NO122125B - - Google Patents

Description

Analogy method for the production of pharmacodynamically active, new, substituted 5-phenyl-6,7-benzomorphans.

The present invention relates to a method for the production of pharmacodynamically active, new, substituted 5-phenyl-6,7-benzomorphans and their salts with valuable pharmacological properties.

Phenyl-substituted benzomorphans in the 5-position are not known to date. It was now surprisingly found that compounds of the general formula I where R. means hydrogen, halogen or the hydroxyl group,

R2 hydrogen, the hydroxyl, lower alkoxy or lower alkanoyloxy group,

X hydrogen or alkyl with 1-3 C atoms, and

Y cycloalkylmethyl with a maximum of 7 C atoms, lower alkyl with a maximum of 5 C atoms, hydroxyl lower alkyl, phenethyl-, nitrophenethyl-°g aminophenethyl residue, lower alkenyl with optionally with halogen when double bonded,

C, cinnamyl or propargyl,

their optically active forms, as well as their salts with inorganic or organic acids possess valuable pharmacological properties, especially analgesic action. Many of these compounds are, in contrast to morphine and other known benzomorphans, surprisingly free of disease-causing properties. Furthermore, the new 5-phenylbenzomorphans show an antitussive effect and some of them are antagonists of morphine. The compounds can be used orally in a normal pharmaceutical administration form, i.e. in the form of tablets, capsules, powders, suspensions, solutions, syrups, etc. Of particular advantage are the forms with delayed active substance release, which can be prepared after a <; >or other known method.

r The compounds of the general formula I are prepared, as mania reacts a compound of the general formula II

where , R 2 and X have the meanings given above, with a compound of the general formula III

where Y has the above meaning and

Hal means a chlorine, bromine or iodine atom,

in the presence of an acid-binding agent and reacts, if desired, a compound thus obtained, which contains a hydroxyl group in the 2'-position, with an alkylating or alkanoylating agent, if desired, cleaves a racemic product into optically active forms and transfers, if desired, a product of an addition salt with an inorganic or organic acid.

As an acid-binding agent suitable for this reaction is an al-potassium bicarbonate or carbonate such as e.g. sodium or potassium carbonate very well. Furthermore, it is advantageous to carry out this reaction in a suitable inert solvent, such as dimethylformamide in particular, since it is usually carried out at an elevated temperature, such as e.g. at the boiling temperature of the reaction mixture.

This method is particularly valuable for the preparation of compounds of the general formula I, where Y represents an alkenyl or alkynyl residue. As compounds with the general formula III, the following alkenyl and alkynyl halides are therefore particularly mentioned: allyl chloride and bromide, propargyl chloride and bromide, 1-bromo-3-methyl-2-butene, 1,3-dichloro-1 -propene, 1,3,3-trichloro-2-propene, 1,3-dichloro-2-butene, 1, 2-dibromo-2-propene, 1,4-dibromo-2-butene, 1,1,3 -tribromo-1-propene, 1,3-dibromo-1-propene, 1,2,3-trichloro-1-propene, 1,2-dichloro-2-propene and 1,1,2,3-tetrachloro-2 -propene. For the introduction of the residue Y, which is an alkyl, hydroxyalkyl or a phenylalkyl group, the formed halides, such as e.g. methyl, ethyl, propyl, butyl and pentyl chloride or bromide, 2-chloro- or -bromoethanol or -propanol, 3-chloro- or -bromopropanol, phenethyl bromide or -chloride and p-nitrophenethyl chloride or -bromide.

The starting materials with the general formula II required for this method can e.g. is obtained by reacting a 2-methyl-5-phenyl-6,7-benzomorphan substituted according to the meaning of , R2 and X with cyanobromide according to von Braun and cleaving the 2-cyano derivative thus obtained, hydrolyzing it or reducing it with a complex metal hydride.

