NO135315B - - Google Patents

Abstract

Analogy process for the preparation of therapeutically active tetrahydro-isoquinoline derivatives.

Description

The present invention relates to a process for the production of isoquinoline derivatives. In particular, it relates to the process for the preparation of 1,2,3,4-tetrahydro-4-phenylisoquinoline derivatives with the general formula,

where R means hydroxy or lower alkoxy,

R, hydrogen, hydroxy or lower alkoxy,

R^ hydrogen or lower alkyl,

R^ lower alkyl or phenyl-lower alkyl,

R^ halogen, nitro or optionally with lower alkyl mono- or disubstituted amino and

n the number 1 or 2,

as well as acid addition salts of these compounds.

The term "lower alkyl" denotes a straight-chain or branched saturated hydrocarbon residue with 1-4 carbon atoms, such as e.g. methyl, ethyl, isopropyl, etc. The term "phenyl-lower alkyl" denotes straight-chain or branched saturated hydrocarbon residues with 1-4 carbon atoms, which are substituted with a phenyl residue, such as e.g. benzyl, 2-phenylethyl, etc. By "lower alkoxy" is meant straight-chain or branched lower alkyl residues, which are attached via an oxygen atom, such as methoxy, ethoxy, iso-propoxy, etc. The term "acyloxy" denotes an acyl residue, which is attached via. an oxygen atom. Lower alkanoyl residues are preferred. The term "lower alkanoyl" denotes the residue of an aliphatic saturated carboxylic acid with at most 4 carbon atoms, such as acetyl, propionyl and the like. Unless otherwise stated, "halogen" means the four halogens fluorine, chlorine, bromine and iodine. Among compounds of formula I, those which have a methoxy or a hydroxy substituent in the 7-position of the isoquinoline skeleton are preferred. In a particularly preferred embodiment, compounds of formula I exhibit only one of the aforementioned substituents in the 7-position, i.e. that the substituent R 1 has the meaning hydrogen;

Among the compounds of formula I, those are preferred where both ortho-positions in the phenyl residue, which sits in the 4-position of the isoquinoline skeleton, are unsubstituted, i.e. the compounds where the said phenyl residue exhibits the substituent(s) indicated under R^ in the para- and/or in meta position. The residue R^ is preferably halogen, and then especially chlorine. Particularly preferred are the compounds of formula I which in the 4-position of the isoquinoline skeleton have a 4-chlorophenyl or a 3,4-dichlorophenyl residue, i.e. compounds where n = 1 and R means chlorine in the para-position or n = 2 and R means chlorine in the para and meta position.

Moreover, within the scope of the present invention, the compounds of formula I are preferred where R 1 denotes a substituent in the 2-position in the isoquinoline structure, whereby R 1 denotes a methyl or ethyl group.

Likewise, such compounds of formula I are preferred, whereby the 1-position in the isoquinoline structure is unsubstituted, i.e. those where R~ means hydrogen.

Within the scope of the present invention is

representative compounds preferred among the following compounds of formula I: 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol, 4_(4-chlorophenyl)-1,2,3,4 -tetrahydro-7-methoxy-2-methyl-isoquinoline, 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol and 4-(3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline.

The 1,2,3,4-tetrahydro-4-phenyl-isoquinoline derivatives, which are obtained according to the invention, differ in a characteristic way from those in Chem.Abstr. 52, 7319h, revealed the 1,2,3,4-tetrahydro-4-phenyl-isoquinoline derivatives by a tertiary nitrogen atom as well as by one or two halogen atoms, respectively nitro- or optionally alkyl-substituted amino groups in the phenyl ring. The 1,2,3,4-tetrahydro-4-phenyl-isoquinoline derivatives disclosed in Norwegian patent no. 121,721 differ from the present ones by an optionally substituted amino group in the 8-position. The 1,2,3,4-tetrahydro-4-phenyl-isoquinoline derivatives of the formula I which are obtained according to the invention and their salts are superior to the known compounds with regard to antidepressant action and therefore constitute a non-adjacent enrichment in the pharmaceutical area.

According to the invention, compounds of formula I and their acid addition salts can be prepared by

a) cyclizes a compound of the general formula

where R, R1, R2, R3, R4 and n have those in formula I

given meanings, and X stands for hydroxy, acyloxy or halogen,

or

b) for the preparation of a compound of the formula I, where R 1 means halogen, nitro or a lower alkyl disubstituted

amino group, lower-alkyler. or phenyl-lower-alkylates a compound of the general formula

where R, R^, R2 and n have the meanings given in formula I, and R^ means halogen, nitro or one with

lower alkyl disubstituted amino group,

or

c) for the preparation of a compound of the formula I, where R^ stands for halogen or a lower alkyl disubstituted amino group, and where R and R^ must be different from hydroxy and R^ from benzyl, reduces a compound of the general formula

where R, R^, R^, R^ and n have the meanings given in formula I, R^ stands for halogen or a lower alkyl disubstituted amino group, and R and R^ must be different from hydroxy and R^ from benzyl, under acidic conditions, or reduces a compound with.. the general formula

where R, R1, R2, R3, R4 and n have those in formula IV

stated meanings,

or

d) for the preparation of a compound of formula I, where R^ stands for halogen or optionally with a lower alkyl, mono- or disubstituted amino group, and R^ is different from benzyl, reduces a compound of the general formula

where R, R^, R2, R^, R^ and n have those under formula I

given meanings and R 3 is different from benzyl, or

e) for the preparation of a compound of formula I, where R and/or R^ means hydroxy, subject a compound with

the general formula

where R2, R3, R4 and n have those in formula I indicated

meanings, and R and/or R.sub.3 means lower alkoxy, an acidic ether cleavage, or

f) for the preparation of a compound of formula I where R 1 means amino and R is different from benzyl, reduces a

connection with the formula

where R, R^, R2, R^°Q n have those in formula I indicated

meanings, and R 1 is different from benzyl,

or

g) for the preparation of a compound of formula I, where R 1 means a lower alkyl mono- or di-substituted amino group, alkylates a compound of formula IX

where R, R1, R2, R^ and n have the meanings given in formula I and one of the substituents R^ and R^ is hydrogen and the other hydrogen or lower alkyl,

optionally for the preparation of an optically uniform compound of formula I cleaves a corresponding racemate or uses an optically uniform starting material, or

optionally separates for the preparation of a single racemate of a compound containing at least two asymmetric centers a corresponding diastereoisomer mixture, or optionally separates for the preparation of an acid addition salt of a compound with the formula I-...treats a corresponding free base with an inorganic or organic acid.

a) According to a first method modification, compounds of formula I are thus obtained by cyclizing one

compound with the above-mentioned formula II. This cyclization takes place in the presence of an acidic condensation agent, whereby - depending on the nature of the substituent - e.g. hydrochloric acid, sulfuric acid,. phosphoric acid, polyphosphoric acid, boron trifluoride, aluminum chloride, stannous tetrachloride, etc. can be used. When choosing an acidic condensing agent, it must be taken into account that, depending on the reaction conditions, any alkoxy groups R and/or R^ present may change into hydroxy groups by ether cleavage or remain unchanged. In many cases, it can be advantageous to carry out the cyclization reaction in the presence of a solvent. The reaction temperature can, according to the other reaction conditions, vary within wide limits, whereby a temperature range between 10° and 150° is preferred.

b) According to another process modification, compounds of formula I are obtained, where R means halogen or nitro

or a lower alkyl with a disubstituted amino group, by lower alkylating or aralkylating a compound of the above formula III. The introduction of alkyl or The aralkyl group in 2-styling in the isoquinoline structure takes place e.g. by reacting the starting product with formula III with a suitable alkyl or ar-alkyl halide such as methyl iodide, ethyl bromide, benzyl bromide;

with a corresponding sulfate, such as dimethyl sulfate5 or with a suitable sulfonic acid ester, such as e.g. benzenesulfonic acid methyl ester, p-toluenesulfonic acid benzyl ester etc. But it is also possible first to introduce in the 2-position in the isoquinoline structure an alkanoyl, benzoyl or phenylalkanoyl group, e.g. with the help of acetic anhydride, acetyl chloride, benzoyl chloride etc., and finally reduce these with the help of lithium aluminum hydride to the corresponding alkyl or the aralkyl group. A methyl group can also be advantageously introduced by treating the compound of formula III with formaldehyde and formic acid, or with formaldehyde and derivatives with catalytically activated hydrogen. The choice of a specific alkylation or aralkylation method naturally depends on the alkyl or the aralkyl residue to be introduced,

and of the substituents present in the starting product, so that e.g. any hydroxy groups present (R and/or R^) are likewise alkylated or they are not attacked. Aralkylation can also occur, which could lead to unwanted products, and this must be avoided.

c) According to a further modified method, compounds of formula I are obtained, where R 1 means halogen or one with

lower alkyl disubstituted amino group, R and R£ must not be hydroxy and R^ must not be benzyl, by reducing a compound of the above formula IV under acidic conditions. Under these acidic reaction conditions, a dehydration can take place to form a compound of formula V.

