CH538477A - Antidepressant 4-phenyl-tetrahydroquino- - lines - Google Patents

Abstract

Antidepressant 4-phenyl-tetrahydroquinolines. Title cpds. of formula (I): (where R is OH or 1-4C alkoxy and R1 is H, OH or 1-4C alkoxy or R, R is methylenedioxy, R2 is H or 1-4C alkyl, R3 is 1-4C alkyl or phenyl-(1-4C alkyl), R4 is F, Cl, Br, I, NO2, NH2 or mono- or di(1-4C alkyl) amino, and n is 1 or 2) and their acid addition salts are claimed. One of a number of claimed processes for the manufacture of these cpds. involves cyclization of a cpd. of formula (II): (where X is OH, acyloxy or halogen).

Description

  

  
 



   The present invention relates to a process for the preparation of isoquinoline derivatives. In particular, it relates to a process for the preparation of 1,2,3,4-tetrahydro-4-phenylisoquinoline derivatives of the general formula
EMI1.1
 where R is hydroxy or alkoxy (1-4 C), R1 is hydrogen, hydroxy or alkoxy (1-4 c), where R and R1 together can also mean a methylenedioxy group R2 hydrogen or alkyl (1-4 Q, R9 alkyl (1- 4 Q or arylalkyl (1-4 C), R4 is halogen, nitro or an amino group disubstituted by alkyl (1-4 Q and n is the number 1 or 2).



   The term alkyl (1-4 Q denotes a straight-chain or branched saturated hydrocarbon radical with 1-4 carbon atoms, such as methyl, ethyl, isopropyl and the like. The term arylalkyl (14 C) relates to straight-chain or branched saturated hydrocarbon radicals with 1- 4 carbon atoms, which are substituted by an aryl radical, preferably a phenyl radical, such as benzyl, 2-phenyl, ethyl and the like. Alkoxy (1-4 C) are straight-chain or branched alkyl radicals with 1-4 carbon atoms, which are bound via an oxygen atom, such as methoxy, ethoxy, isopropoxy, etc.

  Unless otherwise stated, halogen is understood to mean the four halogens fluorine, chlorine, bromine and iodine.



   Of the compounds of the formula I, preference is given to those in which the 7-position of the isoquinoline skeleton has a methoxy or a hydroxy substituent. In a particularly preferred embodiment, the compounds of the formula I have only one of the substituents mentioned in 7 in the benzene ring added to them -Position on, ie the substituent R1 is hydrogen.



   Furthermore, among the compounds of formula 1, those are preferred in which the two ortho positions of the phenyl radical in the 4-position of the isoquinoline structure are unsubstituted, i.e. those who have the bv. have the substituents denoted by R4 in the para and / or in the meta position of the phenyl radical mentioned. The radical R4 is preferably halogen, in particular chlorine.

  Those compounds of the formula I which have a 4-chlorophenyl or a 3,4-dichlorophenyl radical in the 4-position of the isoquinoline structure are very particularly preferred, i.e. those in which al = 1 and R4 is chlorine in the pam position or n = 2 and R! Means chlorine in para and meta position.



   In addition, those compounds of formula 1 are preferred in the context of the present invention in which the substituent denoted by the symbol R3 in the 2-position of the isoquinoline structure is a methyl or ethyl group.



   Likewise preferred are those compounds of the formula I which are unsubstituted in the 1-position of the isoquinoline structure, i.e. those in which R2 is hydrogen.



   Representative representatives of the compounds of the formula 1 prepared in the context of the present invention are, for example: 4- (4-chlorophenyl) -1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol, 4- (4-chlorophenyl) ) - 1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline, 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-2-methyl-7-isoquinoline and 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline.



   The compounds of the formula I can be prepared according to the invention by adding a compound of the general formula
EMI1.2
 in which R, R1, R2, R4 and n have the meaning given in formula I, alkylated or aralkylated with the introduction of R3.



   To prepare a compound of the formula I in which R and / or R1 are hydroxy, a corresponding compound of the formula 1 in which R and / or R1 are alkoxy (1-4 ()) can be subjected to acidic ether cleavage.



   To prepare a compound in which R4 is amino and R is different from benzyl, a corresponding compound of the formula 1 in which R4 is nitro can be reduced.



   To produce an optically uniform compound of the formula I, a corresponding racemate can be split up or an optically uniform starting material can be used.



   To prepare a single racemate of a compound of formula 1 containing at least two centers of asymmetry, a corresponding mixture of diastereoisomers can be separated.



   To prepare an acid addition salt of a compound of formula 1, a corresponding free base can be treated with an inorganic or organic acid.



   The inventive introduction of the alkyl or



  Arylalkyl group in the 2-position of the isoquinoline structure takes place, for example, by reacting the starting product of the formula II with a suitable alkyl or



  Aralkyl halide, such as methyl iodide, ethyl bromide, benzyl bromide, with a corresponding sulfate, such as dimethyl sulfate, or with a suitable sulfonic acid ester, such as methyl benzenesulfonate, benzyl p-toluenesulfonate and the like. Like. It is also possible, in the 2-position of the isoquinoline structure, to initially use an alkanoyl,
Introduce benzoyl or phenylalka oylgruppe, for example by means of acetic anhydride, acetyl chloride, benzoyl chloride and. Like., and then to reduce this to the corresponding alkyl or aralkyl group using lithium aluminum hydride. A methyl group can also be introduced in an advantageous manner by treating the compound of the formula II with formaldehyde and formic acid or with formaldehyde and then with catalytically excited hydrogen.

  The choice of a particular alkylation or aralkylation method depends of course on the nature of the alkyl or aralkyl radical to be introduced and the substituents present in the starting product, so that, for example, any hydroxyl groups (R and / or R1) present are also alkylated or not attacked and aralkylation, which would lead to undesirable products, is avoided.



   Further aftertreatment measures within the scope of the present invention relate to the modification of substituents in the compounds of the formula I.



   For example, a compound of the formula I in which the radicals R and / or R "are alkoxy (1-4 C) can be subjected to acidic ether cleavage and a corresponding compound of the formula I in which R and / or R, The ether cleavage is carried out, for example, by heating in approx.



     48oiger hydrogen bromide solution carried out.



   It is also possible to use a compound of the formula I in which R4 is a nitro group and R3 is of
Benzyl is different to reduce to a corresponding compound in which R4 is an amino group. The reducing agent used here is, for example, nascent or catalytically excited hydrogen, lithium aluminum hydride, etc. The reaction is carried out in a manner known per se.



   Optically uniform compounds of the formula I can also be obtained by splitting a corre sponding racemate. This is because the compounds of the formula I have at least one center of asymmetry, namely the carbon atom in the 4-position of the isoquinoline structure. This racemate resolution takes place according to the usual methods, i.e. by reacting the racemate with a suitable optically active acid, separating the two diastereoisomeric salts obtained, e.g. by fractional crystallization, and subsequent liberation of the optically uniform base.