As can be seen from formula I, the compounds according to the invention can exist in optically isomeric forms. Thus, the presence of an asymmetric carbon atom in the morphan ring leads to the formation of d- and l-forms. If X in formula I is an alkyl residue, then stereoisomers are possible, since the alkyl group can be bound cis or trans to the phenyl group in the 5-position. Furthermore, isomeric forms are formed when the group denoted by Y does not have triplan symmetry. In all these cases, however, the geometric or stereoisomeric forms can be separated, using their different properties, i.e. by fractional crystallization or by distillation.

If one wants to separate enantiomorphic forms, the diastereoisomeric salts are formed in the usual way using an optically active acid. All these isomeric forms are likewise subject to the invention.

With inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanedisulfonic acid, p-hydroxyethanesulfonic acid, acetic acid, propionic acid, maleic acid, fumaric acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid , phenylacetic acid and mandelic acid form the compounds with the general formula I salts, which are partly well soluble in water.

The following examples explain the implementation of the method according to the invention, but are by no means the only embodiments of the same. The temperatures are indicated in degrees Celsius.

EXAMPLE 1

2'- hydroxy- 2- allyl- 5- phenyl- 6, 7- benzomorphan

a) 2.90 g (2.07 ml) of allyl bromide in 50 ml of dimethylformamide are added dropwise while stirring to a suspension of 5.31 g of 2'-hydroxy-5-phenyl-6,7-benzomorphan, m.p. 239 - 241° and 3.02 g of sodium bicarbonate in 100 ml of dimethylformamide. The mixture is stirred for 4 hours under reflux, then evaporated to dryness and triturated with hot water, so that a suspension is obtained. The suspension is cooled, filtered, and the residue obtained is recrystallized from pure ethanol. 2'-hydroxy-2-allyl-5-phenyl-6,7-benzomorphan is obtained, m.p. 231 - 236°. Recrystallization from pure ethanol increases the melting point to 238 - 240°. b) The following alternative method also leads to the same product: 2 g of 2'-hydroxy-5-phenyl-6,7-benzomorphan, 1.12 g of sodium bicarbonate and 1.12 g of allyl bromide are heated in 50 ml of pure ethanol under reflux and stirring 8 hours. The solvent is then removed in vacuo and the residue is dissolved in water and chloroform. The aqueous layer is separated and the chloroform solution is extracted several times with dilute aqueous hydrochloric acid. The acidic extracts are filtered clear and made alkaline by the addition of aqueous ammonia. The solid formed is dissolved in chloroform and this solution is dried over sodium sulphate and the solvent is evaporated. The residue gives after recrystallization from methanol 2'-hydroxy-2-allyl-5-phenyl-6,7-benzomorphan. Temp. 238 - 240°. c) In an analogous manner, using cinnamyl chloride, 2<1->hydroxy-2-cinnamyl-5-phenyl-6,7-benzomorphane, hydrochloride, m.p. 274 - 277°.

The starting material was prepared in the following way:

2'-hydroxy-5-phenyl-6,7-benzomorphan

a) 2'- acetoxy- 2- cyano- 5- phenyl- 6, 7- benzomorphan A solution of 2.59 g (24.4 millimoles) of cyanobromine in 30 ml of chloroform is added to 6.53 g (20.3 millimoles) 2 -acetoxy-2-methyl-5-phenyl-6,7-benzomorphan as free base. The addition extends over 45 minutes at room temperature. The reaction solution is heated for 3 hours under reflux and then concentrated in vacuo. The residue formed is recrystallized from acetone until its melting point is constant (m.p. 207-209°).

b) 2'-hydroxy-5-phenyl-6,7-benzomorphan

A suspension of 5.60 g lithium aluminum hydride in 100 ml torr

tetrahydrofuran is added under anhydrous conditions to 5.00 g of 2'-acetoxy-2-cyano-5-phenyl-6,7-benzomorphan, which had been dissolved during heating in 100 ml of dry tetrahydrofuran. The mixture is heated for 17 hours under reflux and then decomposed by adding 29 ml of saturated sodium chloride solution. The resulting mixture is then heated under reflux for 1 hour and then filtered. The filtrate is concentrated in vacuo, and the residue is recrystallized from isopropanol. 2'-hydroxy-5-phenyl-6,7-benzomorphan is obtained, m.p. 239 - 241°.