Such a compound can, under acidic conditions, disproportionate to a compound of formula I and to a corresponding isoquinoline salt. The latter can in turn be reduced to a compound of formula I. The reduction of compounds of formula IV takes place, as said, under acidic conditions, e.g. in glacial acetic acid, hydrochloric acids of different concentrations, alcoholic hydrogen chloride, etc. In the two embodiments of this method modification, catalytically activated hydrogen is used as a reducing agent, whereby as hydrogenation catalysts you can use e.g. platinum oxide, mixtures of platinum oxide and platinum black, rhodium (on charcoal or alumina) and especially palladium (on charcoal). Reduction of the isoquinoline salt, which is obtained as an intermediate product, can be carried out with complex metal hydrides such as alkali metal hydrides, preferably sodium borohydride, or with catalytically activated hydrogen.

d) According to a further modified method, compounds of formula I are obtained, where R^ means halogen or

optionally lower alkyl with a mono- or disubstituted amino group, and where R^ must not be benzyl, by reducing a compound with the above formula VT. In this reduction, which is carried out using lithium aluminum hydride, it must be taken into account that a nitro group present in the starting material cannot be retained as this is transferred to the corresponding amino group. The reaction is carried out in an inert organic solvent suitable for reduction using lithium aluminum hydride, e.g. in non-cyclic or cyclic ether, such as diethyl ether, tetrahydrofuran, dioxane, etc.

Further modified methods within the scope of the present invention relate to modifications with substituents in compounds of formula I.

e) Thus, one can e.g. obtain a compound of formula I, where the radicals R and/or R 1 mean lower alkoxy, by carrying out

an acidic ether cleavage and thus obtain a corresponding compound of formula I, where R and/or R^ means hydroxy. The ether cleavage is carried out e.g. by heating for approx. 48% hydrogen bromide solution.

f) Furthermore, it is possible to reduce a compound of formula I, where R 4 means a nitro group and R 4 is not benzyl, to

a corresponding compound of formula I, where R 4 means an amino group. In this way, a reducing agent is used, e.g. nasing or catalytically activated hydrogen, lithium aluminum hydride, etc. The reaction is carried out in a known manner.

g) Compounds of formula I, where R^ means an amino group, can be converted into the corresponding compounds by monoalkylation

of formula I, where R 4 means a lower alkyl with a monosubstituted amino group. In an analogous manner, compounds of formula I, where R 4 means a lower alkyl with a monosubstituted amino group, can be converted into the corresponding compounds of formula I, where R . denotes a lower alkyl with disubstituted amino group. This reaction is carried out according to known methods, whereby the choice of a particular method depends, among other things, on the other substituents in the molecule. Thus, it is e.g. possible to choose reaction conditions so that any hydroxy groups present are not attacked.

Compounds of formula I, where at least one of the symbols R and

R^ means a benzyloxy and where R^ is not benzyl, a hydrogenolytic debenzylation gives corresponding compounds of formula I, where at least one of the symbols R and R^ means hydroxy,

and where R 4 must not be benzyl and R 4 must not be nitro.

According to a further modified method, one can

within the scope of the present invention obtain optically uniform compounds of formula I, by splitting up a corresponding racemate. Compounds of formula I exhibit at least one asymmetric center, namely the carbon atom in the 4-

position in the isoquinoline structure. This racemate cleavage takes place according to usual methods, i.e. by reaction of the racemate with a suitable, optically active acid, separation of the two diastereoisomeric salts obtained, e.g. by fractional crystallization, and finally liberation of the optically uniform base.

Another possibility for producing an optically uniform compound consists in using an optically uniform starting material, preferably by using a compound of formula III separated according to known methods.

Compounds of formula I, which exhibit more than one asymmetric center, may exist in various diastereoisomeric forms. According to a further modified method, within the scope of the present invention, mixtures of such diastereoisomers can be separated by means of ordinary and usual separation methods into the individual racemates, which in turn,

and as previously mentioned, can of course be divided into its optically uniform components.

Compounds of formula I are basic substances, and the production of their acid addition salts, and especially those that are pharmaceutically usable, is also covered by the present invention. These salts can be prepared from the corresponding bases according to widely known methods by reaction with suitable inorganic or organic acids. Examples of organic and inorganic acids, which are used for the production of

pharmaceutically usable salts are: chloric or bromohydrogen acid, sulfuric acid, acetic acid, succinic acid, maleic acid, methane, benzene or p-toluenesulfonic acid, etc. Pharmaceutically non-usable acid addition salts of compounds of formula I are suitable as intermediates in the preparation of corresponding pharmaceutically usable acid addition salts, and this can be done by resalting or by releasing the base and then forming a salt with a suitable acid.

They follow the analogical procedures as output products

used compounds, can be produced according to known methods.

In the following reaction scheme are some representative examples

for the manufacture of such output products indicated. Naturally, these synthesis routes for the production of other substituted compounds must be modified accordingly.

1,2,3,4-tetrahydro-4-phenylisoquinoline derivatives of formula I show an antidepressant effect. To demonstrate this, the investigated preparation was administered to groups of 5 rats each in three doses of 50 mg/kg p.o. (twice the day before and once the day of the trial). 6 hours after the last administration, the animals were injected subcutaneously with 20 mg/kg 2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H- benzo[a]quinolizine hydrochloride. The same dose was administered to a group of 5 non-pretreated rats. The assessment included central and peripheral symptoms, which are characteristic of antidepressants [cf. Ann. NEW. Acad. Pollock. 96, 279 (1962)]. One observed special motility (climbing), tolerance to irritation, elimination of ptosis and further with regard to behaving in a searching manner. These changes were expressed in numbers according to a rating scale.

The compounds listed in the following table I show e.g. by this tried a strong anti-depressant effect, and which is expressed in a strong oct, characteristic motility, tolerance of irritation, searching attitude as well as complete abolition of ptosis. The indicated percentages are based on

the value obtained with amitriptyline (Amitriptyline = 100%).

The low toxicity of compounds of formula I can be illustrated by the acute toxicity of the compounds listed in Table 1 on mice (24 hour value).

FORSO KSRAP PORT

Change of Ro 4- 1284 syndrome

The following test is used to examine the imipramine-like antidepressant effect of compounds.

Groups of five rats receive the test compound orally at 29, 22 and 6 hours before subcutaneous injection of 20 mg/kg 2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7 -hexahydro-llbH-benzo /~a7quinoline hydrochloride (Ro 4-1284) in a dosage of either loo or 5o or 25 mg/kg. The 5 animals are kept together in cages of 35 x 25 x 20 cm.

The following symptoms are assessed and scored at 15, 3o, 45, 6o, 9o and 12o minutes after Ro 4-1284 administration:

1) Number of climbing animals (x2) : o - lo

2) Locomotor activity - reduced activity: o

- normal activity: 1

- active activity: 2

3) city width - blepharospasm : o

- normal city width: 1

- exophthalmos : 2

n

4) Reaction to mechanical stimuli - normal reaction : o

- moderate increase in the reaction: 1

- clear increase in the reaction: 2

The total number of points for each observation is plotted against time and the area obtained is determined planimetrically. The effect of the test compound is given as a percentage of the area determined planimetrically after oral administration of imipramine 3 x 50 mg/kg.