   Another possibility for producing an optically uniform compound is to use an optically uniform starting material, preferably by using a compound of formula II which has been separated by conventional methods.



   Compounds of the formula I which have more than one center of asymmetry can occur in various diastereoisomeric forms. According to a further process aspect within the scope of the present invention, mixtures of such diastereoisomers can be separated into the individual raceenates by separation methods generally customary for this purpose, which can of course be broken down into their optically uniform components - as mentioned above.



   The compounds of formula I are basic substances and the preparation of their acid addition salts, in particular those which are pharmaceutically acceptable, is also encompassed by the present invention. These salts can be prepared from the corresponding bases by generally known methods by reaction with suitable inorganic or organic acids. Examples of organic and inorganic acids which can be used for the production of pharmaceutically usable salts are hydrogen chloride or hydrogen bromide, sulfuric acid, acetic acid, succinic acid, maleic acid, methane, benzene or p-toluenesulphonic acid, etc.

  The pharmaceutically usable acid addition salts of the compounds of the formula I are suitable as intermediates for the preparation of corresponding pharmaceutically usable acid addition salts, which can be carried out, for example, by salination or by releasing the base and subsequent salt formation with a suitable acid.



   The compounds used as starting materials in the process according to the invention can be obtained by known methods. The following reaction scheme shows some representative examples for the preparation of such starting materials: of course, these synthetic routes must be modified accordingly for the preparation of other substituted compounds.
EMI3.1
  
EMI4.1




   The 1,2,3,4-tetrahydro-4-phenylisoquinoline derivatives of the formula I show an antidepressant effect. To prove this, groups of 5 rats each were given the preparation to be tested in three doses of 50 mg / kg p.o.



  (twice the day before, once on the day of the experiment).



  Six hours after the last administration, the animals received 20 mg / kg of 2-hydroxy-2-ethyl-3-isobutyl-9,10 -dimethoxy-1,3,4,6,711b-hexashydro - 2H - benzo - [α] quinolizine hydrochloride injected subcutaneously. The same dose was given to a group of 5 treatment-naïve rats. The assessment includes central and peripheral symptoms as they are characteristic of antidepressants [cf. Ann. N.Y. Acad. Sci, 96, 279 (1962)].



  Motility (climbing) in particular was observed.



  Sensitivity to irritation, searching behavior and the elimination of ptosis. These changes were expressed in numbers according to a rating scheme.



   The compounds listed, for example, in Table 1 below showed a strong antidepressant effect in this test, which was expressed in greatly increased, characteristic motility, sensitivity to irritation, searching behavior and complete abolition of the ptosis. The percentages given relate to the value obtained with amitriptyline (amitriptyline = loot7o).



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



   TABLE 1
Effectiveness in% DL-o in mglkg
Link the effectiveness of
Amitriptyline I.v. 5.0. p.o.



  4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-meth- approx. 128 125 - 250 500 - 1000 1000 - 2000 oxy-2-methylisoquinoline 4 (3,4-dichlorophenyl) - 1,2,3,4-tetrahydro-2-methyl- approx. 158 30- 60 250- 500 500 - 1000 -7-isoquinolinol 4- (4-chlorophenyl) -1,2,3,4-tetrahydro-2- methyl-7- approx. 114 30-60 500-1000 1000-2000 -isoquinolinol
The products of the process can be used as medicinal products, e.g.



  in the form of pharmaceutical preparations which use them or their salts in admixture with an enteral, e.g. pharmaceutical, organic or inorganic inert carrier material suitable for oral or parenteral administration, such as e.g. Contain water, gelatine, milk sugar, starch, magnesium stearate, talc, vegetable oils, gum arabic, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers.

  They can also contain other therapeutically valuable substances.



     Appropriate pharmaceutical dosage forms contain about 1 to 200 mg of a compound of formula 1. Appropriate oral dosage ranges for mammals are from about 0.1 mg / kg per day to about 5 mg / kg per day. Suitable parenteral dosage ranges for mammals are from about 0.1 mg / kg per day to about 1.0 mg / kg per day. The ranges mentioned can, however, be expanded upwards or downwards, depending on the individual needs and instructions of the person skilled in the art.



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



   EXAMPLE I The base is released from 1.55 g of rac-4- (4-chlorophenyl) -1,2,3, $ -tetrahydro-7-methoxyisoquinoline hydrochloride, and it is taken up with 1.1 ml of a 35% igen formaldehyde solution and left to stand for 2 hours at room temperature. It is hydrogenated over 1 g of Raney nickel, the catalyst is filtered off, the filtrate is evaporated and the residue is crystallized 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 of melting point 244-2460.



   The starting product can e.g. can be produced as follows:
The cyanohydrin is prepared from 4-chlorobenzaldehyde and reduced to rac-α- (aminomethyl) -4-chlorobenzyl alcohol using lithium aluminum hydride.



   The base is liberated from 41.6 g of rac-c- (aminomethyl) -4-chlorobenzyl alcohol hydrochloride, it is taken up in 400 ml of benzene, 30 g of 3-methoxybenzaldehyde are added and the mixture is refluxed using a Water separator until all water is removed. It is then evaporated, the residue is dissolved in 400 ml of methanol, 15 g of sodium borohydride are added in small portions while cooling with ice and the mixture is stirred for 6 hours at room temperature. Evaporation, shaking out, crystallization with ethanolic hydrogen chloride, methanol and ether and recrystallization from methanol-ether gives 49.5 g of rac-4-chloro-α - {[(3-methoxybenzyl) amino] -methyl} benzyl alcohol hydrochloride of mp 198-1990.



   After recrystallization from ether, petroleum ether, the free base has a melting point of 88-900.



   91.0 g of rac-4-chloro-α - {[3-methoxybenzyl) amino] methyl} benzyl alcohol hydrochloride are treated with 1450 ml of a mixture of 1 part by volume of sulfuric acid (d = 1.84) under argon for one hour. and 1 part by volume of water stirred at 1000. After cooling, the mixture is poured onto about 10 kg of ice and 1.1 kg of sodium hydroxide and extracted with methylene chloride. The extracts washed with saturated sodium chloride solution, after drying and evaporation, yield approx. 78 g of a dark yellow oil.



     Chromatography of this oil on 7 kg of silica gel yields 2 main fractions. The first gives, after addition of ethanolic hydrogen chloride, crystallization with ethyl acetate and ether and recrystallization from methanol, ether 22.0 g of rac-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-5-methoxyisoquinoline hydrochloride with a melting point of 236 -238.



   After a similar treatment, the second fraction yields 43.6 g of rac-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-7- methoxyisoquinoline hydrechloride with a melting point of 200-2020.