EXAMPLE 2

21- hydroxy- 5- phenyl- 2- propargyl- 6, 7- benzomorphan 1.80 ml (2.70 g) of propargyl bromide in 10 ml of dimethylformamide is added dropwise at room temperature with stirring to a suspension of 2.65 g of 2'-hydroxy- 5-phenyl-6,7-benzomorphan and 1.88 g of potassium carbonate in 100 ml of dimethylformamide. The reaction mixture is heated for 14 hours with stirring under reflux, then dried under reduced pressure and the residue triturated with hot water, so that a suspension is formed. This suspension is cooled, filtered, and the residue obtained is washed with water, dried and recrystallized

res from pure ethanol. 2<1->hydroxy-5-phenyl-2-propargyl-6,7-benzomorphan is obtained, m.p. 237 - 239°.

EXAMPLE 3

2'- hydroxy- 2-(3-methyl- 2- buteny1)- 5- phenyl- 6, 7- benzomorphan

a) A mixture of 8.7 g of 2<1->hydroxy-5-phenyl-6,7-benzomorphan, 6.0 g of 1-bromo-3-methyl-2-butene, 5.0 g of sodium bicarbonate and

125 ml of dimethylformamide is heated with stirring for 4 hours at reflux. The solvent is then removed under vacuum, and the remainder is worked up in the usual way. As a product, 2'-hydroxy-2-(3-methyl-2-butenyl)-5-phenyl-6,7-benzomorphan is obtained, m.p.

176 - 178°.

Furthermore, one obtains analogously from racemic or optically active 2'-hydroxy-9-methyl-5-phenyl-6,7-benzomorphan b) (+)-2'-hydroxy-2-(3-methyl-2-butenyl)- 9-methyl-5-phenyl-6,7-benzomorphane, methanesulfonic acid salt, m.p. 264 - 265°; c) (-) form of the base m.p. 164 - 165°; (-)-form hydrochloride, m.p. 271 - 273°; (-)-form as methanesulphonic acid salt, m.p. 226 -

227°, [cc]q<5> = -126° (methanol);

d) (+)-form of the base, m.p. 162 - 165°; [oc]^<6> = + 166°

(methanol) (+)-form hydrochloride, m.p. 278 - 280; [<x]D =

+ 146° (methanol).

EXAMPLE 4

2'-hydroxy-2-(3-chloro-2-propenyl)-5-phenyl-6,7-benzomorphan A solution of 1.8 g of 1,3-dichloro-1-propene in 20 ml of dimethylformamide is added at room temperature under stirring a suspension of 1.2 g of sodium bicarbonate and 3.5 g of 2'-hydroxy-5-phenyl-6,7-benzomorphan in 30 ml of dimethylformamide. The mixture is kept for 4 hours under reflux, cooled and evaporated in vacuo to dryness. The residue is triturated with 100 ml of chloroform and 50 ml of water. The chloroform layer is washed with 20 ml of water, dried over anhydrous sodium sulphate and evaporated to dryness. The residue is then recrystallized from pure ethanol to give 2<1->hydroxy-(3-chloro-2-

propenyl)-5-phenyl-6,7-benzomorphan, m.p. 186 - 190°, which is further purified by recrystallization from pure ethanol. Melting point of the pure product: 197 - 198°.

In a similar way, using 1,3,3-trichloro-2-propene; 1,3-dichloro-2-butene; 1,2-dibromo-2-propene; 1,4-dibromo-2-butene;

, 1,1,3-tribromo-1-propene; 1,3-dibromo-1-propene; 1,2,3-trichloro-1-propene; 1,2-dichloro-2-propene and 1,1,2,3-tetrachloro-2-propene the following compounds are prepared: 2<1->hydroxy-2-(3-(3,3-dichloro-2-propenyl) -5-phenyl-6,7-benzomorph an;

2'-hydroxy-2-(3-chloro-2-butenyl)-5-phenyl-6,7-benzomorphan, m.p. 184 - 186° (from isopropanol);

