopropenyl ether in 20 ml of methylene chloride, stirring the mixture at 0-5 ° for 3 hours. The reaction mixture is stirred for a further 4 hours at room temperature, then neutralized with triethylamine, washed with water and evaporated. The 1-0- (o-benzyloxyphenyl) -3,4-isopropylidene-L-threitol is obtained.

The latter compound is taken up in 50 ml of pyridine at 5 °, treated slowly with 4 g of methanesulfonyl chloride and the mixture allowed to stand overnight at room temperature. The reaction mixture is poured into ice-water, the suspension is filtered and the residue is washed with water. The 1-0- (o-benzyloxyphenyl) -3 _/ 4-isopropylidene-L-threitol-2-mesylate is obtained.

The latter compound is taken up in 100 ml of ethanol and hydrogenated over 1 g of 10% palladium on carbon catalyst at 2.7 atmospheres until one molar equivalent of hydrogen is taken up. The mixture is filtered, the filtrate is treated with 2.5% sodium methoxide and the mixture is refluxed for 48 hours. The reaction mixture is neutralized with concentrated hydrochloric acid, evaporated and the residue is refluxed in a mixture of 30 ml of hydrochloric acid and 60 ml of methanol for 5 hours. The reaction mixture is concentrated to a small volume and treated with methylene chloride.

2! O 688

rid extracted. The extract is washed with aqueous sodium bicarbonate solution, dried and evaporated. The IS- (1,4-benzodioxan-2R-yl) -ethylene glycol is obtained.

The latter compound is dissolved in 30 ml triäthyl orthoacetic acid, treated with 0.2 ml of trifluoroacetic acid and the mixture allowed to stand for 6 hours at room temperature. It is neutralized with triethylamine, evaporated, the residue taken up in water and the mixture extracted with methylene chloride. The extract is dried and evaporated. The corresponding orthoacetate is obtained.

The latter compound is dissolved in 50 ml of methylene chloride and treated with 10 ml of trimethylchlorosilane. After stirring for 4 hours, the mixture is evaporated at room temperature, the residue taken up in 120 ml of methylene chloride, treated with 4 g of tetrabutylammonium bromide and 120 ml of 2 N aqueous sodium hydroxide. The mixture is stirred vigorously for one hour, the organic layer separated, washed with water, dried and evaporated. The desired erythro-2R- (IS-oxiranyl) -1,4-benzodioxane is obtained for the above reaction with 3R-amino-1-phenylbutane.

^i? The crude R, S-epoxide is distilled in a short Kugelrohr distillation apparatus at 13VO, 1 mmHg. The pure R, S-epoxide, which melts at 65 °, gives the optical rotation [a] ^ ⁵ = -48.6 ° (c> = 2% in methylene chloride).

2! O 6BB - 26 -

Example 9

A mixture of 10 g of erythro-2R- (1S-oxiranyl) -1,4-benzodioxane and 100 ml of 10% ammonia in ethanol is heated to 100 ° in a melt tube for 12 hours. After cooling, the reaction mixture is evaporated, the residue dissolved in 100 ml of tetrahydrofuran, and 8.3 g of benzylacetone are added together with 40 g of 3A molecular sieve

added. The mixture is stirred overnight, filtered, diluted with 100 ml of tetrahydrofuran and then stirred in a nitrogen atmosphere at 25 ° with 19 g of lithium-.beta.-isopinocampheyl-9-borabicyclo [3,3,1] nonyl hydride for 24 hours. (The catalyst was prepared according to S. Krishnamurthy et al., Abstracts of Papers, 173rd ACS Meeting, March 20-25, 1977; No. ORGN.17.) The reaction mixture is subsequently treated with 25 ml of 4N aqueous hydrochloric acid and evaporated. The residue is stirred with 100 ml of warm isopropanol, filtered and the residue recrystallized from aqueous isopropanol. The erythro-2R- [2- (4-phenyl-2R-butylamino) -ISS-hydroxyethyl] -1,4-benzodioxane hydrochloride, which melts at 200-202 °, is obtained. The product is identical to that of Example 1.