   Example 2
The base is liberated from 12.2 g of rac-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride and mixed with 150 ml of 48% strength hydrogen bromide solution for 2 hours stirred at reflux at a bath temperature of 1600. After evaporation and Ynjrustakkusucreb ays Netgabik ether, 13.1 g of rac-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-2-methyl-7-isoquinoline hydrobromide of melting point 292.2930 are obtained. The base released therefrom shows, after recrystallization from ether, a melting point of 189-1900, the hydrochloride formed with ethanolic hydrogen chloride and recrystallized from methanol ether has a melting point of 295-2970.

 

   Example 3
The base is released from 8.0 g of rac-4- (3-chlorophenyl) -1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride, it is taken up in 150 ml of methanol, and 6 ml of one are added Add 35% formaldehyde solution and shake until the precipitate that has formed completely dissolves. It is then hydrogenated over 6 g of Raney nickel, filtered 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 a melting point of 250-251.



   The starting product can be produced as follows:
The cyanohydrin is prepared from 3-chlorobenzaldehyde and reduced to rac-α- (aminomethyl) -3-chlorobenzyl alcohol using lithium aluminum hydride
The base is liberated from 18.5 g of rac- (aminomethyl) -3-chlorobenzyl alcohol hydrochloride, it is taken up in 200 ml of benzene, 13.4 g of 3-methoxybenzaldehyde are added and the mixture is heated on the reflux using a water separator, until all the water is removed.



   It is then evaporated, the residue is dissolved in 300 ml of methanol, 8 in sodium borohydride are added while cooling with ice, the mixture is left to stand for 18 hours and then evaporated. After shaking out, acidifying with ethanolic hydrogen chloride and recrystallization from methanol-ether, 23.2 g of rac-3-chloro-α - {[(3-methoxybenzyl) amino] methyl} benzylalkchol hydrochloride of melting point 174-1750 are obtained . After recrystallization from ether-petroleum ether, the free base has a melting point of 98-1000.



   30.0 g of rac-3-chloro-α - {[(3-methoxybenzyl) amino] methyl} -benzyl alcohol hydrochloride -benzyl alcohol hydrochloride are added for 2 hours.



  at 100 in a mixture of equal parts conc.



  Sulfuric acid and water. The cooled solution is poured onto a mixture of ice and sodium hydroxide (excess of alkali) and extracted with methylene chloride. Two uniform substances are separated from one another by chromatography on silica gel, which crystallize after acidification with ethanolic hydrogen chloride and addition of ether.

  Recrystallization of one fraction from methanol-ether gives 7.2 g of rac-4- (3-chlorophenyl) -1,2,3,4-tetrahydro-5-methoxy-isoquinoline hydrochloride with a melting point of 230-2320. After recrystallization from ether-petroleum ether, the base produced therefrom has a melting point of 93-950. After an analogous work-up, the other fraction yields 14.1 g of rac-4- (3-chlorophenyl) -1,2,3,4-tetrahydro- -7-methoxy-isoquinoline hydrochloride with a melting point of 2172190.



   Example 4
The base released from 4.00 g of rac-4- (3-chlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride is treated with 80 ml of 48% strength hydrobromic acid for one hour heated to 1500 (bath temperature). After concentration, it is extracted with ethyl acetate and sodium bicarbonate solution. By acidifying the ethyl acetate extract with ethanolic hydrogen chloride 22.



  by crystallization and recrystallization from methanol / ether, 3.72 g of rac-4- (3-chlorophenyl) -1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol hydrochloride of mp.



     258-2590. The base released therefrom shows, after recrystallization from ether-petroleum ether, a melting point of 1961970.



   Example 5
The base is released from 19 g of rac-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride, and it is taken up with 300 ml of methanol and 15 ml of 35% strength
Formalin solution and left to stand for 2 hours at room temperature. After hydrogenation over Raney nickel, treatment with ethanolic hydrogen chloride and the like.



  Recrystallization from methanol-ether gives 18.7 g of rac-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline hydrochloride with a melting point of 190-2200. The free base crystallizes from ether-petroleum ether with the melting point 101-102.



   The starting product can be produced as follows:
The cyanohydrin is prepared from 4-chlorobenzaldehyde and reduced with lithium aluminum hydride to give rac-α- (aminomethyl) -4-chlorobenzyl alcohol.



   The base is liberated from 6.0 g of rac-α- (aminomethyl) -4-chlorobenzyl alcohol hydrochloride, it is taken up in 200 ml of benzene and boiled with 5.3 g of veratrumaldehyde for one hour using a water separator Reflux. The residue obtained after concentration is taken up in 200 ml of methanol and reduced at 50 with 2.5 g of sodium borohydride. After evaporation, shaking out, acidification with ethanolic hydrogen chloride and recrystallization from methanol / ether, 9.6 g of rac-4-chloro-α - {[(3,4-dimethoxybenzyl) aminojmethyl} benzyl alcohol hydrochloride with a melting point of 220 are obtained -2210. After recrystallization from ether-petroleum ether, the free base has a melting point of 93-94.



   At room temperature and with stirring, 7.12 g of rac-4-chloro-α - {[(3,4-dimethoxybenzyl) amino] methyl} benzyl alcohol hydrochloride in 100 ml of a mixture of equal parts by volume of conc. Sulfuric acid and water and heated to 800 for 30 minutes. After alkalizing, shaking out the base with methylene chloride, acidifying with ethanolic hydrogen chloride and recrystallizing from ethanol-ether, 5.7 g of rac -4- (4-chlorophenyl) -1 are obtained. 2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride, m.p. 186-1870. After recrystallization from ether, the released base has a melting point of 118-1190.



   Example 6
The base released from 1.80 g of rac-4- (4-chlorophenyl) -1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline hydrochloride is treated with 30 ml of 48% for 3 hours iger hydrogen bromide solution at 1500 (bath temperature) stirred. After concentration and recrystallization from methanol-ether, 1.85 g of rac-4- (4-chlorophenyl) -1,2,3,4- -tetrahydro-2-methyl-6,7-isoquinoline-diol-hydrobromide of mp 280-281.



   Example 7
The base released from 5.20 g of rac-41 (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride is mixed with 75 ml of methanol and 3.8 ml of 35% formaldehyde solution at room temperature stirred for 2 hours and then hydrogenated over 2 g of Raney nickel. After filtering off, evaporation, acidification with ethanolic hydrogen chloride, crystallization and recrystallization from methanol-ether, 5.00 g of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2 are obtained -methylisoquinoline hydrochloride of m.p. 273-2750.

