BE830298A - PRODUCTION OF AMINOTETRALINE DERIVATIVES - Google Patents

Description

       

  TAKEDA CHEMICAL INDUSTRIES,

  
The present invention relates to new processes which can be implemented on an industrial scale for the production of new aminotetralin derivatives, of formula

  

 <EMI ID = 1.1>


  
in which R is a hydrogen atom, a hydrocarbon group

  
 <EMI ID = 2.1>

  
 <EMI ID = 3.1>

  
the invention also relates to their physiologically acceptable salts.

  
 <EMI ID = 4.1>

  
for example in the treatment of asthma or arrhythmia in humans, for example. In addition, the present invention relates to part of compound I, that is to say to new aminotetralin derivatives of formula

  

 <EMI ID = 5.1>


  
in which the symbol R has the same meaning as above

  
 <EMI ID = 6.1>

  
as well as their physiologically acceptable salts, which are advantageous also as intermediates in the production of the compound of formula (I) in which the symbols Z and

  
 <EMI ID = 7.1>

  
As drugs for the treatment of asthma, isoproterenol and metaproterenol, both of which have

  
stimulating action of P-adrenergic receptors, have been widely used. However, while isoproterenol has a

  
East

  
 <EMI ID = 8.1>

  
 <EMI ID = 9.1>

  
sound of the strong cardiac stimulation which is associated with the receptors (31-adrenergic; on the other hand, metaproterenol has only moderate side effects of the above type but is markedly inferior in bronchodi- <EMI ID = 10.1>

  
latatrice. Therefore, none of these products is considered satisfactory as a selective bronchodilator.

  
As a result of the foregoing, the Applicant has carried out extensive research which has made it possible to succeed in synthesizing the compound (I), which has a strong bronchodilator activity but has only weak or even zero side effects compared with those which are caused by stimulation
(3, -adrenergic; in addition, the Applicant has succeeded in developing processes that can be implemented industrially for the production of compound (I).

  
Thus, the main subject of the present invention is processes which can be implemented on an industrial scale to produce compound (I) and its physiologically acceptable salts. Another object of the present invention lies in the ncuvcau

  
 <EMI ID = 11.1>

  
sale to be used as medication for the treatment of asthma

  
 <EMI ID = 12.1>

  
will emerge on reading the description and the claims.

  
The new methods of the present invention can be represented as follows:

  
Process 1

  
This process makes it possible to obtain a compound of formula

  

 <EMI ID = 13.1>


  
wherein the symbol R is a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group, and

  
 <EMI ID = 14.1>

  
protector, or salts of such a compound, and it consists in hydrolyzing a compound of formula
 <EMI ID = 15.1>
  <EMI ID = 16.1>

  
where R, Z and Z have the same meanings as above.

  
Process 2

  
This process makes it possible to obtain a compound of formula

  

 <EMI ID = 17.1>


  
 <EMI ID = 18.1>

  
and R * is a hydrogen atom or a hydrocarbon group which may be substituted, or its salts, and it consists in reducing a compound of the formula

  

 <EMI ID = 19.1>


  
 <EMI ID = 20.1>

  
the symbol A is a group which can be covered in a group
-NHR '(where R' has the same meaning as above) by reduction <EMI ID = 21.1>

  
Process 3

  
This process makes it possible to obtain a compound of formula

  

 <EMI ID = 22.1>


  
 <EMI ID = 23.1>

  
 <EMI ID = 24.1>

  
 <EMI ID = 25.1>

  
which R is a hydrogen atom or a lower alkyl group

  
 <EMI ID = 26.1>

  
 <EMI ID = 27.1>

  
together with the neighboring carbon atom), or the salts of such a compound, and it consists in reducing a compound of formula
 <EMI ID = 28.1>
 in which the symbols Z, Z and X have the same meanings

  
 <EMI ID = 29.1>

  
 <EMI ID = 30.1>

  
carbonyl of formula

  

 <EMI ID = 31.1>


  
 <EMI ID = 32.1>

  
as above.

  
Process 4

  
This process makes it possible to obtain a compound of formula

  

 <EMI ID = 33.1>


  
 <EMI ID = 34.1>

  
tions as above, or the salts of such a compound, and it

  
 <EMI ID = 35.1>

  

 <EMI ID = 36.1>


  
in which the symbol R has the same meaning as above

  
 <EMI ID = 37.1>

  
gene or a protecting group, provided that at least one of these symbols represents a protecting group, a reaction leading to the elimination of the protecting group or groups.

  
In the aforementioned methods, it is understood that all the compounds (Ia), (Ib) and (Ic) are related to the compound (I).

  
Regarding formulas (I), (Il), (Ia), (le), <EMI ID = 38.1>

  
acyclic hydrocarbon may be a straight chain or branched, saturated or unsaturated hydrocarbon group, the examples of which are

  
 <EMI ID = 39.1>

  
containing two or more identical or different heteroatoms

  
 <EMI ID = 40.1>

  
carbon (methoxy, ethoxy, propoxy, etc.), an arylcx.y group
(phenoxy, naphthoxy, etc.), a halogen atom (for example an atom of chlorine, fluorine, bromine, iodine, etc.), a group <EMI ID = 41.1>

  
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), an acyl group (eg acetyl, propionyl, butyryl, benzoyl, etc.), an amino or substituted amino group (the substituent (s) may be an alkyl group, acyl or a group d 'another kind), a nitro group, a cyano group and other groups. The aforementioned cycloalkyl, cycloalkenyl, aryl and heterocyclic groups may further contain one or more suitable substituents such as lower alkyl group having 1 to 4 carbon atoms.

  
 <EMI ID = 42.1>

  
lower having 1 to 4 carbon atoms (e.g. methoxy,

  
 <EMI ID = 43.1>

  
of chlorine, bromine, iodine or fluorine Typical examples of such substituted acyl hydrocarbon groups include

  
 <EMI ID = 44.1>

  
3-cyclohexyl-1-methylpropyl, 4-methylcyclohexylmethyl, 1-cyciohexenylmethyl, 1-cyclopentenylmethyl, benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, a-methylbenzyl, 3,4-dimethoxybenzyl, a-methyl-

  
 <EMI ID = 45.1>

  
etc.

  
The cyclic hydrocarbon group mentioned above at

  
 <EMI ID = 46.1>

  
is for example a cycloalkyl group, advantageously having a

  
 <EMI ID = 47.1>

  
cyclcpentyl, cyclohexyl, cycloheptyl, etc.), cyclcalkenyl having advantageously 3 to 7 ring members (for example cyclo-

  
 <EMI ID = 48.1>

  
naphthyl, etc.) etc. Among these hydrocarbon groups, the most advantageous is a cycloalkyl group whose ring has 3 to <EMI ID = 49.1>

  
lower alkyl, hydroxyl, lower alkoxy, halogen and other groups mentioned above for the substituent (s) of the cycloalkyl, cycloalkenyl, aryl and heterocyclic groups mentioned in connection with the substituted acyl hydrocarbon group. Among typical examples of cyclic hydrocarbon groups

  
 <EMI ID = 50.1>

  
pentyl, cyclohexyl, cycloheptyl, 2-methylcyclopropyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 2,2-dimethylcyclobutyl, 3,3dimethylcyclobutyl, 4-methylcyclohexyl, 4-hydroxycyclohexyl.

  
4-methoxycyclohexyl, 2-chlorocyclopentyl, 2-cyclohexenyl,? Cyclopentenyl, phenyl, α-naphthyl, 4-chlorophenyl, 4-methoxy-

  
 <EMI ID = 51.1>

  
etc. With regard to formulas (I), (I ') and (II), the group designated by the symbol R can be for example an acyl group derived from carboxylic acids, carbonic acids, etc., such as for example groups formyl, acetyl, propionyl, butyryl, 2-methyl-2-butenoyl, monochloracetyl, dichl or acetyl,

  
 <EMI ID = 52.1>

  
straight or branched chain alkyl, advantageously having up to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-

  
 <EMI ID = 53.1>

  
etc. The hydrocarbon group designated by the symbol R <2> is for example the hydrocarbon group described above with regard to the symbols R or R '.

  
 <EMI ID = 54.1>

  
 <EMI ID = 55.1>

  
 <EMI ID = 56.1>

  
 <EMI ID = 57.1>

  
cyclopentane, cyclohexane, cycloheptane, etc.), a cyclealkene group the ring of which advantageously has 3 to 7 members

  
 <EMI ID = 58.1>

  
Among these groups, the most advantageous is a cycloalkane group in which the ring contains 3 to 7 members. **

  
 <EMI ID = 59.1>

  
(le), (II), (III &#65533;, (IV) and (VI), the protecting group designated by

  
 <EMI ID = 60.1>

  
is capable of providing the desired protection of the hydroxyl group

  
or amino. Thus, mention may be made of lower alkyl groups having advantageously up to 4 carbon atoms (for example methyl, ethyl, n-propyl, isopropyl, etc.), an alkenyl group

  
having

  
lower / advantageously up to 4 carbon atoms (eg vinyl, allyl, etc.), a lower alkynyl group advantageously having up to 4 carbon atoms (eg propargyl, etc.),

  
 <EMI ID = 61.1>

  
trytyl, etc.), a phenacyl group (e.g. phenacyl, p-bromophenacyl, etc.), an acyl group derived from a carboxylic acid, a sulfonic acid, a carbonic acid or a carbamic acid ( for example formyl, acetyl, propionyl, butyryl, 2-methyl-

  
 <EMI ID = 62.1>

  
xanthene-9-carbonyl, benzenesulfonyl, .toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, benzyloxycarbonyl, tertbutyloxycarbonyl, isobornyloxycarbonyl, carbamoyl, trichloromethylimidcyl, etc.), silyl (eg, trimethylsilyl acid, residue of an ester, etc.) mineral (for example a residue of

  
nitrous acid ester, sulfuric acid ester residue, boric acid ester residue, dibenzylphosphoryl, p-nitrobenzylphosphoryl, p-bromobenzylphosphoryl, etc.), pyranyl, tetrahydropyranyl, tetrahydrofuranyl, thiopyranyl groups, 4-methoxy-

  
 <EMI ID = 63.1>

  
both generate protecting groups, they can be combined

  
 <EMI ID = 64.1>

  
 <EMI ID = 65.1>

  
there may be mentioned, inter alia, lower alkylidene groups, advantageously having up to 6 carbon atoms (for example methylidene, ethylidene, propylidene, iscpropylidene, butylidene, pentylidene, hexylidene, etc.) substituted C.C6 alkylidene groups ( eg 1-methoxyethylidene, 1-ethoxyethylidene, benzylidene (phenylmethylidene), diphenylmethylidene, phenethylidene, 1-phenylethylidene, acetylisopropylidene, oxomethylidene, iminomethylidene, thiomethylidene, etc. and <EMI ID = 66 groups.

  
09 00 to 0.06 00 .0 analogues.

  
 <EMI ID = 67.1>

  
thus gathered is given below:

  

 <EMI ID = 68.1>


  
 <EMI ID = 69.1>

  
above and the symbol R "'denotes a divalent group attached to the a carbon atom of the above-mentioned group R'.

  
 <EMI ID = 70.1>

  
except for a lower alkyl group. In particular, a benzyl group is more advantageous.

  
 <EMI ID = 71.1>

  
form structures given below as examples:

  

 <EMI ID = 72.1>


  
 <EMI ID = 73.1>

  
 <EMI ID = 74.1>

  
meanings that above and the symbol Z5 denotes a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.), aryl (e.g. phenyl, etc.), aralkyl (for example

  
 <EMI ID = 75.1> <EMI ID = 76.1> and these pewert groups carry one or more optional substitution groups (eg, hydroxyl group, lower alkoxy, halogen atom, etc.) in one or more optional positions.

  
Among the aforementioned protecting groups, a group

  
 <EMI ID = 77.1>

  
 <EMI ID = 78.1>

  
each a hydrogen atom.