Summary

The compounds produced according to the invention exhibit a higher level of antidepressant action than the compounds according to the state of the art. This is demonstrated by the fact that the relatively weakly active compounds according to the invention, i.e. the compounds I and J are already more than 30% more active than the compounds according to the state of the art, i.e. the compounds M, N

and 0. The superiority becomes even clearer when the highly active compounds produced according to the invention, i.e.

4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline

4-(3, 4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7 -isoquinolinol

are taken into account, where compounds are 50% more active than compounds M, N and 0 according to the state of the art.

The method products produced according to the method can be used as medicine, e.g. in the form of pharmaceutical preparations, and as such or in the form of their salts occur in a mixture with one for the enteral, e.g. pharmaceutical, organic or inorganic inert carrier materials suitable for oral or parenteral administration, such as e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oil, gum arabic, polyalkylene glycol, vaseline, etc. The pharmaceutical preparations can be in the form of e.g. tablets, dragées, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and resp. or contains auxiliary substances, such as preservatives, stabilisers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

Appropriate pharmaceutical dosage forms contain 1 to 200 mg of a compound of formula I. Appropriate oral dosage ranges for mammals are 0.1 mg/kg per

day to 5 mg/kg per day. Appropriate parenteral dosing doses for mammals are at 0.1 mg/kg per day

"to 1.0 mg/kg per day. However, the mentioned doses can

can be increased or decreased, depending on individual needs and the specialist's recommendations.

In the following examples, which will explain the invention in more detail, all temperatures are given in degrees Celsius.

EXAMPLE 1

The base is liberated from 1.55 g of rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride, this is taken up while shaking with 1.1 ml of a 35% formaldehyde solution and leave it to rest for 2 hours at room temperature. One hydrates over 1 g of Raney nickel, filters from the catalyst, evaporates the filtrate and crystallizes the residue with ethanolic hydrogen chloride, methanol and ether. Recrystallization from methanol-ether gives 1.50 g of rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride with m.p. 244 - 246°.

The output product can e.g. produced as follows:

The cyanohydrin is prepared from 4-chlorobenzaldehyde and this is reduced with the help of lithium aluminum hydride to rac-oc-(amino-methyl)-4-chlorobenzyl alcohol.

41.6 g of rac-oc-(aminomethyl)-4-chlorobenzyl alcohol hydrochloride are liberated, taken up in 400 ml of benzene, 30 g of 3-methoxybenzaldehyde are added and the mixture is heated under reflux using a water separator until all the water has been removed. It is then evaporated, the residue dissolved in 400 ml of methanol, added under ice-cooling in small portions. 15 g of sodium borohydride and stir the mixture for 6 hours at room temperature. Evaporation, shaking off, crystallization with ethanolic hydrogen chloride, methanol and ether and recrystallization in methanol - ether gives 49.5 g of rac-4-chloro-α-£[(3-methoxybenzyl)aminojmethyl} benzyl alcohol hydrochloride with m.p. 198 - 199°.

After recrystallization in ether-petroleum ether, the free base shows a m.p. at 88 - 90°.

91.0 g of rac-4-chloro-α-£[0-methoxybenzyl)amino]methyl}benzyl alcohol hydrochloride is stirred under argon for one hour with 1450 ml of a mixture of 1 part by volume of sulfuric acid (d=1.84) and 1 volume fraction of water at 100°. After cooling, the mixture is poured into approx. 10 kg of ice and 1.1 kg of sodium hydroxide and extracted with methylene chloride. The extracts washed with saturated sodium chloride solution yield

absorption and evaporation approx. 78 g of a dark yellow oil.

Chromatography of this oil on 7 kg silica gel gives 2 main fractions. The first gives, after addition of ethanolic hydrogen chloride, crystallization with ethyl acetate and ether and recrystallization in methanol-ether, 22.0 g of rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-5-methoxyisoquinoline hydrochloride with m.p.

236 - 238°. '

The second fraction gives, after analogous treatment, 43.6 g of rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride with m.p. 200 - 202°. - '

EXAMPLE 2

From 12.2 g of rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride, the base is liberated and stirred with 150 ml of 48% hydrogen bromide solution for 2 hours at a bath temperature of 160° at reflux. After evaporation and recrystallization in methanol-ether, 13.1 g of rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol hydrobromide are obtained with m.p. 292 - 293°. The resulting base shows, after recrystallization in ether, a m.p. on. 189 - 190°, and the hydrochloride formed with ethanolic hydrogen chloride and recrystallized in methanol ether has m.p. 295 - 297°.

EXAMPLE 3

The base of 8.0 g of rac-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride is released, it is taken up in 150 ml of methanol, 6 ml of a 35% formaldehyde solution and shake until the precipitate formed is completely dissolved. It is then hydrated over 6 g of Raney nickel filters and crystallized after acidification with ethanolic hydrogen chloride. Recrystallization from methanol-ether gives 8.3 g of rac-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride with m.p. 250 - 251°.

The starting product can be produced as follows:

Cyanohydrin is produced from 3-chlorobenzaldehyde, and this is reduced with the help of lithium aluminum hydride to rac-α-(aminomethyl)-3-chlorobenzyl alcohol.

18.5 g of rac-a-(aminomethyl)-3-chlorobenzylalcohol hydrochloride is released, it is taken up in 200 ml of benzene, 13.4 g of 3-methoxybenzaldehyde is added and heated using reflux <p>g a water separator until all water is removed.

It is then evaporated, the residue is dissolved in 300 ml of methanol, 8 g of sodium borohydride are added under ice-cooling, this is allowed to stand for 18 hours and evaporated. After shaking out and acidifying with ethanol-containing hydrogen chloride and after recrystallization in methanol-ether, 23.2 g of rac-3-chloro-α-[[(3-methoxybenzyl)amino]methyl}benzyl alcohol hydrochloride with m.p. 174 - 175°. After recrystallization in ether-petroleum ether, the free base shows a m.p. of 98 - 100°.

30.0 g rac-3-chloro~a-|[(3-methoxybenzyl)amino]methyl| -benzyl alcohol hydrochloride is stirred for 2 hours at 100° in a mixture of equal parts conc. sulfuric acid and water. The cooled solution is poured into a mixture of ice and sodium hydroxide (excess alkali) and extracted with methylene chloride. Chromatography using silica gel separates two uniform substances, which crystallize after acidification with ethanol-containing hydrogen chloride and addition of ether. The recrystallization of one fraction in methanol-ether gives 7.2 g of rac-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-5-methoxy-isoquinoline hydrochloride with m.p. 230 - 232°. The resulting base shows, after recrystallization in ether-petroleum ether, a m.p. of 93 - 95°. The second fraction gives, after analogous work-up, 14.1 g of rac-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-isoquinoline hydrochloride with m.p. 217 - 219°.

EXAMPLE 4

The base liberated from 4.00 g of rac-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride is heated for 1 hour with 80 ml of 48% hydrobromic acid at 150 ° (bath temperature). After evaporation, this is shaken out with vinegar and sodium bicarbonate solution. By acidifying the acetic ester extract with ethanolic hydrogen chloride and by crystallization and recrystallization in methanol-ether, 3.72 g of rac-4-(3-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7- isoquinolinol hydrochloride with m.p.

258 - 259°. The base released therefrom shows, after recrystallization in ether-petroleum ether, a m.p. of 196 - 197°.

EXAMPLE 5

The base is released from 19 g of rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride, it is taken up with 300 ml of methanol and 15 ml of a 35% formalin solution, and let this stand at room temperature for 2 hours. After hydration over Raney nickel, addition of ethanolic hydrogen chloride and recrystallization in methanol-ether, 18.7 g of rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy- 2-methylisoquinoline hydrochloride with m.p. 190 - 220°. The free base crystallizes in ether-petroleum ether and has m.p. 101 - 102°,

The starting product can be produced as follows:

Cyanohydrin is produced from 4-chlorobenzaldehyde, and this is reduced with lithium aluminum hydride to rac-α-(amino-methyl)-4-chlorobenzyl alcohol.