 

   The starting product can e.g. can be produced as follows:
The cyanohydrin is prepared from 3,4-dichlorobenzaldehyde and this is reduced with lithium aluminum hy.



  three or one reduces α-chloro-3,4-dichloroacetophenone with sodium borohydride and reacts the chlorohydrin obtained with ammonia, whereby in both cases rac-α- (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 refluxed in 1 liter of benzene with 40.8 g of 3-methoxybenzaldehyde using a water separator until no more water comes out. After concentration and dissolving in 1 liter of methanol, the mixture is reduced below 50 g with 30 g of sodium borohydride, evaporated and extracted with methylene chloride and water. The methylene chloride extract acidified with ethanolic hydrogen chloride crystallizes with ethyl acetate and after recrystallization from methanol ether gives 104 g of rac-3,4-dichloro-α - {[(3-methoxybenzyl) amino] methyl} benzyl alcohol hydrochloride of mp. 1982000.

  The free base recrystallized from methanol-petroleum ether showed a srap. from 94-950.



   100 g of rac-3,4-dichloro-α - {[(3-methoxybenzyl) amino] - methyl} -benzyl alcohol hydrochloride are added to 1 liter of a mixture of 1 part by volume of sulfuric acid (d = 1.84) and 1 Part by volume of water entered and heated in a bath of 1000 for 8 hours.



  After cooling, the mixture is poured into a cooled solution of 1 kg of sodium hydroxide in ice water and extracted with methylene chloride. Chromatography of the extract (80 g of crude product) on 4 kg of silica gel yields two main fractions which are uniform according to thin-layer chromatograms. Acidification with ethanolic HCl, crystallization with ethyl acetate and recrystallization from methanol ether give 19.8 g of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-5-methoxyisoquinoline hydrochloride of mp.



  255-256 and 45.1 g of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride of m.p.



  243-2440.



   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 mixed with 48% hydrogen bromide solution for one hour a bath temperature of
160 heated to reflux. After evaporation and recrystallization from methanol-ether, 2.0 g of rac -s (3,4-dichlorophenyl) -1, 2,3,4-tetrahydro-2-methyl-7-isochinoline hydrobromide with a melting point of 284 are obtained -2850. The base released therefrom with methylene chloride and sodium bicarbonate solution shows, after recrystallization from ether-petroleum ether, the melting point 212-212.50, the hydrochloride prepared with ethanolic hydrogen chloride, after recrystallization from methanol-ether, has a melting point of 287-2880 (decomposition, sintering at 2800).



   Example 9
The base released from 11.6 g of rac-1,2,3,4-tetrahydro-7-methoxy-4 - (4-nitrophenyl) -isoquinoline hydrochloride is mixed with 14 ml of formic acid and 14 ml of 35% formaldehyde solution for one hour at reflux it is heated. After evaporation in vacuo, shaking between methylene chloride and sodium bicarbonate solution, adding ethanolic hydrogen chloride to the organic phase and recrystallization from methanol-ether, 10.2 g of almost white rac-1,2,3,4-tetrahydro-7imethoxy-2 are obtained -methyl-4- (4-nitrophenyl) isoquinoline hydrochloride of m.p. 250-2510 (decomposition).



   The starting product can be produced as follows:
4. Nitroacetophenone is brominated in cc-Stedlung, the product obtained is reduced to the corresponding bromohydrin using sodium borohydride and this is treated with ammonia to give rac-a (aminomethyl) -4-nitrobenzyl alcohol of melting point 138-1390 (from ethyl acetate) .



   4 g of rac-α- (aminomethyl) -4-nitrobenzyl alcohol are refluxed in 50 ml of benzene with 3.4 g of 3-methoxybenzaldehyde using a water separator until no more water emerges. After evaporation, the product is reduced in 200 mg of methanol with a total of 2 g of sodium borohydride while cooling with ice, and the mixture is stirred for a further hour at room temperature. After concentration, extraction with methylene chloride and water, acidification with ethanolic hydrogen chloride and recrystallization from methanol-ether, 6.9 g of rac-a - {- [(3-methoxybenzyl) amino] methyl} -4-nitrobenzyl alcohol hydrochloride vom M.p. 248-2490. After recrystallization from ether-petroleum ether, the free base has a melting point of 117-119.



      51 g of rac-α - {[(3-methoxybenzyl) amino] methyl} -4-nitrobenzyl alcohol hydrochloride are heated to 1000 with 125 ml of polyphosphoric acid for half an hour.



  After adding ice and making alkaline with sodium carbonate, extraction with methylene chloride and evaporation of the organic phase, 43 g of a red-brown oil are obtained. Chromatography on 3.5 kg of silica gel with ether-cyclohexane. Diethylamine 40: 10: 1 yields two pure main fractions, which crystallize after addition of ethanolic hydrogen chloride and ethyl acetate.

  After recrystallization from methanol-ether, 9.9 g of pale yellowish rac-1,2,3,4-tetrahydro-5-methoxy-4- (4-nitrophenyl) isoquinoline hydrochloride with a melting point of 260-2610 (the free base shows the melting point 159) and 12.5 g of slightly yellowish rac-1,2,3,4-tetrahydro-7-methoxy-4- (4-nitrophenyl) isoquinoline hydrochloride with a melting point of 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 dissolved in 200 ml of methanol with 200 mg of platinum oxide at room temperature and Hydrogenated at atmospheric pressure.



  After addition of ethanolic hydrogen chloride and recrystallization from methanol-ether, 2.1 g of rac-4- (4-aminophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline dihydrochloride with a melting point of 250 are obtained -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-nitrophenyl) isoquinoline hydrochloride and mixed with 60 ml of 48% strength hydrogen bromide solution for 1 1 / 2 hours at 150 (bath temperature) stirred.



  After concentration, shaking with ethyl acetate and sodium bicarbonate solution, acidification with ethanolic hydrogen chloride and recrystallization from methanol ether, 4.2 g of almost colorless rac-1,2,3,4-tetrahydro-2-methyl-4- (4-nitrophenyl) - 7-isoquinolinol hydrochloride of melting point 263.2650 (decomposition).

 

   Example 12
The base released from 13.5 g of rac-1,2,3,4-tetrahydro-7-methoxy-4- (3-nitrophenyl) -isoquinoline hydrochloride is mixed with 15.9 ml of formic acid and 16.7 ml of 35% strength Formaldehyde solution heated to 1200 (bath temperature) for 1 hour. After concentration, shaking with methylene chloride and sodium bicarbonate solution, acidification with ethanolic hydrogen chloride, crystallization and recrystallization from methanol-ether, 9.5 g of slightly brownish rac-1, 2,3,4.Tetrahydro.7.methoxy-2.methyl-4 are obtained - -3 (3-nitrphenyl) isoquinoline hydrochloride of m.p. 247-2480 (sintering at 2390).



   The starting product can be produced as follows:
3Nitroacetophenone is brominated in a-position, the bromination product is reduced using sodium borohydride to give the corresponding bromohydrin and this is treated with ammonia; racr- (aminomethyl) -3-nitrobenzyl alcohol is obtained which, after crystallization from ethyl acetate-ether, melts at 107-1080 (sintering at 1050).