  
 <EMI ID = 79.1>

  
a-methylbenzyl, p-methoxy-benzyl, etc. Among these, the benzyl group is especially advantageous.

  
With regard to formula (III), the group which can be converted to -NHR 'by reduction, as represented by A, is for example, inter alia, a nitro, nitroso, isonitroso (oxyimino), hydroxylamino, imino group , acyloxyimino, diazo, azido, phenylhydrazono, = NR '(R' having the meaning given above), etc.

  
Among these groups, the most advantageous are the nitro, nitroso or isonitroso groups. When the starting compound of for-

  
 <EMI ID = 80.1>

  
troso is used in method 2, the compound (Ia) is obtained in which R 'is a hydrogen atom.

  
With respect to formula (IV), the group which can be converted to an amino group by reduction, as represented by A <2>, can be any group capable of being converted to an amino group by any. reduction mode in process 3. Thus, for example, there may be mentioned nitro, nitroso, isonitroso (oxyimino), hydroxylamino, imino, acyloxyimino, diazo, azido, phenylhydrazono, etc. groups.

  
Among these groups, the most advantageous are the nitro, nitroso or isonitroso groups.

  
As will be understood from reading the description

  
1 which follows, the aforementioned symbols, such as R, R ', R, R,

  
 <EMI ID = 81.1>

  
and the compounds obtained in these methods only mean that each group belongs to the domain of the same definition and does not necessarily mean that each group remains as it was before the reaction.

  
 <EMI ID = 82.1>

  
following.

  
 <EMI ID = 83.1>

  
Process 1

  
Method 1 of the present invention comprises hydrolysis of compound (II) which selectively yields compound (I). This hydrolysis is normally carried out in water, an organic solvent (e.g. methanol, ethanol, chloroform, benzene, tetrahydrofuran, ethyl ether, acetone, dioxane, dichloromethane, etc. ) or a mixture of such solvents and, if necessary, in the presence of a suitable catalyst. As a catalyst in such an operation, an acid or a base can be used.

  
advantageously and an especially advantageous acid. In this

  
As regards acid, we can mention mineral acids (for example hydrochloric, sulfuric, nitric, phosphoric acids, etc.), organic acids (for example formic, acetic, propionic, trifluoroacetic, methanesulfonic, toluenesulfonic, etc. .) or Lewis acids (eg aluminum chloride, boron trifluoride, zinc chloride, ferric chloride, etc.) by way of example. The base can be

  
 <EMI ID = 84.1>

  
potassium hydroxide, potassium carbonate, sodium hydrogencarbonate, sodium sulfite, etc.) or an organic base (eg triethylamine, pyridine, piperidine,

  
N-methylaniline, triethanolamine, etc.). Although the hydrolysis reaction according to the invention progresses suitably at room temperature, it cannot be accelerated or slowed down by heating.

  
 <EMI ID = 85.1>

  
is normally between about -40 [deg.] C and about 150 [deg.] C, especially between 20 and 100 [deg.] C. The reaction time is virtually optional but is usually preferably between about 5 minutes and 40 hours.

  
1 2

  
In this process, when the symbol Z, Z or R for example, represents a hydrolyzable group, it can be concurrently hydrolyzed by the hydrolysis reaction of this process, giving the compound constituting the product of formula (I) in which the group corresponding was hydrolyzed. For example, when the

  
 <EMI ID = 86.1>

  
have a benzyl group, the product obtained can be a compound

  
 <EMI ID = 87.1>

  
hydrogen; when the symbol R of the starting compound (II) is an acyl group, the acyl group can be removed so that the product obtained which is the compound (I) has an amino group;

  
 <EMI ID = 88.1>

  
when R of the starting compound (II) is an acyloxyalkyl group, a compound (I) containing a hydroxyalkylamino group can be obtained as a product. Such hydrolysis can be carried out gradually.

  
The starting compound (II) in this process can be prepared, for example, by the process shown below.

  

 <EMI ID = 89.1>


  
In these formulas R, Z <1> and Z2 have the same meanings as above and NBS represents N-bromosuccinimidE.

  
Process 1 is characterized by the hydrolysis of the compound
(II) and obtaining the contemplated compound (I) in which the hydroxyl group is introduced in position 1 of the tetralin nucleus and an amino or substituted amino group is introduced in position 2. Thus, this reaction is an unknown reaction until to date, especially suitable for producing the compound (I) in which the symbol R is a hydrocarbon group branching at its a position.

  
Processes 2 and 3

  
The reduction in process 2 or 3 is usually carried out by a reducing process suitably selected, depending on the substance used initially, from processes such as (1) a

  
 <EMI ID = 90.1>

  
nickel or a similar metal as a catalyst, (2) reduction by means of a metal hydride such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, etc. ., (3) Meerwein-Ponndorf-Verley reduction using an aluminum alkoxide such as aluminum isopropoxide, (4) reduction using metallic sodium, metallic magnesium, or the like with , for example, an alcohol, (5) reduction using zinc powder with a base such as caustic alkali, (6) reduction using a metal such as iron or zinc with an acid such than hydrochloric acid or

  
 <EMI ID = 91.1>

  
 <EMI ID = 92.1>

  
(1) and (2) are the most advantageous. It is understood that in addition to the methods which are mentioned above, any method can be applied provided that it makes it possible to achieve the object of the present invention. Although the reaction temperature which is advantageous will vary depending on the starting materials and reduction methods chosen, it is usually between about -20 [deg.] C and 100 [deg.] C. This reaction is ordinarily carried out at atmospheric pressure but, if desired, it can be carried out at higher or lower pressure than atmospheric pressure. The reduction is usually carried out in the presence of a suitable solvent.

   The type of solvent is optional, provided that it is capable of dissolving to a greater or lesser degree the starting material and that it does not adversely affect the reaction, this solvent being for example water,

  
 <EMI ID = 93.1>

  
propanol, etc.), an ether (for example dimethyl ether, diethyl ether, methyl ethyl ether, tetrahydrofuran,

  
dioxane, etc.), an ester (eg ethyl acetate, butyl acetate, etc.), a ketone (eg acetone, methyl ethyl ketone etc.), an aromatic hydrocarbon (eg the

  
 <EMI ID = 94.1>

  
example acetic acid, propionic acid, etc.) and analogous compounds or a mixture of two or more such compounds.

  
When reducing according to Method 3, it is possible to carry out the reaction using an excess of the carbonyl compound
(V) in place of the solvent.

  
The reduction in process 2 or process 3 can be carried out gradually, for example when the starting material has more than two groups which can be reduced, it is <EMI ID = 95.1>

  
pements gradually.

  
In process 2 or 3 of the present invention, the starting materials comprise various compounds, respectively giving the corresponding desired compounds. Thus, depending on the material

  
starting point and the desired compound sought, the mode of reduction and the conditions of reduction which are suitable are chosen from those which have been mentioned above.

  
With regard to the starting compounds (III), (IV) and

  
 <EMI ID = 96.1>

  
 <EMI ID = 97.1>

  
cases in which these groups are simultaneously reduced by the reduction reaction of Method 2 and Method 3, resulting in the corresponding desired compounds in which the above groups have been reduced. By way of example, when the symbol R 'or R <2> in the starting compound represents an unsaturated group, it is possible to obtain a final compound comprising the corresponding saturated group and when the symbols Z <1> and / or Z2 of the starting compound are benzyl groups, one can obtain a final compound having a hydroxyl group.

  
 <EMI ID = 98.1>

  
in methods 2 and 3 can be synthesized by methods well known in themselves, for example by the following methods.

  

 <EMI ID = 99.1>
 

  
 <EMI ID = 100.1>

  
 <EMI ID = 101.1>

  
above).

  
Processes 2 and 3 are characterized by a reduction in the number of steps in the production processes of the compounds

  
 <EMI ID = 102.1>

  
starting se (III) or (IV) having a group which can be converted to -NHR 'or to an amino group by reduction in the form of

  
 <EMI ID = 103.1>

  
that it allows to easily produce the various desired products

  
 <EMI ID = 104.1>

  
corresponding (V) that can be easily obtained.

  
Process 4

  
The reaction in Method 4 is carried out by subjecting the compound (VI) to a reaction resulting in the removal of the protecting group (s). This reaction can be any as long as it is capable of removing at least one of the protecting groups. Advantageous examples of such reactions include reduction, oxidation, solvolysis (eg hydrolysis, alcoholysis, etc.) and the like. We will give more detailed examples of these reactions:

  
(1) catalytic reduction with platinum, palladium, rhodium, Raney nickel or the like as a catalyst,

  
 <EMI ID = 105.1>

  
or an analogous compound using liquid ammonia or an alcohol such as ethanol or butanol, (3) reduction using a metal hydride such as lithium aluminum hydride, sodium-ah minium, sodium borohydride or a similar hydride, (4) reduction by means of a metal such as zinc, iron or a similar metal with an acid such as an organic acid (e.g. acid formic acid, acetic acid, etc.), a mineral acid
(for example: hydrochloric acid, sulfuric acid, etc.) or analogous products, (5) a reaction by means of a Lewis acid such as aluminum chloride, aluminum bromide, zinc chloride, magnesium iodide, farric chloride, boron trichloride, boron tribromide or the like, (6) a

  
 <EMI ID = 106.1>

  
that (e.g. hydrofluoric acid, concentrated hydrobromic acid, a mixture of hydrobromic acid and acetic acid, hydrochloric acid, hydroiodic acid, etc.), sulfuric acid,

  
 <EMI ID = 107.1> <EMI ID = 108.1>

  
acid such as an aqueous solution, an alcoholic solution or the like, (7) a reaction by means of an organic acid such as trifluoroacetic acid, acetic acid, oxalic acid, paratoluenesulfonic acid, l formic acid or the like, or an aqueous solution of such an organic acid, (8) a reaction by means of an inorganic base such as sodium hydroxide, potassium hydroxide, hydroxide barium, potassium carbonate, sodium hydrogen carbonate, aqueous ammonia solution, hydrazine hydrate or the like, or an organic base such as pyridine hydrochloride, hydroxide tetramethylammonium, iodide

  
collidine-lithium or a similar product, (9) a reaction using an oxidizing agent such as concentrated nitric acid, chromic anhydride, potassium permanganate, ozone,

  
benzoyl peroxide or the like, (10) a reaction using a chemical such as thiourea, a mercaptide, lead acetate or the like, (11) a reaction using a solvent such as water, methanol, ethanol or the like, (12) physical treatment such as electrolytic reduction, electrolytic oxidation, ultraviolet irradiation or the like,

  
(13) an enzymatic reaction, etc. The reaction is usually carried out in the presence of a suitable solvent. The type of this

  
 <EMI ID = 109.1>

  
to a greater or lesser degree the starting material and that it has no adverse effect on the reaction, this solvent being by

  
 <EMI ID = 110.1>

  
methanol, ethanol. oropanol, etc. ', an ether (e.g.' diethyl dimethyl ether, diethyl ether, methyl ethyl ether, tetrahydrofuran, dioxane, etc.), a halogenated hydrocarbon
(eg chloroform, dichloromethane, etc.) and like solvents or a mixture of two or more thereof. Although the preferred reaction temperature varies with the methods used, it is usually between about
-40 [deg.] C and 150 [deg.] C. This reaction is ordinarily carried out at atmospheric pressure, but, if not desired, it can be carried out at a pressure above or below atmospheric pressure.

  
The reaction in method 4 can be implemented <EMI ID = 111.1>

  
stage by stage; for example when the starting compound (VI) has more than two protecting groups, it is possible to obtain the compound (Ie) by eliminating these protecting groups gradually.

  
 <EMI ID = 112.1>

  
advantageously in the compound envisaged a hydrogen atom.