Claims (7)

invention claim 1 · A process for the preparation of a specific diastereomer of ei ^ thro-2- (2-aralkylamino-1-hydroxyethyl) -1,4-benzodioxanen of the general formula I. Ji ^{0H C} m ^H 2in ₊ l wherein each of X and Y represents Y, oxygen, alkyl, lower alkoxy, halogen or trifluoromethyl, each of the symbols ρ and q is the integer 1 or 2, and each of the symbols m and η is the integer 1 to. 4, and their salts, characterized by being one 1) Compounds of the general formulas III and IV f * ^ · ' ^, CH ₀ R ^{0 C} m ^H 2rn + l CE) in which all symbols have the meanings given above, condenses _: or 30.5 * 1979 ...._ APC07D / 210 688 54 920 18 2) Compounds of the general formula VIII 4-y OH CH ₀ ^ ₁ m 2m + l in which all symbols have the meanings given above, with complex chiral alkali metal organoboranes or alanines, chirally reduced or 3) a d, t -erythro ~ 2-0xirany1-1,4 ~ benzodioxane compound of general formula XI HW with a "£ -R-amino compound of the general formula XII R ^ ^ H N-CH - (CH ₉ ) "J ^C m ^i! 2m + 1 in which all symbols have the meanings given above, the diastereoisers obtained 210 6.88 - ^2S 30.5.1979 _._ APC07D / 210 688 - ₄ * · 54 920 18 Converting compounds into their acid addition salts and separating the erythro mixture of salts of the diastereomeric compounds corresponding to formula I which mixture containing 'R, S,' R-% and, S, R, R diastereomers, by selective crystallization or 4) an (erythro) -R, S and S, R mixture of a compound corresponding to formula VIII shown above, wherein all symbols have the meanings given above, with complex chiral alkali metal organoboranes or - alans, chirally reduced, the obtained converts diastereomeric compounds into their acid addition salts and separates the erythro mixture of salts of the diastereomeric compounds corresponding to formula I, the mixture containing R, S, R and S, R, R diastereomers, by selective crystallization and, if desired, a free compound obtained in a salt or a salt obtained in the free compound or transferred to another salt « 2. Method according to item 1, reaction 1), characterized in that one carries out the reaction at elevated temperature. 3 »method according to item 1, characterized in that one carries out the reduction in the reaction 2) with lithium-ß-isopinocampheyl -9-borabicyclo Z3,3 ~ l7nonyl hydride or with substitution products of lithium aluminum hydride with chiral bases. 4.-method according to item 1, characterized in that one AP C 07 D / 210 688 54 920 18 21 0 - 30 - in reaction 3) the reaction of compounds of formulas XI and XII is carried out at elevated temperature » Process according to one of the items 1 to 4, characterized in that compounds of the formula I shown in point 1, wherein each of the symbols X and Y is hydrogen, fluorine, chlorine, trifluoromethyl, or alkyl or alkoxy, each having at most 4 carbon atoms , ρ is the number one, q is 1 or 2 and each of the symbols m and η is the number 1 or 2, and produces their pharmaceutically acceptable acid addition salts. 6. The method according to any one of items 1 to 4, characterized in that compounds of the general formula II ^{s R} Il -H-υ · (H) CH-CH ₂ -IIH-CH- (CH ₂ ) - K ^ _Q ffi » OH GH, -5 wherein Y ¹ "is hydrogen, alkyl or alkoxy, each having at most 4 carbon atoms, and η is the number 1 or 2, and produces their pharmaceutically acceptable acid addition salts. 7. The method according to any one of items 1 to 4, characterized in that one ε-erythro-2R - /? ~ (4-phenyl-2R ~ butylamiriü) AP C 07 ": D / 21Ö 688 54 920 18 210 6 & Q - 31 -. -IS-hydroxy-ethyl-1-j4-benzodioxan and its pharmaceutically acceptable acid addition salts, 8. The method according to any one of items 1 to 4, characterized in that man- ^ -erythro-2R- / 2- (3-p-methoxyphenyl-2K-propylaaino) ~ 1S-hydroxyäthyl.7 ~ 1,4 ~ ben2odiOxan and its pharmaceutically useful acid addition salts manufactures.