   38.3 g of rac-α- (aminomethyl) -3-nitrobenzyl alcohol are refluxed with 32.5 g of 3-l-methoxybenzaldehyde in 500 ml of benzene using a water separator, until no more water emerges. 5 liters of methanol were taken up, 20 g of sodium borohydride were gradually added with stirring and ice cooling and the mixture was stirred for a further 3 hours at room temperature. Shaking with methylene chloride-water, acidifying with ethanolic hydrogen chloride, crystallizing and recrystallizing from methanol-ether gives 63.8 g of rac-α - {[(3-methoxybenzyl) amino] methyl} -3- -nitrobenzyl alcohol hydrochloride of mp 193-195 (sintering at 186).



   55 g of rac-α - {[(3-methoxybenzyl) amino] methyl} -3-nitrobenzyl alcohol hydrochloride and 165 g of polyphosphoric acid (84.1% P2O5) are absorbed over 45 minutes
1000 heated After adding some ice and ethyl acetate, the mixture is made alkaline with sodium carbonate and extracted. The ethyl acetate extract (46 g) is chromatographed on 3.7 kg of silica gel. With ether-acetone-diethylamine 19: 1: 1, two uniform main fractions of 7.0 g and 22.2 g are eluted.

  After acidification with ethanolic acidic acid, crystallization and recrystallization from methanol-ether, yellowish rac-1,2,3,4-tetrahydro-5-methoxy-4- (3-nitrophenyl) isoquinoline hydrochloride of melting point is obtained from the first fraction 217.2190 and from the second brownish rac-l, 2,3,4-tetrahydrc-7- methoxy-4- (3-nitrophenyl) isoquinoline hydrochloride from
M.p. 253-2550.



   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 mixed with 250 mg
Platinum oxide hydrogenated for half an hour. After acidification with ethanolic hydrogen chloride, crystallization with ether and recrystallization from methanol ether, 2.1 g of rac-4- (3-aminophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline are obtained dihydrochloride of m.p. 250-2510.



   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 treated with 60 ml of 48% strength for 11M hours Hydrogen bromide solution heated to 1500 (bath temperature). After concentration and shaking between sodium bicarbonate solution and ethyl acetate, acidification with ethanolic hydrogen chloride, crystallization with ether and recrystallization from methanol-ether - one obtains rac-1,2,3,4-tetrahydro-2-methyl-443-nitrophenyl) - 7-iso ehinolin hydrochloride of m.p. 257-2580 (decomposition).



   Example 15
The liberated from 3.7 g of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol hydrochloride
Base is mixed with 100 ml of methanol and 5 ml of 35% formaldehyde solution and, after standing for 2 hours at room temperature, hydrogenated with 5 g of Raney-Nickl. After filtering off, evaporation and acidification with ethanolic hydrogen chloride, a crystallized product is obtained. Dissolution from methanol-ether gives 3.65 g of rac -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-6-methoxy-2-methyl-7-isoquinolinol hydrochloride with a melting point of 2532540C.



   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 dissolved in 500 ml of benzene with 13.7 g of isovanillin (3-hydroxy-4-methoxybenzaldehyde) for 11 Held at reflux for hours, the separated water being collected by means of a water separator. After a short time, the imine formed (melting point 149-1500) crystallizes out.



  After evaporation of the benzene, the imine is reduced at 100 ml with 10 g of sodium borohydride in 500 ml of methanol.



  After concentration, extraction with methylene chloride and water, acidification with ethanolic hydrogen chloride, crystallization and recrystallization from methanol, 24.1 g of pure rac-3,4-dichloro-α - {[(3-hydroxy-4-methoxybenzyl) amino are obtained ] methyl} benzyl alcohol hydrochloride of m.p. 230-2310.



   After recrystallization from ether, petroleum ether, the free base has a melting point of 119-1200.



   To 14 g of rac-3,4-dichloro-α - {[(3-hydroxybenzyl) amino] methyl} benzyl alcohol hydrochloride are added 40 ml of conc. Sulfuric acid to u. shakes for 5 minutes. Ice is then added to the clear solution, made alkaline with sodium bicarbonate and extracted with methylene chloride. After acidification with ethanolic hydrogen chloride, a still inconsistent substance crystallizes, which is extracted again with ethyl acetate and naftium bicarbonate solution. After acidification and recrystallization from methanol-ether, 5.5 g of pure rac-4- (3,4-dichloro-phenyl) -1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol hydrochloride of mp 257-2580.



   Example 16
The base released from 6.5 g of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride is treated with 10 ml of formic acid and 10 ml of 35% formalin solution during 1 hour heated to 1200 (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- hydrochloride, which is recrystallized from methanol ether u. then melts at 243-2460 (sintering at 2380). After recrystallization from ether-petroleum ether, the free base has a melting point of 115-1160.

 

   The starting product can be produced as follows:
The base is liberated from 7.0 g of rac-α- (aminomethyl) -3,4-dichlorobenzyl alcohol hydrochloride, s: e is taken up in 100 ml of benzene and boiled with 5.8 g of veratrum aldehyde for one hour Use of a water separator. The residue obtained after concentration is taken up in 100 ml of methanol and reduced at 50 with 3 g of sodium borohydride. After evaporation. Shaking out, acidifying with ethanolic hydrogen chloride and recrystallization from methanol-ether gives 10.6 g of rac-3,4-dichloro-α - {[(3,4-dimethoxybenzyl) amino] - -methyl} benzyl alcohol hydrochloride of mp. 209-2100.



  The free base shows after recrystallization from ether.



  Petroleum ether has a m.p. 126-1270.



   At room temperature and with stirring, 9.5 g of rac-3,4-dichloro-α - {[(3,4-dimethoxybenzyl) amino] methyl} benzyl alcohol hydrochloride are added to 100 ml of a mixture of equal parts by volume of conc. Sulfuric acid u.



  Water and heated to 1000 for 60 minutes. After making alkaline while cooling with ice, shaking out the base with methylene chloride, acidifying with ethanolic hydrogen chloride and recrystallization from methanol-ethyl acetate, 6.5 g of rac-4- (3,4-dichlorophenyl) -1 are obtained. 2,3,4-tetrahydro-6,7-dimethoxy-isoquinoline hydrochloride of m.p. 247-2480 (sintering at 2400).



   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, dissolved in 100 ml of methanol, left to stand for 3 hours at room temperature with 3.6 ml of 35% formaldehyde solution u. then hydrogenated over about 3 g of Raney nickel. 5.4 g of a yellow oil are obtained, which is chromatographed on silica gel, two main fractions being eluted with cyclohexane-ether-diethyglamine 50: 50: 1.