  
 <EMI ID = 113.1>

  
example of the type (1), (2), (3), (4), etc.7 as a reaction allowing the elimination of the protecting group (s), an advanced group

  
 <EMI ID = 114.1>

  
or an analogous group, a benzyl or benzyloxy carbonyl group, especially a benzyl group, being more advantageous. In the case where solvolysis is used / for example (5), (6), (7), (8) ),

  
 <EMI ID = 115.1>

  
/ Z and / or Z / lower alkyl, lower alkenyl, lower alkynyl, substituted lower alkyl, aralkyl, acyl, silyl, a mineral acid ester residue, a tetrahydropyranyl group, tetrahydrofuranyl, thiopyranyl or the like and more advantageously a methyl, ethyl, benzyl, acetyl, benzyloxycarbonyl or trifluoroacetyl group, an advantageous protecting group Z is an acyl group, especially acetyl, benzyloxycarbonyl or trifluoroacetyl.

  
Among the aforementioned processes, especially advantageous reactions in process 4 are the reactions :. (1), (5),

  
(6) and (7). An advantageous temperature in these reactions :; is between about 0 and 100 [deg.] C. than,

  
It can also occur / when R ', in the starting compound (VI) has substituents capable of modification in the above-mentioned reactions, they can be modified according to method 4. For example, when the symbol R' in the starting compound (VI) represents the reducible group, the envisaged compound (the) containing the corresponding reduced group can be

  
 <EMI ID = 116.1>

  
when R 'represents the group capable of undergoing solvolysis, the desired compound containing the corresponding solvolysis group can be obtained by using solvolysis as the reaction of method 4.

  
The starting compound (VI) for process 4 can be synthesized, for example, by the following processes.

  

 <EMI ID = 117.1>
 

  

 <EMI ID = 118.1>


  
 <EMI ID = 119.1>

  
In the above-mentioned processes (a) and (b), the reaction of Step A is suitably selected from reactions known per se according to the nature of each group Z and Z;

  
 <EMI ID = 120.1>

  
 <EMI ID = 121.1>

  
a corresponding halogenated aralkyl or halogenated alkyl group,

  
 <EMI ID = 122.1>

  
have an acyl group, a corresponding acid halide or a corresponding acid anhydride is used. The reaction of Stage B is illustrated by a reduction reaction after acylation, a reductive alkylation with a carbonyl compound, i.e. the carbonyl compound (V), a reaction with a compound of the formula R'-Q (where Q is an active group which can replace

  
the group R 'when it represents a hydrogen atom in an amino group; this active group is a halogen atom, lower alkyl (ulfonyloxy, arylsulfonyloxy, etc.) or the like.

  
The reduction and reductive alkylation which are mentioned above are fully illustrated by the reaction identical to that mentioned above for Process 2 and Process

  
3. The reactions of stages C, E and G are illustrated by a reaction identical to that of stage B, and reactions of stage D and F are illustrated by a reaction identical to that of stage A.

  
Method 4 is characterized by the fact that it is possible to easily obtain a desirable isomer (for example a trans or cis isomer) of the compound (Ie) envisaged by using a starting compound (VI) which has the corresponding isomeric form . Further, method 4 is suitable for producing compound (Ie) in

  
 <EMI ID = 123.1>

  
obtained by methods 1 to 4 of the present invention can <EMI ID = 124.1>

  
be easily isolated from the respective reaction mixtures by separation and purification methods which are well known in themselves, such as concentration, filtration, recrystallization, column chromatography etc.

  
 <EMI ID = 125.1>

  
of several stereoisomers such as geometric isomers and optical isomers due to the presence of a few asymmetric carbon atoms and, therefore, they are commonly obtained as mixtures of such isomers.

  
If desired, an optional geometric isomer (eg trans or cis isomer) can be obtained by suitable methods such as eg (1) stereospecific reaction,

  
(2) reaction using the starting compound having the same configuration as the desired compound, (3) isolating the optical isomer from a mixture of isomers using methods suitably selected from methods of aforementioned separation and purification, such as, for example, recrystallization, column chromatography, etc.

  
If desired, a racemic mixture can be resolved by conventional methods, for example by causing it to form a salt with an acid or base having optical activity or, alternatively, by physical adsorption on a porous adsorbent resin. .

  
It is understood that all of these individual isomeric forms as well as their mixtures come within the scope of the present invention.

  
The contemplated compounds (I), (Ia), (lb) and (Ie) according to the present invention can be isolated in the form of salts which include physiologically acceptable salts such as

  
 <EMI ID = 126.1>

  
such acid addition salts include addition salts.

  
 <EMI ID = 127.1>

  
drates, sulphates, etc., addition salts with an organic acid such as maleates, fumarates, tartrates,

  
toluenesulphonates, naphthalenesulphonates, methanesulphonates, etc., and the like.

  
The products according to the present invention which are thus obtained, that is to say the compounds (I), (Ia), (Ib) and (Ic) and their physiologically acceptable salts, are new compounds: and have activities pharmacological such as <EMI ID = 128.1> activity

  
stimulation or blocking of receptors (3-adrenergic, vasodilatory activity of the coronary artery, analgesic activity etc., towards mammals and also towards man. Especially the activity of stimulating the receptors

  
 <EMI ID = 129.1>

  
 <EMI ID = 130.1>

  
(Ia), (lb) and (le) and their salts, they are valuable in the treatment and prophylaxis of diseases such as asthma,

  
 <EMI ID = 131.1>

  
During the pharmaceutical use of the compounds envisaged

  
and their salts according to the present invention, they can be administered to mammals, as well as to man, as such or in admixture with one or more adjuvants suitable in pharmacy orally or otherwise, in forms. dosage forms such as powders, granules, tablets, capsules, injections, inhalations, etc.

  
Pharmaceutical compositions containing one or more of compounds (I), (Ia), (Ib) and (Ic) or their salts can be prepared by conventional methods in the preparation of powders, granules, tablets, capsules, injections, inhalations and similar forms. The choice of adjuvants can be determined by the mode of administration, the solubility of the compounds contemplated and their salts, etc.

  
 <EMI ID = 132.1>

  
of the symptoms and the symptoms to be treated, the mode of administration, the type of mammals and other cones, advantageous doses in the treatment of asthma in adult men are between about 1 and 100 mg per day for oral administration, between about 0.01 and 1 mg per day intravenously and between about 0.1 and 10 mg per dose when administered topically in dosage forms such as nebulized products (inhalations of aerosols ).

  
The products according to the present invention are also advantageous as intermediates in the production of various medicaments.

  
The compound of formula (II) which constitutes a part of the compounds (I), (la), (Ib) and (Ic) according to the present invention, and the salts of this compound, are new products and are also useful as compounds intermediaries, for example in the

  
 <EMI ID = 133.1> both hydrogen, using method 4.

  
The reference examples and the examples given below further illustrate the present invention. It is understood, however, that the scope of the latter is not limited by such examples.

  
In the description which follows, the abbreviation "NMR" means "nuclear magnetic resonance".

Reference example 1

  
(a) While cooling with ice, add 6.0 g <EMI ID = 134.1>

  
3,4-dihydro-1 (2H) -naphthalenone in 200 ml of methanol, then the mixture is stirred for 30 minutes. Then after adding

  
1 liter of water, the reaction mixture is extracted with chloroform.

  
The extract is washed with water, dried and concentrated under reduced pressure and the residue is recrystallized from benzene,

  
 <EMI ID = 135.1> 0.5 g of potassium bisulphate dissolved in 100 ml of benzene, the water constituting the by-product being eliminated in the form of an azeotrope with the benzene.

  
The reaction mixture is washed with water, dried and

  
it is concentrated under reduced pressure. 13 g of 7,8-dimethoxy-1,2-dihydronaphthalene are thus obtained in the form of colorless needles, melting at 38-39 [deg.] C.

  
(c) To a solution of 13 g of 7,8-dimethoxy-1,2-dihydronaphthalene in 130 ml of dimethylsulfoxide, 3 g of water are added and
18 g of N-bromosuccinimide, then the mixture is stirred at 10-15 [deg.] C for 20 minutes. The reaction mixture is diluted with 1 liter of water and entered with benzene. The extract is washed with water, dried and concentrated under reduced pressure. Then, the residue is recrystallized from a mixture of benzene.

  
and petroleum ether, which gives 11 g of 2-bromo-1-hydroxy-5,6-

  
 <EMI ID = 136.1>

  
(d) In a sealed tube, 5.0 g of the bromo derivative obtained in (c) and 50 ml of tert-butylamine are heated at 110-120 [deg.] C for 1 hour and a half. The tert-butylamine is distilled off and the residue is washed with water, then extracted with benzene. The extract is washed with water, dried and concentrated under reduced pressure. The residue is dissolved in alcoholic hydrochloric acid and, after treatment with activated charcoal,

  
ethyl ether is added. Filtered to collect the resulting crystals, giving 3.1 g of 1-tertbutylamino-2-hydroxy-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalene hydrochloride.

  
 <EMI ID = 137.1>

  
 <EMI ID = 138.1>

  
alcohol obtained in d) and the solution is made alkaline with sodium bicarbonate and extracted with chloroform. The extract is washed with water and dried. The chloroform is distilled off and the residue is dissolved in 100 ml of dry benzene. After the addition of 0.9 g of anhydrous triethylamine sulfate, the solution is heated for 1 hour. Then 6.0 g of anhydrous potassium carbonate is added and the solution is refluxed for 3 hours. After cooling, the reaction mixture is washed with water, dried and concentrated under reduced pressure. 0.4 g of 1,2-tert-butylamino-

  
 <EMI ID = 139.1>

Reference example 2

  
In a similar manner to that of Reference Example 1-d and 1-e, 3 g of 2-bromo-1-hydroxy-5,6-dimethoxy1,2,3,4-tetrahydronaphthalene are reacted with 11 g of cyclohexylamine and the product is dehydrated to give 1,2-cyclohexylimino-5,6dimethoxy-1,2,3,4-tetrahydronaphthalene as an oil.

  
 <EMI ID = 140.1>

Reference example 3

  
In a manner similar to that of reference examples 1-d and 1-e., 1.5 g of 2-bromo-1-hydroxy-5,6-dimethoxy-l, 2,3,4-tetrahydronaphthalene are reacted with 20 ml of isopropylamine and the product is dried to give 0.15 g of 1,2-isopropylamino-

  
 <EMI ID = 141.1>

  
 <EMI ID = 142.1>

Reference example 4

  
a) 3 g of 5,6-dimethoxy3,4-dihydro-1 (2H) -naphthalenone and 9 g of aluminum trichloride are added to 60 ml of anhydrous benzene, then the mixture is refluxed for 2 hours. After cooling- <EMI ID = 143.1>

  
Then, 18 ml of 3N hydrochloric acid was gradually added to the reaction mixture and filtered to collect the precipitate. After recrystallization from water, 2.3 g are obtained

  
 <EMI ID = 144.1> talenone. The mixture is stirred for 5 minutes, then 0.25 ml of benzyl chloride and 332 mg of powdered potassium iodide are added. The mixture is refluxed for 3 hours. After cooling, the acetone is removed by distillation and diluted.

  
 <EMI ID = 145.1>

  
The chloroform layer is washed with water, dried and concentrated. After recrystallization from methanol, 5,6-dibenzyloxy-3,3-dihydro-1 (2H) -naphthalenone, melting point 104- is obtained.
106 [deg.] C.

  
 <EMI ID = 146.1>

  

 <EMI ID = 147.1>

Reference example 5

  
In a similar manner to that of Reference Examples 1-a to 1-e, 1,2-tert-butylimino-5,6-dibenzyloxy-1,2, 3,4-tetrahydronaphthalene is obtained in the form of a oil from the

  
 <EMI ID = 148.1>

Reference example 6

  
(a) To colorless powdered sodium methoxide, prepared from 313 mg of metallic sodium, is added dropwise
12 ml of a solution of 1.1 ml of ethyl formate in anhydrous benzene. The reaction mixture is cooled to 0 [deg.] C and, in a stream of nitrogen gas, 9 ml of a so- <EMI ID = 149.1> are gradually added.