2'-hydroxy-2-(2-bromo-2-propenyl)-5-phenyl-6,7-benzomorphan, m.p. 158 - 160° (from ether);

2'-hydroxy-2-(4-bromo-2-butenyl)-5-phenyl-6,7-benzomorphan;

2'-hydroxy-2-(3,3-dibromo-2-propenyl)-5-phenyl-6,7-benzomorphan;

2'-hydroxy-2-(3-bromo-2-propenyl)-5-phenyl-6,7-benzomorphan;

2'-hydroxy-2-(2,3-dichloro-2-propenyl)-5-phenyl-6,7-benzomorphan;

2'-hydroxy-2-(2-chloro-2-propenyl)-5-phenyl-6,7-benzomorphan as well as

2'-hydroxy-2-(2,3,3-trichloro-2-propenyl)-5-phenyl-6,7-benzomorphan, m.p. 109 - 110° (from isopropanol).

EXAMPLE 5

2' - hydroxy- 2- ((3- ph enethyl) - 5- ph enyl- 6, 7- benzomorph an

a) A mixture of 2.00 g of 2'-hydroxy-5-phenyl-6,7-benzomorphan, 0.76 g of sodium bicarbonate, 1.74 g of fresh distillate (3-phenethyl bromide) and 50 ml of dimethylformamide is heated for 4 hours at an oil -bath temperature of 145° and then stirred overnight at room temperature. The mixture is concentrated in vacuo, and the residue is washed with 100 ml of water and dried. 2'-hydroxy-2-((3-phenethyl)-5-phenyl- 6,7-benzomorphan, m.p. 219 - 228°. If this product is washed with 50 ml of ethanol, the melting point rises to 225 - 229°. 2 g of this product is suspended in 150 ml of boiling methanol and this suspension is added to 4.0 ml of 2 ,4-n ethanolic hydrochloric acid. After cooling and standing, 2<1->hydroxy-2-(B-phenethyl)-5-phenyl-6,7-benzomorphan is obtained in the form of the hydrochloride, m.p. 346 - 348° (decomposition , which after recrystallization from 60 ml of dimethylsulfoxide at 95°, with the addition of lOO ml of water at 95° and cooling, melts at 347 - 349° (decomposition). b) In a similar way, one obtains when instead of 8-phenethyl bromide, an equivalent lean amount of pentyl bromide, 2'-hydroxy-2-n-pentyl-5-phenyl-6,7-benzomorphan, m.p. 194 - 196°. The hydrochloride has a melting point of 314 - 316°. c) If methyl bromide is used instead of pentyl bromide, then 2'-hydroxy-2-methyl-5-phenyl-6,7-benzomorphane is obtained,

m.p. 249 - 252°, hydrochloride, m.p. 294 - 296°.

d) In an analogous way, from 2<1->hydroxy-9-methyl-5-phenyl-6,7-benzomorphan and methyl bromide, 2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan is obtained , m.p. 227 - 228°. e) If 1-bromo-2-methyl-2-butene is used instead of methyl bromide, 2'-hydroxy-2-(3-methylbut-2-enyl)-9-methyl-5-phenyl-6 is obtained, 7-benzomorphane, m.p. 161 - 164°. f) If in the above-mentioned method 2'-hydroxy-5-phenyl-6,7-benzomorphan is replaced by 2<1->hydroxy-5-(p-chlorophenyl)-6,7-benzomorphan, m.p. 267 - 27 2°, then 2'-hydroxy-2-(B-phenethyl)-5-(p-chlorophenyl)-6,7-benzomorphan is obtained, m.p. 270 - 27 2°. The hydrochloride melts above 350°.