The base is liberated from 6.0 g of rac-α-(aminomethyl)-4-chlorobenzyl alcohol hydrochloride, taken up in 200 ml of benzene and boiled for one hour with 5.3 g of veratrum aldehyde using a water separator and reflux. The residue obtained after evaporation is taken up in 200 ml of methanol and reduced at 5° with 2.5 g of sodium borohydride. After evaporation, shaking, acidification with ethanol-containing hydrogen chloride and recrystallization in methanol-ether, 9.6 g of rac-4-chloro-α- (3,4-dimethoxybenzyl) aminojmethyl} benzyl alcohol hydrochloride with m.p. 220 - 221°.

The free base shows after recrystallization in ether-petroleum ether

one m.p. at 93 - 94°.

At room temperature and with stirring, 7.12 g of rac-4-chloro-α-|[(3,4-dimethoxybenzyl)aminojmethyl}benzyl alcohol hydrochloride are added to 100 ml of a mixture of equal parts conc. sulfuric acid and water, and this is then heated for 30 minutes at 80°. After making alkaline, shaking off the base with methylene chloride, acidifying with ethanolic hydrogen chloride and recrystallization in ethanol-ether, 5.7 g of rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6 are obtained ,7-dimethoxyisoquinoline hydrochloride with m.p. 186 - 187°. The liberated base shows, after recrystallization in ether, a m.p. of 118 - 119°.

EXAMPLE 6

The base liberated from 1.80 g of rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline hydrochloride is stirred for 3 hours with 30 ml of 48% hydrogen bromide - unloading at 150°

(bath temperature). After evaporation and recrystallization in methanol-ether, 1.85 g of rac-4(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-6,7-isoquinoindiol hydrobromide are obtained with m.p.

280 - 281°.

EXAMPLE 7

The base released from 5.20 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride is stirred for 2 hours with 75 ml of methanol and 3.8 ml of 35% ig formaldehyde solution and then hydrated over 2 g of Ifeney nickel. After filtration, evaporation, acidification with ethanolic hydrogen chloride, crystallization and recrystallization in methanol-ether, 5.00 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2 is obtained -methylisoquinoline hydrochloride with m.p. 2 73 - 2 75°.

The output product can e.g. produced as follows:

Cyanohydrin and

this is reduced with lithium aluminum hydride or tx-chloro-3,4-dichloroacetof enone is reduced with sodium borohydride, and the resulting chlorohydrin is reacted with ammonia, whereby in both cases rac-a-(aminomethyl)-3,4-dichlorobenzyl alcohol is obtained.

The base is liberated from 70.0 g of rac-α-(aminomethyl)-3,4-dichlorobenzyl alcohol hydrochloride, and this is heated for 2 hours in one liter of benzene with 40.8 g of 3-methoxybenzaldehyde under reflux and using a water separator until no more water can be removed.

After evaporation and dissolution in 1 liter of methanol is reduced

with 30 g of sodium borohydride under a temperature of 5°, after which one evaporates and shakes out with methylene chloride and water. The methylene chloride extract acidified with ethanolic hydrogen chloride crystallizes with ethyl acetate, and after recrystallization in methanol ether yields 104 g of rac-3,4-dichloro-a-£[(3-methoxybenzyl)amino]methyl}benzyl alcohol hydrochloride with m.p. 198 - 200°. The free base recrystallized in methanol-petroleum ether shows a m.p.

at 94 - 95°.

100 g of rac-3,4-dichloro-oc-£[(3-methoxybenzyl)aminojmethyl}-benzyl alcohol hydrochloride is added with stirring to 1 liter of a mixture of 1 part by volume of sulfuric acid (d = 1.84) and 1 part by volume of water and is then heated for 8 hours in a bath at 100°. After cooling, the mixture is poured into a cooled solution consisting of 1 kg of sodium hydroxide in ice water, and then shaken out with methylene chloride. Chromatography of the extract (80 g of crude product) using 4 kg of silica gel gives, according to the thin-layer chromatograms, 2 uniform main fractions. Acidification with ethanolic HCl, crystallization with acetic ester and recrystallization in methanol-ether gives 19.8 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-5-methoxyisoquinoline hydrochloride with m.p. 255 - 256° and 45.1 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride with m.p. 243 - 244°.

EXAMPLE 8

The base is liberated from 2.00 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride and heated at reflux for one hour with 48% hydrogen bromine solution at a bath temperature of 160°. After evaporation and recrystallization of methanol-ether, 2.0 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol hydrobromide with m.p. 284 - 285°. The base liberated therefrom with methylene chloride and sodium bicarbonate solution shows, after recrystallization in ether-petroleum ether, m.p.

212 - 212.5°, and the hydrochloride obtained with ethanolic hydrogen chloride shows, after recrystallization in methanol-ether, m.p. 287 - 288° (decomposition, sinters at 2 80°).

EXAMPLE 9

The base liberated from 11.6 g of rac-1,2,3,4-tetrahydro-7-methoxy-4-(4-nitrophenyl)-isoquinoline hydrochloride is heated with 14 ml of formic acid and 14 ml of 35% formaldehyde solution for 1 hour under

backflow. After evaporation in vacuum, shaking between methylene chloride and sodium bicarbonate solution, addition of the organic phase with ethanol-containing hydrogen chloride and recrystallization in methanol-ether, 10.2 g of almost white rac-1,2,3,4-tetrahydro-7-methoxy is obtained -2-methyl-4-(4-nitrophenyl)isoquinoline hydrochloride with m.p. 250 - 251° (decomposition).

The starting product can be produced as follows:

Bromination of 4-nitroacetophenone in the oc position reduces it

obtained the product with sodium borohydride to the corresponding bromohydrin, and treats this with ammonia, thereby obtaining rac-α-(aminomethyl)-4-nitrobenzyl alcohol with m.p. 138 -

139° (in acetic ester) .._ 4 g of rac-α-(aminomethyl)-4-nitrobenzyl alcohol in 50 ml of benzene are boiled with 3.4 g of 3-methoxybenzaldehyde under reflux and by using a water separator until no more water can be removed. After evaporation, the product is reduced in 200 ml of methanol under ice cooling with a total of 2 g of sodium borohydride, and this is finally boiled for 1 hour at room temperature. One obtains after evaporation,

shaking off with methylene chloride and water, acidification with ethanolic hydrogen chloride and recrystallization in methanol-ether 6.9 g rac-α-£[ (3-methoxy-benzyl)aminojmethyl}-4-nitrobenzylalcohol-

hydrochloride with m.p. 248 - 249°. After recrystallization in ether-petroleum ether, the free base shows a m.p. of 117 - 119°.

51 g of rac-a-^[(3-methoxybenzyl)aminojmethyl]}-4-nitro-benzyl alcohol hydrochloride is heated for 1/2 hour with 125 ml of polyphosphor-

acid at 100°. After adding ice and after making the solution alkaline with sodium carbonate, the solution is extracted with methylene chloride. After evaporation of the organic phase, 43 g of red-brown oil is obtained. Chromatography using 3.5

kg of silica gel and with ether-cyclohexane-diethylamine 40:10:1 gives two pure main fractions, which after addition of ethanol-containing

hydrogen chloride and acetic acid crystallize. After recrystallization in methanol-ether, 9.9 g of slightly yellow rac-1,2,3,4-tetrahydro-5-methoxy-4-(4-nitrophenyl)isoquinoline hydrochloride with m.p. 260 - 261° (the free base shows m.p. 159°) and 12.5 g of pale yellow rac-1,2,3,4-tetrahydro-7-methoxy-4-(4-nitrophenyl)isoquinoline hydrochloride with m.p. 225 - 226°.

EXAMPLE 10

The base released from 2.0 g of rac-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(4-nitrophenyl)isoquinoline hydrochloride is hydrated in 200 ml of methanol with 200 ml of platinum oxide at room temperature and atmospheric pressure. After adding ethanolic hydrogen chloride and recrystallization in methanol-ether, 2.1 g of rac-4-(4-aminophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline dihydrochloride are obtained with m.p. 250 - 255°. (Sintering at 210°).

EXAMPLE 11

The base is liberated from 4.5 g of rac-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(4-nitro-phenyl)isoquinoline hydrochloride, and this is stirred with 60 ml of 48% hydrogen bromide solution 1 1/2 hours at 150°

(bath temperature). After evaporation, shaking out with vinegar and sodium bicarbonate solution, acidification with ethanol-containing

•'chlorohydrogen and recrystallization in methanol ether yield 4.2 g of almost colorless rac-1,2,3,4-tetrahydro-2-methyl-4-(4-nitrophenyl)-7-isoquinolinol hydrochloride with m.p. 263 - 265°

(fission).