  The first crystallizes with ethanolic hydrogen chloride and ether and gives 2.3 g of the hydrochloride of one of the two diastereoisomeric rac-4 - (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy -1 , 2-dimethylisoquinolines of m.p. 253-2550. The second fraction crystallizes after addition of citric acid in methanol and after recrystallization from methanol gives 2.3 g of the citrate of the other of the two diastereoisomers rac-4. '(3,4-dichlorophenyl) -1, 2,3,4- tetrahydro-7.



     methoxy-1,2-dimethylisoquinolines of m.p. 175-1760.



  By releasing the base from the citrate mentioned, acidifying with ethanolic hydrogen chloride and recrystallizing from methanol-ether, the corresponding hydrochloride of melting point 206-2070 is obtained.



   The starting product can be manufactured as follows:
The base released from 35.0 g of rac-α- (aminomethyl) -3,4-dichlorobenzylaic alcohol hydrochloride is mixed with 22.5 g of 3-methoxyacetophenone in 500 ml of toluene for 16
Heated at reflux for hours, with the deposited
Water is collected by means of a water separator. After evaporation, 400 ml of methanol are added, the mixture is reduced with a total of 10 g of sodium borohydride while cooling with ice, and stirring is continued at about 150 for 3 hours.

  After concentration, shaking out with methylene chloride and water, treatment with ethanolic hydrogen chloride, crystallization from ethyl acetate-petroleum ether and repeated recrystallization from methanol-ether, 18 g of the hydrochloride of one of the two diastereosomeric racemic 3,4-dichloro-α- {[(3-methoxy-α-methylbenzyl) amino] methyl} benzyl alcohols from
M.p. 183-1840. After shaking out with methylene chloride and 3N sodium hydroxide solution and adding ether, 13.1 g of the other diastereomer crystallized from the mother liquor as a free base of melting point 80-810. Their hydrochloride shows after recrystallization from methanol-ether the melting point 130-1310.



   10.4 g of rac-3,4-dichloro-α - [[(3-methoxy-α-methylbenzyl) amno3methylbenzyl alcohol (diastereoisomer of
80-810) are heated to 1000 in 55 ml of polyphosphoric acid under nitrogen for 30 minutes.



   The reaction mixture is then poured onto ice, extracted with methylene chloride and 3N sodium hydroxide solution and 9.9 g of an oily base are obtained, which is chromatographed on 560 g of silica gel. With cyclohexane-ether-diethyl.



  amine 25: 25: 1, 2 main fractions are eluted. After acidification with ethanolic hydrogen chloride, crystallization and recrystallization from methanol-ether, 2.5 g of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-5-methoxy-1-methyl- isoquinoline hydrochloride of m.p.



  243-2440 and 6.0 g of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetralhydro-7-methoxy-1-methylisoquinoline hydrochloride of m.p. 179-1800. The base released from the first product, i. rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-5-methoxy-1-methylisoquinoline has the melting point 70710 after recrystallization from ether-petroleum ether.



   According to the nuclear magnetic resonance spectrum, the first product consists of a mixture of equal parts of two diastereomers and the second product consists of a mixture of diastereoisomers in a ratio of approx. 3: 2.



   Example 18
1.00 g of the hydrochloride of one of the two diastereoisomeric rac-3,4-dichloro-α - {[(3-methoxy-α-methylbenzyl) amino] methyl} benzyl alcohols (m.p. 183-184) is mixed with 5 ml of polyphosphoric acid heated to 1000 for half an hour. After making the mixture alkaline with sodium hydroxide solution, it is extracted with methylene chloride, evaporated, dissolved in 20 ml of methanol and left to stand for 2 hours with 1 ml of 35% formalin solution. Hydrogenation over 1 g of Raney nickel gives 950 mg of an almost colorless oil which, according to thin-layer chromatography, consists of two main products and two by-products.

  Chromatography on 360 g of silica gel with cyclohexane-ether-diethylamine 50: 50: 1 gives an oil as the third substance, from which, after acidification with ethanolic hydrogen chloride and crystallization with methanol-ether, 450 mg of the hydrochloride of one of the two rac-4 - (3,4-Dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-1,2-dimethylisoquinolines of m.p. 218-2200. By redissolving from methanol-ether and inoculating with the hydrochloride obtained according to Example 17 of melting point.



  253-2550 another crystal modification with the m.p. 253-2550 is obtained.



   Example 19 a) From 1.25 g of the rac-4- (3,4-. Dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-1,2-dimethylisoquinoline hydrochloride obtained in Example 17 of melting point 253.2550, the base is released and heated with 30 ml of 48% hydrogen bromide solution for 6 hours to 1500 (bath temperature). After evaporation and alkalization with sodium bicarbonate, shaking with methylene chloride, acidification with ethanolic hydrogen chloride, crystallization with ethyl acetate and recrystallization from methanol ether, 1.1 g of the hydrochloride of one of the two diastereoisomeric rac4- (3, 4th dichlorophenyl) are obtained. 1,2,3, - $ -tetrahydro-1,2-dimethyl-7-isoquinolinols of m.p. 254-2550.

  Shaking with sodium bicarbonate and methylene chloride gives the corresponding free base with a melting point of 1800.



   b) The from 750 mg of the rac -443,4-dichlorophenyl) -1, 2,3,4-tetrahydro.7-methoxy-1,2- dimethylisoquinoline hydrochloride obtained in Example 17 with a melting point of 206-2070 The base released is heated to 1500 (bath temperature) for one hour with 10 ml of 48% strength bromine water. After evaporation, shaking out with methylene chloride and saturated sodium bicarbonate solution, evaporation, acidification with ethanolic hydrochloric acid, crystallization with ethyl acetate and recrystallization from methanol-ether, 710 mg of the hydrochloride of the other of the two diastereoisomers rac-4- (3,4-dichlorophenyl) are obtained -1,2,3,4-tetrahydro-1,2-dimethyl-7-isoquinolinols of m.p. 254-255. The base released by shaking out with methylene chloride and sodium bicarbonate shows after recrystallization from ether-petroleum ether an mp.



  from 219-220.



   Example 20
The base released from 3.1 g of rac-4 (3, 4-dichlorophenyl) -1,2,3,4-tetra-hydro-6,7-dimethoxy-2-methylisoquinoline hydrochloride in methylene chloride with sodium hydroxide is in 2 hours 100 ml of 48% hydrobromic acid heated to reflux at a bath temperature of 160. Crystallization sets in with strong foaming after only 2 hours. After cooling, about 80 mol of water are added, suction filtered and the like. after Umkri crystallize from methanol ether, 2.6 g of the hydrobromide of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-2-methyl-6,7-isoquinolinediol with the mp 2852860.



   Example 21
The free base is isolated from 500 mg of rac-4- (3,4-dichlorophenyl-1,2,3,4-tetrahydro-7-isoquinolinol hydrochloride by shaking with chloroform / ethyl acetate 9: 1 and sodium bicarbonate solution 0.75 ml of 35% formaldehyde solution is added to 15 ml of methanol, the mixture is left to stand for 2 hours at room temperature and hydrogenated with 1 g of Raney nickel.