In an analogous way, according to the aforementioned method, 2'-hydroxy-5-phenyl-6,7-benzomorphan is obtained (m.p. 239 - 241°; prepared from 2'-acetoxy-2-methyl-5-phenyl-6,7 -benzomorphane by means of cyanogen bromide decomposition) and the corresponding alkylating agents: g) 2'-hydroxy-2-cyclobutylmethyl-5-phenyl-6,7-benzomorphane, hydrochloride, m.p. 310 - 312°; h) 2<1->hydroxy-2-cyclopropylmethyl-5-phenyl-6,7-benzomorphane, m.p. 225 - 229°5 hydrochloride, m.p. 264 - 266°; methanesulfonic acid

salt, m.p. 263 - 264°5 and using 2'-hydroxy-9-methyl-5-phenyl-6,7-benzomorphan;

i) 2'-hydroxy-2-cyclobutylmethyl-9-methyl-5-phenyl-6,7-benzomorphanet, hydrochloride of (-)-form, m.p. 291 - 292°; methanesulphonic acid salt of (-) form, m.p. 271 - 273°;

k) 2'-hydroxy-2-cyclopentylmethyl-9-methyl-5-phenyl-6,7-benzomorphine, m.p. of (-)-form 285 - 286°, [oc]^<5> 149° (methanol) .

Analogously, one obtains from 2'-hydroxy-9-methyl-5-(4-fluorophenyl)-6,7-benzomorphan: 1) 2'-hydroxy-2,9-dimethyl-5-(4-fluorophenyl)-6, 7-benzomorphane, m.p. 214 215°; (-)-form, m.p. 215 - 217°, [α]^<5> = -112°; (+)-form, m.p. 216 - 217°, [a]" = +118°;

and from 2'-hydroxy-5-(4-hydroxyphenyl)-6,7-benzomorphan:

m) 2'-hydroxy-2-methyl-5-(4-hydroxyphenyl)-6,7-benzomorphane, m.p. 295 - 297°, hydrobromide, m.p. 329 - 330°;

as well as from (-)-2'-methoxy-9-methyl-5-phenyl-6,7-benzomorphan:

n) (-)- 21-methoxy-2,9-dimethyl-5-phenyl-6,7-benzomorphane, hydrochloride (hydrate) m.p. 233 - 235°, [ct]£<5> = -83° (water).

The same product is obtained from (-)-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan (solution in chloroform-methanol 1:1) and ethereal diazomethane solution.

The starting material can be prepared as follows:

21- hydroxy- 5-( p- chlorophenyl)- 6, 7- benzomorphan

0.453 g of cyanogen bromide in 15 ml of chloroform is added slowly over the course of 1 hour to 1.27 g of 2'-acetoxy-5-(p-chlorophenyl)-2-methyl-6,7-

benzomorphan in 30 ml of chloroform. The solution is heated for 3 hours under reflux and then concentrated in vacuo. The residue is treated with 50 ml of 2-N hydrochloric acid and heated for 20 hours under reflux. The mixture is then made alkaline by the addition of concentrated aqueous ammonia and the residue formed is isolated. 2'-Hydroxy-5-(p-chlorophenyl)-6,7-benzomorphan is obtained, which after several times of recrystallization from isopropanol (with clarification) exhibits a melting point of 267 - 27 2°.

EXAMPLE 6

2'- hydroxy- 2- 6-( 4- aminophenyl)- ethyl- 5- phenyl- 6, 7- benzomorphan A mixture of 12 g of 2'-hydroxy-5-phenyl-6,7-benzomorphan, 12 g of 2- (4-nitrophenyl)-ethyl bromide and 8 g of potassium carbonate in 180 ml of dimethylformamide are stirred for 8 hours at 95 - 99°. The cooled mixture is then poured into a liter of water and extracted with acetic ester. After evaporation of the extract, 2'-hydroxy-2-B-(4-nitrophenyl)-ethyl-5-phenyl-6,7-benzomorphan is obtained, m.p. 254 - 256°.

A suspension of 4.5 g of 2'-hydroxy-2-B-(4-nitrophenyl)-ethyl-5-phenyl-6,7-benzomorphan and 3 g of 10% palladium/charcoal in 200 ml of ethanol is hydrated in a Parr apparatus under a pressure of approx. 3 ato (40 lbs/in ). After the theoretical amount of hydrogen has been absorbed, the catalyst is removed by filtration and the filtrate is evaporated to dryness. The residue thus obtained, 2'-hydroxy-2B-(4-aminophenyl)-ethyl-5-phenyl-6,7-benzomorphan, is recrystallized from methanol, m.p. 235 - 238°.