EXAMPLE 12

The base released from 13.5 g of rac-1,2,3,4-tetrahydro-7-methoxy-4-(3-erythrophenyl)-isoquinoline hydrochloride is heated with 15.9 ml of formic acid and 16.7 ml of 35% ig formaldehyde solution for 1 hour at 120°

(bath temperature). After evaporation, shaking with methylene chloride and sodium bicarbonate solution, acidification with ethanolic hydrogen chloride, crystallization and recrystallization in methanol-ether, 9.5 g of slightly brown rac-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4 are obtained - (3-nitrophenyl)isoquinoline hydrochloride with m.p. 247 - 248° (sintering at 239°).

The starting product can be produced as follows:

3-nitroacetophenone is brominated in the oc position, the bromination product is reduced using sodium borohydride to the corresponding bromohydrin, and this is treated with ammonia. Rac-α-(aminomethyl)-3-nitrobenzyl alcohol is obtained, which

after recrystallization in acetate ether melts at 107 -

108° (sintering at 105°).

38.3 g of rac-α-(aminomethyl)-3-nitrobenzyl alcohol is boiled with 32.5

g of 3-methoxybenzaldehyde in 500 ml of benzene under reflux with a water separator until no more water can be removed. After evaporation, the residue is taken up in 1.5 liters of methanol, and to this is successively added, while stirring and cooling with ice, 20 g of sodium borohydride, after which stirring is continued for a further 3 hours at room temperature. Evaporation with methylene chloride-water, acidification with ethanol-containing hydrogen chloride, crystallization and recrystallization in methanol-ether gives 63.8

g rac-α-[[ (3-methoxybenzyl)aminojmethyl}-3-nitrobenzyl alcohol hydrochloride with m.p. 193 - 195° (sintering at 186°).

55 g of rac-α-(3-methoxybenzyl)aminojmethyl}-3-nitrobenzyl alcohol hydrochloride and 165 g of polyphosphoric acid (84.1% P2°5^ are heated for 45 minutes at 100°. After adding some ice and acetic acid, the solution is made alkaline with sodium carbonate and shake off.The acetic ester extract (46 g) is chromatographed using 3.7

kg silica gel. Elute with ether-acetone-diethylamine 19:1:1

and gets two uniform main fractions of respectively 7, And and 22.2g. After acidification with ethanolic hydrochloric acid, crystallization bg recrystallization in methanol-ether, a yellowish rac-1,2-3,4-tetrahydro-5-methoxy-4-(3-nitrophenyl)isoquinoline hydrochloride is obtained from the first fraction with m.p. 217 - 219°, and the second fraction gives a brownish rac-1,2,3,4-tetrahydro-7-methoxy-4-(3-nitrophenyl)isoquinoline hydrochloride with m.p. 253 - 255°.

EXAMPLE 13

The base released from 2.5 g of rac-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(3-nitrophenyl)isoquinoline hydrochloride is dissolved in 250 ml of methanol and hydrated for 1/2 hour with 250 mg platinum oxide. After acidification with ethanolic hydrogen chloride, crystallization with ether and recrystallization in methanol-ether, 2.1 g of rac-4-(3-aminophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline are obtained -dihydrochloride with m.p. 250 - 251°.

EXAMPLE 14

The base liberated from 4.0 g of rac-1,2,3,4-tetrahydro-7-methoxy-2-methyl-4-(3-nitrophenyl)isoquinoline hydrochloride is heated for 1 1/2 hours with 60 ml of 48% ig hydrogen bromine solution at 150°

(bath temperature). After evaporation and shaking between sodium bicarbonate solution and ethyl acetate, acidification with ethanolic hydrogen chloride, crystallization with ether and recrystallization in methanol-ether, rac-1,2,3,4-tetrahydro-2-methyl-4-(3-nitrophenyl)-7 is obtained -isoquinolinol hydrochloride with m.p. 257 - 258° (decomposition).

EXAMPLE 15

100 ml of methanol and 5 ml of 35% formaldehyde release. After this solution has stood for 2 hours at room temperature, hydrate with 5 g

Raney nickel. After filtration, evaporation and acidification with ethanol-containing hydrogen chloride, a crystallized product is obtained.

Recrystallization in methanol-ether gives 3.65 g of rac-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-6-methoxy-2-methyl-7-isoquinolinol-. hydrochloride with m.p. 253 - 254°.

The starting product can be produced as follows:

The base released from 20.0 g of rac-α-(aminomethyl)-3,4-dichlorobenzyl alcohol hydrochloride is kept in 500 ml of benzene with 13.7 g of isoaniline (3-hydroxy-4-methoxybenzaldehyde) for 1 1/2 hours under reflux , whereby the separated water is collected by means of a water separator. After a short time, the formed imine crystallizes (m.p. 149 - 150°). After evaporation of the benzene, the imine is reduced in 500 ml of methanol with 10 g of sodium borohydride. After evaporation, shaking with methylene chloride and water, acidification with ethanolic hydrogen chloride, crystallization and recrystallization in methanol, 24.1 g of pure rac-3,4-dichloro-oc-[(3-hydroxy-4-methoxybenzyl) aminojmethyl} benzyl alcohol is obtained -hydrochloride with m.p. 230 - 231°. After recrystallization in ether-petroleum ether, the free base shows a m.p. of 119 - 120°.

40 ml of conc. sulfuric acid and shake for 5 minutes. The clear solution is then added to ice, the solution is made alkaline with sodium bicarbonate and shaken out with methylene chloride. After acidification with ethanol-containing hydrogen chloride, a still non-uniform substance crystallizes out, which is once again shaken with vinegar and sodium bicarbonate solution. After acidification and recrystallization in methanol-ether, 5.5 g of pure rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol hydrochloride are obtained with m.p. 257 - 258°.

EXAMPLE 16

The base liberated from 6.5 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride is heated with 10 ml of formic acid and 10 ml of 35% formalin solution 1 hour" at 120°

(bath temperature) . After evaporation, shaking with sodium carbonate solution and methylene chloride and acidification with ethanolic hydrogen chloride, rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-isoquinoline is obtained -hydrochloride,

which is recrystallized in methanol-ether and which then melts at 243 - 246° (sintering at 238°). After recrystallization in ether-petroleum ether, the free base shows a m.p. of 115 - 116°.

The starting product can be produced as follows:

From 7.0 g of rac-α-(aminomethyl)-3,4-dichloro-benzyl alcohol-

hydrochloride, the base is released, which is taken up in 100 ml of benzene and boiled for 1 hour with 5.8 g of veratrum aldehyde using a water separator. The residue obtained after evaporation is taken up in 100 ml of methanol and reduced at 5° with 3 g of sodium borohydride. After evaporation, shaking, acidification with ethanol-containing hydrogen chloride and recrystallization in methanol-ether, 10.6 g of rac-3,4-dichloro-a-([(3T4-dimethoxybenzyl)amino]-methyl} are obtained

benzyl alcohol hydrochloride with m.p. 209 - 210°. After recrystallization in ether-petroleum ether, the free base has a m.p. on

126 - 127°.

At room temperature and with stirring, 9.5 g of rac-3,4-dichloro-oc-{[ (3,4-dimethoxybenzyl) aminojmethyl} benzyl alcohol hydrochloride is added to 100 ml of a mixture of equal parts by volume conc. sulfuric acid and water, and this is then heated for 60 minutes at 100°. After making alkaline under ice-cooling, stripping the base with methylene chloride, acidifying with ethanolic hydrogen chloride and recrystallizing in methanol-acetic ester, 6.5 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro are obtained -6,7-dimethoxy-isoquinoline hydrochloride with m.p. 247 - 248° (sintering at 240°).