  
 <EMI ID = 150.1>

  
stir the mixture at room temperature for 1 hour. Ice-water is added to the reaction mixture, then the latter is extracted with chloroform. The chloroform layer is washed with water,

  
it is dried and concentrated. The residue is subjected to chromatography on a column of silica gel and the product obtained is recrystallized from cyclohexane to give 2-hydroxy-

  
 <EMI ID = 151.1> <EMI ID = 152.1>
(b) In a mixture comprising 1 ml of dichloromethane, 5 ml of acetic acid and 0.25 ml of water, 84 mg of the hydroxymethylene derivative obtained in (a) are dissolved and introduced dropwise at 1 [deg.] C, a solution of 50 mg of sodium nitrite in water <EMI ID = 153.1>

  
it is extracted with dichloromethane. The dichloromethane layer is washed thoroughly with water, dried and concentrated.

  
After recritallization of the residue in ethyl acetate, one obtains

  
 <EMI ID = 154.1>

  
tion).

  
 <EMI ID = 155.1>

  

 <EMI ID = 156.1>

Reference example 7

  
(a) In a similar manner to that of Reference Examples 6-a to 6-b, 2-isonitroso-5,6-dibenzyloxy-3,4-dihydrol (2H) -naphthalenone (melting point 203-) is obtained. 208 [deg.] C, in benzene) from 5,6-dibenzyloxy-3,4-dihydro-1 (2H) -naphthalenone.
(b) In 10 ml of anhydrous tetrahydrofuran, 150 mg of the isonitroso derivative obtained in a) are dissolved and, while cooling, 70 mg of sodium borohydride are added in small portions.

  
 <EMI ID = 157.1>

  
water and acetone, the mixture is extracted with dichloromethane. The dichloromethane layer is dried and concentrated.

  
 <EMI ID = 158.1>

  
2-isonitroso-1-hydroxy-5,6-dibenzyloxy-l, 2,3,4-tetrahydronaphthalene in the form of colorless needles melting at 14l-l45 [deg.] C.

  
 <EMI ID = 159.1>

  

 <EMI ID = 160.1>


  
Reference example 8

  
; (a) In 300 ml of chloroform, 10 g of 5,6-dim-

  
thoxy-3,4-dihydro-1 (2H) -naphthalenone, then 16 g of pyridinium hydrobromide perbromide are added. We react the mixture

  
at 60 [deg.] C for 5 minutes and, after cooling, it is poured into 200 ml of ice water. The chloroform layer is washed with water, dried and concentrated. The resulting yellow crystals are recrystallized from a mixture of chloroform and n-hexane, <EMI ID = 161.1>

  
which gives 2-bromo-5,6-dimethoxy-3,4-dihydro-1 (2H) -naphthalenone, melting at 108.5-109 [deg.] C.

  
(b) In 30 ml of dimethylsulfoxide, 2.7 g of the derivative is dissolved <EMI ID = 162.1>

  
phloroglucin. The mixture is stirred at room temperature for
30 minutes, it is poured into water and extracted with chloroform. The extract is washed with water, dried and concentrated. After recrystallization of the residue from aqueous alcohol, 2-nitro-5,6-dimethoxy-3,4-dihydro-l (2H) -naphthalenone is obtained,

  
 <EMI ID = 163.1>

  
 <EMI ID = 164.1>

  

 <EMI ID = 165.1>


  
Reference example 9 <EMI ID = 166.1>
(2H) -naphthalenone in 60 ml of dichloromethane, 1.7 g of anhydrous calcium carbonate are introduced, then a solution of 3.20 g of bromine in 40 ml of dichloromethane is added dropwise. After stirring at room temperature for 4 hours n

  
 <EMI ID = 167.1>

  
residue on chromatography on a column of silica gel and the product of the benzene elution is recrystallized from cyclo-

  
 <EMI ID = 168.1>

  
Naphthalenone in the form of colorless crystals melting at 106-108 [deg.] C.

  
(b) In 20 ml of tetrahydrofuran, 875 mg of the brcmé derivative cbtenuated in (a) and 609 mg of benzylmethylamine are dissolved and the mixture is then refluxed for 21 hours in a stream of nitrogen gas. 200 ml of benzene are added to the reaction mixture and, after washing the entire mixture with chlo- <EMI ID = 169.1>

  
dissolves the residue in a mixture of 10 ml of tetrahydrofuran

  
 <EMI ID = 170.1>

  
790 mg of sodium borohydride, while cooling with ice. Acetic acid is added to the reaction mixture while cooling with ice, then another 50 ml of ethanol is added. Filtered to collect the resulting crystals and extracted with benzene. The benzene solution is washed with water, dried and concentrated. After recrystallization

  
 <EMI ID = 171.1>

  
205 mg of 1-hydroxy-2- (N-benzyl-N-methylamino) -5,6-dibenzyloxy-

  
 <EMI ID = 172.1>

  
of yellow petals melting at 116-117 [deg.] C.

  
seen Reference example 10

  
To a suspension of 2.0 g of 1,5,6trihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene hydrobromide in 60 ml of acetic acid anhydride, 20 ml of pyridine is added and the mixture is stirred. mixing overnight at room temperature. The reaction mixture is concentrated under reduced pressure and, after adding 70 ml of water and a few drops of pyridine, it is extracted with chloroform. The extract is washed with water,

  
it is dried and concentrated. After dissolving the residue in acetone, ether is added. The resulting precipitate was filtered to give 2.03 g of crude 1,5,6-triacetoxy-2-acetylamino-1,2,3,4-tetrahydronaphthalene. This product is dissolved in 10 ml of acetone, then 100 ml of ether is added. After allowing to stand overnight at room temperature, filtered to separate the resulting crystals, yielding 525 mg of

  
 <EMI ID = 173.1>

  
lene melting at 196-197 [deg.] C.

  
 <EMI ID = 174.1>

  
50 ml of ether is added to the mother liquor and, after cooling, the resulting crystals are filtered off to give

  
 <EMI ID = 175.1>

  
hydronaphthalene; this compound first melts at 140-145 [deg.] C, then solidifies and melts again at 183 [deg.] C.

  
 <EMI ID = 176.1>

Reference example 11

  
(a) To a mixture of 358 mg of 5,6-dibenzyloxy-3,4dihydro-1 (2H) -naphthalenone, 117 mg of potassium carbonate and 3 ml of methanol is added a solution of 117 mg of hydrochloride. hydroxylamine in 0.3 ml of water. The mixture is refluxed for 2 hours and after having removed the solvent by distillation, 50 ml of water and 50 ml of chloroform are added. The organic layer was washed with water, dried and concentrated to give 350 mg of 5,6-dibenzyloxy-3,4dihydro-1 (2H) -naphthalenone oxime, mp 135-137 [deg.] C (in methanol).
(b) To a solution of 381 mg of p-toluenesulfonyl chloride in 2 ml of pyridine is added dropwise, at 2-4 [deg.] C, a solution of 373 mg of the oxime obtained in (a ) in 2 ml of pyridine. The mixture was stirred overnight at 5 [deg.] C and poured into ice-water to give 500 mg of <EMI ID = 177.1>

  
 <EMI ID = 178.1>

  
(c) To a solution of 8.2 g of O-p-toluenesulfonyl oxime is added dropwise at 4-5 [deg.] C, a solution of potassium ethoxide prepared from 700 mg of potassium metallic and 7 ml of anhydrous ethanol. After adding 20 ml of anhydrous ethanol, the mixture is stirred overnight at 5-7 [deg.] C. The reaction mixture is poured into 10 ml of 3N hydrochloric acid while cooling and concentrated to half the initial volume, which determines the separation of the 2-amino-5,6-dibenzyloxy-3,4-dihydro-1 hydrochloride. (2H) -naphthalenone.

  
 <EMI ID = 179.1>

  
Reference example] 2

  
 <EMI ID = 180.1>

  
1.0 g of 2-amino-5,6-dibenzyloxy-3,4-dihydro-1 (2H) -naphthalenone hydrochloride and 50 ml of acetic anhydride. After evaporating the excess acetic anhydride under reduced pressure, 20 ml of ethyl ether and 50 ml of petroleum ether are added to the residue, and the resulting colorless crystals are collected by filtration, to give 0.8 g of 2-acetylamino-

  
 <EMI ID = 181.1>

  
l84 [deg.] C.

  
Elemental analysis for C26H2504N

  

 <EMI ID = 182.1>


  
Reference example 13

  
 <EMI ID = 183.1>

  
and 20 ml of methanol, 4 g of sodium borohydride are added in portions, while stirring, at room temperature. After stirring for a further 1 hour, 500 ml of water is added to the mixture and the chloroform layer is separated. The aqueous layer is further extracted with chloroform. The combined chloroform solutions are dried and evaporated under reduced pressure. Addition of 50 ml of ethyl ether to the residue gives

  
 <EMI ID = 184.1>

  
tetrahydronaphthalene in the form of colorless crystals melting
200-203 [deg.] C.

  
 <EMI ID = 185.1>

  
 <EMI ID = 186.1>

  

 <EMI ID = 187.1>


  
 <EMI ID = 188.1>

Reference Example 14

  
To a solution of 7 g of lithium aluminum hydride in 150 ml of tetrahydrofuran is added a solution of

  
 <EMI ID = 189.1>

  
tetrahydronaphthalene in 200 ml of tetrahydrofuran and, while stirring the mixture, it is brought to reflux for 2 hours.

  
While cooling the reaction mixture with ice, 300 ml of ether is added thereto and then water is introduced dropwise to determine the precipitation of a complex hydroxide which is filtered and washed with 300 ml of chloroform. . The filtrate and the washings are combined. The organic layer is separated, dried and evaporated. We add to the residue
100 ml of ether. After allowing to stand, the resulting crystals were filtered off to give 5.4 g of trans-5,6-dibenzyloxy2-ethylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene as

  
 <EMI ID = 190.1>

  
Elemental analysis for C26H2903N

  

 <EMI ID = 191.1>


  
 <EMI ID = 192.1>

Reference example 15

  
0.8 g is added to a mixture of 100 ml of tetrahydrofuran and 1.5 g of lithium aluminum hydride.

  
 <EMI ID = 193.1>

  
tetrahydronaphthalene and the whole is brought to reflux for 3.5 hours. After cooling, 200 ml of ether and excess water are added to the reaction mixture and the organic layer is separated. After drying the organic layer,

  
evaporated and the residue recrystallized from ether to give 0.35 g of cis-5,6-dibenzyloxy-2-ethylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene as of a colorless powder melting at 115-117 [deg.] C.

  
 <EMI ID = 194.1>

  
It is transformed into fumarate by a known process; Colorless crystals, melting at 192-195 [deg.] C (decomposition).

  
..........

  
 <EMI ID = 195.1>

  

 <EMI ID = 196.1>

Reference example 16

  
In a mixture comprising 10 ml of anhydrous methanol and 5 ml of cyclopentanone, 377 mg of 1-hydroxy-2-amino-5,6-dibenzyloxy-l, 2,3,4-tetrahydronaphthalene p-toluenesulfonate are dissolved, while cooling to 0 [deg.] C, 400 mg of a lithium cyanoborohydride complex are added in small portions.

  
and dioxane. The mixture is stirred at 0 [deg.] C for 2 hours and

  
it is stirred overnight at room temperature. We hunt

  
methanol from the reaction mixture by distillation and water and ethyl acetate are added to the residue. The organic layer is washed with water, dried, and evaporated under reduced pressure. The residue is dissolved in ether and an ethereal solution of 77 mg of oxalic acid anhydride is added. Filtered to collect the resulting colorless precipitate and, after recrystallization from 95% ethanol, 1-hydroxy-2-cyclopentylamino-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene oxalate is obtained. , melting at 198-202 [deg.] C
(decomposition).