EXAMPLE 7

2-phenethyl-5-phenyl-6,7-benzomorphan-hydrochloride 0.87 g of (B-bromomethyl)-benzene in 5 ml of dimethylformamide is added dropwise with stirring at room temperature to a suspension of 1.10 g of 5-phenyl-6,7 -benzomorphan hydrochloride and 0.80 g of sodium bicarbonate in 20 ml of dimethylformamide. The reaction mixture is heated for 4 hours with stirring under reflux and then concentrated under reduced pressure to dryness. The remainder is treated with aqueous ammonia and chloroform. The chloroform layer is separated, washed with water, dried over anhydrous sodium sulfate and evaporated to an oil.

The oil is dissolved in 10 ml of isopropanol. Alcoholic hydrogen chloride (1.60 ml 2.52-n) is added to the solution, and the solid formed is isolated and dried. 2-phenethyl-5-phenyl-6,7-benzomorphan hydrochloride is obtained, m.p. 313 - 315°.

EXAMPLE 8

2'-acetoxy-5-(p-chlorophenyl)-2-methyl-6,7-benzomorphan A solution of 1.02 g of 2'-hydroxy-5-(p-chloro-phenyl)-2-methyl-6, 7-benzomorphan, m.p. 272 - 274° in 7.00 ml of acetic anhydride is heated for 1 hour at 100°, then poured into 20 ml of cold water and made alkaline by the addition of 50% aqueous potassium hydroxide. The mixture is quickly extracted with ether, dried and concentrated. The residue is recrystallized from isopropyl ether-petroleum ether (2:1) and gives 2'-acetoxy-2-methyl-5-(p-chloro-phenyl)-6,7-benzomorphan with a melting point of 113 - 114°. Upon further recrystallization, the melting point increases to 115 - 117°.

EXAMPLE 9

2'- acetoxy- 2- methyl- 5- phenyl- 6, 7- benzomorphan

A mixture of 1.68 g of 2'-hydroxy-2-methyl-5-phenyl-6,7-benzomorphine (cf. Example 5) and 8.4 ml of acetic anhydride is heated for 45 minutes at 100°. The solution is then poured into 20 ml of cold water. After 5 minutes, an aqueous solution of 50% potassium hydroxide is added in small excess while cooling. The released base is quickly extracted with ether. After drying and evaporation of the ethereal solution and subsequent recrystallization from isopropyl ether, 2'-acetoxy-2-methyl-5-phenyl-6,7-benzomorphan is obtained with a melting point of 120 - 122°.

The free base can be converted to the hydrochloride by dissolving it in a minimum of absolute ethanol and treating the solution with ethanolic hydrogen chloride until the Congorod indicator shows an acidic reaction. The solution is then diluted with 5 parts by volume of anhydrous ether and allowed to crystallize. 2<1->acetoxy-2-methyl-5-phenyl-6,7-benzomorphan hydrochloride is obtained in the form of the monohydrate, which melts partially at 180 - 190°, completely at 250 - 253°.

Analogously, by using a corresponding alkanoylation agent, the corresponding 2'-alkanoyloxy derivatives can be prepared. E.g. 2<1->propionyloxy-2-methyl-5-phenyl-6,7-benzomorphan is obtained by using propionyl chloride in the above method.

EXAMPLE 10

Racemate resolution of 2'-hydroxy-2-methyl-5-phenyl-6,7-benzomorphan A solution of 43.94 g of dl-2'-hydroxy-2-methyl-5-phenyl-6,7-benzomorphan and 24, 04 g d-mandelic acid in 1250 ml methanol and 500

ml isopropanol is concentrated to a volume of approx. 700 ml. The mixture is cooled, and the diastereomeric mandelic acid salt is separated from the mother liquor and dried: melting point 233 - 237°, [a]p° = -13.5° (c = 1.0 in methanol). This salt is partially dissolved in 250 ml of boiling water and then 75 ml of 5% aqueous ammonium hydroxide solution is added. After cooling, the residue is separated and recrystallized from n-butanol. 1-2'-hydroxy-2-methyl-5-phenyl-6,7-benzomorphan is obtained, m.p. 267 - 273°, [a]p°

-92.4° + 1.5 (c = 0.66 in methanol).