EXAMPLE 17

From 5.4 g of a mixture of the two diastereoisomers of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1-methyl-isoquinoline hydrochloride (ratio approx. 3:2) the base is released. It is then dissolved in 100 ml of methanol, and is then allowed to stand with 3.6 ml of 35% formaldehyde solution for 3 hours at room temperature. Finally, hydrate over approx. 3 g Raney nickel. One obtains 5.4 g of one

yellow oil, which is chromatographed using silica gel and eluted with cyclohexane-ether-diethylamine 50:50:1. This results in two main factions. The first crystallizes in ethanolic hydrogen chloride and ether and gives 2.3 g of the hydrochloride of one of the two diastereoisomers rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1 ,2-dimethylisoquinoline with m.p. 253 - 255°. The second fraction crystallizes after addition of citric acid in methanol and after recrystallization in methanol gives 2.3 g of the citrate of the second of the two diastereoisomers rac-4-(3,4-dichlorophenyl).-1,2,3,4 -tetrahydro-7-methoxy-1,2-dimethylisoquinoline with m.p. 175 - 176°. After liberation of the base from the aforementioned citrate, acidification with ethanol-containing hydrogen chloride and recrystallization in methanol-ether, the corresponding hydrochloride with m.p. 206 - 207°.

The starting product can be produced as follows:

The base released from 35.0 g of rac-α-(aminomethyl)-3,4-dichlorobenzyl alcohol hydrochloride is heated with 22.5 g of 3-methoxyacetophenone in 500 ml of toluene for 16 hours under reflux, whereby the separated water at with the help of a water separator is collected. After evaporation, add 400 ml of methanol, reduce with a total of 10 g of sodium borohydride under ice-cooling and stir for a further 3 hours at approx. 15°. After evaporation, shaking off with methylene chloride and water, addition of ethanol-containing hydrogen chloride, crystallization in ethyl acetate-petroleum ether and several times of recrystallization in methanol-ether, 18 g of the hydrochloride of one of the two diastereoisomeric racemic 3,4-dichloro-a-^ are obtained [(3-methoxy-α-methylbenzyl)aminojmethyl} benzyl alcohol with m.p. 183 - 184°. From the mother liquor, after shaking with methylene chloride and 3-n caustic soda and addition of ether, 13.1 g of the second diastereomer crystallizes as a free base with m.p. 80 - 81°. Its hydrochloride shows after recrystallization in methanol-ether > m.p. 130 - 131°.

10.4 g of rac-3,4-dichloro-α-£[(3-methoxy-α-methylbenzyl)-amino] methyl}-benzyl alcohol (dtastereoisomer with m.p. 80 - 81 ) is heated for 30 minutes in 55 ml of polyphosphoric acid under nitrogen at 100°.

The reaction mixture is then poured into ice, shaken out with methylene chloride and 3-n caustic soda and 9.9 g of an oily base is obtained, which is chromatographed using 560 g of silica gel.

2 main fractions are eluted using cyclohexane-ether-diethylamine 25:25:1. After acidification with ethanolic hydrogen chloride, crystallization and recrystallization in methanol-ether, 2.5 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-5-methoxy-1-methyl-isoquinoline are obtained -hydrochloride with m.p. 243 - 244°

and 6.0 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1-methylisoquinoline hydrochloride with m.p. 179 - 180°. The base liberated from the first product, i.e. the rac-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-5-methoxy-1-methylisoquinoline shows after recrystallization in ether-petroleum ether m.p. . 70 - 71°.

According to the nuclear resonance spectrum, the first product consists of

of a mixture of equal parts of the two diastereoisomers and the second product consists of a diastereoisomer mixture in the ratio approx. 3:2.

EXAMPLE 18

1.00 g of the hydrochloride of one of the two diastereoisomers rac-3,4-dichloro-α-[[(3-methoxy-α-methylbenzyl)-amino]-methyl} benzyl alcohol (m.p. 183 - 184°) heated with 5 ml of polyphosphoric acid for 1 hour at 100°. After making alkaline with caustic soda, methylene chloride is added, evaporated, dissolved in 20 ml of methanol and left for 2 hours with 1 ml of 35% formalin solution. When hydrating over 1 g of Raney nickel, 950 mg of it is obtained

an almost colorless oil, which, according to the thin-film chromatogram, consists of two main and two secondary products. Chromatography with 360 g of silica gel and with cyclohexane-ether-diethylamine 50:50:1 gives as the third substance an oil, from which, after acidification with ethanol-containing hydrogen chloride and crystallization with methanol

ether obtains 450 mg of the hydrochloride of one of the two rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1,2-dimethyl-isoquinoline with m.p. 218 - 220°. After redissolving in methanol-ether and grafting with the hydrochloride obtained according to example 17 with m.p. 253 - 255°, another crystal modification is obtained with m.p. 253 - 255°.

EXAMPLE 19

a) From 1.25 g of the rac-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-7-methoxy-1,2-dimethylisoquinoline hydrochloride obtained in example 17 with m.p. . 253 - 255° the base is released, and this is heated with 30 ml of 48% hydrogen bromine solution for 6 hours at 150°

(bath temperature). After evaporation and after making alkaline with sodium bicarbonate, shake out with methylene chloride.

After acidification with ethanolic hydrogen chloride, crystallization

in ethyl acetate and recrystallization in methanol-ether yields 1.1 g of the hydrochloride of one of the two diastereoisomers rac-4-(3,4-dichlorophenyl)-ly!,3,4-tetrahydro-1,2-dimethyl- The 7-isoquinolinols with m.p. 254 - 255°. Shaking with sodium bicarbonate and methylene chloride gives the corresponding free base with m.p. 180°. b) Of the 750 mg of the rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-1,2-dimethyl-isoquinoline hydrochloride obtained in example 17 with m.p. . 206 - 207 the liberated base is heated with 10 ml of 48% brpmhydrogen solution for 1 hour at 150

(bath temperature). After evaporation, shaking with methylene-

chloride and saturated sodium bicarbonate solution, evaporation, acidification with ethanolic hydrochloric acid, crystallization with acetic ester and recrystallization in methanol-ether gives 710 mg of the hydrochloride of the second of the two diastereoisomers rac-4-(3,4-dichlorophenyl)-1, The 2,3,4-tetrahydro-1,2-dimethyl-7-i soquinolinols with m.p. 254 - 255 . The base released by shaking with methylene chloride and sodium bicarbonate shows after recrystallization.

in ether-petroleum ether a m.p. at 219 - 220°.

EXAMPLE 20

The base liberated from 3.1 g of rac-4-(3-4-dichlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline hydrochloride in methylene chloride with sodium hydroxide is heated for 2 hours in lOO ml of 48% hydrobromic acid at a bath temperature of 160° under reflux. Already after 1/2 hour, crystallization begins under strong foam formation. After cooling, add 80 ml of water.

It is filtered off and after recrystallization in methanol-ether, 2.6 g of the hydrobromide of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-6,7-i are obtained. soquinolinediol with m.p. 285 - 286°.

EXAMPLE 21

1.50 g of rac-3,4-dichloro-α-[£(3-methoxybenzyl)methylamino]methyl} benzyl alcohol hydrochloride is dissolved in 20 ml of a mixture of 1 volume part conc. sulfuric acid and 1 part by volume of water with shaking and heated for 1 1/2 hours in a bath at 100°. After making alkaline with 3-n NaOH under ice-cooling, shake off with chloroform, dry with Na2S0^ and evaporate in vacuo. The base mixture

.is then chromatographed using 60 g of silica gel (0.05-0.20

mm) and using chloroform-diethylamine 99:1. 2 uniform substances according to the thin-film chromatogram are eluted one after the other, which after acidification with ethanolic hydrochloric acid crystallize in acetic acid. After recrystallization in methanol-ether, colorless rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-5-methoxy-2-methylisoquinoline hydrochloride is obtained with m.p. 264 - 265° and colorless rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride with m.p. 273 - 275°.

The starting product can be produced as follows:

4.5 g of rac-3,4-dichloro-α-|[ (3-methoxybenzyl) aminojmethyl^benzyl alcohol is allowed to stand for 1 hour at room temperature in 100 ml of methanol and 2.5 ml of a 35% formaldehyde solution, after which it is hydrated with Raney - nickel. After extracting the catalyst using diatomaceous earth, evaporation in a vacuum, dissolution in ether, drying over sodium sulphate and evaporation again, hydrochloric acid containing ethanol is added. It is then crystallized and recrystallized in ethanol-ether. 5.1 g of colorless rac-3,4-dichloro-cc-^[(3-methoxybenzyl)-methylamino]methyl] benzyl alcohol hydrochloride with m.p. 166 - 167 .