  
 <EMI ID = 197.1>

  

 <EMI ID = 198.1>


  
Reference Example 17

  
Has a suspension of 2.1 g of p-toluenesulfonate

  
 <EMI ID = 199.1>

  
in 30 ml of methanol and 35 ml of acetone, 2 g of lithium cyanoborohydride are added in portions at 0-2 [deg.] C, in

  
a stream of nitrogen gas. The mixture is stirred at 0-2 [deg.] C for 2 hours and then at room temperature overnight.

  
After adding 3 ml of water, the mixture is evaporated under reduced pressure and the residue is extracted with ethyl acetate. The extract is washed with sodium hydroxide.

  
 <EMI ID = 200.1>

  
After adding 0.3 ml of acetic acid to the extract, the solvent is evaporated off under reduced pressure and the residue is recrystallized from a mixture of ethanol and ether, which gives <EMI ID = 201.1>

  
Amino-1,2,3,4-tetrahydronaphthalene in colorless crystals, melting at 111-112 [deg.] C (decomposition).

  
 <EMI ID = 202.1>

  

 <EMI ID = 203.1>


  
 <EMI ID = 204.1>

  
The above mother liquor from the recrystallization was evaporated from a mixture of ethanol and ether and, after neutralizing the residue with 1N sodium hydroxide, it was extracted with chloroform.

  
The extract is washed with water, dried and evaporated. Recrystallization of the residue from n-hexane gives 460 mg of trans-5,6-dibenzyloxy-1-hydroxy-2-isopropylamino-1,2,3,4-tetrahydronaphthalene in colorless crystals melting at 94-99 [deg.] vs.

  
 <EMI ID = 205.1>

Reference Example 18

  
To a solution of 838 mg of trans-2-amino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene and 1 g of cyclobutanone in 30 ml of methanol is added in portions 2 g of 'a lithium-dioxane cyanoborohydride complex and stirred

  
mixing at 6-7 [deg.] C for 2 hours. After addition of 3 ml of water, the solvent is evaporated and the residue is extracted.

  
with ethyl acetate. A solution of 89 mg of fumaric acid in 2 ml of ethanol is added to the extract, which is washed with water and dried. After recrystallization of the resulting precipitate from ethanol, 480 mg of trans 5,6-dibenzyloxy-2-cyclobutylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene fumarate are obtained in colorless crystals, melting at 174-175 [ deg.] C (decomposition).

  
 <EMI ID = 206.1>

  

 <EMI ID = 207.1>


  
 <EMI ID = 208.1>

Reference Example 19

  
To a solution of 1 g of cis-2-amino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene p-toluenesulfonate and 1 g of cyclobutanone in 30 ml of methanol is added < EMI ID = 209.1>

  
 <EMI ID = 210.1>

  
the mixture is reacted and processed in a manner similar to that of Reference Example 18, which gives 0.58 g

  
 <EMI ID = 211.1>

  

 <EMI ID = 212.1>


  
 <EMI ID = 213.1>

  
Reference example 20

  
1.2 g of 2-amino p-toluenesulfonate are reacted.

  
 <EMI ID = 214.1>

  
1.7 g of 3-indolylacetone in a similar manner to Reference Example 16 and the product is purified as a fumaric acid salt to give 0.7 g of fumarate

  
 <EMI ID = 215.1>

  
ethylamino-1,2,3,4-tetrahydronaphthalene in the form of a colorless powder, melting at 114-118 [deg.] C.

  
 <EMI ID = 216.1>

  

 <EMI ID = 217.1>

Example 1

  
 <EMI ID = 218.1>

  
dimethoxy-1,2,3,4-tetrahydronaphthalene in 20 ml of dioxane

  
 <EMI ID = 219.1>

  
room temperature for 10 hours. The reaction mixture is diluted with water, made alkaline with 20% sodium hydroxide and extracted with benzene. The extract is washed with water and dried. The benzene is then removed by distillation under reduced pressure. An ethereal solution of fumaric acid is added to the residue and the resulting fumarate is recrystallized from a mixture of methanol and ethyl ether.

  
0.2 g of 2-tert.-butylamino-1- fumarate is thus obtained.

  
 <EMI ID = 220.1>

  

 <EMI ID = 221.1>


  
\ &#65533; - - 0 and ..........

Example 2

  
In 5 ml of dioxane, 0.25 g of 1.2-

  
 <EMI ID = 222.1>

  
after addition of 2 ml of a 5% aqueous solution of sulfuric acid, the mixture is allowed to stand for 1 hour. The reaction mixture is neutralized with aqueous sodium hydrogencarbonate and extracted with chloroform. The extract is dried and distilled under reduced pressure. The residue is dissolved in a small amount of ethanol &#65533; an ethereal solution of fumaric acid is added. The resulting crystals are collected by filtration. This gives 0.1 g of fumarate

  
 <EMI ID = 223.1>

  

 <EMI ID = 224.1>

Examples 3-5

  
By hydrolysis of the corresponding 1,2-substituted imino-5,6-dimethoxy-1,2,3,4tetrahydronaphthalenes in a manner similar to that of Example 1, the compounds of Table 1 are obtained.

  
Table 1
 <EMI ID = 225.1>
  <EMI ID = 226.1>

Example 6

  
While cooling to a temperature of -70 to
-75 [deg.] C, a solution of 1.5 g of boron tribromide in 10 ml of dichloromethane is added dropwise to a solution <EMI ID = 227.1>

  
hydronaphthalene in 50 ml of dichloromethane. The reaction mixture is stirred for 3 hours, then concentrated under reduced pressure.

  
The residue is diluted with 5 ml of water and stirred

  
at room temperature for 2 hours. The reaction mixture is treated with activated charcoal and concentrated to 40 [deg.] C. The residue is dissolved in a small amount of ethanol, then ether is added. Filter to recover the resulting crystals. In this way 472 mg of hydrobromide of 1,5,6-

  
 <EMI ID = 228.1>

  
melting at 167-169 [deg.] C (decomposition).

Examples 7 to 16

  
Hydrolysis of the 5,6-dibenzyloxy-1,2-imino (substituted) 1,2,3,4-tetrahydronaphthalenes in a manner similar to that of Example 6 gives the compounds given in Table 2.

Table 2

  

 <EMI ID = 229.1>
 

  
 <EMI ID = 230.1>

  

 <EMI ID = 231.1>

Example 17

  
To a solution of 1 g of 5,6-dibenzyloxy-1,2-cyclopentylimino-l, 2,3,4-tetrahydronaphthalene in 50 ml of dioxane,

  
 <EMI ID = 232.1>

  
100 [deg.] C for about 2 hours. After cooling, the reaction mixture is made alkaline with sodium hydrogencarbonate and extracted with ethyl acetate. The resulting extract is washed with water, dried and concentrated under reduced pressure. The oil thus obtained is dissolved in ethyl ether and an ethereal solution of oxalic acid is added. Filter to recover the resulting crystals and recrystallize from 95% ethanol. In this way 483 mg of 5,6-dibenzyloxy-2-cyclopentylamino-1-hydroxy- oxalate is obtained.

  
 <EMI ID = 233.1>

  

 <EMI ID = 234.1>

Example 18

  
Has a solution of 1 g of 5,6-dibenzyloxy-1,2-isopro-

  
 <EMI ID = 235.1>

  
A 5% palladium on charcoal catalyst is added and the catalytic reduction is carried out at room temperature and pressure until 2 mole equivalents of hydrogen have been absorbed.

  
 <EMI ID = 236.1>

  
The resulting solution of 5,6-dihydroxy-1,2-isopropylimino-1,2,3,4-tetrahydronaphthalene is filtered, then the filtrate is concentrated under reduced pressure. 20 ml of dioxane are added to the residue.

  
 <EMI ID = 237.1>

  
room temperature for 10 hours. The reaction mixture is neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with n-butanol. A small amount of hydrobromic acid is added to the butanolic layer and the mixture is concentrated under reduced pressure, after which ethyl ether is added. In this way 53 mg of 1,5,6-trihydroxy-2-isopropylamino-1,2,3,4-tetrahydronaphthalene hydrobromide is obtained. It is observed that the melting point of this product does not drop after mixing with the compound according to Example 6.

Example 19

  
By a process similar to that described in the example

  
 <EMI ID = 238.1>

  
156-159 [deg.] C (decomposition).

Example 20

  
By a process similar to that described in Example 18, 1,5,6-trihydroxy-2- fumarate is obtained.

  
 <EMI ID = 239.1>

  
tetrahydronaphthalene. Melting point: 150-153 [deg.] C (decomposition).

Example 21

  
By a process similar to that described in the example

  
 <EMI ID = 240.1>

  
2-yl) methylimino-1,2,3,4-tetrahydronaphthalene until 3 mole equivalents of hydrogen have been absorbed, after which hydrolysis gives 1,5,6-trihydroxy-2- (tetrahydropyran-2 -yl) -methylamino-1,2,3,4-tetrahydronaphthalene. Melting point: 155-158 [deg.] C (decomposition).

Example 22

  
By a process similar to that described in Example 21, 1,5,6-trihydroxy2-n-propylamino-1,2,3,4-tetrahydronaphthalene hydrobromide is obtained from

  
 <EMI ID = 241.1>

  
Melting point: 167-168 [deg.] C (decomposition).

Example 23

  
Has a solution of 1.0 g of 5,6-diacetoxy-1,2-

  
 <EMI ID = 242.1>

  
 <EMI ID = 243.1>

  
mixing at room temperature for 10 hours. The reaction mixture is neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with n-butanol. A small amount of hydrobromic acid is added to the butanolic layer and the mixture is concentrated under reduced pressure. Ethyl ether is added to the residue to give 98 mg

  
of 1,5,6-trihydroxy-2-isopropylamino-1,2,3,4tetrahydronaphthalene hydrobromide. This product does not show lowering

  
of the melting point mixed with the compound according to Example 6.

Example 24

  
By a process similar to that described in Example 23, 95 mg of 1,5,6-trihydroxy hydrobromide are obtained.

  
 <EMI ID = 244.1>

  
1,2-isopropylimino-5,6-dimethoxymethyl-1,2,3,4-tetrahydronaphthalene.

Example 25

  
In 20 ml of dioxane, 0.5 g of 5.6-

  
 <EMI ID = 245.1>

  
then 5 ml of 5% sulfuric acid are added. The mixture is allowed to stand at room temperature for 5 hours. The reaction mixture is neutralized with an aqueous solution of sodium bicarbonate and extracted with chloroform. The extract is dried and concentrated under reduced pressure. The residue is dissolved in a small amount of ethanol, and then an ethereal solution of fumaric acid is added dropwise. 0.2 g of 5,6-dibenzyl- fumarate is thus obtained.

  
 <EMI ID = 246.1>

  
melting at 118-121 [deg.] C.

  
 <EMI ID = 247.1>

  

 <EMI ID = 248.1>

Example 26

  
In 1 ml of acetone, 150 mg of 1,2-

  
 <EMI ID = 249.1>

  
then 1 ml of a 5% aqueous solution of sulfuric acid is added. The mixture is allowed to stand at room temperature for 5 minutes. The reaction mixture is neutralized by adding an aqueous solution of sodium bicarbonate and extracted with chloroform. The extract is dried and distilled under reduced pressure. The residue is dissolved in a small amount of ethanol and, after adding alcoholic hydrochloric acid, ethyl ether is added dropwise. This gives 100 mg of hydrochloride

  
 <EMI ID = 250.1>

  
napthalene, melting at 198-200 [deg.] C.

  
 <EMI ID = 251.1>

  

 <EMI ID = 252.1>

Example 27

  
By a process similar to that described in Example 18, 1 g of 5,6-dibenzyloxy-1,2-tert.

  
 <EMI ID = 253.1>

  
lene via 1,2-tert.-butylimino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene.

  
 <EMI ID = 254.1>

  
 <EMI ID = 255.1>

  

 <EMI ID = 256.1>

Example 28

  
By a method similar to that described in Example 25, 5,6-dibenzyloxy-1,2-cyclobutylimino1,2,3,4-tetrahydronaphthalene is subjected to hydrolysis and one obtains

  
 <EMI ID = 257.1>

  
1,2,3,4-tetrahydronaphthalene, melting at 160-165 [deg.] C.