The above-mentioned mother liquor is evaporated to dryness, and the remainder is partially dissolved in 300 ml of boiling water. 150 ml of 5% aqueous ammonium hydroxide is added to this solution. The solid formed by cooling (25.1 g) is added to 13.70 g of 1-mandelic acid in 1250 ml of methanol and 500 ml of isopropanol, and this solution is then concentrated to a volume of approx. 700 ml. The residue formed on cooling is taken up, dried and dissolved in 400 ml of boiling water. 100 ml of 5% aqueous ammonia is then added. The solid formed is taken up and recrystallized from n-butanol. One obtains d-2'-hydroxy-2-methyl-5-phenyl-6,7-benzomorphan, m.p. 273 - 275°, [<x]p° = 91.4 + 1.8 (c = 0.66 in methanol).

Both the d- and the 1-form of the hydrochloride are prepared, as a hot solution of the free base in n-butanol is treated with ethanolic hydrogen chloride. Both forms melt at 308-313°.

EXAMPLE 11

Cleavage of d, 1- 2'- hydroxy- 2, 9- dimethyl- 5- phenyl- 6, 7- benzomorphan

A warm solution of racemic d,l-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan in lOO ml of absolute alcohol is added with stirring and heating 1.52 g of L-(+)-mandelic acid , after which a clear solution is obtained. After standing at room temperature, white needles of the acid addition salt of levorotatory 2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan with L-(+)-mandelic acid separate out from the solution; 1.78 g, m.p. 223 - 227°. Recrystallization of the crystals from absolute methanol brings the melting point to 226 - 228°C, [aj^<6> = -38°.

To release the free base, the mandelate is treated with aqueous ammonia and ether. The ethereal extract is washed with water, dried over anhydrous sodium sulfate and concentrated, whereupon colorless prisms with a melting point of 198 - 199°C are obtained; [α]^<8> = -113° (c = 0.81, 1=1 dem, methanol).

About. 100 ml of the mother liquor are concentrated to about half the volume and then allowed to stand, whereupon colorless prisms of the acid addition salt<*>of hbyrotating 2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan separate out with L-(+)-mandelic acid, 1.62 g, m.p. 227 - 233°C. Recrystallization from absolute ethanol raises the melting point to 235 - 238 o , [αJD28 ;= +118° (c = 1.015, MeOH). ;The right-hand rotating free base is released and isolated according to the procedure mentioned above for the left-hand rotating base. ;One obtains colorless prisms with m.p. 196 - 197°, [cc]<q8><= >+127° (c = 1.05, 1=1 dem, methanol). Using the same weight of D-(-)-mandelic acid instead of L-(+)-mandelic acid, the above-mentioned cleavage procedure is repeated. The acid addition salt of hbyrotating 2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan with D-(-)-mandelic acid is obtained, 1.78 g, m.p. 223 - 227°. After recrystallization from absolute ethanol, the melting point is at 226 - 228°, [ a]* 6 = +47° (c = 1.23, MeOH).

On concentration of the mother liquor, the acid addition salt of levorotatory 2<1->hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan with D-(-)-mandelic acid precipitates, m.p. 235 - 238°, [α]^<8> = -118°

(c = 1.05, MeOH).

Using the hydrochloric acid addition salt of d,1-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphine in place of the free base, the procedure is repeated on a stoichiometric equivalent basis. The results are essentially the same; but achieves the antipodes of the free base in good yield.

As described above, both optically active antipodes are converted with ammonia to the physiologically active form of the free base and with pharmaceutically acceptable, non-toxic acids to their valuable acid addition salts.