EXAMPLE 22

From 500 mg of rac-4-(3,4-dichlorophenyl-1,2,3,4-tetrahydro-7-iso-quinolinol hydrochloride), the free base is isolated by shaking with chloroform-acetic ester 9:1 and sodium bicarbonate solution. After dissolution in 15 ml of methanol is added to 0.75 ml of a 35% formaldehyde solution. After standing for 2 hours at room temperature, hydrate with 1 g of Raney nickel. After filtration, evaporation and acidification with ethanolic hydrochloric acid, crystallization and recrystallization in methanol-ether, the colored compounds are obtained The -4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol hydrochloride with mp 287 - 288° (decomposition, sintering at 280°).

The starting material can be produced in the following way:

500 mg of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-isoquinoline hydrochloride are heated with 10 ml of 48% hydrogen bromide solution under nitrogen for 2 hours at a bath temperature of 150° and below return flow. After evaporation in vacuum and shaking between chloroform-acetic ester 9:1 and saturated sodium bicarbonate solution, the organic phase is used, which is then evaporated. 300 mg of colorless rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-isoquinolinol with m.p. 243 - 244°.

After acidification with ethanol-containing hydrogen chloride and after crystallization and recrystallization in methanol-ether, the hydrochloride is obtained with m.p. 270 - 272°.

EXAMPLE 2 3

10.0 g of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-isoquinoline hydrochloride is added to 100 ml of ethanol and heated with 4 g of solid sodium hydroxide and 12 g of ethyl bromide for 3 hours at a bath temperature of 100° under reflux. After evaporation in a vacuum, this is shaken out with methylene chloride and 3-n caustic soda and dried over Na 2 SO 4 . Ethanol-containing hydrochloric acid is added to the base obtained by evaporation, and after crystallization and recrystallization in methanol, 9.5 g of colorless rac-4-(3,4-dichloro-phenyl)-2-ethyl-1,2,3,4-tetrahydro is obtained -7-Methoxyisoquinoline hydrochloride with m.p. 269 - 270° (sintering at 267°).'

EXAMPLE 24

From 4.50 g of rac-4-(3,4-dichlorophenyl)-2-ethyl-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride, the free base is isolated by shaking with chloroform and saturated sodium bicarbonate solution. After adding 100 ml of 48% hydrobromic acid, whereby hydrobromide is immediately formed as a precipitate, the solution is heated for 4 hours with stirring at a bath temperature of 160° and under reflux. It is shaken out with 500 ml of chloroform and 300 ml of saturated sodium bicarbonate solution, after which it is dried with Na^SO^ and evaporated in vacuo. After acidification with ethanolic hydrochloric acid, crystallization with ethanol-ether and recrystallization in methanol, 3.0 g of colorless rac-4-(3,4-dichlorophenyl)-2-ethyl-1,2,3,4-tetrahydro-7- isoquinolinol hydrochloride with m.p.

-305 - 307°, (sintering at 260°).

EXAMPLE 25

From 500 mg of rac^4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-isoquinoline hydrochloride, the free base is isolated by shaking between chloroform and saturated sodium bicarbonate solution.

In an autoclave, this is heated together with 5 ml of isopropyl bromide and 200 mg of finely grated soda for 3 hours at 150°. After evaporation, shaking between chloroform and 3-n sodium hydroxide solution, drying, acidification with ethanolic hydrochloric acid and crystallization and recrystallization in ethanol, 300 mg of colorless rac-4-(3,4-dichlorophenyl)-2-isopropyl-1,2,3 ,4-tetrahydro-7-methoxyisoquinoline hydrochloride

with m.p. 245 - 246°.

EXAMPLE 26

Under nitrogen, 500 mg of rac-4-(3,4-dichlorophenyl)-2-isopropyl-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride are heated in 1-10 ml of 48% hydrobromic acid for 2 hours at a bath temperature of 160° and under reflux. The reaction mixture is evaporated there-

after in vacuum, shake out with chloroform and soda solution and evaporate. After crystallization with petroleum ether and recrystallization

lysis in ether-petroleum ether yields 300 mg of colorless rac-4-(3,4-dichlorophenyl)-2-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinol with m.p. 155 - 156°.

After acidification with ethanolic hydrochloric acid, crystallization

and recrystallization in ethanol-ether yields the colorless hydrochloride with m.p. 274 - 277° (decomposition).

EXAMPLE 27

500 mg of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-isoquinoline hydrochloride are shaken in 20 ml of ethanol with 200 mg of solid sodium hydroxide and 5 ml of benzyl bromide for 45 minutes at room temperature.

temperature. After evaporation in vacuum, shaking out with chloroform and 3-n caustic soda, drying and evaporation and acidification with ethanol-containing hydrogen chloride, colorless crystals are obtained in chloroform ether. Recrystallization in ethanol gives 300 mg of rac-2-benzyl-4-(3,4-dichlorophenyl)-i,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride with m.p. 26.3 - 264° (sintering at 245°).

EXAMPLE 28

The base liberated by shaking with chloroform and 3 N sodium hydroxide from 250 mg (0.733 mmol) rac-4-(p-aminophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline dihydrochloride is mixed with 30 ml methanol and 2 ml 35% formalin solution.

After standing for 1 hour at room temperature, hydrate for 1 hour

with approx. 1 g Raney nickel. After filtration through diatomaceous

soil, evaporation, shaking between chloroform and 3N sodium hydroxide and evaporation is mixed with ether and a small amount of insoluble impurities is removed by filtration. After sur-

reaction with ethanolic hydrochloric acid, evaporation with benzene, crystallization and recrystallization from ethanol-ether yields the colorless dihydrochloride of rac-4-/4-(dimethylamino)phenyl7-1,2,3,4-tetrahydro-7-methoxy-2- methylisoquinoline with m.p. 259 - 26o°C.

EXAMPLE 29

To a solution of 5.6 g of rac-4-[4-(dimethylamino)phenyl]-1,2,3,4-tetrahydro-4-hydroxy-7-methoxy~2-methyl-isoquinoline,

which was set free from the hydrochloride, in glacial acetic acid add o.8 g lo% Pd-C and the solution is hydrated for 15 hours at 6o°C and 3.5 atm. After filtering off the catalyst, evaporate in vacuum, shake out between ethylene chloride and caustic soda; - evaporate, acidify with ethanolic hydrochloric acid and crystallize from ethanol-ether. Colorless dihydrochloride of rac-4-(dimethylamino)phenyl 17-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline is obtained with m.p.

259 - 26o°C.

EXAMPLE 3o

One reduces rac-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-isoquinolin-3-one hydrochloride in tetrahydrofuran with lithium aluminum hydride and, after usual work-up, obtain 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline hydrochloride with m.p. 19o - 22o°C. The free base crystallizes from ether-petroleum ether with m.p. lol-lo2°C.

EXAMPLE 31

10.76 g (30 mmol) of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride are transferred by shaking between 2N soda solution and chloroform in the oily free base and mixed with a solution of 11.60 g (30 mmol) (-)-2,3-di-0-p toluyl (RR) tartaric acid (M = 386.36) in 300 ml of methanol. The clear solution is seeded with some 2,3-di-O-p-toluyl-(R,R)-tartrate of (-)-(R)-4-(3,4-dichlorophenyl)-1,2,3, 4-tetrahydro-7-methoxy-2-methylisoquinoline and allowed to stand at room temperature until a large amount of this salt has formed. The solution may have to be slightly evaporated in a vacuum. After filtration, the 2,3-di-0-p-toluyl-(R,R)-tartrate of (-)-(R)-4-(3,4-dichlorophenyl)-1,2,3,4- tetrahydro-7-methoxy-2-methylisokiriolin whose purity is tested by shaking out the salt between 2N soda solution and chloroform, acidifying the free base with ethanolic hydrochloric acid and crystallization of the hydrochloride from methanol-ether. The 2,3-di-O-p-toluyl-(R,R)-tartrate of (-)-(R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy- The 2-methylisoquinoline may have to be recrystallized from methanol until its hydrochloride shows the desired rotation.