  
 <EMI ID = 258.1>

  

 <EMI ID = 259.1>

Example 29

  
A mixture of 3.8 g of 7,8-dibenzyloxy1,2-dihydronaphthalene, 80 ml of dimethoxyethane, 10 g of sodium azide and 20 ml of water is prepared. The mixture is cooled with c

  
ice and sodium chloride. While stirring vigorously, 4.9 g of N-bromosuccinimide are added to the mixture in

  
10 minutes. After stirring for a further 10 minutes, the reaction mixture is poured into excess water and extracted with 200 ml of ethyl ether. A solution of 20 g of lithium aluminum hydride is added to the dried extract.

  
in 300 ml of ethyl ether. The mixture is stirred while refluxing for 2.5 hours and water is added to the cooled reaction mixture, to decompose the excess reagent. The ethereal layer is separated, dried and evaporated to give 5,6-dibenzyloxy-1,2-imino1,2,3,4-tetrahydronaphthalene as a syrup.

  
This substance is dissolved in 100 ml of dioxane, left to stand overnight at room temperature after adding 100 ml of 5% sulfuric acid, then poured into water. The mixture is neutralized with sodim bicarbonate and extracted with chloroform. The extract is dried and evaporated. Methanol is added to the residue as well as an excess of oxalic acid, to obtain a homogeneous solution,

  
to which ethyl ether is added, which determines

  
precipitation of crystals. Recrystallization of these crystals from methanol gives 1.0 g of cis-2amino-5,6-dibenzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene oxalate as colorless crystals, melting at 185-195 [deg .] C (decomposition).

  
 <EMI ID = 260.1>

  

 <EMI ID = 261.1>


  
1 g of this substance is dissolved in methanol while heating, neutralized with aqueous sodium bicarbonate, extracted with chloroform and dried. The extract is evaporated and ethyl ether is added to the residue to determine the crystallization of the free base of the substance <EMI ID = 262.1>

  
above in the form of colorless crystals melting at 126-129 [deg.] C,
(decomposition).

  
 <EMI ID = 263.1>

  

 <EMI ID = 264.1>


  
 <EMI ID = 265.1>

Example 30

  
1-Cyclopropylamino-5,6-dibenzyloxy2-hydroxy-l, 2,3,4-tetrahydronaphthalene fumarate (3.5 g), prepared from 6.9 g of 2-bromo-1-hydroxy-5, 6-dibenzyloxy-l, 2,3,4-tetrahydronaphthalene and 17 g of cyclopropylamine according to the process described in Reference Example 1-d, allows to obtain when it is subjected to a reaction by the process described in Reference example 1-e, 1.65 g of 1,2-cyclopropylimino5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene in the form of an oil.

  
This substance is dissolved in 100 ml of dioxane and 40 ml of water and 9 ml of acetic acid are added to the solution. The mixture is heated at 50-60 [deg.] C for 3 hours, diluted with excess water and extracted with chloroform. The extract is dried and evaporated under reduced pressure. The oily material obtained is subjected to chromatography

  
on a silica gel column and the purified substance is dissolved in methanol. After having dissolved 0.3 g of oxalic acid in this solution, the latter is diluted with

  
of ethyl ether, which determines the precipitation of

  
0.45 g of 2-cyclopropylamino-5,6-dibenzyloxyl-hydroxy-l, 2,3,4-tetrahydronaphthalene acid oxalate in the form of a colorless powder melting at 193-195 [deg.] C.

  
 <EMI ID = 266.1>

  

 <EMI ID = 267.1>

Example 31

  
In a mixture of 20 ml of anhydrous ethanol, 20 ml of anhydrous acetone, 48 mg of triethylamine and 54 mg of a 5% palladium on charcoal catalyst, 100 mg are subjected to

  
 <EMI ID = 268.1>

  
catalytic reduction at ordinary temperature and pressure until the hydrogen gas is no longer absorbed.

  
 <EMI ID = 269.1>

  
The reaction mixture is then filtered and, after adding 3N HCl to the filtrate, the solvent is removed by distillation. The residue was subjected to chromatography on an XAD-2 resin column and eluted with water. The product is recrystallized from

  
elution in a mixture of ethanol and ethyl ether. In this way 1-hydroxy-2-isopropylamino-5,6- hydrochloride is obtained.

  
 <EMI ID = 270.1>

  
colorless, melting at 190-192 [deg.] C (decomposition).

Example 32

  
In a manner similar to that described in Example 31, 50 mg of 2-isonitroso-5,6-dibenzyloxy- are subjected to

  
 <EMI ID = 271.1>

  
filter the reaction mixture and a small amount of hydrobromic acid is added to the filtrate. The solvent is distilled off and the residue is dissolved in ethanol, followed by addition of ethyl ether. This gives the hydrobromide of

  
 <EMI ID = 272.1>

  
at 192-200 [deg.] C (decomposition).

Example 33

  
In a mixture comprising 5 ml of anhydrous acetone, 3 ml of anhydrous tetrahydrofuran, 2 ml of anhydrous methanol, and 0.1 ml of triethylamine, 20 mg of 2-isonitroso-5,6- are subjected to

  
 <EMI ID = 273.1>

  
lytic in the presence of a 5% palladium on charcoal catalyst. The reaction mixture is filtered and dilute hydrobromic acid is added to the filtrate. The solvent is removed by distillation at low temperature and the residual aqueous solution is lyophilized. The residue is recrystallized from a mixture of ethanol and ethyl ether and the hydrobromide is obtained.

  
of 1,5,6-trihydroxy-2-isopropylamino-1,2,3,4-tetrahydronaphthalene melting at 167-168 [deg.] C (decomposition).

Example 34

  
By a process similar to that described in Example 33, 20 mg of 2-isonitroso-5,6-dibenzyloxy3,4-dihydro-1 (2H) -naphthalenone and 200 mg of &#65533; -phenylpropionaldehyde are subjected to to catalytic reduction in a mixture comprising

  
3 ml of anhydrous tetrahydrofuran, 2 ml of anhydrous methanol and 0.1 ml of triethylamine. The reaction mixture is filtered and

  
dilute hydrobromic acid is added to the filtrate. After washing with ethyl ether, the aqueous layer is lyophilized.

  
The residue is dissolved in ethanol, then ethyl ether is added. This gives crystals of hydrobromide

  
 <EMI ID = 274.1>

  
hydronaphthalene, melting at 136-138 [deg.] C (decomposition).

Examples 35 to 48

  
By methods similar to that described in Example 34, 2-isonitroso-5,6-dibenzyloxy-

  
 <EMI ID = 275.1>

  
bonyle indicated in the second column of Table 3, which gives the compounds indicated in the third column of this table.

  

 <EMI ID = 276.1>


  

 <EMI ID = 277.1>
 

  

 <EMI ID = 278.1>
 

Example 49

  
To 10 ml of anhydrous tetrahydrofuran is added
50 mg of lithium aluminum hydride and, while cooling, 50 mg of 1-hydroxy-2- are introduced in portions.

  
 <EMI ID = 279.1>

  
The reaction mixture is refluxed for 4 hours

  
and, after cooling, it is diluted with water and then extracted with ethyl acetate. The organic layer is extracted with dilute hydrochloric acid and the aqueous layer is made alkaline with dilute sodium hydroxide solution, then extracted again with ethyl acetate. We wash

  
the ethyl acetate layer with water, dried and concentrated. The residue is dissolved in a small amount

  
a mixture of ethyl acetate and ethyl ether, then

  
an ethereal solution of p-toluenesulfonic acid is added.

  
The resulting precipitate is collected by filtration and recrystallized from a mixture of ethanol and ethyl ether. This gives 1-hydroxy-2- p-toluenesulfonate

  
 <EMI ID = 280.1>

  

 <EMI ID = 281.1>

Example 50

  
In 50 ml of anhydrous tetrahydrofuran, dissolve

  
 <EMI ID = 282.1>

  
naphthalenone and, while cooling, 0.53 g of lithium aluminum hydride is added in small portions. We wear

  
the reaction mixture under reflux for 5 hours and then treated in the same manner as in Example 49. In this way 1-hydroxy-2-amino-p-toluenesulfonate is obtained.

  
 <EMI ID = 283.1>

Example 51

  
In a mixture of 10 ml of anhydrous acetone and 5 ml of anhydrous methanol, 20 mg of 1-hydroxy-2-isonitroso5,6-dibenzyloxy-l, 2,3,4-tetrahydronaphthalene are subjected to a catalytic reduction at temperature and ordinary pressure using
23 mg of a 5% palladium on charcoal catalyst. Filter to separate the catalyst and add dilute hydrobromic acid to the filtrate. The methanol and <EMI ID = 284.1> acetone are then removed by distillation at low temperature. We freeze-dry. the residue and recrystallized from a mixture of ethanol

  
and ethyl ether. This gives the hydrobromide of

  
 <EMI ID = 285.1>

  
This product is identical to that of Example 33.

Example 52

  
The process of Example 51 is repeated, but using cyclobutanone instead of acetone and the product is obtained.

  
 <EMI ID = 286.1>

  
tetrahydronaphthalene, melting at 195-200 [deg.] C (decomposition).

Example 53

  
In 6 ml of anhydrous tetrahydrofuran, subject
164 mg of 1-hydroxy-2-inonitroso-5,6-dibenzyloxy-1,2,3,4tetrahydronaphthalene catalytically reduced with 5% palladium on charcoal catalyst. It is filtered to separate the catalyst and, after adding dilute hydrobromic acid to the filtrate, the tetrahydrofuran is removed by distillation at low temperature. The residue is lyophilized and dissolved in ethanol, followed by addition of ether.

  
 <EMI ID = 287.1>

  
2-amino-1,2,3,4-tetrahydronaphthalene which is identical to the product according to Example 32.

Example 54

  
2.5 g are dissolved in 100 ml of acetic acid

  
2-nitro-5,6-dimethoxy-3,4-dihydro-1 (2H) -naphthalenone and

  
Catalytic reduction is carried out using a 10% palladium on charcoal catalyst. The reaction mixture is filtered and the solvent is removed by distillation under reduced pressure. The residue is neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform layer is dried and concentrated under reduced pressure. After recrystallization of the residue from ethyl ether, 2-amino-1-

  
 <EMI ID = 288.1>

  
122-124 [deg.] C.

  
Elemental analysis for C12H1703N
 <EMI ID = 289.1>
  <EMI ID = 290.1>

  
 <EMI ID = 291.1>

  
 <EMI ID = 292.1>

  
dihydro-1 (2H) -naphthalenone in a manner similar to that of Example 54, except that the reaction is carried out in the presence of 10 g of benzaldehyde. The reaction mixture is filtered and a small amount of hydrochloride is added.

  
 <EMI ID = 293.1>

  
reduced pressure and a small amount of water is added to the residue, followed by extraction with ethyl ether. The aqueous layer is made alkaline using aqueous sodium hydroxide

  
 <EMI ID = 294.1>

  
chloroform and concentrated. The residue is then recrystallized from ethyl ether to give crystals of 2-benzylamino-5,6-dimethoxy-1-hydroxy-1,2,3,4-tetrahy-.

  
 <EMI ID = 295.1>

  
Elemental analysis for C19H2303N

  

 <EMI ID = 296.1>

Example 56

  
In 400 ml of anhydrous ethanol, 2.2 g of 2-nitro-5,6-dihydroxy-3,4-dihydro-l (2H) -naphthalenone are dissolved and after addition of 25 g of p-hydroxyphenylacetone and 1 g

  
of triethylamine, a catalytic reduction is carried out at

  
ordinary temperature and pressure with a palladium-on-carbon catalyst. Filter to separate the catalyst and add 1.1 g of fumaric acid to the filtrate. Then, the solvent is removed by distillation under reduced pressure,

  
the residue is diluted with water and washed with ethyl ether. The aqueous layer was neutralized with an aqueous solution of sodium bicarbonate and extracted with chloroform. After addition of 1.1 g of fumaric acid, the extract is concentrated under reduced pressure. The residue is dissolved in ethanol, then ethyl acetate is added.