  After filtering off, evaporation and acidification with ethanolic hydrochloric acid, crystallization and recrystallization from methanol-ether, the colorless rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-2-methyl'- 7th isoquinolinol is obtained - hydrochloride with the m.p. 287-288 (decomposition, sintering at 280).



   The starting material can be obtained as follows:
500 mg rac.4. (3,4-dichlorophenyl). 1,2,3,4-tetrahydro- 7-methoxyisoquinoline hydrochloride are refluxed in 10 ml of 48% strength hydrogen bromide solution under nitrogen for 2 hours at a bath temperature of 150. After evaporation in vacuo and shaking between chloroform / ethyl acetate 9: 1 and saturated sodium bicarbonate solution, the organic phase is dried and concentrated. This gives 300 mg of colorless rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-isoquinolinol with a melting point of 243-244.



   The hydrochloride with the melting point 2702720 is obtained by acidification with ethanolic hydrogen chloride and crystallization and recrystallization from methanol ether.



   Example 22
10.0 g of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride are mixed with 100 ml of ethanol and with 4 g of solid sodium hydroxide and 12 g of ethyibromide for 3 hours heated to reflux at a bath temperature of 1000. After concentration in vacuo, it is extracted with methylene chloride and 3N sodium hydroxide solution and dried over Na2 SO4. Ethanolic hydrochloric acid is added to the base obtained by concentration and, after crystallization and recrystallization from methanol, 9.5 g of colorless rac -4- (3,4-dichlorohenyl) -2-ethyl-1,2,3,4-tetrahydro are obtained -7-methoxyisoquinoline hydrochloride with melting point 269.2700 (Sin ternbei2670).



   Example 23
The free base is isolated from 4.50 g of rac-4- (3,4-dichlorophenyl) -2-ethyl-1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride by shaking with chloroform and saturated sodium bicarbonate solution. After adding 100 ml of 48% hydrobromic acid, a precipitate of the hydrobromide immediately forming, the mixture is refluxed with stirring for 4 hours at a bath temperature of 1600. It is extracted with 500 ml of chloroform and 300 ml of saturated sodium bicarbonate solution, dried with Na2SO4 and evaporated in vacuo.

  After acidification with ethanolic hydrochloric acid, crystallization with ethanol-ether and recrystallization from methanol, 3.0 g of colorless rac -4- (3,4-dichlorophenyl) -2-ethyl-1,2,3,4-tetrahydro-7- are obtained isoquinolinol hydrochloride with m.p. 305-307 (sintering at 260)
Example 24
The free base is isolated from 500 mg of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride by shaking between chloroform and saturated sodium bicarbonate solution. In an autoclave, it is heated to 1500 for 3 hours together with 5 ml of isopropyl bromide and 200 mg of finely ground soda.

  After concentration, shaking between chloroform and 3N sodium hydroxide solution, drying, acidification with ethanolic hydrochloric acid and crystallization and recrystallization from ethanol, 300 mg of colorless rac-4- (3,4-dichlorophenyl) -2-isopropyl-1,2,3,4 are obtained -tetrahydro-7-methoxiisoquinoline hydrochloride with the m.p. 245-246.



   Example 2S
Under nitrogen, 500 mg of rac-4 (3,4-dichlorophenyl) -2-isopropyl-1, 2,3,4.tetrahydro.7.methoxyisochi.



     nolin-hydrochloride in 10 ml of 48% hydrobromic acid for 2 hours at a bath temperature of 1600 under reflux. The reaction mixture is then concentrated in vacuo, extracted with chloroform and soda solution and evaporated. After crystallization with petroleum ether and recrystallization from ether-petroleum ether, 300 mg of colorless rac.4. '(3,4-dichlorophenyl) are obtained.



     -2-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinol of m.p.



     155.1560.



   By acidifying with ethanolic hydrochloric acid, crystallizing and recrystallizing from ethanol-ether, the colorless hydrochloride with the melting point 274-2770 (decomposition) is obtained.



   Example 26
500 rog rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro- 7-methoxyisoquinoline 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 . After concentration in vacuo, shaking out with chloroform and 3N sodium hydroxide solution, drying and evaporation and acidification with ethanolic hydrogen chloride, colorless crystals are obtained from chloroform-ether. Recrystallization from ethanol gives 400 mg of rac-2-benzyl-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxyisoquinoline hydrochloride with a melting point of 263-2640 (Sin ternbei2450).

 

   Example 27
10.76 g (30 mmol) of rac-4- (3,4-dichlorophenyl) -1,2,3,4- -tetrahydro-7-methoxy-2-methylisoquinoline hydrochloride are extracted by shaking between 2N soda solution and the like.



  Chloroform converted into the oily free base and treated with a solution of 11.60 g (30 mmol) of (-) - 2,3-di-Op- toluoyl (RR) -tartaric acid (M = 386.36) in 300 ml of methanol offset. The clear solution is with some 2,3-di-O-p-toluoyl- (R, R) -tartrate of (-) - (R) -4- (3,4-dichlorophenyl) -1, 2,3 , tetrahydro.7.methoxy.2.methylisoquinoline inoculated and left to stand at room temperature until a large amount of this salt has formed. The solution may have to be slightly concentrated in vacuo.

  After suction filtration, the 2,3-di-op-toluoyl - (R, R) -tartrate of (-) - (R) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro is obtained -7-methoxy-2-methylisoquinoline, the purity of which is checked by shaking the salt between 2N soda solution and chloroform, acidifying the free base with ethanolic hydrochloric acid and crystallizing the hydrochloride from ethanol ether. The 2,3-di-O-p-toluoyl- (R, R) -tartrate of (-) - (R) -4- (3,4-dichlorophenyl) -1,2,3,4 - tetrahydro- 7-methoxy - 2 - methylisoquinoline may have to be recrystallized from methanol until its hydrochloride shows the desired rotation.



  The pure 2,3-di-Op-toluoyl- (R, R) -tartrate of -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline has a melting point of 188 -1890 from methanol.



     [α] D25 = -83.



   The hydrochloride of (-) - (R) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline has a melting point of 240-2420 from methanol-ether.



     [α] D25 = -8.5, [α] 54625 = -10, [α] 43625 = -14.



   The oily free is obtained by shaking out the hydrochloride of (-) - (R) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline with 2N sodium carbonate solution and chloroform Base (-) - (R) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline.



     [α] D25 = -30.



   The methanolic mother liquors of (-) - (R) -4 - (3,4.Dichlorophenyl) - 1, 2,3,4.tetrahydro.7-methoxy-2.methylisoquinoline are concentrated until again a large amount Has formed crystals. After recrystallization from methanol, the 2,3-di-Op-toluoyl- (R, R) -tartrate of (+) - (S) -4- (3,4-dichlorophenyl) -1,2,3, 4-tetrahydro-7-methoxy-2-methylisoquinoline with the m.p.