The pure 2,3-di-O-p-toluyl-(R,R)-tartrate of (-)-(R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7- the methoxy-2-methylisoquinoline shows a melting point of 188 - 189° from methanol.

The hydrochloride of (-)-(R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline shows a melting point of 24° - 242° from methanol-ether.

By shaking off the hydrochloride of (-)-(R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline with 2N soda solution and chloroform, the oily free the base (_)_(R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline.

The methanolic mother liquors of (-)-(R)-4-(3,4-dichlorophenyl)-1, 2, 3,4-tetrahydro-7-methoxy-2-methylisoquinoline are evaporated until a large amount of crystals. After recrystallization from methanol, the 2,3-di-O-p-toluyl-(R,R)-tartrate of (+)-(S)-4-(3,4-dichlorophenyl)-1,2,3, 4- tetrahydro-7-methoxy-2-methylisoquinoline with a melting point of 186 - 187°. Its optical purity is again proved by the conversion into the hydrochloride of (+)-(S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline and the determination of the rotation of the hydrochloride.

2,3-di-O-p-toluyl-(R,R)-tartrate of (+)-(S)-4-(3,4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-7-methoxy- 2-methylisoquinoline; Z~ 3<i7>^~ -7o°.

By shaking out the base of the 2,3-di-O-p-toluyl-(R,R)-tartrate of (+)-(S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro -7-methoxy-2-methylisoquinoline with 2N sodium hydroxide solution and chloroform, acidification with ethanolic hydrochloric acid and crystallization from methanol-ether yields the hydrochloride of (+)-(S)-4-(3,4-dichlorophenyl)-1,2, 3,4-tetrahydro-7-methoxy-2-methylisoquinoline with melting point 24o - 242°.

The hydrochloride can also be isolated directly when the methanolic mother liquors of (-)-(R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisbquinoline are shaken with 2N soda ash and . chloroform and acidified with ethanolic hydrochloric acid. After separation of a small amount of rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methyl-isoquinoline hydrochloride and recrystallization of the mother liquor, pure (+) -(S)-4-(3,4-dichloro-phenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline are obtained.

Hydrochloride of (+)-(S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline:

By shaking out the hydrochloride of (+)-(S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline with 2N soda solution and chloroform, the oily free the base 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline:

The hydrochloride of (+)-(S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline can furthermore also be recovered from 2,3-di-0- The benzyl-(S,S)-tartrate of (+)-(S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline: That from the methanolic mother liquors of (-)-(R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline as above-described liberated base are crystallized with an equivalent of (+)- 2,3-di-O-benzyl-(S,S)-tartaric acid from methanol-ether and 2,3-di-O-benzyl-(S,S)-tartrate is obtained from (+)-(S)- 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline with melting point 157 - 158°.

The cleanliness is again checked by turning the forward

prepared the hydrochloride from the 2,3-di-O-benzyl-(S,S)-tartrate of (+)_(S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7 -methoxy-2-methylisoquinoline.

2,3-di-O-benzyl-(S;S)-tartrate of (+)-(S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy- 2-methylisoquinoline:

EXAMPLE 32

By shaking off the evaporated mother liquors of the 2,3-di-O-p-toluyl-(RR)-tartrate of (-)-(R)-4-(3,4-dichlorophenyl)-1,2,3,4- . tetrahydro-7-methoxyisoquinoline with 2N soda solution and chloroform is obtained approx. 12 g (approx. 39 mmol) of a mixture of the oily free bases rac-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-isoquinoline hydrochloride and (+)- (S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline. It is dissolved in 2oo ml of methanol, mixed with 10 ml (126 mmol) of 35% formaldehyde solution (Merck) and shaken for 2 hours until the resinous precipitate has practically dissolved again. After adding 5 g of Raney nickel, approx. 1 hour under shaking at room temperature, filtered through diatomaceous earth, acidified with ethanolic hydrochloric acid and evaporated in vacuum. 4.2 g of a mixture with a melting point of 245° crystallizes from ethanol-ether, which, according to the rotation, mainly consists of racemic 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2 -methylisoquinoline. The following crystallisates give a total of 6.4 g (17.8 mmol) (+)-(S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxyisoquinoline with a melting point of 24o - 242 o and / — a7D 25 <= >+8.2°, f* 72s\ e +lo.4° and Z"a7436 +14, o°.

Claims (6)

1. Analogous process for the preparation of therapeutically active 1,2,3,4-tetrahydro-4-phenyl-isoquinoline derivatives with the general formula where R means hydroxy or lower alkoxy, R1 hydrogen, hydroxy or lower alkoxy, r2 hydrogen or lower alkyl, R3 lower alkyl or phenyl-lower alkyl, R4 halogen, nitro or optionally with lower alkyl mono- or disubstituted amino, and n means the number 1 or 2, or their acid addition salts or the corresponding optically active compounds, characterized by a) cyclizing a connection with the general formula. where R, R-^, R2, R3, R^ and n have the meanings given in formula I, and X stands for hydroxy, acyloxy or halogen, or b) for the preparation of a compound of the formula I, where R^ means halogen, nitro or a lower alkyl disubstituted amino group, lower-alkylates or phenyl-lower-alkylates a compound of the general formula where R, R-^, R 2 and n have the meanings given in formula I, and R^ means halogen, nitro or a lower alkyl disubstituted amino group, or c) for the preparation of a compound of the formula I, where, stands for halogen or a lower alkyl disubstituted amino group, and where R and R1 must be different from hydroxy. and R^ from benzyl, reduces a compound of the general formula where R, R^, <R>2, R^ and n have the meanings given in formula I, R4 stands for halogen or a lower alkyl disubstituted amino group, and R and R^ must be different from hydroxy and R^ from benzyl , under acidic conditions, or reduces a compound of the general formula where R, R1? R2, R3, R4 and n have the meanings given in formula IV, or d) for the preparation of a compound of formula I, where R4 stands for halogen or optionally with a lower alkyl mono- or disubstituted amino group, and R^ is different from benzyl, reduces a compound of the general formula where R, R^, R2 . formula where <R> 2 , R 3 , R 4 and n have the meanings given in formula I, and R and/or R 2 means lower alkoxy, an acidic ether cleavage, or f) for the preparation of a compound of formula I where R 2 means amino and R^ is different from benzyl, reduces a compound of the formula where R, R^, R2, R^ and n have de. in formula I meanings given, and R 3 is different from benzyl, or g) for the preparation of a compound of formula I, where R 1 means a lower alkyl mono- or di-substituted amino group, alkylates a compound of formula IX where R, R^, R2, R3 and n have the meanings given in formula I and one of the substituents R^ and R^ is hydrogen and the other hydrogen or lower alkyl, optionally for the preparation of an optically uniform compound of formula I cleaves a corresponding racemate or uses an optically uniform starting material, or optionally separate for the preparation of a single racemate of a compound containing at least two asymmetric centers a corresponding diastereoisomer mixture, or optionally for the preparation of an acid addition salt of a compound of the formula I treat a corresponding free base with an inorganic or organic acid. 2. Process according to process variants a), b) and d) in claim 1 for the production of 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol, characterized in that starting material uses compounds of the formulas II, III and VI, where R means hydroxy, R^ hydrogen, R2 hydrogen, R^ methyl, R^ chlorine in the para position and n the number 1. 3. Process according to method variant e) in claim 1 for the production of 4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol, characterized in that one subjects 4-(4-chlorophenyl )-1,2,3,4-tetrahydro-7-lower-alkoxy-2-methylisoquinoline an acidic ether cleavage. 4. Method according to method variants a), b) and d) in claim 1 for the production of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol, characterized in that compounds with the formulas II, III and VI are used as starting materials, where R means hydroxy, R^ hydrogen, R2 hydrogen, R^ methyl, R^ chlorine in the para- and meta-position and n the number 2. 5. Method according to method variant e) in claim 1 for the production of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol, characterized in that one subjects 4-(3 ,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-lower alkyloxy-2-methylisoquinoline an acidic ether cleavage. 6. Process according to process variants a) to d) in claim 1 for the production of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline, characterized in that starting material uses compounds with the formulas II to VI, where R means methoxy, R1 hydrogen, R2 hydrogen, R3 methyl, R^ chlorine in the para-pg meta position and n the number 2.