  
 <EMI ID = 297.1>

  
p-hydroxy-phenethylamino) -1,2,3,4-tetrahydronaphthalene, melting at 136-14 [deg.] C (decomposition).

Example 57

  
In 50 ml of dichloromethane, 251 mg are dissolved

  
 <EMI ID = 298.1>

  
naphthalene. In this solution, a solution of 750 g of boron tribromide in 10 ml of dichloromethane is introduced dropwise. After stirring for several hours, the reaction mixture is brought to room temperature and concentrated under reduced pressure. Ethanol is added to the residue and after heating for 10 minutes, treat with activated charcoal. Adding ethyl ether to the mixture

  
 <EMI ID = 299.1>

  
tetrahydronaphthalene, melting at 170-171 [deg.] C (decomposition).

Example 58

  
In 100 ml of water, 1.0 g of p-toluene is dissolved.

  
 <EMI ID = 300.1>

  
hydronaphthalene and, using a 5% palladium on charcoal catalyst, catalytic reduction was performed at room temperature and pressure. After absorption of a stoichiometric amount of hydrogen, the reaction mixture is filtered to separate the catalyst and, after adding a small amount of hydrobromic acid, the mixture is concentrated under reduced pressure. The residue is dissolved in a small amount of water and the mixture is washed with ethyl ether. The aqueous layer is neutralized with an aqueous solution of sodium bicarbonate and extracted with chloroform. The extract is dried and, after adding a small amount of hydrobromic acid, it is concentrated under reduced pressure. After recrystallization of the residue from a mixture of water, methanol and ethyl ether, the bromhy-

  
 <EMI ID = 301.1>
 <EMI ID = 302.1>
 <EMI ID = 303.1>

Examples 59-71

  
In a similar manner to that of Example 58, using the compounds given in the second column of Table 4 as starting compounds instead of 1-hydroxy-2-

  
 <EMI ID = 304.1>

  
the compounds shown in the third column.

  
Table 4
 <EMI ID = 305.1>
 Examples 72 to 74

  
In a similar manner to that of Example 58, from the compound appearing in the second column of Table 5, the compounds appearing in the third column of this table are obtained by using fumaric acid instead of. hydrobromic acid.

  
Table 5

  

 <EMI ID = 306.1>
 

Example 75

  
In 50 ml of a 1% aqueous hydrochloric acid solution, 1.0 g of 2-acetylamino-1-hydroxy-

  
 <EMI ID = 307.1>

  
mix on a water bath for 3 hours. After cooling, the reaction mixture is washed with ethyl ether, neutralized with aqueous sodium bicarbonate solution and extracted with chloroform. The extract is dried and concentrated under reduced pressure. After recrystallization of the residue from ethyl ether, one obtains

  
 <EMI ID = 308.1>

  
hydronaphthalene in the form of colorless crystals melting
122-124 [deg.] C.

  
Elemental analysis for C12H1703N

  

 <EMI ID = 309.1>

Example 76

  
In 100 ml of ethanol, 0.5 g of 1-hydroxy-

  
 <EMI ID = 310.1>

  
performs catalytic reduction using a catalyst

  
at 5% palladium on charcoal. After separating the catalyst by filtration, the filtrate is concentrated under reduced pressure. Recrystallization of the residue from ethyl ether

  
 <EMI ID = 311.1>

  
hydronaphthalene. This compound is identical to the compound

  
according to example 75.

Example 77

  
To a mixture of 5 ml of 47% hydrobromic acid and 1.5 ml of acetic acid, 0.36 g of 1,5,6-triac

  
 <EMI ID = 312.1>

  
under reflux in a stream of nitrogen gas, the

  
the reaction mixture under reduced pressure. Recrystallization of the residue from an ethyl ether-methanol-water mixture

  
 <EMI ID = 313.1>

  
tetrahydronaphthalene. This compound is identical to the compound according to Example 58.

  
itself

Example 78

  
In 150 ml of ethanol, 0.7 g of 1-hydroxy-2- (N-benzyl-N-methylamino) -5,6-dibenzyloxy1,2,3,4-tetrahydronaphthalene is suspended and one proceeds to a catalytic reduction in the presence of a 5% palladium catalyst

  
on carbon and hydrogen under a pressure of 5 kg / cm. It is filtered to separate the catalyst and, after adding a small amount of hydrobromic acid, the filtrate is concentrated. Recrystallization of the residue from a mixture of methanol and ethyl ether gives 1,5,6-trihydroxy-2-methylamino-1,2,3,4-tetrahydronaphthalene hydrobromide, melting point.
165-169 [deg.] C (decomposition).

Example 79

  
In a manner similar to that of Example 78,

  
using 1,5-dihydroxy-2- (N-benzyl-N-methylamino) -6-

  
 <EMI ID = 314.1>

  
1,5,6-trihydroxy-2-methylamino1,2,3,4-tetrahydronaphthalene hydrobromide is obtained. This compound is identical to the compound according to Example 78.

Example 80

  
In a mixture of 15 ml of ethanol and 10 ml of acetone, 548 mg of 1-hydroxy-2- p-toluenesulfonate are dissolved.

  
 <EMI ID = 315.1>

  
resulting in catalytic reduction with a 5% palladium on charcoal catalyst. It is filtered to separate the catalyst and, after adding a small amount of hydrobromic acid, the filtrate is concentrated under reduced pressure. Recrystallization of the residue from a mixture of ethanol and ethyl ether gives 1,5,6-trihydroxy- hydrobromide.

  
 <EMI ID = 316.1>

  
(decomposition).

Example 81

  
In a similar manner to that of Example 80, using acetaldehyde instead of acetone, through 5,6-dibenzyloxy-2-ethylideneamino-1-hydroxy-1,2 , 3, 4-tetrahydronaphthalene, 2-ethylamino-1,5,6- hydrobromide

  
 <EMI ID = 317.1>

  
composition).

Example 82

  
 <EMI ID = 318.1>

  
reading cyclobutanone instead of acetone, through 5,6-dibenzyloxy-2-cyclobutylideneamino-1-hydroxy1,2,3,4-tetrahydronaphthalene, 2-cyclobutylamino- hydrobromide is obtained

  
 <EMI ID = 319.1>

  
(decomposition).

Example 33

  
To a mixture of 10 ml of 1.5 N potassium carbonate and 10 ml of chloroform, 0.24 g of 1-hydroxy-2-trifluor-

  
 <EMI ID = 320.1>

  
Having stirred vigorously at room temperature for 2 hours in a stream of nitrogen gas, the chloroform layer is separated from the reaction mixture, washed with water and dried. The chloroform is removed by distillation under reduced pressure and the residue is dissolved in ethyl ether. We add to the solution

  
 <EMI ID = 321.1>

  
nique in ethyl ether, the resulting precipitates are collected by filtration and recrystallized from a mixture of ethanol and ethyl ether, to give p-toluene sulfonate

  
 <EMI ID = 322.1>

  
This compound is identical to the compound obtained according to Example 49.

Example 84

  
To a mixture of 5 ml of 47% hydrobromic acid and 1.5 ml of acetic acid, 0.25 g of 2-methyl-6,7-dimethoxy3a, 4,5,9b-tetrahydronaphto (2, 1d) oxazole. After subjecting the mixture to reflux in a stream of nitrogen gas, it is concentrated under reduced pressure. After recrystallization of the residue from a mixture comprising ethyl ether, methanol and water, 1,5,6-trihydroxy-2-amino-1,2,3,4tetrahydronaphthalene hydrobromide is obtained. This product is identical to that which was prepared by the process according to Example 58.

  
 <EMI ID = 323.1>

Example 85

  
0.24 g of 1-hydroxy- hydrochloride is refluxed.

  
 <EMI ID = 324.1>

  
5 ml of 57% hydroiodic acid. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in a small amount of water, then neutralized with an aqueous solution of sodium bicarbonate. Treatment of this solution in a manner similar to that described in Example 58 makes it possible to obtain

  
 <EMI ID = 325.1>

  
dronaphthalene.

Example 86

  
A solution of 1.0 g of 2-tert-butylaminc-1- fumarate

  
 <EMI ID = 326.1>

  
Amount of water is made alkaline with sodium bicarbonate, after which it is extracted using 100 ml of dichloromethane. The extract is washed with water, dried and 1.5 g of a solution of boron tribromide in 20 ml of dichloromethane are added to the solution thus obtained, dropwise, while cooling to a temperature of between -70 [deg.] C and -75 [deg.] C. The resulting mixture is stirred

  
 <EMI ID = 327.1>

  
at room temperature and then concentrated under reduced pressure. The residue is dissolved again in a small amount of water, the solution is made alkaline with sodium bicarbonate and extracted with n-butanol. The extract is concentrated under reduced pressure and an ethereal solution of fumaric acid is added to the residue. After recrystallization of the precipitate from a mixture of ethanol and ethyl ether, 2-tert-butylamino- fumarate is obtained.

  
 <EMI ID = 328.1>

Example 87

  
A solution of 0.6 g of 2- / I-methyl-2- (3-indo-

  
 <EMI ID = 329.1>

  
lene in 20 ml of methanol to catalytic reduction in the presence of palladium on charcoal. The catalyst is removed by filtration and, after dissolution of the fumaric acid, the filtrate is concentrated under reduced pressure. Ethyl ether is added to the residue and the mixture is cooled to give 0.2 g of fumarate.

  
 <EMI ID = 330.1>

  
tetrahydronaphthalene. This compound does not have a definite melting point and decomposes slowly when heated.

  
 <EMI ID = 331.1>

  

 <EMI ID = 332.1>

Example 88

  
100 g of 5,6-dibenzyloxy-2-tert- fumarate are dissolved.

  
 <EMI ID = 333.1>

  
The solution is neutralized with an aqueous solution of sodium bicarbonate and extracted with chloroform. The extract is dried and concentrated under reduced pressure. The obtained residue is dissolved in ethanol and subjected to catalytic reduction using a palladium-on-charcoal catalyst. Filter to separate the catalyst and dissolve fumaric acid in the filtrate. After concentration of the solution and addition of ethyl ether to it, 33 mg of 2- fumarate are obtained.

  
 <EMI ID = 334.1>

  

 <EMI ID = 335.1>

Example 89

  
A solution of 1.10 g of trans-1-hydroxy-2- is subjected to
(N-benzyl-N-methylamino) -5,6-dibenzyloxy-1,2,3,4-tetrahydronaphta-

  
 <EMI ID = 336.1>

  
generation, on a 10% palladium-on-charcoal catalyst, at ordinary temperature and pressure. After removing the catalyst by filtration, the filtrate is added dropwise to a solution of 190 ml of fumaric acid in 450 ml of ethyl ether. The resulting mixture is evaporated under reduced pressure, leaving a pale yellow oily substance which is dissolved in a mixture of 5 ml of water and 20 ml of ethanol, after decolorizing with charcoal. 200 ml of ethyl ether are added to the solution and the mixture is allowed to stand overnight at 5 [deg.] C. Filtration of the resulting crystals gives 171 mg of trans-1 fumarate,

  
 <EMI ID = 337.1>

Example 90

  
1.10 g of cis-1-hydroxy-2- (N-benzyl-N-methyl-

  
 <EMI ID = 338.1>

  
catalytic conversion, as described in Example 89. The catalyst is removed by filtration and the filtrate is introduced dropwise into a solution of 180 mg of fumaric acid in 15 ml of ethanol. After adding 30 ml of ethyl ether, 10 ml of ethanol and 10 ml of water, the mixture is allowed to stand overnight.

  
at 5 [deg.] C. Filter to collect the resulting crystals which are recrystallized from a mixture comprising 10 ml of water and 100 ml of acetic acid.