  186-1870. Its optical purity is in turn 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 checked.



   2,3-di-Op-toluoyl- (R, R) -tartrate of (+) - (S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy- 2-methylisoquinoline: [α] D25 = -70.



   By shaking the base out of 2,3-di-Op-toluoyl - (R, R) -tartrate of (+) - (S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro -7-methoxy-2-methylisoquinoline with 2N soda solution and chloroform, acidification with ethanolic hydrochloric acid and crystallization from methanol. Ether gives the hydrochloride of (+) - (S) -4- (3,4-dichlorophenyl) -1, 2, - 3,4-tetrahydro-7-methoxy-2-methylisoquinoline with m.p. 240-2420.



   The hydrochloride can also be isolated directly if the methanolic mother liquors of (-) - (R) -4- - (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline with 2N soda solution and chloroform are extracted and acidified with ethanolic hydrochloric acid. After separating a small amount of rac-4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methyl isoquinoline hydrochloride and recrystallizing the mother liquor, pure (+) - (S) -4- (3,4-dichlorophenyl). 1, 2,3,4-tetrahydro-7.methoxy.2.methylisoquinoline was obtained.



   Hydrochloride of (+) - (S) -4- (3,4-dichlorophenyl) -1,2, 3, 4-tetrahydro.7-methoxy-2-methylisoquinoline: = +8.5, [α] 54625 = +10, [α] 43625 = +14.



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



     [α] D25 = +36.



   The hydrochloride of (+) - (S) -4- (3,4-dichlorophenyl) - -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline can also be obtained from the 2,3-di- O-benzoyl- (S, S) -tartrate can be obtained from (+) - (S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline : The base released from the methanolic mother liquors of (-) - (R) -4- (3.4 D-chlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline as above is with one equivalent of (+) - 2,3-di-O-benzoyl- (S, S) -tartaric acid crystallized from methanol ether and 2,3-di-O-benzoyl- (S, S) -tartrate of ( +) - (S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy-2-methylisoquinoline with the m.p.



   157-1580. The purity is again determined by rotating the 2,3-di-O-benzoyl- (S, S) -tartrate from (+) - (S) -4- (3,4-dichlorophenyl) -1,2,3 , 4-tetrahydro-7-methoxy-2-methylisoquinoline represented hydrochloride controlled.



   2,3-Di-O-benzoyl- (S, S) -tartrate of (+) - (S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxy- 2-methylisoquinoline: [α] 25 D = +69.



   Example 28
By shaking out the evaporated mother liquors of 2-3-Di-Op-teluoyl- (RR) -tartrate of (-) - (R) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro- 7-methoxyisoquinoline with 2N soda solution and chloroform are 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 - methoxyiso quinoline hydrochloride and (+) - (S) 4- (3,4 -Dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxyisoquinoline. It is dissolved in 200 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 is hydrogenated for about 1 hour while shaking at room temperature, sucked through diatomaceous earth, acidified with ethanolic hydrochloric acid and concentrated in vacuo.

  First 4.2 g of a mixture with the melting point 2450 crystallize from ethanol-ether, which after rotation mainly consists of racemic 4- (3,4-dichlorophenyl) -1,2,3,4-tetra-hydro-7 -methoxy-2-methylisoquinoline be available. The following crystals give a total of 6.4 g (17.8 mmol) (+) - (S) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-7-methoxyisoquinoline with the melting point. 240-242 and [α] D25 = +8.2, [α] 54625 = +10.40 and [1: Ç] 43525 = + 14.00.

 

Claims (1)

PATENT CLAIM Process for the preparation of 1,2,3,4-tetrahydro-4-phenyl-isoquinoline derivatives of the general formula EMI12.1 wherein R is hydroxy or Cl-C4-alleoxy, R1 is hydrogen, hydroxy or C1-C4-alkoxy, where R and R1 together can also mean a methylenedioxy group, R2 is hydrogen or Cl-C4-alkyl, R2 is Cl-C4-alkyl or aryl Cl -C4-alkyl, R4 halogen, nitro or an amino group n disubstituted by C1-C4-alkyl denotes the number 1 or 2, characterized in that a compound of the general formula EMI12.2 in which R, Rz, R2, R4 and n have the meaning given in formula I with the introduction of R3 alkylated or aralkylated. SUBCLAIMS 1. The method according to claim, characterized in that a compound of formula 1, wherein R and / or R1 are Cl-C4-alkoxy, is subjected to acidic ether cleavage. 2. The method according to claim, characterized in that one obtained connection of the pile. mel I, in which R4 is nitro and R5 is different from benzyl, to a compound in which R4 is amino. 3. The method according to claim, characterized in that a resulting racemate of the formula I is split into optically uniform compounds or an optically uniform starting material is used. 4. The method according to claim, characterized in that one obtained diastereoisomeric set. wisch separates into the individual racemates. 5. The method according to claim, characterized in that a free base obtained is converted into an acid addition salt with an inorganic or organic acid. 6. The method according to claim or sub-claim 1, characterized in that R and / or R1 in the meaning Ci-C4-alkoxy stand for a methoxy group. 7. The method according to claim, characterized in that a compound of the formula I is prepared which is unsubstituted in position 6 of the isoquinoline structure. 8. The method according to claim, characterized in that a compound of formula I is produced. represents, in which the substituent (s) denoted by R4 in the para and / or in the meta position of the phenylre located in the 4 position of the isoquinoline skeleton. always sit. 9. The method according to claim, characterized in that a compound of the formula I is prepared in which R4 is halogen. 10. The method according to dependent claim 9, characterized in that the halogen is chlorine. 11. The method according to claim, characterized in that a compound of the formula I is prepared in which n = 1 and R 1 is chlorine in the para position. 12. The method according to claim, characterized in that a compound of the formula I is prepared in which n = 2 and R4 is chlorine in the para and meta positions. 13. The method according to claim, characterized in that R3 in the meaning Cl-C4-alkyl is a methyl or ethyl group. 14. The method according to claim, characterized in that in the compound of formula I R2 is hydrogen. 15. The method according to claim or one of the dependent claims 1, 7 to 11, 13 and 14, characterized in that 4- (4-chlorophenyl) -1,2,3,4-tetrahydro-2-methyl-7-isoquinolinol manufactures. 16. The method according to claim or one of the dependent claims 1, 7 to 10 and 12 to 14, characterized in that 4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro-2-methyl- 7-isoquinoline produces. 17. The method according to claim or one of the dependent claims 6 to 10 and 12 to 14, characterized in that 4. (3, 4.dichlorophenyl) .1, 2,3,4-tetrahydro-7-methoxy-2- produces methylisoquinoline.