EXAMPLE 12

Cleavage of racemic d,1-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan with an acetic acid-mandelic acid combination 58.7 g racemic 2'-hydroxy-2,9-dimethyl-5 -phenyl-6,7-benzomorphan is suspended in 450 ml of absolute methanol, and the mixture is heated with stirring to 60 - 75°. Next, 6.0 g of acetic acid in 25 ml of ethanol are added and then 15.2 g of solid L-(+)-mandelic acid. The reaction components are washed with 75 ml of ethanol in the reaction vessel. When L-(+)-mandelic acid is added, complete dissolution of the reaction mixture takes place. The clear light yellow solution is kept for a few minutes at 60-70°, then it is cooled slowly with stirring to room temperature. The reaction product precipitates at approx. 65°. This takes place after approx. 10 minutes when the solution is cooled to 75°, and after approx. 1 minute, when the solution is already at 60 - 65°. The crystalline precipitate is filtered off, washed with ethanol and dried in vacuum until constant weight. The yield amounts to 38.4 g (86% of the theoretical), m.p. 220 - 223° (cleavage), [a]^<7> = -2.5°

(c = 1.4; MeOH). Recrystallization of 18.4 g of crude product into 350 ml of 92% ethanol (parts by volume) gives 11.7 g of pure levorotatory 2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan-L-(+ )-mandelic acid addition salt with m.p. 227 - 228° (dec.), La]^<8> = -41° (c = 1.78; MeOH).

EXAMPLE 13

a) A mixture of 2'-hydroxy-5-phenyl-6,7-benzomorphan (2.65 g),

2-Bromoethanol (1.50 g) and 1.01 g of sodium bicarbonate are heated

with stirring for 4 hours under reflux. The reaction mixture is then evaporated to dryness under vacuum. The pink-coloured residue is divided between water (50 ml) and ether (250 ml), the ether phase is separated and extracted with 1-n hydrochloric acid (2 x 50 ml). The acidic aqueous phase is extracted with ether (10 ml), then neutralized with concentrated ammonium hydroxide solution and then extracted with ether (2 x 100 ml). The ether phase is washed with water, dried

washed over sodium sulfate and evaporated. The rest (2.25 g) crystal

is lysed from ether to give 2'-hydroxy-2-(2-hydroxyethyl)-5-phenyl-6,7-benzomorphan as pale orange crystals, m.p.

178 - 181°.

In an analogous way, one obtains from

b) 2'-hydroxy-9-methyl-5-phenyl-6,7-benzomorphane 2'-hydroxy-2-(2-hydroxyethyl)-9-methyl-5-phenyl-6,7-benzomorphane, m.p. 183 -

184°;

c) the left-turning form in section b) applied output

substance (-)-2'-hydroxy-2-(2-hydroxyethyl)-9-methyl-5-phenyl-6,7-

benzomorphane, m.p. 173 - 175°, [α]p<7> = -136° (methanol).

Claims (1)

Analogous process for the preparation of pharmacodynamically active, new substituted 5-phenyl-6,7-benzomorphans of the general formula I where means hydrogen, halogen or the hydroxyl group, R2 hydrogen, the hydroxyl, lower alkoxy or lower alkanoyloxy group, X hydrogen or alkyl with 1-3 C atoms, and Y cycloalkylmethyl with at most 7 C atoms, lower alkyl with at most 5 C atoms, hydroxyl lower alkyl, phenethyl, nitrophenethyl and aminophenethyl residues, lower alkenyl with optionally with halogen at double-bonded C, cinnamyl or propargyl, their optically active forms and their acid addition salts, characterized in that a compound of the general formula II is reacted where R 1 , R 2 and X have the meanings given above, with a compound of the general formula III where Y has the above meaning and Hal means a chlorine, bromine or iodine atom, in the presence of an acid-binding agent and reacts, if desired, a compound thus obtained, which contains a hydroxyl group in the 2'-position, with an alkylating or alkanoylating agent, cleaves, if desired, a racemic product into optically active forms and transfers, if desired, a product of an addition salt with an inorganic or organic acid.