  
 <EMI ID = 339.1>

  

 <EMI ID = 340.1>


  
 <EMI ID = 341.1>

  
 <EMI ID = 342.1>

  
A solution of 410 mg of trans-1-hydroxy-2isopropylamino-5,6-dibenzyloxy-1,2,3,4-tetrahydronaphthalene in 2 ml of water and 20 ml of ethanol is subjected to catalytic hydrogenation on

  
 <EMI ID = 343.1>

  
ordinary pressure. When the theoretical amount of hydrogen is absorbed, the catalyst is removed by filtration and the filtrate is introduced dropwise into a mixture of 5 ml of ethanol and

  
2 ml of water. The resulting mixture is cooled overnight to give colorless crystals which, after filtration, leave

  
 <EMI ID = 344.1>

  

 <EMI ID = 345.1>


  
 <EMI ID = 346.1>

  
i Example 92

  
 <EMI ID = 347.1>

  
a catalytic reduction as described in Example 91. After having removed the catalyst by filtration, the filtrate is introduced dropwise into a solution of 6 mg of fumaric acid in 5 ml of ethanol. The mixture is evaporated to almost dryness and 150 ml of ethyl ether is added to the residue. Filter to collect the resulting precipitate which is recrystallized from water to give cis-1,5,6-trihydroxy-2-isopropylamino1,2,3,4-tetrahydronaphthalene fumarate as prisms melting at
179-181 [deg.] C.

  
 <EMI ID = 348.1>

  

 <EMI ID = 349.1>


  
 <EMI ID = 350.1>

Example 93

  
A solution of 0.75 g of trans-2-amino-5,6- is subjected to

  
 <EMI ID = 351.1>

  
 <EMI ID = 352.1>

  
on charcoal at ordinary temperature and pressure. 0.5 g of 47% hydrobromic acid was added to the solution and the catalyst was removed by filtration while introducing the filtrate dropwise into 200 ml of ethyl ether. The resulting crystals were collected by filtration and dissolved in a mixture comprising 15 ml of ethanol and 4 ml of water. We slowly add to

  
 <EMI ID = 353.1>

  
 <EMI ID = 354.1>

  

 <EMI ID = 355.1>


  
 <EMI ID = 356.1>

Example 94

  
455 mg of trans-2-cyclobutylamino- fumarate are added.

  
 <EMI ID = 357.1>

  
 <EMI ID = 358.1>

  
the residue is extracted with water, dried and evaporated. After dissolving the residue in 25 ml of ethanol and 2 ml of water, it is subjected to catalytic reduction over a 5% palladium on carbon catalyst at ordinary temperature and pressure. The catalyst is removed by filtration and the filtrate is introduced dropwise into a solution of 56.5 mg of fumaric acid in 5 ml of ethanol. The mixture is allowed to stand at room temperature. The resulting precipitate is filtered and washed with a small amount of cold ethanol to give the fumarate <EMI ID = 359.1>

  

 <EMI ID = 360.1>


  
NMR spectrum (DMSO-d6) cf 4.52 (1H, d, J = 8.2Hz)

Example 95

  
0.7 g of cis-5,6-dibenzyloxy-2-tert- oxalate is added.

  
 <EMI ID = 361.1>

  
neutralized with a 10% solution of caustic soda and extracted with chloroform. The extract is evaporated off under reduced pressure. 30 ml of methanol are added to the residue and hydrogenated.

  
on a 10% palladium-on-charcoal catalyst, at ordinary temperature and pressure. After removing the catalyst by filtration, 0.16 g of fumaric acid is added to the filtrate and the mixture is concentrated. Ethyl ether was added to the concentrated solution to give 0.3 g of cis-2-tert-butylamino- fumarate.

  
 <EMI ID = 362.1>

  

 <EMI ID = 363.1>


  
NMR spectrum (DMSO-d6 + D20). 1.40 (9H, s); 4.66 (1H, d, J = 3Hz)

Example 96

  
By a process similar to that of Example 95, the reaction of 0.7 g of trans-5,6-dibenzyloxy-2-tert-butylamino-1-hydroxy-1,2,3,4-tetrahydronaphthalene oxalate gives 0.32 g of trans-2-butylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate, melting point 185-186 [deg.] C.

  
 <EMI ID = 364.1>

  

 <EMI ID = 365.1>


  
 <EMI ID = 366.1>

Example 97

  
A solution of 5.4 g of trans-5,6-dibenzyloxy-

  
 <EMI ID = 367.1>

  
methanol to catalytic reduction, using a catalyst

  
 <EMI ID = 368.1>

  
47% iron and 10 ml of water to the reaction mixture. After filtration, the filtrate is added to 1.5 1 of ethyl ether, which gives colorless pulverulent crystals which are collected by filtration and which are dissolved in a mixture of 50 ml of methanol and 10 ml of water. Slowly introduced into the solution "liter of ether

  
 <EMI ID = 369.1>

  
 <EMI ID = 370.1>

  

 <EMI ID = 371.1>


  
 <EMI ID = 372.1>

Example 98

  
0.4 g of 2-cyclopropylamino-5,6- oxalate is neutralized.

  
 <EMI ID = 373.1>

  
aqueous sodium bonate, and the free base is extracted with chloroform. After having dried the extract, it is evaporated under reduced pressure. The residue is dissolved in 20 ml of methanol and subjected to catalytic reduction in the presence of a 10% palladium on charcoal catalyst. After eliminating

  
After filtering the catalyst, 0.1 g of fumaric acid was added to the filtrate and the mixture was concentrated under reduced pressure. 300 ml of ethyl ether is added to the residue and allowed to stand for two days, giving 0.1 g of P-cyclo-fumarate.

  
 <EMI ID = 374.1>

  

 <EMI ID = 375.1>

Example 99

  
A process similar to that of Example 98 and using

  
 <EMI ID = 376.1>

  

 <EMI ID = 377.1>


  
 <EMI ID = 378.1>

Example 100

  
 <EMI ID = 379.1>

  
thanol to a catalytic reduction in the presence of 0.7 g of a catalyst containing 10% palladium on charcoal, at original temperature and pressure. After removing the catalyst by wire

  
 <EMI ID = 380.1>

  
of ethyl ether containing at least an equimolar amount of hydrobromic acid to give 0.15 g of cis2-amino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide as Colorless crystals melting at 180-190 [deg.] C (decomposition).

  
 <EMI ID = 381.1>

  

 <EMI ID = 382.1>


  
NMR spectrum (DMSO-d6 + D20): 4.59 (1H, dJ = 2Hz)

Example 101

  
 <EMI ID = 383.1>

  
 <EMI ID = 384.1>

  
 <EMI ID = 385.1>

  
of a fumaric acid salt by adding a methanolic solution of fumaric acid to the product, gives 0.2 of cis2-cyclobutylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene fumarate melting at 171-172 [deg.] C (decomposition) ..

  
 <EMI ID = 386.1>

  

 <EMI ID = 387.1>


  
NMR spectrum (DMSO-d6 + D20): 4.66 (1H, d, J = 3Hz) <EMI ID = 388.1>

CLAIMS

  
1. A process for producing a compound of the formula

  

 <EMI ID = 389.1>


  
wherein R is hydrogen, a hydrocarbon group which

  
 <EMI ID = 390.1>

  
represent a hydrogen atom or a protecting group, or

  
many salts of such a compound, this process being characterized by

  
the fact that it consists in hydrolyzing a compound of formula

  

 <EMI ID = 391.1>


  
 <EMI ID = 392.1>

  
as above.


    

Claims (1)

2. Method according to claim 1, characterized by the <EMI ID = 393.1> fication in position a. 3. Method according to claim 1, characterized in that the hydrolysis is carried out in the presence of an acid. 4. A process for producing a compound of the formula <EMI ID = 394.1> in which the symbol R 'represents a hydrogen atom or a hydrocarbon group which may have a substituent and Z <1> and Z2 represent a hydrogen atom or a protecting group, or <EMI ID = 395.1> fact that it consists in reducing a compound of formula <EMI ID = 396.1> <EMI ID = 397.1> <EMI ID = 398.1> <EMI ID = 399.1> converted to a -NHR 'group (formula wherein R' has the same <EMI ID = 400.1> feel <EMI ID = 401.1> <EMI ID = 402.1> causes the group that can be converted to a -NH group ,; ' by reduction is a nitro, nitroso or isonitroso group. 6. Method according to claim 4, characterized in that the reduction is of the type of a catalytic reduction <EMI ID = 403.1> 7. A process for producing a compound of the formula <EMI ID = 404.1> in which R "represents a group 1 <EMI ID = 405.1> (formula in the- which R is a hydrogen atom or a lower alkyl group, <EMI ID = 406.1> <EMI ID = 407.1> together with the adjacent carbon atom) and the symbols <EMI ID = 408.1> Z and Z represent., / Hydrogen or a protecting group, or <EMI ID = 409.1> it consists in reducing an "omoose of forr.:ule <EMI ID = 410.1> <EMI ID = 411.1> the symbol A2 represents a group which can be converted to an amino group by reduction and the symbol X represents a group <EMI ID = 412.1> in the presence of a carbonyl compound of formula <EMI ID = 413.1> in which the symbols R <1> and R2 have the same meanings as above. 8. Method according to claim 7, characterized in that the group which can be converted into an amino group by <EMI ID = 414.1> <EMI ID = 415.1> that the reduction is carried out by operating by catalytic reduction or by using a metal hydride. 10. A process for the production of a compound of the formula <EMI ID = 416.1> in which the symbol R is a hydrogen atom or a hydrocarbon group which may be substituted and the symbols Z1 and Z2 represent a hydrogen atom or a protecting group, or else salts of such a compound, this process being characterized by the fact that it consists in submitting a compound of formula <EMI ID = 417.1> in which R 'has the same meaning as above and the symbols <EMI ID = 418.1> <EMI ID = 419.1> a protecting group, provided that at least one of them represents a protecting group, in a reaction leading to the elimination of the protecting group (s). <EMI ID = 420.1> causes the symbols Z <1> and Z2 to both represent a hydrogen atom. 12. The method of claim 10, characterized in that the symbols Z1 and Z2 both represent an atom. <EMI ID = 421.1> a benzyl group. 13. The method of claim 10, characterized in that the reaction to remove the protective group (s) is a reduction or a solvolysis. 14. The method of claim 13, characterized in that the reduction is a catalytic reduction. 15. The method of claim 13, characterized in that the solvolysis is carried out using a Lewis acid, <EMI ID = 422.1> <EMI ID = 423.1> <EMI ID = 424.1> wherein the symbol R represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group and <EMI ID = 425.1> of such a compound. <EMI ID = 426.1> causes the aralkyl group to be a benzyl group. . 18. Compound according to claim 16, characterized in that the symbol R represents a hydrogen atom or a hydrocarbon group. 19. A compound according to claim 18, characterized in that the hydrocarbon group is a lower alkyl group or a cycloalkyl group. <EMI ID = 427.1> that it occurs as a mixture of trans and cis -isomers. 21. A compound according to claim 16, characterized in that it is essentially in the form of a trans isomer. 22. A compound according to claim 16, characterized by the <EMI ID = 428.1> hydronaphthalene. 23. Compound according to claim 16, characterized in that it is 5,6-dibenzyloxy-2-ethylamino-1-hydroxy-l, 2,3,4tetrahydronaphthalene. 24. A compound according to claim 16, characterized by 3e <EMI ID = 429.1> fact that it is 5,6-dibenzyloxy-2-tert-butylamino-1-hydroxy-1,2, 3,4-tetrahydronaphthalene. 26. A compound according to claim 16, characterized in that it is 2-cyclopropylamino-5,6-dibenzyloxy-1-hydroxy-l, 2,3,4-tetrahydronaphthalene. <EMI ID = 430.1> 3,4-tetrahydronaphthalene.